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Synaptic phospholipids as a new target for cortical hyperexcitability and E/I balance in psychiatric disorders
Author(s): Thalman, C; Horta, G; Qiao, L; Endle, H; Tegeder, I; Cheng, H; Laube, G; Sigrudsson, T; Hauser, MJ; Tenzer, S; Distler, U; Aoki, J; Morris, AJ; Geisslinger, G; Röper, J; Kirischuk, S; Luhmann, HJ; Radyushkin, K; Nitsch, R; Vogt, J
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Lysophosphatidic acid (LPA) is a synaptic phospholipid, which regulates cortical excitation/inhibition (E/I) balance and controls sensory information processing in mice and man. Altered synaptic LPA signaling was shown to be associated with psychiatric disorders. Here, we show that the LPA-synthesizing enzyme autotaxin (ATX) is expressed in the astrocytic compartment of excitatory synapses and modulates glutamatergic transmission. In astrocytes, ATX is sorted toward fine astrocytic processes and transported to excitatory but not inhibitory synapses. This ATX sorting, as well as the enzymatic activity of astrocyte-derived ATX are dynamically regulated by neuronal activity via astrocytic glutamate receptors. Pharmacological and genetic ATX inhibition both rescued schizophrenia-related hyperexcitability syndromes caused by altered bioactive lipid signaling in two genetic mouse models for psychiatric disorders. Interestingly, ATX inhibition did not affect naive animals. However, as our data suggested that pharmacological ATX inhibition is a general method to reverse cortical excitability, we applied ATX inhibition in a ketamine model of schizophrenia and rescued thereby the electrophysiological and behavioral schizophrenia-like phenotype. Our data show that astrocytic ATX is a novel modulator of glutamatergic transmission and that targeting ATX might be a versatile strategy for a novel drug therapy to treat cortical hyperexcitability in psychiatric disorders.
Non-rectangular waveforms are more charge-efficient than rectangular one in eliciting network-mediated responses of ON type retinal ganglion cells
Author(s): Lee, J; Im, M
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Objective. For individuals blinded by outer retinal degenerative diseases, retinal prostheses would be a promising option to restore sight. Unfortunately, however, the best performance of existing devices is still far removed from normal vision. One possible reason for the shortcoming is thought to be suboptimal stimulation conditions such as the waveform shape of electric stimulus. In this study, we explored the effects of varying waveforms on network-mediated responses arising in retinal ganglion cells (RGCs). Approach. We used a cell-attached patch clamp technique to record RGC spiking activities in the isolated mouse retina. ON alpha RGCs were targeted by soma size and their light responses to stationary spot flashes. Spiking in targeted RGCs was measured in response to an epiretinally-delivered cathodal current pulse in four waveforms: rectangular, center triangular, increasing and decreasing ramp shapes. Each waveform was tested at three durations (20, 10, and 5 ms) with adjusted amplitude for a range of total charges (50–400 nC). Main results. ON alpha RGCs always generated two bursts of spikes in responses to all stimuli conditions we tested. However, at a given charge, effects of differing waveforms were distinct in the two bursts.
Ovine model of neuropathic pain for assessing mechanisms of spinal cord stimulation therapy via dorsal horn recordings, von Frey filaments, and gait analysis
Author(s): Reddy, CG; Miller, JW; Abode-Iyamah, KO; Safayi, S; Wilson, S; Dalm, BD; Fredericks, DC; Gillies, GT; Howard, MA; Brennan, TJ
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It is becoming increasingly important to understand the mechanisms of spinal cord stimulation (SCS) in alleviating neuropathic pain as novel stimulation paradigms arise. Additionally, the small anatomic scale of current SCS animal models is a barrier to more translational research. Using chronic constriction injury (CCI) of the common peroneal nerve (CPN) in sheep (ovine), we have created a chronic model of neuropathic pain that avoids motor deficits present in prior large animal models. This large animal model has allowed us to implant clinical grade SCS hardware, which enables both acute and chronic testing using von Frey filament thresholds and gait analysis. Furthermore, the larger anatomic scale of the sheep allows for simultaneous single-unit recordings from the dorsal horn and SCS with minimal electrical artifact. etectable tactile hypersensitivity occurred 21 days after nerve injury, with preliminary indications that chronic SCS may reverse it in the painful limb. Gait analysis revealed no hoof drop in the CCI model. Single neurons were identified and discriminated in the dorsal horn, and their activity was modulated via SCS. Unlike previous large animal models that employed a complete transection of the nerve, no motor deficit was observed in the sheep with CCI. To our knowledge, this is the first reported large animal model of chronic neuropathic pain which facilitates the study of both acute and chronic SCS using complementary behavioral and electrophysiologic measures. As demonstrated by our successful establishment of these techniques, an ovine model of neuropathic pain is suitable for testing the mechanisms of SCS.
Synaptic phospholipids as a new target for cortical hyperexcitability and E/I balance in psychiatric disorders
Author(s): Thalman, C; Horta, G; Qiao, L; Endle, H; Tegeder, I; Cheng, H; Laube, G; Sigrudsson, T; Hauser, MJ; Tenzer, S; Distler, U; Aoki, J; Morris, AJ; Geisslinger, G; Röper, J; Kirischuk, S; Luhmann, HJ; Radyushkin, K; Nitsch, R; Vogt, J
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Lysophosphatidic acid (LPA) is a synaptic phospholipid, which regulates cortical excitation/inhibition (E/I) balance and controls sensory information processing in mice and man. Altered synaptic LPA signaling was shown to be associated with psychiatric disorders. Here, we show that the LPA-synthesizing enzyme autotaxin (ATX) is expressed in the astrocytic compartment of excitatory synapses and modulates glutamatergic transmission. In astrocytes, ATX is sorted toward fine astrocytic processes and transported to excitatory but not inhibitory synapses. This ATX sorting, as well as the enzymatic activity of astrocyte-derived ATX are dynamically regulated by neuronal activity via astrocytic glutamate receptors. Pharmacological and genetic ATX inhibition both rescued schizophrenia-related hyperexcitability syndromes caused by altered bioactive lipid signaling in two genetic mouse models for psychiatric disorders. Interestingly, ATX inhibition did not affect naive animals. However, as our data suggested that pharmacological ATX inhibition is a general method to reverse cortical excitability, we applied ATX inhibition in a ketamine model of schizophrenia and rescued thereby the electrophysiological and behavioral schizophrenia-like phenotype. Our data show that astrocytic ATX is a novel modulator of glutamatergic transmission and that targeting ATX might be a versatile strategy for a novel drug therapy to treat cortical hyperexcitability in psychiatric disorders.
Corrosion protection properties of inhibitor containing hybrid PEO-epoxy coating on magnesium
Author(s): Yang, J; Blawert, C; Lamaka, S; Snihirova, D; Lu, X; Di, S; Zheludkevich, M
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A hybrid PEO-epoxy coating was developed for magnesium. A highly-efficient corrosion inhibitor (3-methysalicylate) was impregnated into the anodized layer, which was sealed by an epoxy layer through dip-coating process. Influence of dip-coating parameters on coating properties was investigated. The corrosion performance was evaluated through general and localized electrochemical techniques. As a result, the epoxy layers registered superior resistance, whereas the anodized layer suppressed corrosion expansion. Longer immersion and triple-dipping favored the production of better sealed epoxy layer. The active protection mechanism was achieved by suppression the re-deposition of detrimental impurity and/or adsorption upon the exposed surface from incorporated inhibitor.
Corrosion behaviour of galvanized steel studied by electrochemical microprobes applied on low-angle cross sections
Author(s): Manhabosco, S; Manhabosco, T; Geoffroy, N; Vignal, V; Dick, L
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The combined use of the microcapillary cell (MEC) and scanning vibrating electrode technique (SVET) and low-angle cross sections was employed to elucidate the role of each coating region on the protection of the cut-edge corrosion of galvanized steels. Different compounds are involved in the blocking action of the corrosion products: Zincite (ZnO) on the steel substrate, hydrozincite (Zn5(OH)6(CO3)2) at the coating/steel interface, and Simonkolleite (Zn5(OH)8Cl2) and ZnO on the different coating regions in different proportions. The coating surface is also active at the initial stage and during long-term protection and thus, must be considered in experimental simulation of the cut-edge corrosion.
Non-rectangular waveforms are more charge-efficient than rectangular one in eliciting network-mediated responses of ON type retinal ganglion cells
Author(s): Lee, J; Im, M
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Objective. For individuals blinded by outer retinal degenerative diseases, retinal prostheses would be a promising option to restore sight. Unfortunately, however, the best performance of existing devices is still far removed from normal vision. One possible reason for the shortcoming is thought to be suboptimal stimulation conditions such as the waveform shape of electric stimulus. In this study, we explored the effects of varying waveforms on network-mediated responses arising in retinal ganglion cells (RGCs). Approach. We used a cell-attached patch clamp technique to record RGC spiking activities in the isolated mouse retina. ON alpha RGCs were targeted by soma size and their light responses to stationary spot flashes. Spiking in targeted RGCs was measured in response to an epiretinally-delivered cathodal current pulse in four waveforms: rectangular, center triangular, increasing and decreasing ramp shapes. Each waveform was tested at three durations (20, 10, and 5 ms) with adjusted amplitude for a range of total charges (50–400 nC). Main results. ON alpha RGCs always generated two bursts of spikes in responses to all stimuli conditions we tested. However, at a given charge, effects of differing waveforms were distinct in the two bursts. For the first burst, the increasing ramp was most effective among the four waveforms (p  
Effect of twins on the corrosion behavior of Mg–5Y–7Gd–1Nd–0.5Zr Mg alloy
Author(s): Liu, J; Han, E; Song, Y; Shan, D
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Deformation treatment is an efficient method to improve the mechanical properties of Mg alloys. However, twins inevitably arise during the deformation treatment due to the hexagonal closed–packed crystal structure of Mg. The role of twins in the corrosion behavior of Mg–5Y–7Gd–1Nd–0.5Zr (EW75) Mg alloy was studied by scanning electron microscopy (SEM) observations, scanning Kelvin probe force microscopy (SKPFM), zero–resistance ammeter (ZRA) measurements, scanning vibrating electrode technique (SVET), electrochemical tests and weight loss measurements. It is found that the micro–galvanic corrosion between twins and matrix plays the dual roles: accelerate the dissolution reaction of Mg substrate and promote the formation of surface film. The formation of compact surface film dominates the reactions in the EW75 alloy with twins. As a result, the twins in EW75 alloy can improve the corrosion resistance.
Ovine model of neuropathic pain for assessing mechanisms of spinal cord stimulation therapy via dorsal horn recordings, von Frey filaments, and gait analysis
Author(s): Reddy, CG; Miller, JW; Abode-Iyamah, KO; Safayi, S; Wilson, S; Dalm, BD; Fredericks, DC; Gillies, GT; Howard, MA; Brennan, TJ
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It is becoming increasingly important to understand the mechanisms of spinal cord stimulation (SCS) in alleviating neuropathic pain as novel stimulation paradigms arise. Additionally, the small anatomic scale of current SCS animal models is a barrier to more translational research. Using chronic constriction injury (CCI) of the common peroneal nerve (CPN) in sheep (ovine), we have created a chronic model of neuropathic pain that avoids motor deficits present in prior large animal models. This large animal model has allowed us to implant clinical grade SCS hardware, which enables both acute and chronic testing using von Frey filament thresholds and gait analysis. Furthermore, the larger anatomic scale of the sheep allows for simultaneous single-unit recordings from the dorsal horn and SCS with minimal electrical artifact. Detectable tactile hypersensitivity occurred 21 days after nerve injury, with preliminary indications that chronic SCS may reverse it in the painful limb. Gait analysis revealed no hoof drop in the CCI model. Single neurons were identified and discriminated in the dorsal horn, and their activity was modulated via SCS. Unlike previous large animal models that employed a complete transection of the nerve, no motor deficit was observed in the sheep with CCI. To our knowledge, this is the first reported large animal model of chronic neuropathic pain which facilitates the study of both acute and chronic SCS using complementary behavioral and electrophysiologic measures. As demonstrated by our successful establishment of these techniques, an ovine model of neuropathic pain is suitable for testing the mechanisms of SCS.
Selective Silencing of Hippocampal Parvalbumin Interneurons Induces Development of Recurrent Spontaneous Limbic Seizures in Mice
Author(s): Drexel, M; Romanov, RA; Wood, J; Weger, S; Heilbronn, R; Wulff, P; Tasan, RO; Harkany, T; Sperk, G
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Temporal lobe epilepsy (TLE) is the most frequent form of focal epilepsies and is generally associated with malfunctioning of the hippocampal formation. Recently, a preferential loss of parvalbumin (PV) neurons has been observed in the subiculum of TLE patients and in animal models of TLE. To demonstrate a possible causative role of defunct PV neurons in the generation of TLE, we permanently inhibited GABA release selectively from PV neurons of the ventral subiculum by injecting a viral vector expressing tetanus toxin light chain in male mice. Subsequently, mice were subjected to telemetric EEG recording and video monitoring. Eighty-eight percent of the mice presented clusters of spike-wave discharges (C-SWDs; 40.0 ± 9.07/month), and 64% showed spontaneous recurrent seizures (SRSs; 5.3 ± 0.83/month). Mice injected with a control vector presented with neither C-SWDs nor SRSs. No neurodegeneration was observed due to vector injection or SRS. Interestingly, mice that presented with only C-SWDs but no SRSs, developed SRSs upon injection of a subconvulsive dose of pentylenetetrazole after 6 weeks. The initial frequency of SRSs declined by ∼30% after 5 weeks. In contrast to permanent silencing of PV neurons, transient inhibition of GABA release from PV neurons through the designer receptor hM4Di selectively expressed in PV-containing neurons transiently reduced the seizure threshold of the mice but induced neither acute nor recurrent seizures. Our data demonstrate a critical role for perisomatic inhibition mediated by PV-containing interneurons, suggesting that their sustained silencing could be causally involved in the development of TLE.SIGNIFICANCE STATEMENT Development of temporal lobe epilepsy (TLE) generally takes years after an initial insult during which maladaptation of hippocampal circuitries takes place. In human TLE and in animal models of TLE, parvalbumin neurons are selectively lost in the subiculum, the major output area of the hippocampus. The present experiments demonstrate that specific and sustained inhibition of GABA release from parvalbumin-expressing interneurons (mostly basket cells) in sector CA1/subiculum is sufficient to induce hyperexcitability and spontaneous recurrent seizures in mice. As in patients with nonlesional TLE, these mice developed epilepsy without signs of neurodegeneration. The experiments highlight the importance of the potent inhibitory action mediated by parvalbumin cells in the hippocampus and identify a potential mechanism in the development of TLE.
Resistance to action potential depression of a rat axon terminal in vivo
Author(s): Martijn C. Sierksma and J. Gerard G. Borst
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The shape of the presynaptic action potential (AP) has a strong impact on neurotransmitter release. Because of the small size of most terminals in the central nervous system, little is known about the regulation of their AP shape during natural firing patterns in vivo. The calyx of Held is a giant axosomatic terminal in the auditory brainstem, whose biophysical properties have been well studied in slices. Here, we made whole-cell recordings from calyceal terminals in newborn rat pups. The calyx showed a characteristic burst firing pattern, which has previously been shown to originate from the cochlea. Surprisingly, even for frequencies over 200 Hz, the AP showed little or no depression. Current injections showed that the rate of rise of the AP depended strongly on its onset potential, and that the membrane potential after the AP (Vafter) was close to the value at which no depression would occur during high-frequency activity. Immunolabeling revealed that Nav1.6 is already present at the calyx shortly after its formation, which was in line with the fast recovery from AP depression that we observed in slice recordings. Our findings thus indicate that fast recovery from depression and an inter-AP membrane potential that minimizes changes on the next AP in vivo, together enable high timing precision of the calyx of Held already shortly after its formation.
Altered Expression of Reorganized Inputs as They Ascend From the Cuneate Nucleus to Cortical Area 3b in Monkeys With Long-Term Spinal Cord Injuries.
Author(s): Halder, P; Kambi, N; Chand, P; Jain, N
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Chronic deafferentations in adult mammals result in reorganization of the brain. Lesions of the dorsal columns of the spinal cord at cervical levels in monkeys result in expansion of the intact chin inputs into the deafferented hand representation in area 3b, second somatosensory (S2) and parietal ventral (PV) areas of the somatosensory cortex, ventroposterior lateral nucleus (VPL) of the thalamus, and cuneate nucleus of the brainstem. Here, we describe the extent and nature of reorganization of the cuneate and gracile nuclei of adult macaque monkeys with chronic unilateral lesions of the dorsal columns, and compare it with the reorganization of area 3b in the same monkeys. In both, area 3b and the cuneate nucleus chin inputs expand to reactivate the deafferented neurons. However, unlike area 3b, neurons in the cuneate nucleus also acquire receptive fields on the shoulder, neck, and occiput. A comparison with the previously published results shows that reorganization in the cuneate nucleus is similar to that in VPL. Thus, the emergent topography following deafferentations by spinal cord injuries undergoes transformation as the reorganized inputs ascend from subcortical nuclei to area 3b. The results help us understand mechanisms of the brain plasticity following spinal cord injuries.
Giant modulation of the electronic band gap of carbon nanotubes by dielectric screening.
Author(s): Aspitarte, L; McCulley, DR; Bertoni, A; Island, JO; Ostermann, M; Rontani, M; Steele, GA; Minot, ED
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Carbon nanotubes (CNTs) are a promising material for high-performance electronics beyond silicon. But unlike silicon, the nature of the transport band gap in CNTs is not fully understood. The transport gap in CNTs is predicted to be strongly driven by electron-electron (e-e) interactions and correlations, even at room temperature. Here, we use dielectric liquids to screen e-e interactions in individual suspended ultra-clean CNTs. Using multiple techniques, the transport gap is measured as dielectric screening is increased. Changing the dielectric environment from air to isopropanol, we observe a 25% reduction in the transport gap of semiconducting CNTs, and a 32% reduction in the band gap of narrow-gap CNTs. Additional measurements are reported in dielectric oils. Our results elucidate the nature of the transport gap in CNTs, and show that dielectric environment offers a mechanism for significant control over the transport band gap.
Application of SVET/SIET Techniques to Study Healing Processes in Coated Metal Substrates
Author(s): Bastos, A
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Self-healing has become a hot topic in the field of protective coatings where an intense effort is being carried out to find ways to prolong the service life of both coating and metal substrate. This chapter reviews the use of two localized electrochemical techniques, the Scanning Vibrating Electrode Technique (SVET) and the Scanning Ion-Selective Electrode Technique (SIET) for studying the performance, degradation, and healing processes of coated metals. First, a brief outline of corrosion and corrosion protection, with emphasis on organic coatings, is given to provide the context of the work. This is followed by the concept of self-healing coatings. The principles of SVET and SIET are then presented, together with selected examples of their use. The chapter closes with a discussion on the strategies to probe healing processes and a review of published work.
Influence of the Polyethyleneglycol Plasticizer on the on the Mechanical and Electrochemical Properties of Siloxane Hybrid Films Applied on Tinplate
Author(s): Marcolin, P; Beltrami, L; de Souza, JM; Boniatti, R; Menezes, T; Correa, C; Quevedo, M; Bastos, A; Ferreira, M; Oliveira, C; Moura, A; Führ, LT; Schneider, EL; Kunst, CM
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The coatings developed by s ol - gel process have been proven to be an efficient alternative for corrosion protection of metal surfaces, especially to replace the chromate technique. The sol - gel processes have several advantages, such as their high purity and an excellent distribution of the components. The objective of this work is to characterize the hybrid films morphologically and electrochemically with different plasticizer concentrations, obtained by sol - gel process applied on tinplate. The film was prepared with two alkoxide pre cursor, 3 - trimethoxysilylpropyl methacrylate (TMSPMA) and tetraethoxysilane (TEOS) with addition of cerium nitrate. The polyethyleneglycol (PEG) was added in four different concentrations and their effect on the film was evaluated. The morphological charac terization was performed by scanning electron microscopy and profilometry. The electrochemical characterization was performed using the electrochemical impedance spectroscopy (EIS) and the scanning vibrating electrode technique (SVET). The results showed t hat the enhanced performance was obtained with the coating containing PEG 20 g.L - 1 because the corrosion of the system, which was detected after 120 hours, showed only two small points of corrosion and only one active. The lowest amount of PEG improved the plasticity and the barrier properties of the hybrid film.
Vision Recovery and Connectivity by Fetal Retinal Sheet Transplantation in an Immunodeficient Retinal Degenerate Rat Model
Author(s): Seiler, MJ; Lin, RE; McLelland, BT; Mathur, A; Lin, B; Sigman, J; De Guzman, AT; Kitzes, LM; Aramant, RB; Thomas, BB
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Purpose: To characterize a recently developed model, the retinal degenerate immunodeficient S334ter line-3 rat (SD-Foxn1 Tg(S334ter)3Lav) (RD nude rat), and to test whether transplanted rat fetal retinal sheets can elicit lost responses to light. Methods: National Institutes of Health nude rats (SD-Foxn1 Tg) with normal retina were compared to RD nude rats with and without transplant for morphology and visual function. Retinal sheets from transgenic rats expressing human placental alkaline phosphatase (hPAP) were transplanted into the subretinal space of RD nude rats between postnatal day (P) 26 and P38. Transplant morphology was examined in vivo using optical coherence tomography (OCT). Visual function was assessed by optokinetic (OKN) testing, electroretinogram (ERG), and superior colliculus (SC) electrophysiology. Cryostat sections were analyzed for various retinal/synaptic markers and for the expression of donor hPAP. Results: Optical coherence tomography scans showed the placement and laminar development of retinal sheet transplants in the subretinal space. Optokinetic testing demonstrated a deficit in visual acuity in RD nude rats that was improved after retinal sheet transplantation. No ERG responses were detected in the RD nude rats with or without transplantation. Superior colliculus responses were absent in age-matched control and sham surgery RD nude rats; however, robust light-evoked responses were observed in a specific location in the SC of transplanted RD nude rats. Responsive regions corresponded to the area of transplant placement in the eye. The quality of visual responses correlated with transplant organization and placement. Conclusions: The data suggest that retinal sheet transplants integrate into the host retina of RD nude rats and recover significant visual function.
SVET Study of Galvanic Corrosion of Al/Mg2Si Couple in Aqueous Solutions at Different pH
Author(s): Lia, LL; b, ; Zhanga, B; z, ; Tianb, B; Zhoua, Y; Wanga, JQ; Hana, EH; Ke, W
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The galvanic corrosion behavior between pure Al and synthesized bulk Mg2Si in 0.01 M NaCl solution at different pH values has been investigated by the scanning vibrating electrode technique (SVET). At pH 2, bulk Mg2Si actively dissolves and it acts as an anode. With the increase of exposure time, the anodic activity of Mg2Si decreases drastically and eventually anodic activity appears on Al surface. In alkaline solution, Mg2Si phase always acts as the cathode. The preferential dissolution of Mg and enrichment of Si found by energy dispersive X-ray spectroscopy are responsible for the observed anodic activity decay of Mg2Si in acidic solution. At pH 6, the galvanic corrosion current of Al/Mg2Si couple is much less than those at pH 2 and pH 13, and Mg2Si mainly undergoes self-dissolution. These results indicate that the dealloying of binary Mg2Si phase depends on the solution pH value and corrosion time, which subsequently have a great influence on the galvanic corrosion current of Al/Mg2Si couple.
The BET/BRD inhibitor JQ1 improves brain plasticity in WT and APP mice
Author(s): Benito, E; Ramachandran, B; Schroeder, H; Schmidt, G; Urbanke, H; Burkhardt, S; Capece, V; Dean, C; Fischer, A
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Histone acetylation is essential for memory formation and its deregulation contributes to the pathogenesis of Alzheimer's disease. Thus, targeting histone acetylation is discussed as a novel approach to treat dementia. The histone acetylation landscape is shaped by chromatin writer and eraser proteins, while readers link chromatin state to cellular function. Chromatin readers emerged novel drug targets in cancer research but little is known about the manipulation of readers in the adult brain. Here we tested the effect of JQ1-a small-molecule inhibitor of the chromatin readers BRD2, BRD3, BRD4 and BRDT-on brain function and show that JQ1 is able to enhance cognitive performance and long-term potentiation in wild-type animals and in a mouse model for Alzheimer's disease. Systemic administration of JQ1 elicited a hippocampal gene expression program that is associated with ion channel activity, transcription and DNA repair. Our findings suggest that JQ1 could be used as a therapy against dementia and should be further tested in the context of learning and memory.
Ablation of neuropsin-neuregulin 1 signaling imbalances ErbB4 inhibitory networks and disrupts hippocampal gamma oscillation
Author(s): Kawata, M; Morikawa, S; Shiosaka, S; Tamura, H
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Parvalbumin-expressing interneurons are pivotal for the processing of information in healthy brain, whereas the coordination of these functions is seriously disrupted in diseased brain. How these interneurons in the hippocampus participate in pathological functions remains unclear. We previously reported that neuregulin 1 (NRG1)-ErbB4 signaling, which is actuated by neuropsin, is important for coordinating brain plasticity. Neuropsin cleaves mature NRG1 (bound to extracellular glycosaminoglycans) in response to long-term potentiation or depression, liberating a soluble ligand that activates its receptor, ErbB4. Here, we show in mice that kainate-induced status epilepticus transiently elevates the proteolytic activity of neuropsin and stimulates cFos expression with a time course suggesting that activation of ErbB4- and parvalbumin-expressing interneurons follows the excitation and subsequent silencing of pyramidal neurons. In neuropsin-deficient mice, kainate administration impaired signaling and disrupted the neuronal excitation-inhibition balance (E/I balance) in hippocampal networks, by decreasing the activity of parvalbumin-positive interneurons while increasing that of pyramidal neurons, resulting in the progression of status epilepticus. Slow, but not fast, gamma oscillations in neuropsin-deficient mice showed reduced power. Intracerebroventricular infusion of the soluble NRG1 ligand moiety restored the E/I balance, status epilepticus and gamma oscillations to normal levels. These results suggest that the neuropsin-NRG1 signaling system has a role in pathological processes underlying temporal lobe epilepsy by regulating the activity of parvalbumin-expressing interneurons, and that neuropsin regulates E/I balance and gamma oscillations through NRG1-ErbB4 signaling toward parvalbumin-expressing interneurons. This neuronal system may be a useful target of pharmacological therapies against cognitive disorders.
An Integrated Circuit for Simultaneous Extracellular Electrophysiology Recording and Optogenetic Neural Manipulation
Author(s): Chen, CH; McCullagh, EA; Pun, SH; Mak, PU; Vai, MI; Mak, PI; Klug, A; Lei, TC
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The ability to record and to control action potential firing in neuronal circuits is critical to understand how the brain functions. The objective of this study is to develop a monolithic integrated circuit (IC) to record action potentials and simultaneously control action potential firing using optogenetics. A low-noise and high input impedance (or low input capacitance) neural recording amplifier is combined with a high current laser/light-emitting diode (LED) driver in a single IC. The low input capacitance of the amplifier (9.7 pF) was achieved by adding a dedicated unity gain stage optimized for high impedance metal electrodes. The input referred noise of the amplifier is [Formula: see text], which is lower than the estimated thermal noise of the metal electrode. Thus, the action potentials originating from a single neuron can be recorded with a signal-to-noise ratio of at least 6.6. The LED/laser current driver delivers a maximum current of 330 mA, which is adequate for optogenetic control. The functionality of the IC was tested with an anesthetized Mongolian gerbil and auditory stimulated action potentials were recorded from the inferior colliculus. Spontaneous firings of fifth (trigeminal) nerve fibers were also inhibited using the optogenetic protein Halorhodopsin. Moreover, a noise model of the system was derived to guide the design. A single IC to measure and control action potentials using optogenetic proteins is realized so that more complicated behavioral neuroscience research and the translational neural disorder treatments become possible in the future.
julius seizure, a Drosophila Mutant, Defines a Neuronal Population Underlying Epileptogenesis
Author(s): Horne, M; Krebushevski, K; Wells, A; Tunio, N; Jarvis, C; Francisco, G; Geiss, J; Recknagel, A; Deitcher, DL
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Epilepsy is a neural disorder characterized by recurrent seizures. Bang-sensitive Drosophila represent an important model for studying epilepsy and neuronal excitability. Previous work identified the bang-sensitive gene slamdance (sda) as an allele of the aminopeptidase N gene. Here we show through extensive genetic analysis, including recombination frequency, deficiency mapping, transposon insertion complementation testing, RNA interference (RNAi), and genetic rescue that the gene responsible for the seizure sensitivity is julius seizure (jus), formerly CG14509, which encodes a novel transmembrane domain protein. We also describe more severe genetic alleles of jus RNAi-mediated knockdown of jus revealed that it is required only in neurons and not glia, and that partial bang-sensitivity is caused by knockdown in GABAergic or cholinergic but not glutamatergic neurons. RNAi knockdown of jus at the early pupal stages leads to strong seizures in adult animals, implicating that stage as critical for epileptogenesis. A C-terminal-tagged version of Jus was generated from a fosmid genomic clone. This fosmid fusion rescued the bang-sensitive phenotype and was expressed in the optic lobes and the subesophageal and thoracic abdominal ganglia. The protein was primarily localized in axons, especially in the neck connectives, extending into the thoracic abdominal ganglion.
Water diffusion closely reveals neural activity status in rat brain loci affected by anesthesia
Author(s): Abe, Y; Tsurugizawa, T; Le Bihan, D
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Diffusion functional MRI (DfMRI) reveals neuronal activation even when neurovascular coupling is abolished, contrary to blood oxygenation level-dependent (BOLD) functional MRI (fMRI). Here, we show that the water apparent diffusion coefficient (ADC) derived from DfMRI increased in specific rat brain regions under anesthetic conditions, reflecting the decreased neuronal activity observed with local field potentials (LFPs), especially in regions involved in wakefulness. In contrast, BOLD signals showed nonspecific changes, reflecting systemic effects of the anesthesia on overall brain hemodynamics status. Electrical stimulation of the central medial thalamus nucleus (CM) exhibiting this anesthesia-induced ADC increase led the animals to transiently wake up. Infusion in the CM of furosemide, a specific neuronal swelling blocker, led the ADC to increase further locally, although LFP activity remained unchanged, and increased the current threshold awakening the animals under CM electrical stimulation. Oppositely, induction of cell swelling in the CM through infusion of a hypotonic solution (-80 milliosmole [mOsm] artificial cerebrospinal fluid [aCSF]) led to a local ADC decrease and a lower current threshold to wake up the animals. Strikingly, the local ADC changes produced by blocking or enhancing cell swelling in the CM were also mirrored remotely in areas functionally connected to the CM, such as the cingulate and somatosensory cortex. Together, those results strongly suggest that neuronal swelling is a significant mechanism underlying DfMRI.
Microprofiling real time nitric oxide flux for field studies using a stratified nanohybrid carbon–metal electrode
Author(s): Chaturvedi, P; Vanegas, DC; Hauser, BA; Foster, JS; Sepúlveda, MS; McLamore, ES
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Nitric oxide (NO) is an important signaling molecule that is involved in stress response, homeostasis, host defense, and cell development. In most cells, NO levels are in the femtomolar to micromolar range, with extracellular concentrations being much lower. Thus, real time measurement of spatiotemporal NO dynamics near the surface of living cells/tissues is a major challenge. Here, we report the development, application, and validation of a self referencing (i.e., oscillating) NO microelectrode for field studies of biological cells and tissues. The durable microelectrode is based on a hybrid nanomaterial composed of nanoceria, reduced graphene oxide and nanoplatinum and is intended for field use. One of the main focuses was to address the common pitfall of high overpotential through use of hydrophobic, and size/charge-selective materials in a thin film coated on top of the nanocatalyst sensor. The sensitivity (0.95 ± 0.03 pA nM−1), response time (1.1 ± 0.1 s), operating potential (+720 mV), and selectivity of the nanomaterial-modified microelectrode are similar to laboratory microelectrode designs, enabling studies of NO flux in field studies. NO efflux was first measured from chitosan and alginate polymers in abiotic studies, and a deterministic model used to determine the effective diffusion coefficient for each polymer composite. To demonstrate the practicality of the sensor, NO flux was quantified in three model organisms with known NO pathways, including: bacteria, plant, and an invertebrate animal. For each organism, an established hypothesis was validated based on NO flux measurement and the results confirm data collected using standard analytical techniques. The sensor can be used to expand our fundamental knowledge of NO transport by facilitating field experiments which are not possible with standard techniques.
Sniff invariant odor coding
Author(s): Shusterman, R; Sirotin, YB; Smear, MC; Ahmadian, VO; Rinberg, VO
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Sampling regulates stimulus intensity and temporal dynamics at the sense organ. Despite variations in sampling behavior, animals must make veridical perceptual judgments about external stimuli. In olfaction, odor sampling varies with respiration, which influences neural responses at the olfactory periphery. Nevertheless, rats were able to perform fine odor intensity judgments despite variations in sniff kinetics. To identify the features of neural activity supporting stable intensity perception, in awake mice we measured responses of Mitral/Tufted (MT) cells to different odors and concentrations across a range of sniff frequencies. Amplitude and latency of the MT cells' responses vary with sniff duration. A fluid dynamics (FD) model based on odor concentration kinetics in the intranasal cavity can account for this variability. Eliminating sniff waveform dependence of MT cell responses using the FD model significantly improves concentration decoding. This suggests potential schemes for sniff waveform invariant odor concentration coding.
A CMOS Current Steering Neurostimulation Array With Integrated DAC Calibration and Charge Balancing.
Author(s): Greenwald, E; Maier, C; Wang, Q; Beaulieu, R; Etienne-Cummings, R; Cauwenberghs, G; Thakor, N
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An 8-channel current steerable, multi-phasic neural stimulator with on-chip current DAC calibration and residue nulling for precise charge balancing is presented. Each channel consists of two sub-binary radix DACs followed by wide-swing, high output impedance current buffers providing time-multiplexed source and sink outputs for anodic and cathodic stimulation. A single integrator is shared among channels and serves to calibrate DAC coefficients and to closely match the anodic and cathodic stimulation phases. Following calibration, the differential non-linearity is within ±0.3 LSB at 8-bit resolution, and the two stimulation phases are matched within 0.3%. Individual control in digital programming of stimulation coefficients across the array allows altering the spatial profile of current stimulation for selection of stimulation targets by current steering. Combined with the self-calibration and current matching functions, the current steering capabilities integrated on-chip support use in fully implanted neural interfaces with autonomous operation for and adaptive stimulation under variations in electrode and tissue conditions. As a proof-of-concept we applied current steering stimulation through a multi-channel cuff electrode on the sciatic nerve of a rat.
Sensitivity of neurons in the middle temporal area of marmoset monkeys to random dot motion
Author(s): Chaplin, TA; Allitt, BJ; Hagan, MA; Price, NSC; Rajan, R; Rosa, MGP; Lui, LL
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Neurons in the middle temporal area (MT) of the primate cerebral cortex respond to moving visual stimuli. The sensitivity of MT neurons to motion signals can be characterized by using random-dot stimuli, in which the strength of the motion signal is manipulated by adding different levels of noise (elements that move in random directions). In macaques, this has allowed the calculation of neurometric thresholds. We characterized the responses of MT neurons in sufentanil/nitrous oxide-anesthetized marmoset monkeys, a species that has attracted considerable recent interest as an animal model for vision research. We found that MT neurons show a wide range of neurometric thresholds and that the responses of the most sensitive neurons could account for the behavioral performance of macaques and humans. We also investigated factors that contributed to the wide range of observed thresholds. The difference in firing rate between responses to motion in the preferred and null directions was the most effective predictor of neurometric threshold, whereas the direction tuning bandwidth had no correlation with the threshold. We also showed that it is possible to obtain reliable estimates of neurometric thresholds using stimuli that were not highly optimized for each neuron, as is often necessary when recording from large populations of neurons with different receptive field concurrently, as was the case in this study. These results demonstrate that marmoset MT shows an essential physiological similarity to macaque MT and suggest that its neurons are capable of representing motion signals that allow for comparable motion-in-noise judgments.NEW & NOTEWORTHY We report the activity of neurons in marmoset MT in response to random-dot motion stimuli of varying coherence. The information carried by individual MT neurons was comparable to that of the macaque, and the maximum firing rates were a strong predictor of sensitivity. Our study provides key information regarding the neural basis of motion perception in the marmoset, a small primate species that is becoming increasingly popular as an experimental model.
Representation of egomotion in rat's trident and E-row whisker cortices
Author(s): Chorev, E; Preston-Ferrer, P; Brecht, M
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The whisker trident, a three-whisker array on the rat's chin, has been implicated in egomotion sensing and might function as a tactile speedometer. Here we study the cortical representation of trident whiskers and E-row whiskers in barrel cortex. Neurons identified in trident cortex of anesthetized animals showed sustained velocity-sensitive responses to ground motion. In freely moving animals, about two-thirds of the units in the trident and E-row whisker cortices were tuned to locomotion speed, a larger fraction of speed-tuned cells than in the somatosensory dysgranular zone. Similarly, more units were tuned to acceleration and showed sensitivity to turning in trident and E-row whisker cortices than in the dysgranular zone. Microstimulation in locomoting animals evoked small but significant speed changes, and such changes were larger in the trident and E-row whisker representations than in the dysgranular zone. Thus, activity in trident and E-row cortices represents egomotion information and influences locomotion behavior.
Spatiotemporal trajectories of reactivation of somatosensory cortex by direct and secondary pathways after dorsal column lesions in squirrel monkeys
Author(s): Qi, HX; Wang, F; Liao, CC; Friedman, RM; Tang, C; Kaas, JH; Avison, MJ
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After lesions of the somatosensory dorsal column (DC) pathway, the cortical hand representation can become unresponsive to tactile stimuli, but considerable responsiveness returns over weeks of post-lesion recovery. The reactivation suggests that preserved subthreshold sensory inputs become potentiated and axon sprouting occurs over time to mediate recovery. Here, we studied the recovery process in 3 squirrel monkeys, using high-resolution cerebral blood volume-based functional magnetic resonance imaging (CBV-fMRI) mapping of contralateral somatosensory cortex responsiveness to stimulation of distal finger pads with low and high level electrocutaneous stimulation (ES) before and 2, 4, and 6weeks after a mid-cervical level contralateral DC lesion. Both low and high intensity ES of digits revealed the expected somatotopy of the area 3b hand representation in pre-lesion monkeys, while in areas 1 and 3a, high intensity stimulation was more effective in activating somatotopic patterns. Six weeks post-lesion, and irrespective of the severity of loss of direct DC inputs (98%, 79%, 40%), somatosensory cortical area 3b of all three animals showed near complete recovery in terms of somatotopy and responsiveness to low and high intensity ES. However there was significant variability in the patterns and amplitudes of reactivation of individual digit territories within and between animals, reflecting differences in the degree of permanent and/or transient silencing of primary DC and secondary inputs 2weeks post-lesion, and their spatio-temporal trajectories of recovery between 2 and 6weeks. Similar variations in the silencing and recovery of somatotopy and responsiveness to high intensity ES in areas 3a and 1 are consistent with individual differences in damage to and recovery of DC and spinocuneate pathways, and possibly the potentiation of spinothalamic pathways. Thus, cortical deactivation and subsequent reactivation depends not only on the degree of DC lesion, but also on the severity and duration of loss of secondary as well as primary inputs revealed by low and high intensity ES.
Parabrachial complex links pain transmission to descending pain modulation
Author(s): Roeder, Z; Chen, Q; Davis, S; Carlson, JD; Tupone, D; Heinricher, MM
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The rostral ventromedial medulla (RVM) has a well-documented role in pain modulation and exerts antinociceptive and pronociceptive influences mediated by 2 distinct classes of neurons, OFF-cells and ON-cells. OFF-cells are defined by a sudden pause in firing in response to nociceptive inputs, whereas ON-cells are characterized by a burst of activity. Although these reflex-related changes in ON- and OFF-cell firing are critical to their pain-modulating function, the pathways mediating these responses have not been identified. The present experiments were designed to test the hypothesis that nociceptive input to the RVM is relayed through the parabrachial complex (PB). In electrophysiological studies, ON- and OFF-cells were recorded in the RVM of lightly anesthetized male rats before and after an infusion of lidocaine or muscimol into PB. The ON-cell burst and OFF-cell pause evoked by noxious heat or mechanical probing were substantially attenuated by inactivation of the lateral, but not medial, parabrachial area. Retrograde tracing studies showed that neurons projecting to the RVM were scattered throughout PB. Few of these neurons expressed calcitonin gene-related peptide, suggesting that the RVM projection from PB is distinct from that to the amygdala. These data show that a substantial component of bottom-up nociceptive drive to RVM pain-modulating neurons is relayed through the PB. While the PB is well known as an important relay for ascending nociceptive information, its functional connection with the RVM allows the spinoparabrachial pathway to access descending control systems as part of a recurrent circuit.
Active corrosion protection coating for a ZE41 magnesium alloy created by combining PEO and sol–gel techniques
Author(s): logo, DK; logo, KA; Kallip, S; Lisenkov, AD; logo, MS; Lamakac, SV; Ferreira, MG; Zheludkevich, ML
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An active protective coating for ZE41 magnesium alloy was produced by sealing an anodic layer, loaded with 1,2,4-triazole, with a sol–gel film. An anodic oxide layer was formed using PEO in a silicate–fluoride alkaline solution. This thin (1.8 μm) porous PEO layer was impregnated with corrosion inhibitor 1,2,4-triazole and sealed with a silica-based sol–gel film modified with titanium oxide. For the first time it was demonstrated that this relatively thin PEO-based composite coating revealed high barrier properties and provided superior protection against corrosion attack during 1 month of continuous exposure to 3% NaCl. A scanning vibrating electrode technique showed a sharp decrease (100 times) of corrosion activity in micro defects formed in the 1,2,4-triazole doped composite coating, when compared to blank samples.
Ipsilateral cortical inputs to the rostral and caudal motor areas in rats
Author(s): Mohammed, H; Jain, N
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Rats have a complete body representation in the primary motor cortex (M1). Rostrally there are additional representations of the forelimb and whiskers, called the rostral forelimb area (RFA) and the rostral whisker area (RWA). Recently we showed that sources of thalamic inputs to RFA and RWA are similar, but they are different from those for the caudal forelimb area (CFA) and the caudal whisker area (CWA) of M1 (Mohammed and Jain [2014] J Comp Neurol 522:528-545). We proposed that RWA and RFA are part of a second motor area, the rostral motor area (RMA). Here we report ipsilateral cortical connections of whisker representation in RMA, and compare them with connections of CWA. Connections of RFA, CFA, and the caudally located hindlimb area (CHA), which is a part of M1, were determined for comparison. The most distinctive features of cortical inputs to RWA compared with CWA include lack of inputs from the face region of the primary somatosensory cortex (S1), and only about half as much inputs from S1 compared with the lateral somatosensory areas S2 (second somatosensory area) and the parietal ventral area (PV). A similar pattern of inputs is seen for CFA and RFA, with RFA receiving smaller proportion of inputs from the forepaw region of S1 compared with CFA, and receiving fewer inputs from S1 compared with those from S2. These and other features of the cortical input pattern suggest that RMA has a distinct, and more of integrative functional role compared with M1. J. Comp. Neurol. 524:3104-3123, 2016. © 2016 Wiley Periodicals, Inc.
Temporal properties of network-mediated responses to repetitive stimuli are dependent upon retinal ganglion cell type.
Author(s): Im, M; Fried, SI
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To provide artificially-elicited vision that is temporally dynamic, retinal prosthetic devices will need to repeatedly stimulate retinal neurons. However, given the diversity of physiological types of retinal ganglion cells (RGCs) as well as the heterogeneity of their responses to electric stimulation, temporal properties of RGC responses have not been adequately investigated. Here, we explored the cell type dependence of network-mediated RGC responses to repetitive electric stimulation at various stimulation rates.
A role for acoustic distortion in novel rapid frequency modulation behaviour in free-flying male mosquitoes
Author(s): Simões, PM; Ingham, RA; Gibson, G; Russell, IJ
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We describe a new stereotypical acoustic behaviour by male mosquitoes in response to the fundamental frequency of female flight tones during mating sequences. This male-specific free-flight behaviour consists of phonotactic flight beginning with a steep increase in wing-beat frequency (WBF) followed by rapid frequency modulation (RFM) of WBF in the lead up to copula formation. Male RFM behaviour involves remarkably fast changes in WBF and can be elicited without acoustic feedback or physical presence of the female. RFM features are highly consistent, even in response to artificial tones that do not carry the multi-harmonic components of natural female flight tones. Comparison between audiograms of the robust RFM behaviour and the electrical responses of the auditory Johnston's organ (JO) reveals that the male JO is tuned not to the female WBF per se but, remarkably, to the difference between the male and female WBFs. This difference is generated in the JO responses as a result of intermodulation distortion products (DPs) caused by non-linear interaction between male-female flight tones in the vibrations of the antenna. We propose that male mosquitoes rely on their own flight tones in making use of DPs to acoustically detect, locate and orientate towards flying females. We argue that the previously documented flight-tone harmonic convergence of flying male and female mosquitoes could be a consequence of WBF adjustments so that DPs generated through flight-tone interaction fall within the optimal frequency ranges for JO detection.
Neural correlates of behavioral amplitude modulation sensitivity in the budgerigar midbrain
Author(s): Henry, KS; Neilans, EG; Abrams, KS; Idrobo, F; Carney, LH
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Amplitude modulation (AM) is a crucial feature of many communication signals, including speech. Whereas average discharge rates in the auditory midbrain correlate with behavioral AM sensitivity in rabbits, the neural bases of AM sensitivity in species with human-like behavioral acuity are unexplored. Here, we used parallel behavioral and neurophysiological experiments to explore the neural (midbrain) bases of AM perception in an avian speech mimic, the budgerigar (Melopsittacus undulatus). Behavioral AM sensitivity was quantified using operant conditioning procedures. Neural AM sensitivity was studied using chronically implanted microelectrodes in awake, unrestrained birds. Average discharge rates of multiunit recording sites in the budgerigar midbrain were insufficient to explain behavioral sensitivity to modulation frequencies < 100 Hz for both tone- and noise-carrier stimuli, even with optimal pooling of information across recording sites. Neural envelope synchrony, in contrast, could explain behavioral performance for both carrier types across the full range of modulation frequencies studied (16-512 Hz). The results suggest that envelope synchrony in the budgerigar midbrain may underlie behavioral sensitivity to AM. Behavioral AM sensitivity based on synchrony in the budgerigar, which contrasts with rate-correlated behavioral performance in rabbits, raises the possibility that envelope synchrony, rather than average discharge rate, might also underlie AM perception in other species with sensitive AM detection abilities, including humans. These results highlight the importance of synchrony coding of envelope structure in the inferior colliculus. Furthermore, they underscore potential benefits of devices (e.g., midbrain implants) that evoke robust neural synchrony.
Social context differentially modulates activity of two interneuron populations in an avian basal ganglia nucleus
Author(s): Woolley, SC
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Basal ganglia circuits are critical for the modulation of motor performance across behavioral states. In zebra finches, a cortical-basal ganglia circuit dedicated to singing is necessary for males to adjust their song performance and transition between spontaneous singing, when they are alone (undirected song), and a performance state, when they sing to a female (female-directed song). However, we know little about the role of different basal ganglia cell types in this behavioral transition or the degree to which behavioral context modulates the activity of different neuron classes. To investigate whether interneurons in the songbird basal ganglia encode information about behavioral state, I recorded from two interneuron types, fast-spiking interneurons (FSI) and external pallidal (GPe) neurons, in the songbird basal ganglia nucleus area X during both female-directed and undirected singing. Both cell types exhibited higher firing rates, more frequent bursting, and greater trial-by-trial variability in firing when male zebra finches produced undirected songs compared with when they produced female-directed songs. However, the magnitude and direction of changes to the firing rate, bursting, and variability of spiking between when birds sat silently and when they sang undirected and female-directed song varied between FSI and GPe neurons. These data indicate that social modulation of activity important for eliciting changes in behavioral state is present in multiple cell types within area X and suggests that social interactions may adjust circuit dynamics during singing at multiple points within the circuit.
Development of semi-chronic microdrive system for large-scale circuit mapping in macaque mesolimbic and basal ganglia systems
Author(s): Shaoyu Qiao, ; Brown, KA; Orsborn, AL; Ferrentino, B; Pesaran, B
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The development of novel neurotechnologies for treating refractory neuropsychiatry disorders depends on understanding and manipulating the dynamics of neural circuits across large-scale brain networks. The mesolimbic pathway plays an essential role in reward processing and mood regulation and disorders of this pathway underlie many neuropsychiatric disorders. Here, we present the design of a customized semi-chronic microdrive array that precisely targets the anatomical structures of non-human primate (NHP) mesolimbic and basal ganglia systems. We present an integrated experimental paradigm that uses this device to map and manipulate large-scale neural circuits. The system combines electrophysiology, spatiotemporal multisite patterned intracortical microstimulation (ICMS), and diffusion tractography. We propose that this system provides a flexible platform for exploring and identifying neural signatures which can serve as novel targets for closed-loop stimulation in the clinical treatment of neuropsychiatric disorders.
Median nerve stimulation reduces ventricular arrhythmias induced by dorsomedial hypothalamic stimulation
Author(s): Zhao, S; Tang, M; Yuan, K; Gu, J; Yu, J; Long, X; Liu, M; Cao, JM; Zhang, S
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This study tested the hypothesis that median nerve stimulation (MNS) prevents ventricular arrhythmias (VAs) induced by dorsomedial hypothalamus stimulation (DMHS) and investigated the electrophysiological mechanisms underlying the anti-arrhythmic effects of MNS by recording left stellate ganglion activity (LSGA). Eighteen rabbits were anesthetized, the median nerve was anchored by stimulating electrodes, and a bipolar electrode was implanted into the LSG to record nerve activity. The DMH was stimulated to induce arrhythmia. All animals underwent six repetitions of DMHS (30 s). The 18 rabbits were divided into the following 3 groups: a control group, which underwent only DMHS (n = 6); an MNS group, which underwent MNS during both the third and fourth DMHS repetitions (n = 6); and an LSGA-recording group, for which LSGA was recorded at baseline, immediately following DMHS and again immediately following MNS and DMHS (n = 6). Repeated DMHS-induced multiple VAs, in the rabbits. Compared with the DMHS-only group, the concurrent administration of MNS during DMHS significantly reduced the incidence of VAs (7 ± 3 and 9 ± 2 beats for the third and fourth DMHS + MNS repetitions vs. 29 ± 8 and 27 ± 9 beats for the first two DMHS repetitions, p < 0.05). The total duration of the abnormal discharges of the LSG (ADLSG) following MNS and DMHS was significantly reduced compared with that of the DMHS-only group (40 ± 18 vs. 14 ± 6 s, p < 0.05). MNS reduced VAs induced by DMHS, which is thought to be mediated through suppressing of ADLSG. Median nerve electrical stimulation prevented ventricular arrhythmias induced by DMHS through the mechanism of suppressing abnormal discharges of left stellate ganglion.
Fabrication and Microassembly of a mm-Sized Floating Probe for a Distributed Wireless Neural Interface
Author(s): Yeon, P; Mirbozorgi, SA; Ash, B; Eckhardt, H; Ghovanloo, M
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A new class of wireless neural interfaces is under development in the form of tens to hundreds of mm-sized untethered implants, distributed across the target brain region(s). Unlike traditional interfaces that are tethered to a centralized control unit and suffer from micromotions that may damage the surrounding neural tissue, the new free-floating wireless implantable neural recording (FF-WINeR) probes will be stand-alone, directly communicating with an external interrogator. Towards development of the FF-WINeR, in this paper we describe the micromachining, microassembly, and hermetic packaging of 1-mm3 passive probes, each of which consists of a thinned micromachined silicon die with a centered Ø(diameter) 130 μm through-hole, an Ø81 μm sharpened tungsten electrode, a 7-turn gold wire-wound coil wrapped around the die, two 0201 surface mount capacitors on the die, and parylene-C/Polydimethylsiloxane (PDMS) coating. The fabricated passive probe is tested under a 3-coil inductive link to evaluate power transfer efficiency (PTE) and power delivered to a load (PDL) for feasibility assessment. The minimum PTE/PDL at 137 MHz were 0.76%/240 μW and 0.6%/191 μW in the air and lamb head medium, respectively, with coil separation of 2.8 cm and 9 kΩ receiver (Rx) loading. Six hermetically sealed probes went through wireless hermeticity testing, using a 2-coil inductive link under accelerated lifetime testing condition of 85 °C, 1 atm, and 100%RH. The mean-time-to-failure (MTTF) of the probes at 37 °C is extrapolated to be 28.7 years, which is over their lifetime.
Rebuilding motor function of the spinal cord based on functional electrical stimulation
Author(s): Shen, XY; Du, W; Huang, W; Chen, Y
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Rebuilding the damaged motor function caused by spinal cord injury is one of the most serious challenges in clinical neuroscience. The function of the neural pathway under the damaged sites can be rebuilt using functional electrical stimulation technology. In this study, the locations of motor function sites in the lumbosacral spinal cord were determined with functional electrical stimulation technology. A three-dimensional map of the lumbosacral spinal cord comprising the relationship between the motor function sites and the corresponding muscle was drawn. Based on the individual experimental parameters and normalized coordinates of the motor function sites, the motor function sites that control a certain muscle were calculated. Phasing pulse sequences were delivered to the determined motor function sites in the spinal cord and hip extension, hip flexion, ankle plantarflexion, and ankle dorsiflexion movements were successfully achieved. The results show that the map of the spinal cord motor function sites was valid. This map can provide guidance for the selection of electrical stimulation sites during the rebuilding of motor function after spinal cord injury.
Information Accumulation over Time in Monkey Inferior Temporal Cortex Neurons Explains Pattern Recognition Reaction Time under Visual Noise
Author(s): Kuboki, R; Sugase-Miyamoto, Y; Matsumoto, N; Richmond, BJ; Shidara, M
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We recognize objects even when they are partially degraded by visual noise. We studied the relation between the amount of visual noise (5, 10, 15, 20, or 25%) degrading 8 black-and-white stimuli and stimulus identification in 2 monkeys performing a sequential delayed match-to-sample task. We measured the accuracy and speed with which matching stimuli were identified. The performance decreased slightly (errors increased) as the amount of visual noise increased for both monkeys. The performance remained above 80% correct, even with 25% noise. However, the reaction times markedly increased as the noise increased, indicating that the monkeys took progressively longer to decide what the correct response would be as the amount of visual noise increased, showing that the monkeys trade time to maintain accuracy. Thus, as time unfolds the monkeys act as if they are accumulating the information and/or testing hypotheses about whether the test stimulus is likely to be a match for the sample being held in short-term memory. We recorded responses from 13 single neurons in area TE of the 2 monkeys. We found that stimulus-selective information in the neuronal responses began accumulating when the match stimulus appeared. We found that the greater the amount of noise obscuring the test stimulus, the more slowly stimulus-related information by the 13 neurons accumulated. The noise induced slowing was about the same for both behavior and information. These data are consistent with the hypothesis that area TE neuron population carries information about stimulus identity that accumulates over time in such a manner that it progressively overcomes the signal degradation imposed by adding visual noise.
Implantable microcoils for intracortical magnetic stimulation
Author(s): Lee, SW; Fallegger, F; Casse, BD; Fried, SI
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Neural prostheses that stimulate the neocortex have the potential to treat a wide range of neurological disorders. However, the efficacy of electrode-based implants remains limited, with persistent challenges that include an inability to create precise patterns of neural activity as well as difficulties in maintaining response consistency over time. These problems arise from fundamental limitations of electrodes as well as their susceptibility to implantation and have proven difficult to overcome. Magnetic stimulation can address many of these limitations, but coils small enough to be implanted into the cortex were not thought strong enough to activate neurons. We describe a new microcoil design and demonstrate its effectiveness for both activating cortical neurons and driving behavioral responses. The stimulation of cortical pyramidal neurons in brain slices in vitro was reliable and could be confined to spatially narrow regions ( < 60 μm). The spatially asymmetric fields arising from the coil helped to avoid the simultaneous activation of passing axons. In vivo implantation was safe and resulted in consistent and predictable behavioral responses. The high permeability of magnetic fields to biological substances may yield another important advantage because it suggests that encapsulation and other adverse effects of implantation will not diminish coil performance over time, as happens to electrodes. These findings suggest that a coil-based implant might be a useful alternative to existing electrode-based devices. The enhanced selectivity of microcoil-based magnetic stimulation will be especially useful for visual prostheses as well as for many brain-computer interface applications that require precise activation of the cortex.
Corticotropin releasing factor receptor type 1 signaling in epilepsy and traumatic brain injury
Author(s): Narla, VV
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A platinum-iridium electrode (Microprobes, Inc., MD, USA) with a tip diameter of 200- 300 micrometers was used to stimulate the lateral olfactory tract of the piriform cortex. The stimulation of each slice was in the range of 160-200 µA, each square pulse was 2.0 ms in length.
Suppression of piriform cortex activity in rat by corticotropin-releasing factor 1 and serotonin 2A/C receptors
Author(s): Narla, C; Dunn, HA; Ferguson, SS; Poulter, MO
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The piriform cortex (PC) is richly innervated by corticotropin-releasing factor (CRF) and serotonin (5-HT) containing axons arising from central amygdala and Raphe nucleus. CRFR1 and 5-HT2A/2CRs have been shown to interact in manner where CRFR activation subsequently potentiates the activity of 5-HT2A/2CRs. The purpose of this study was to determine how the activation of CRFR1 and/or 5-HT2Rs modulates PC activity at both the circuit and cellular level. Voltage sensitive dye imaging showed that CRF acting through CRFR1 dampened activation of the Layer II of PC and interneurons of endopiriform nucleus. Application of the selective 5-HT2A/CR agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) following CRFR1 activation potentiated this effect. Blocking the interaction between CRFR1 and 5-HT2R with a Tat-CRFR1-CT peptide abolished this potentiation. Application of forskolin did not mimic CRFR1 activity but instead blocked it, while a protein kinase A antagonist had no effect. However, activation and antagonism of protein kinase C (PKC) either mimicked or blocked CRF modulation, respectively. DOI had no effect when applied alone indicating that the prior activation of CRFR1 receptors was critical for DOI to show significant effects similar to CRF. Patch clamp recordings showed that both CRF and DOI reduced the synaptic responsiveness of Layer II pyramidal neurons. CRF had highly variable effects on interneurons within Layer III, both increasing and decreasing their excitability, but DOI had no effect on the excitability of this group of neurons. These data show that CRF and 5-HT, acting through both CRFR1 and 5-HT2A/CRs, reduce the activation of the PC. This modulation may be an important blunting mechanism of stressor behaviors mediated through the olfactory cortex.
The influence of vibration and probe movement on SVET measurements
Author(s): Bastos, AC; Quevedo, MC; Ferreira, MGS
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This communication describes a set of experiments performed to evaluate the influence of SVET vibration and movement of the probe on the obtained results. Both vibration and movement during scanning stir the solution with the risk of enhancing the oxygen transport to the surface thus increasing the measured currents and accelerating the corrosion process. It is shown that, for the SVET system used, due to its small probe, the effect of the vibration is negligible in normal operation. On the contrary, the movement of the probe during scanning increases the cathodic reaction and smaller excursions or slower movements just marginally reduce this effect. It is also shown that only the region of the sample under the probe is affect and for just brief instants. The overall corrosion in the long run is not influenced and the measured maps only scarcely show any evidences of artifacts introduced by the probe movement.
Evaluation of poly(3,4-ethylenedioxythiophene)/carbon nanotube neural electrode coatings for stimulation in the dorsal root ganglion.
Author(s): Kolarcik, CL; Catt, K; Rost, E; Albrecht, IN; Bourbeau, D; Du, Z; Kozai, TD; Luo, X; Weber, DJ; Cui, XT
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The dorsal root ganglion is an attractive target for implanting neural electrode arrays that restore sensory function or provide therapy via stimulation. However, penetrating microelectrodes designed for these applications are small and deliver low currents. For long-term performance of microstimulation devices, novel coating materials are needed in part to decrease impedance values at the electrode-tissue interface and to increase charge storage capacity.
Subthalamic deep brain stimulation reduces pathological information transmission to the thalamus in a rat model of parkinsonism
Author(s): Anderson, CJ; Sheppard, DT; Huynh, R; Anderson, DN; Polar, CA; Dorval, AD
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The degeneration of dopaminergic neurons in the substantia nigra pars compacta leads to parkinsonian motor symptoms via changes in electrophysiological activity throughout the basal ganglia. High-frequency deep brain stimulation (DBS) partially treats these symptoms, but the mechanisms are unclear. We hypothesize that motor symptoms of Parkinson's disease (PD) are associated with increased information transmission from basal ganglia output neurons to motor thalamus input neurons and that therapeutic DBS of the subthalamic nucleus (STN) treats these symptoms by reducing this extraneous information transmission. We tested these hypotheses in a unilateral, 6-hydroxydopamine-lesioned rodent model of hemiparkinsonism. Information transfer between basal ganglia output neurons and motor thalamus input neurons increased in both the orthodromic and antidromic directions with hemiparkinsonian (hPD) onset, and these changes were reversed by behaviorally therapeutic STN-DBS. Omnidirectional information increases in the parkinsonian state underscore the detrimental nature of that pathological information and suggest a loss of information channel independence. Therapeutic STN-DBS reduced that pathological information, suggesting an effective increase in the number of independent information channels. We interpret these data with a model in which pathological information and fewer information channels diminishes the scope of possible motor activities, driving parkinsonian symptoms. In this model, STN-DBS restores information-channel independence by eliminating or masking the parkinsonism-associated information, and thus enlarges the scope of possible motor activities, alleviating parkinsonian symptoms.
Guard cell SLAC1-type anion channels mediate flagellin-induced stomatal closure
Author(s): Guzel Deger, A; Scherzer, S; Nuhkat, M; Kedzierska, J; Kollist, H; Brosché, M; Unyayar, S; Boudsocq, M; Hedrich, R; Roelfsema, MR
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During infection plants recognize microbe-associated molecular patterns (MAMPs), and this leads to stomatal closure. This study analyzes the molecular mechanisms underlying this MAMP response and its interrelation with ABA signaling. Stomata in intact Arabidopsis thaliana plants were stimulated with the bacterial MAMP flg22, or the stress hormone ABA, by using the noninvasive nanoinfusion technique. Intracellular double-barreled microelectrodes were applied to measure the activity of plasma membrane ion channels. Flg22 induced rapid stomatal closure and stimulated the SLAC1 and SLAH3 anion channels in guard cells. Loss of both channels resulted in cells that lacked flg22-induced anion channel activity and stomata that did not close in response to flg22 or ABA. Rapid flg22-dependent stomatal closure was impaired in plants that were flagellin receptor (FLS2)-deficient, as well as in the ost1-2 (Open Stomata 1) mutant, which lacks a key ABA-signaling protein kinase. By contrast, stomata of the ABA protein phosphatase mutant abi1-1 (ABscisic acid Insensitive 1) remained flg22-responsive. These data suggest that the initial steps in flg22 and ABA signaling are different, but that the pathways merge at the level of OST1 and lead to activation of SLAC1 and SLAH3 anion channels.
Spatial properties of network-mediated response of retinal ganglion cells to electric stimulation
Author(s): Im, M; Fried, SI
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Retinal prosthetics consistently demonstrate the ability to restore limited visual perception to those blinded from outer retinal degenerative diseases. However, the performance of retinal implants is highly inconsistent and high-density arrays have proven only marginally better than much sparser ones suggesting that improving the overall quality of elicited vision may require more than just a high density electrode array. Existing devices are also implanted subretinally and epiretinally raising the possibility that electrode location also contributes to percept quality. Here, we compared the responses to stimulation from subretinal and epiretinal electrodes in the same cell. Use of a 4×4 subretinal electrode array allowed us to also compare responses to different numbers of electrodes activated simultaneously. Surprisingly, responses showed minimal dependence of both the electrode position (epiretinal vs. subretinal) as well as on electrode size (one vs. up to nine electrodes). However, when charge density considerations are implemented, such as those that are necessary during clinical use, the responses arising from smaller electrodes were less effective. This finding may help to explain the inconsistency between theoretical visual acuity and achievement in clinical testing with the high density implanted arrays.
Conjunctive input processing drives feature selectivity in hippocampal CA1 neurons
Author(s): Bittner, KC; Grienberger, C; Vaidya, SP; Milstein, AD; Macklin, JJ; Suh, J; Tonegawa, S; Magee, JC
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Feature-selective firing allows networks to produce representations of the external and internal environments. Despite its importance, the mechanisms generating neuronal feature selectivity are incompletely understood. In many cortical microcircuits the integration of two functionally distinct inputs occurs nonlinearly through generation of active dendritic signals that drive burst firing and robust plasticity. To examine the role of this processing in feature selectivity, we recorded CA1 pyramidal neuron membrane potential and local field potential in mice running on a linear treadmill. We found that dendritic plateau potentials were produced by an interaction between properly timed input from entorhinal cortex and hippocampal CA3. These conjunctive signals positively modulated the firing of previously established place fields and rapidly induced new place field formation to produce feature selectivity in CA1 that is a function of both entorhinal cortex and CA3 input. Such selectivity could allow mixed network level representations that support context-dependent spatial maps.
Reward modulates the effect of visual cortical microstimulation on perceptual decisions
Author(s): Cicmil, N; Cumming, BG; Parker, AJ; Krug, K
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Effective perceptual decisions rely upon combining sensory information with knowledge of the rewards available for different choices. However, it is not known where reward signals interact with the multiple stages of the perceptual decision-making pathway and by what mechanisms this may occur. We combined electrical microstimulation of functionally specific groups of neurons in visual area V5/MT with performance-contingent reward manipulation, while monkeys performed a visual discrimination task. Microstimulation was less effective in shifting perceptual choices towards the stimulus preferences of the stimulated neurons when available reward was larger. Psychophysical control experiments showed this result was not explained by a selective change in response strategy on microstimulated trials. A bounded accumulation decision model, applied to analyse behavioural performance, revealed that the interaction of expected reward with microstimulation can be explained if expected reward modulates a sensory representation stage of perceptual decision-making, in addition to the better-known effects at the integration stage.
Genetic dissection of the Down syndrome critical region
Author(s): Jiang, X; Liu, C; Yu, T; Zhang, L; Meng, K; Xing, Z; Belichenko, PV; Kleschevnikov, AM; Pao, A; Peresie, J; Wie, S; Mobley, WC; Yu, YE
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Down syndrome (DS), caused by trisomy 21, is the most common chromosomal disorder associated with developmental cognitive deficits. Despite intensive efforts, the genetic mechanisms underlying developmental cognitive deficits remain poorly understood, and no treatment has been proven effective. The previous mouse-based experiments suggest that the so-called Down syndrome critical region of human chromosome 21 is an important region for this phenotype, which is demarcated by Setd4/Cbr1 and Fam3b/Mx2. We first confirmed the importance of the Cbr1-Fam3b region using compound mutant mice, which carry a duplication spanning the entire human chromosome 21 orthologous region on mouse chromosome 16 [Dp(16)1Yey] and Ms1Rhr. By dividing the Setd4-Mx2 region into complementary Setd4-Kcnj6 and Kcnj15-Mx2 intervals, we started an unbiased dissection through generating and analyzing Dp(16)1Yey/Df(16Setd4-Kcnj6)Yey and Dp(16)1Yey/Df(16Kcnj15-Mx2)Yey mice. Surprisingly, the Dp(16)1Yey-associated cognitive phenotypes were not rescued by either deletion in the compound mutants, suggesting the possible presence of at least one causative gene in each of the two regions. The partial rescue by a Dyrk1a mutation in a compound mutant carrying Dp(16)1Yey and the Dyrk1a mutation confirmed the causative role of Dyrk1a, whereas the absence of a similar rescue by Df(16Dyrk1a-Kcnj6)Yey in Dp(16)1Yey/Df(16Dyrk1a-Kcnj6)Yey mice demonstrated the importance of Kcnj6. Our results revealed the high levels of complexities of gene actions and interactions associated with the Setd4/Cbr1-Fam3b/Mx2 region as well as their relationship with developmental cognitive deficits in DS.
Indirect activation elicits strong correlations between light and electrical responses in ON but not OFF retinal ganglion cells
Author(s): Im, M; Fried, SI
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To improve the quality of vision elicited by retinal prosthetics, elicited neural activity should resemble physiological signalling patterns; here, we hypothesized that electric stimulation that activates the synaptic circuitry of the retina would lead to closer matches than that which activates ganglion cells directly. We evaluated this hypothesis by comparing light and electrical responses in different types of ganglion cells. In contrast to the similarity in their light responses, electrical responses in ON and OFF cells of the same type were quite distinct. Further, electrical and light responses in the same cell were much better correlated in ON vs. OFF ganglion cells. Stimuli that activated photoreceptors yielded better correlations than those which activated bipolar cells. Our results suggest that the closer match to physiology in the ON signal transmitted to the brain may help to explain preferential reports of 'bright' phosphenes during earlier clinical trials. To improve the efficacy of microelectronic retinal prosthetics it will be necessary to better understand the response of retinal neurons to electric stimulation. While stimulation that directly activates ganglion cells generally has the lowest threshold, the similarity in responsiveness across cells makes it extremely difficult for such an approach to re-create cell-type specific patterns of neural activity that arise normally in the healthy retina. In contrast, stimulation that activates neurons presynaptic to ganglion cells utilizes at least some of the existing retinal circuitry and therefore is thought to produce neural activity that better matches physiological signalling. Surprisingly, the actual benefit(s) of this approach remain unsubstantiated. Here, we recorded from ganglion cells in the rabbit retinal explant in response to electrical stimuli that activated the network. Targeted cells were first classified into known types via light responses so that the consistency of electrical responses within individual types could be evaluated. Both transient and sustained ON ganglion cells exhibited highly consistent electrical response patterns which were distinct from one another. Further, properties of the response (interspike interval, latency, peak firing rate, and spike count) in a given cell were well correlated to the corresponding properties of the light response for that same cell. Electric responses in OFF ganglion cells formed two groups, distinct from ON groups, and the correlation levels between electric and light responses were much weaker. The closer match in ON pathway responses may help to explain some preferential reporting of bright stimuli during psychophysical testing.
Deep brain stimulation of the subthalamic nucleus reestablishes neuronal information transmission in the 6-OHDA rat model of parkinsonism
Author(s): Dorval, AD; Grill, WM
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Pathophysiological activity of basal ganglia neurons accompanies the motor symptoms of Parkinson's disease. High-frequency (>90 Hz) deep brain stimulation (DBS) reduces parkinsonian symptoms, but the mechanisms remain unclear. We hypothesize that parkinsonism-associated electrophysiological changes constitute an increase in neuronal firing pattern disorder and a concomitant decrease in information transmission through the ventral basal ganglia, and that effective DBS alleviates symptoms by decreasing neuronal disorder while simultaneously increasing information transfer through the same regions. We tested these hypotheses in the freely behaving, 6-hydroxydopamine-lesioned rat model of hemiparkinsonism. Following the onset of parkinsonism, mean neuronal firing rates were unchanged, despite a significant increase in firing pattern disorder (i.e., neuronal entropy), in both the globus pallidus and substantia nigra pars reticulata. This increase in neuronal entropy was reversed by symptom-alleviating DBS. Whereas increases in signal entropy are most commonly indicative of similar increases in information transmission, directed information through both regions was substantially reduced (>70%) following the onset of parkinsonism. Again, this decrease in information transmission was partially reversed by DBS. Together, these results suggest that the parkinsonian basal ganglia are rife with entropic activity and incapable of functional information transmission. Furthermore, they indicate that symptom-alleviating DBS works by lowering the entropic noise floor, enabling more information-rich signal propagation. In this view, the symptoms of parkinsonism may be more a default mode, normally overridden by healthy basal ganglia information. When that information is abolished by parkinsonian pathophysiology, hypokinetic symptoms emerge
Ultra-low power neural stimulator for electrode interfaces
Author(s): Nag, S; Sharma, D; Thakor, NV
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Power loss at the output stage of conventional constant current neural stimulators is notably high. This is particularly disadvantageous for applications in implantable systems where power budget is limited. We present a novel electrical stimulator architecture for significantly reduced power loss and low noise operation. The system generates a calibrated output voltage profile for driving electrode impedance with an approximate biphasic current stimulation. The stimulator utilizes switched-capacitor output driver stage and low speed operations for substantial reduction in power loss. The hardware is capable of generating on-demand clock signals for appropriate switching events through a feedback mechanism. The self-clocking ultra-low power stimulator front-end and its controller exhibits quasi-stable quiescent power consumption of 3.75 μW and raw efficiency up to 98%. The low power stimulator architecture consumes nearly 70% less power than conventional linear mode stimulators and half of the reported state-of-the art design. Output peak-to-peak noise down to 20 mV is achieved through this design. Demonstrations are shown with RC impedance, platinum-iridium electrode in saline solution and in-vivo somatosensory cortex stimulation.
A graphene oxide nanocomposite for neural interfacing applications
Author(s): Weaver, CL
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… GO/PEDOT films were electrodeposited onto platinum/iridium (Pt/Ir) microelectrodes (standard tip, diameter: 2-3 m, MicroProbes, Gaithersburg, MD) for electrochemical characterization or gold sputtered plastic microscope coverslips (macroelectrode area: 0.38 cm2) for surface …
Tunable, spatially addressable functionalization strategies for micro/nano scale, multi-analyte biosensors
Author(s): Madangopal, R
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… Platinum/Iridium (Pt/Ir) microelectrodes (PI20033.0A10, Microprobes Inc., Gaithersburg, MD) with 256 m diameter shaft, 3 m parylene C insulation, 13 m exposed tip diameter and, 3.0M impedance were used for the design and characterization of the three-layer functionalization …
Large-scale reorganization of the somatosensory cortex following spinal cord injuries is due to brainstem plasticity
Author(s): Kambi, N; Halder, P; Rajan, R; Arora, V; Chand, P; Arora, M; Jain, N
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Adult mammalian brains undergo reorganization following deafferentations due to peripheral nerve, cortical or spinal cord injuries. The largest extent of cortical reorganization is seen in area 3b of the somatosensory cortex of monkeys with chronic transection of the dorsal roots or dorsal columns of the spinal cord. These injuries cause expansion of intact face inputs into the deafferented hand cortex, resulting in a change of representational boundaries by more than 7 mm. Here we show that large-scale reorganization in area 3b following spinal cord injuries is due to changes at the level of the brainstem nuclei and not due to cortical mechanisms. Selective inactivation of the reorganized cuneate nucleus of the brainstem eliminates observed face expansion in area 3b. Thus, the substrate for the observed expanded face representation in area 3b lies in the cuneate nucleus.
The degradation of glial scar and enhancement of chronic intracortical recording electrode performance through the local delivery of dexamethasone and chondroitinase
Author(s): Alba, NA
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… (a and d Microprobes for Life Science, Inc … Simple electrode/cannula implants were hand-fabricated by adhering two tungsten microwire electrodes (Microprobes for Life Science, Gaithersburg MD) to opposite sides of CMA cannulae using UV-activated cement (Fig. 2.4) …
Novel flexible Parylene neural probe with 3D sheath structure for enhancing tissue integration
Author(s): Kuo, JT; Kim, BJ; Hara, SA; Lee, CD; Gutierrez, CA; Hoang, TQ; Meng, E
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A Parylene C neural probe with a three dimensional sheath structure was designed, fabricated, and characterized. Multiple platinum (Pt) electrodes for recording neural signals were fabricated on both inner and outer surfaces of the sheath structure. Thermoforming of Parylene was used to create the three dimensional sheath structures from flat surface micromachined microchannels using solid microwires as molds. Benchtop electrochemical characterization was performed on the thin film Pt electrodes using cyclic voltammetry and electrochemical impedance spectroscopy and showed that electrodes possessed low impedances suitable for neuronal recordings. A procedure for implantation of the neural probe was developed and successfully demonstrated in vitro into an agarose brain tissue model. The electrode-lined sheath will be decorated with eluting neurotrophic factors to promote in vivo neural tissue ingrowth post-implantation. These features will enhance tissue integration and improve recording quality towards realizing reliable chronic neural interfaces.
Midbrain raphe stimulation improves behavioral and anatomical recovery from fluid-percussion brain injury
Author(s): Carballosa Gonzalez, MM; Blaya, MO; Alonso, OF; Bramlett, HM; Hentall, ID
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The midbrain median raphe (MR) and dorsal raphe (DR) nuclei were tested for their capacity to regulate recovery from traumatic brain injury (TBI). An implanted, wireless self-powered stimulator delivered intermittent 8-Hz pulse trains for 7 days to the rat's MR or DR, beginning 4-6 h after a moderate parasagittal (right) fluid-percussion injury. MR stimulation was also examined with a higher frequency (24 Hz) or a delayed start (7 days after injury). Controls had sham injuries, inactive stimulators, or both. The stimulation caused no apparent acute responses or adverse long-term changes. In water-maze trials conducted 5 weeks post-injury, early 8-Hz MR and DR stimulation restored the rate of acquisition of reference memory for a hidden platform of fixed location. Short-term spatial working memory, for a variably located hidden platform, was restored only by early 8-Hz MR stimulation. All stimulation protocols reversed injury-induced asymmetry of spontaneous forelimb reaching movements tested 6 weeks post-injury. Post-mortem histological measurement at 8 weeks post-injury revealed volume losses in parietal-occipital cortex and decussating white matter (corpus callosum plus external capsule), but not hippocampus. The cortical losses were significantly reversed by early 8-Hz MR and DR stimulation, the white matter losses by all forms of MR stimulation. The generally most effective protocol, 8-Hz MR stimulation, was tested 3 days post-injury for its acute effect on forebrain cyclic adenosine monophosphate (cAMP), a key trophic signaling molecule. This procedure reversed injury-induced declines of cAMP levels in both cortex and hippocampus. In conclusion, midbrain raphe nuclei can enduringly enhance recovery from early disseminated TBI, possibly in part through increased signaling by cAMP in efferent targets. A neurosurgical treatment for TBI using interim electrical stimulation in raphe repair centers is suggested.
The inferior colliculus encodes the Franssen auditory spatial illusion
Author(s): Rajala, AZ; Yan, Y; Dent, ML; Populin, LC
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Illusions are effective tools for the study of the neural mechanisms underlying perception because neural responses can be correlated to the physical properties of stimuli and the subject's perceptions. The Franssen illusion (FI) is an auditory spatial illusion evoked by presenting a transient, abrupt tone and a slowly rising, sustained tone of the same frequency simultaneously on opposite sides of the subject. Perception of the FI consists of hearing a single sound, the sustained tone, on the side that the transient was presented. Both subcortical and cortical mechanisms for the FI have been proposed, but, to date, there is no direct evidence for either. The data show that humans and rhesus monkeys perceive the FI similarly. Recordings were taken from single units of the inferior colliculus in the monkey while they indicated the perceived location of sound sources with their gaze. The results show that the transient component of the Franssen stimulus, with a shorter first spike latency and higher discharge rate than the sustained tone, encodes the perception of sound location. Furthermore, the persistent erroneous perception of the sustained stimulus location is due to continued excitation of the same neurons, first activated by the transient, by the sustained stimulus without location information. These results demonstrate for the first time, on a trial-by-trial basis, a correlation between perception of an auditory spatial illusion and a subcortical physiological substrate.
Gain control of γ frequency activation by a novel feed forward disinhibitory loop: implications for normal and epileptic neural activity
Author(s): Birjandian, Z; Narla, C; Poulter, MO
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The inhibition of excitatory (pyramidal) neurons directly dampens their activity resulting in a suppression of neural network output. The inhibition of inhibitory cells is more complex. Inhibitory drive is known to gate neural network synchrony, but there is also a widely held view that it may augment excitability by reducing inhibitory cell activity, a process termed disinhibition. Surprisingly, however, disinhibition has never been demonstrated to be an important mechanism that augments or drives the activity of excitatory neurons in a functioning neural circuit. Using voltage sensitive dye imaging (VSDI) we show that 20-80 Hz stimulus trains, β-γ activation, of the olfactory cortex pyramidal cells in layer II leads to a subsequent reduction in inhibitory interneuron activity that augments the efficacy of the initial stimulus. This disinhibition occurs with a lag of about 150-250 ms after the initial excitation of the layer 2 pyramidal cell layer. In addition, activation of the endopiriform nucleus also arises just before the disinhibitory phase with a lag of about 40-80 ms. Preventing the spread of action potentials from layer II stopped the excitation of the endopiriform nucleus, abolished the disinhibitory activity, and reduced the excitation of layer II cells. After the induction of experimental epilepsy the disinhibition was more intense with a concomitant increase in excitatory cell activity. Our observations provide the first evidence of feed forward disinhibition loop that augments excitatory neurotransmission, a mechanism that could play an important role in the development of epileptic seizures.
Pure Graphene Oxide Doped Conducting Polymer Nanocomposite for Bio-interfacing
Author(s): Luo, X; Weaver, CL; Tan, S; Cui, XT
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Advanced materials that are highly biocompatible and easily modifiable with biomolecules are of great importance for bio-interfacing and the development of biodevices. Here, a biocompatible conducting polymer based nanocomposite was electrochemically synthesized through the electropolymerization of poly(3, 4-ethylene dioxythiophene) (PEDOT) in the presence of graphene oxide (GO) as the only dopant. GO contains many negatively charged carboxyl functional groups and is highly dispersible in aqueous solutions, enabling its facile incorporation and even distribution throughout the conducting polymer. PEDOT/GO films exhibited minimal cytotoxicity after 24 h and supported neuron growth with significantly longer neurites than a control PEDOT/PSS film, indicating that the PEDOT/GO film provides a positive growth signal to developing neurons. While some of the negatively charged functional carboxyl groups of GO dope the PEDOT, others are exposed freely on the surface of the nanocomposite allowing easy functionalization of the PEDOT/GO composite with biomolecules. Functional laminin peptide, RNIAEIIKDI (p20), was covalently bound to the surface of the PEDOT/GO film and maintained its bioactivity, as evidenced by an increased neurite outgrowth from neurons cultured on the functionalized composite surface. The ease of biomolecule functionalization of the PEDOT/GO nanocomposite, along with its low electrochemical impedance, minimal toxicity and permissiveness to neuron growth, underlines its potential as a material for widespread biosensing, neural interfacing and tissue engineering applications.
Effect of hypothermia on cortical and thalamic signals in anesthetized rats
Author(s): Chen, C; Maybhate, A; Thakor, NV; Jia, X
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Beneficial effects of hypothermia on subjects with neuro-pathologies have been well demonstrated in both animal studies and clinical trials. Although it is known that temperature significantly impacts neurological injuries, the underlying mechanism remains unclear. We studied the effect of temperature modulation on neural signals in the cortex and the thalamus in uninjured brains of anesthetized rats. Six rats were divided into a hypothermic (32 to 34 °C, n=3) and a hyperthermic group (38.5 to 39.5 °C, n=3). EEG, and extracellular signals from somatosensory cortex and the ventral posterolateral nucleus of thalamus were recorded at different temperature phases (normothermia (36.5 to 37.5 °C) and hypothermia or hyperthermia). During hypothermia, similar burst suppression (BS) patterns were observed in cortical and thalamic signals as in EEG, but thalamic activity was not completely under suppression when both EEG and cortical signals were electrically silent. In addition, our results showed that hypothermia significantly increased the burst suppression ratio (BSR) in EEG, cortical and thalamic signals by 3.42, 3.25, 7.29 times respectively (P<0.01), and prolonged the latency of neuronal response in cortex to median nerve stimulation from 9 ms to 16 ms (P<0.01). Furthermore, during normothermia, the correlation coefficient between thalamic and cortical signals was 0.35±0.02 while during hypothermia, it decreased to 0.16±0.03 with statistical significance (P<0.01). These results can potentially assist in better understanding the effects of hypothermia.
A long-lasting wireless stimulator for small mammals
Author(s): Hentall, ID
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The chronic effects of electrical stimulation in unrestrained awake rodents are best studied with a wireless neural stimulator that can operate unsupervised for several weeks or more. A robust, inexpensive, easily built, cranially implantable stimulator was developed to explore the restorative effects of brainstem stimulation after neurotrauma. Its connectorless electrodes directly protrude from a cuboid epoxy capsule containing all circuitry and power sources. This physical arrangement prevents fluid leaks or wire breakage and also simplifies and speeds implantation. Constant-current pulses of high compliance (34 volts) are delivered from a step-up voltage regulator under microprocessor control. A slowly pulsed magnetic field controls activation state and stimulation parameters. Program status is signaled to a remote reader by interval-modulated infrared pulses. Capsule size is limited by the two batteries. Silver oxide batteries rated at 8 mA-h were used routinely in 8 mm wide, 15 mm long and 4 mm high capsules. Devices of smaller contact area (5 by 12 mm) but taller (6 mm) were created for mice. Microstimulation of the rat's raphe nuclei with intermittent 5-min (50% duty cycle) trains of 30 μA, 1 ms pulses at 8 or 24 Hz frequency during 12 daylight hours lasted 21.1 days ±0.8 (mean ± standard error, Kaplan-Meir censored estimate, n = 128). Extended lifetimes (>6 weeks, no failures, n = 16) were achieved with larger batteries (44 mA-h) in longer (18 mm), taller (6 mm) capsules. The circuit and electrode design are versatile; simple modifications allowed durable constant-voltage stimulation of the rat's sciatic nerve through a cylindrical cathode from a subcutaneous pelvic capsule. Devices with these general features can address in small mammals many of the biological and technical questions arising neurosurgically with prolonged peripheral or deep brain stimulation.
Blink perturbation effects on saccades evoked by microstimulation of the superior colliculus
Author(s): Katnani, HA; Van Opstal, AJ; Gandhi, NJ
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Current knowledge of saccade-blink interactions suggests that blinks have paradoxical effects on saccade generation. Blinks suppress saccade generation by attenuating the oculomotor drive command in structures like the superior colliculus (SC), but they also disinhibit the saccadic system by removing the potent inhibition of pontine omnipause neurons (OPNs). To better characterize these effects, we evoked the trigeminal blink reflex by delivering an air puff to one eye as saccades were evoked by sub-optimal stimulation of the SC. For every stimulation site, the peak and average velocities of stimulation with blink movements (SwBMs) were lower than stimulation-only saccades (SoMs), supporting the notion that the oculomotor drive is weakened in the presence of a blink. In contrast, the duration of the SwBMs was longer, consistent with the hypothesis that the blink-induced inhibition of the OPNs could prolong the window of time available for oculomotor commands to drive an eye movement. The amplitude of the SwBM could also be larger than the SoM amplitude obtained from the same site, particularly for cases in which blink-associated eye movements exhibited the slowest kinematics. The results are interpreted in terms of neural signatures of saccade-blink interactions.
A test of spatial temporal decoding mechanisms in the superior colliculus.
Author(s): Katnani, HA; Van Opstal, AJ; Gandhi, NJ
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Population coding is a ubiquitous principle in the nervous system for the proper control of motor behavior. A significant amount of research is dedicated to studying population activity in the superior colliculus (SC) to investigate the motor control of saccadic eye movements. Vector summation with saturation (VSS) has been proposed as a mechanism for how population activity in the SC can be decoded to generate saccades. Interestingly, the model produces different predictions when decoding two simultaneous populations at high vs. low levels of activity. We tested these predictions by generating two simultaneous populations in the SC with high or low levels of dual microstimulation. We also combined varying levels of stimulation with visually induced activity. We found that our results did not perfectly conform to the predictions of the VSS scheme and conclude that the simplest implementation of the model is incomplete. We propose that additional parameters to the model might account for the results of this investigation.
The relative impact of microstimulation parameters on movement generation
Author(s): Katnani, HA; Gandhi, NJ
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Microstimulation is widely used in neurophysiology to characterize brain areas with behavior and in clinical therapeutics to treat neurological disorder. Current intensity and frequency, which respectively influence activation patterns in spatial and temporal domains, are typically selected to elicit a desired response, but their effective influence on behavior has not been thoroughly examined. We delivered microstimulation to the primate superior colliculus while systematically varying each parameter to capture effects of a large range of parameter space. We found that frequency was more effective in driving output properties, whereas properties changed gradually with intensity. Interestingly, when different parameter combinations were matched for total charge, effects on behavioral properties became seemingly equivalent. This study provides a first level resource for choosing desired parameter ranges to effectively manipulate behavior. It also provides insights into interchangeability of parameters, which can assist clinical microstimulation that looks to appropriately control behavior within designated constraints, such as power consumption.
Spatial manipulation of cells and organelles using single electrode dielectrophoresis
Author(s): Graham, DM; Messerli, MA; Pethig, R
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The selection, isolation, and accurate positioning of single cells in three dimensions are increasingly desirable in many areas of cell biology and tissue engineering. We describe the application of a simple and low cost dielectrophoretic device for picking out and relocating single target cells. The device consists of a single metal electrode and an AC signal generator. It does not require microfabrication technologies or sophisticated electronics. The dielectrophoretic manipulator also discriminates between live and dead cells and is capable of redistributing intracellular organelles.
Mineral fine structure of the American lobster cuticle
Author(s): Kunkel, JG; Nagel, W; Jercinovic, MJ
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A major role of lobster integument is protection from microbes. Calcite and amorphous calcium carbonate are the most abundant and most acid vulnerable of the cuticle minerals. We propose that calcite is invested in neutralizing an acidifying environment modulated by the epicuticle. A minor cuticle component is carbonate apatite (CAP), proposed to play critical roles in the integument's structural protective function. The CAP of lobster exhibits a flexible composition; its least soluble forms line the cuticular canals most exposed to the environment. A trabecular CAP structure illustrates efficient use of a sparse phosphate resource, cooperating in the hardness of the inner exocuticle. A schematic model of the cuticle emphasizes structural and chemical diversity. A thin outer calcite layer provides a dense microbial barrier that dissolves slowly through the epicuticle, providing an external, alkaline, unstirred layer that would be inhibitory to bacterial movement and metabolism. Injury to the epicuticle covering this mineralized surface unleashes an immediate efflux of carbonate, accentuating the normal alkalinity of an antimicrobial unstirred layer. The trabecular CAP inner exocuticle provides rigidity to prevent bending and cracking of the calcite outer exocuticle. The combined mineral fine structure of lobster cuticle supports antimicrobial function as well as plays a structural protective role.
Subspace matching thalamic microstimulation to tactile evoked potentials in rat somatosensory cortex
Author(s): Brockmeier, AJ; Choi, JS; Emigh, MS; Li, L; Francis, JT; Principe, JC
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We show experimental results that the evoked local field potentials of the rat somatosensory cortex from natural tactile touch of forepaw digits and matched thalamic microstimulation can be qualitatively and quantitively similar. In ongoing efforts to optimize the microstimulation settings (e.g., location, amplitude, etc.) to match the natural response, we investigate whether subspace projection methods, specifically the eigenface approach proposed in the computer vision community (Turk and Pentland 1991 [1]), can be used to choose the parameters of microstimulation such that the response matches a single tactile touch realization. Since the evoked potentials from multiple electrodes are high dimensional spatio-temporal data, the subspace projections improve computational efficiency and can reduce the effect of noisy realizations. In computing the PCA projections we use the peristimulus averages instead of the realizations. The dataset is pruned of unreliable stimulation types. A new subspace is computed for the pruned stimulation type, and is used to estimate a sequence of microstimulations to best match the natural responses. This microstimulation sequence is applied in vivo and quantitative analysis shows that per realization matching does statistically better than choosing randomly from the pruned subset.
Characterization of the auditory system responses to infrared neural stimulation of the cochlear nucleus
Author(s): Guex, A
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… Systems, Carlsborg WA). Current pulses were delivered to the exposed CN using a parylene-insulated platinum-iridium twisted electrode (51mm length, impedance = 0.1-0.5 MΩ) (Microprobe Inc., Gaithersburg, MD). Bipolar stimuli …
System level assessment of motor control through patterned microstimulation in the superior colliculus
Author(s): Katnani, HA
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… liquid reward. As the animal performed this task, a platinum iridium microelectrode (1.0-1.5 M; MicroProbes for Life Science, Inc., Gaithesburg, MD) was advanced with a hydraulic microdrive (Narashigie, Tokyo, Japan). The …
Bursts and oscillations as independent properties of neural activity in the parkinsonian globus pallidus internus
Author(s): Chan, V; Starr, PA; Turner, RS
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Bursts and oscillatory modulations in firing rate are hallmark features of abnormal neuronal activity in the parkinsonian Globus Pallidus internus (GPi). Although often implicated together in the pathophysiology of parkinsonian signs, little is known about how burst discharges and oscillatory firing (OF) relate to each other. To investigate this question, extracellular single-unit neuronal activity was recorded from 132 GPi cells in 14 Parkinson's disease patients. We found that burst firing was equally prevalent in OF and non-oscillatory firing (NOF) cells (p>0.5). More than half of the cells were characterized by either aperiodic bursty activity or OF, but not both. OF and NOF cells had statistically-indistinguishable levels of mean burstiness (p=0.8). Even when bursting and OF co-existed in individual cells, levels of burstiness and oscillatory power were seldom correlated across time. Interestingly, however, the few OF cells with spectral peaks between 8-13 Hz (α-range) were substantially burstier than other cells (p < 0.01) and showed an unique burst morphology and stronger temporal correlations between oscillatory power and burstiness. We conclude that independent mechanisms may underlie the burst discharges and OF typical of most neurons in the parkinsonian GPi.
Optogenetic manipulation of cerebellar Purkinje cell activity in vivo
Author(s): Tsubota, T; Ohashi, Y; Tamura, K; Sato, A; Miyashita, Y
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Purkinje cells (PCs) are the sole output neurons of the cerebellar cortex. Although their anatomical connections and physiological response properties have been extensively studied, the causal role of their activity in behavioral, cognitive and autonomic functions is still unclear because PC activity cannot be selectively controlled. Here we developed a novel technique using optogenetics for selective and rapidly reversible manipulation of PC activity in vivo. We injected into rat cerebellar cortex lentiviruses expressing either the light-activated cationic channel channelrhodopsin-2 (ChR2) or light-driven chloride pump halorhodopsin (eNpHR) under the control of the PC-specific L7 promoter. Transgene expression was observed in most PCs (ChR2, 92.6%; eNpHR, 95.3%), as determined by immunohistochemical analysis. In vivo electrophysiological recordings showed that all light-responsive PCs in ChR2-transduced rats increased frequency of simple spike in response to blue laser illumination. Similarly, most light-responsive PCs (93.8%) in eNpHR-transduced rats decreased frequency of simple spike in response to orange laser illumination. We then applied these techniques to characterize the roles of rat cerebellar uvula, one of the cardiovascular regulatory regions in the cerebellum, in resting blood pressure (BP) regulation in anesthetized rats. ChR2-mediated photostimulation and eNpHR-mediated photoinhibition of the uvula had opposite effects on resting BP, inducing depressor and pressor responses, respectively. In contrast, manipulation of PC activity within the neighboring lobule VIII had no effect on BP. Blue and orange laser illumination onto PBS-injected lobule IX didn't affect BP, indicating the observed effects on BP were actually due to PC activation and inhibition. These results clearly demonstrate that the optogenetic method we developed here will provide a powerful way to elucidate a causal relationship between local PC activity and functions of the cerebellum.
Order of operations for decoding superior colliculus activity for saccade generation.
Author(s): Katnani, HA; Gandhi, NJ
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To help understand the order of events that occurs when generating saccades, we simulated and tested two commonly stated decoding models that are believed to occur in the oculomotor system: vector averaging (VA) and center-of-mass. To generate accurate saccades, each model incorporates two required criteria: 1) a decoding mechanism that deciphers a population response of the superior colliculus (SC) and 2) an exponential transformation that converts the saccade vector into visual coordinates. The order of these two criteria is used differently within each model, yet the significance of the sequence has not been quantified. To distinguish between each decoding sequence and hence, to determine the order of events necessary to generate accurate saccades, we simulated the two models. Distinguishable predictions were obtained when two simultaneous motor commands are processed by each model. Experimental tests of the models were performed by observing the distribution of endpoints of saccades evoked by weighted, simultaneous microstimulation of two SC sites. The data were consistent with the predictions of the VA model, in which exponential transformation precedes the decoding computation.
Stimulation of the nucleus accumbens as behavioral reward in awake behaving monkeys
Author(s): Bichot, NP; Heard, MT; Desimone, R
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It has been known that monkeys will repeatedly press a bar for electrical stimulation in several different brain structures. We explored the possibility of using electrical stimulation in one such structure, the nucleus accumbens, as a substitute for liquid reward in animals performing a complex task, namely visual search. The animals had full access to water in the cage at all times on days when stimulation was used to motivate them. Electrical stimulation was delivered bilaterally at mirror locations in and around the accumbens, and the animals' motivation to work for electrical stimulation was quantified by the number of trials they performed correctly per unit of time. Acute mapping revealed that stimulation over a large area successfully supported behavioral performance during the task. Performance improved with increasing currents until it reached an asymptotic, theoretically maximal level. Moreover, stimulation with chronically implanted electrodes showed that an animal's motivation to work for electrical stimulation was at least equivalent to, and often better than, when it worked for liquid reward while on water control. These results suggest that electrical stimulation in the accumbens is a viable method of reward in complex tasks. Because this method of reward does not necessitate control over water or food intake, it may offer an alternative to the traditional liquid or food rewards in monkeys, depending on the goals and requirements of the particular research project.
Applications of noninvasive physiological sensing to measure indole acetic acid transport
Author(s): Diggs, AR
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… Briefly platinum iridium microelectrodes from Micro MicroProbes(Gaithersburg MD), tapered and insulated all the way to a 2-4 M tip was platinized for forty seconds and exposed to 3-(mercaptopropyl) trimethoxysilane for 6 hours …
Ventral root or dorsal root ganglion microstimulation to evoke hindlimb motor responses
Author(s): Bourbeau, DJ
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… potassium chloride. 2.2.2 Stimulation and data acquisition. Using a micromanipulator, we implanted a single wire electrode (MicroProbes, Gaithersburg, MD) for electrical microstimulation into the exposed DRG. These parylene …
Plasma Sterilization of Root Canal Abscess
Author(s):Huynh, A
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We perform in vitro validation of two plasma systems to determine whether bacteria inactivation occurs in a root canal abscess during root canal dental surgery. Results indicate that plasma may be a very effective tool for minimally invasive inactivation of bacteria deep inside the tooth, without causing excessive damage to the tooth surface. We show effective inactivation of ~ 104 colony forming units of Enterococcus faecalis following 10-s treatment by nanosecond-pulsed corona discharge that is ignited using a standard dental tool (Pathfinder®) as the plasma guide.
Plasma Sterilization of Root Canal Abscess
Author(s): Huynh, A
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We perform in vitro validation of two plasma systems to determine whether bacteria inactivation occurs in a root canal abscess during root canal dental surgery. Results indicate that plasma may be a very effective tool for minimally invasive inactivation of bacteria deep inside the tooth, without causing excessive damage to the tooth surface. We show effective inactivation of ~ 104 colony forming units of Enterococcus faecalis following 10-s treatment by nanosecond-pulsed corona discharge that is ignited using a standard dental tool (Pathfinder®) as the plasma guide.
The habenula as a critical node in chronic stress-related anxiety
Author(s): Jacinto, LR; Mata, R; Novais, A; Marques, F; Sousa, N
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The habenula is activated in response to stressful and aversive events, resulting in exploratory inhibition. Although possible mechanisms for habenula activation have been proposed, the effects of chronic stress on the habenular structure have never been studied. Herein, we assessed changes in volume, cell density and dendritic structure of habenular cells after chronic stress exposure using stereological and 3D morphological analysis. This study shows for the first time that there is a hemispherical asymmetry in the medial habenula (MHb) of the adult rat, with the right MHb containing more neurons than its left counterpart. Additionally, it shows that chronic stress induces a bilateral atrophy of both the MHb and the lateral habenula (LHb). This atrophy was accompanied by a reduction of the number of neurons in the right MHb and the number of glial cells in the bilateral LHb, but not by changes in the dendritic arbors of multipolar neurons. Importantly, these structural changes were correlated with elevated levels of serum corticosterone and increased anxious-like behavior in stressed animals. To further assess the role of the habenula in stress-related anxiety, bilateral lesions of the LHb were performed; interestingly, in lesioned animals the chronic stress protocol did not trigger increases in circulating corticosterone or anxious-like behavior. This study highlights the role of the habenula in the stress responses and how its sub-regions are structurally impacted by chronic stress with physiological and behavioral consequences.
The medullary dorsal reticular nucleus as a relay for descending pronociception induced by the mGluR5 in the rat infralimbic cortex
Author(s): David-Pereira, A; Sagalajev, B; Wei, H; Almeida, A; Pertovaara, A; Pinto-Ribeiro, F
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Metabotropic glutamate receptor 5 (mGluR5) activation in the infralimbic cortex (IL) induces pronociceptive behavior in healthy and monoarthritic rats. Here we studied whether the medullary dorsal reticular nucleus (DRt) and the spinal TRPV1 are mediating the IL/mGluR5-induced spinal pronociception and whether the facilitation of pain behavior is correlated with changes in spinal dorsal horn neuron activity. For drug administrations, all animals had a cannula in the IL as well as a cannula in the DRt or an intrathecal catheter. Heat-evoked paw withdrawal was used to assess pain behavior in awake animals. Spontaneous and heat-evoked discharge rates of single DRt neurons or spinal dorsal horn wide-dynamic range (WDR) and nociceptive-specific (NS) neurons were evaluated in lightly anesthetized animals. Activation of the IL/mGluR5 facilitated nociceptive behavior in both healthy and monoarthritic animals, and this effect was blocked by lidocaine or GABA receptor agonists in the DRt. IL/mGluR5 activation increased spontaneous and heat-evoked DRt discharge rates in healthy but not monoarthritic rats. In the spinal dorsal horn, IL/mGluR5 activation increased spontaneous activity of WDR neurons in healthy animals only, whereas heat-evoked responses of WDR and NS neurons were increased in both experimental groups. Intrathecally administered TRPV1 antagonist prevented the IL/mGluR5-induced pronociception in both healthy and monoarthritic rats. The results suggest that the DRt is involved in relaying the IL/mGluR5-induced spinal pronociception in healthy control but not monoarthritic animals. Spinally, the IL/mGluR5-induced behavioral heat hyperalgesia is mediated by TRPV1 and associated with facilitated heat-evoked responses of WDR and NS neurons.
Feasibility of deep brain stimulation for controlling the lower urinary tract functions: An animal study
Author(s): Chen, SC; Chu, PY; Hsieh, TH; Li, YT; Peng, CW
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To evaluate the feasibility of deep brain stimulation (DBS) and compare the potential of four DBS targets in rats for regulating bladder activity: the periaqueductal gray (PAG), locus coeruleus (LC), rostral pontine reticular nucleus (PnO), and pedunculopontine tegmental nucleus (PPTg). A bipolar stimulating electrode was implanted. The effects of DBS on the inhibition and activation of micturition reflexes were investigated by using isovolumetric intravesical pressure recordings. PAG DBS at 2-2.5 V, PnO DBS at 2-2.5 V, and PPTg DBS at 1.75-2.5 V nearly completely inhibited reflexive isovolumetric bladder contractions. By contrast, LC DBS at 1.75 and 2 V slightly augmented reflexive isovolumetric bladder contractions in rats. DBSs on PnO and PPTg at higher intensities (2.5-5 V) demonstrated a higher success rate and larger contraction area evocation in activating bladder contractions in a partially filled bladder. DBS targeting the PPTg was most efficient in suppressing reflexive isovolumetric bladder contractions. PPTg DBS demonstrated stable results and high potency for controlling bladder contractions. PPTg might be a promising DBS target for developing new neuromodulatory approaches for the treatment of bladder dysfunctions. DBS could be a potential approach to manage bladder function under various conditions.
Selective Silencing of Hippocampal Parvalbumin Interneurons Induces Development of Recurrent Spontaneous Limbic Seizures in Mice
Author(s): Drexel, M; Romanov, RA; Wood, J; Weger, S; Heilbronn, R; Wulff, P; Tasan, RO; Harkany, T; Sperk, G
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Temporal lobe epilepsy (TLE) is the most frequent form of focal epilepsies and is generally associated with malfunctioning of the hippocampal formation. Recently, a preferential loss of parvalbumin (PV) neurons has been observed in the subiculum of TLE patients and in animal models of TLE. To demonstrate a possible causative role of defunct PV neurons in the generation of TLE, we permanently inhibited GABA release selectively from PV neurons of the ventral subiculum by injecting a viral vector expressing tetanus toxin light chain in male mice. Subsequently, mice were subjected to telemetric EEG recording and video monitoring. Eighty-eight percent of the mice presented clusters of spike-wave discharges (C-SWDs; 40.0 ± 9.07/month), and 64% showed spontaneous recurrent seizures (SRSs; 5.3 ± 0.83/month). Mice injected with a control vector presented with neither C-SWDs nor SRSs. No neurodegeneration was observed due to vector injection or SRS. Interestingly, mice that presented with only C-SWDs but no SRSs, developed SRSs upon injection of a subconvulsive dose of pentylenetetrazole after 6 weeks. The initial frequency of SRSs declined by ∼30% after 5 weeks. In contrast to permanent silencing of PV neurons, transient inhibition of GABA release from PV neurons through the designer receptor hM4Di selectively expressed in PV-containing neurons transiently reduced the seizure threshold of the mice but induced neither acute nor recurrent seizures. Our data demonstrate a critical role for perisomatic inhibition mediated by PV-containing interneurons, suggesting that their sustained silencing could be causally involved in the development of TLE.SIGNIFICANCE STATEMENT Development of temporal lobe epilepsy (TLE) generally takes years after an initial insult during which maladaptation of hippocampal circuitries takes place. In human TLE and in animal models of TLE, parvalbumin neurons are selectively lost in the subiculum, the major output area of the hippocampus. The present experiments demonstrate that specific and sustained inhibition of GABA release from parvalbumin-expressing interneurons (mostly basket cells) in sector CA1/subiculum is sufficient to induce hyperexcitability and spontaneous recurrent seizures in mice. As in patients with nonlesional TLE, these mice developed epilepsy without signs of neurodegeneration. The experiments highlight the importance of the potent inhibitory action mediated by parvalbumin cells in the hippocampus and identify a potential mechanism in the development of TLE.
Resistance to action potential depression of a rat axon terminal in vivo
Author(s): Martijn C. Sierksma and J. Gerard G. Borst
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The shape of the presynaptic action potential (AP) has a strong impact on neurotransmitter release. Because of the small size of most terminals in the central nervous system, little is known about the regulation of their AP shape during natural firing patterns in vivo. The calyx of Held is a giant axosomatic terminal in the auditory brainstem, whose biophysical properties have been well studied in slices. Here, we made whole-cell recordings from calyceal terminals in newborn rat pups. The calyx showed a characteristic burst firing pattern, which has previously been shown to originate from the cochlea. Surprisingly, even for frequencies over 200 Hz, the AP showed little or no depression. Current injections showed that the rate of rise of the AP depended strongly on its onset potential, and that the membrane potential after the AP (Vafter) was close to the value at which no depression would occur during high-frequency activity. Immunolabeling revealed that Nav1.6 is already present at the calyx shortly after its formation, which was in line with the fast recovery from AP depression that we observed in slice recordings. Our findings thus indicate that fast recovery from depression and an inter-AP membrane potential that minimizes changes on the next AP in vivo, together enable high timing precision of the calyx of Held already shortly after its formation.
Altered Expression of Reorganized Inputs as They Ascend From the Cuneate Nucleus to Cortical Area 3b in Monkeys With Long-Term Spinal Cord Injuries.
Author(s): Halder, P; Kambi, N; Chand, P; Jain, N
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Chronic deafferentations in adult mammals result in reorganization of the brain. Lesions of the dorsal columns of the spinal cord at cervical levels in monkeys result in expansion of the intact chin inputs into the deafferented hand representation in area 3b, second somatosensory (S2) and parietal ventral (PV) areas of the somatosensory cortex, ventroposterior lateral nucleus (VPL) of the thalamus, and cuneate nucleus of the brainstem. Here, we describe the extent and nature of reorganization of the cuneate and gracile nuclei of adult macaque monkeys with chronic unilateral lesions of the dorsal columns, and compare it with the reorganization of area 3b in the same monkeys. In both, area 3b and the cuneate nucleus chin inputs expand to reactivate the deafferented neurons. However, unlike area 3b, neurons in the cuneate nucleus also acquire receptive fields on the shoulder, neck, and occiput. A comparison with the previously published results shows that reorganization in the cuneate nucleus is similar to that in VPL. Thus, the emergent topography following deafferentations by spinal cord injuries undergoes transformation as the reorganized inputs ascend from subcortical nuclei to area 3b. The results help us understand mechanisms of the brain plasticity following spinal cord injuries.
Giant modulation of the electronic band gap of carbon nanotubes by dielectric screening.
Author(s): Aspitarte, L; McCulley, DR; Bertoni, A; Island, JO; Ostermann, M; Rontani, M; Steele, GA; Minot, ED
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Carbon nanotubes (CNTs) are a promising material for high-performance electronics beyond silicon. But unlike silicon, the nature of the transport band gap in CNTs is not fully understood. The transport gap in CNTs is predicted to be strongly driven by electron-electron (e-e) interactions and correlations, even at room temperature. Here, we use dielectric liquids to screen e-e interactions in individual suspended ultra-clean CNTs. Using multiple techniques, the transport gap is measured as dielectric screening is increased. Changing the dielectric environment from air to isopropanol, we observe a 25% reduction in the transport gap of semiconducting CNTs, and a 32% reduction in the band gap of narrow-gap CNTs. Additional measurements are reported in dielectric oils. Our results elucidate the nature of the transport gap in CNTs, and show that dielectric environment offers a mechanism for significant control over the transport band gap.
Representation of egomotion in rat's trident and E-row whisker cortices
Author(s): Chorev, E; Preston-Ferrer, P; Brecht, M
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The whisker trident, a three-whisker array on the rat's chin, has been implicated in egomotion sensing and might function as a tactile speedometer. Here we study the cortical representation of trident whiskers and E-row whiskers in barrel cortex. Neurons identified in trident cortex of anesthetized animals showed sustained velocity-sensitive responses to ground motion. In freely moving animals, about two-thirds of the units in the trident and E-row whisker cortices were tuned to locomotion speed, a larger fraction of speed-tuned cells than in the somatosensory dysgranular zone. Similarly, more units were tuned to acceleration and showed sensitivity to turning in trident and E-row whisker cortices than in the dysgranular zone. Microstimulation in locomoting animals evoked small but significant speed changes, and such changes were larger in the trident and E-row whisker representations than in the dysgranular zone. Thus, activity in trident and E-row cortices represents egomotion information and influences locomotion behavior.
Conjunctive input processing drives feature selectivity in hippocampal CA1 neurons
Author(s): Bittner, KC; Grienberger, C; Vaidya, SP; Milstein, AD; Macklin, JJ; Suh, J; Tonegawa, S; Magee, JC
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Feature-selective firing allows networks to produce representations of the external and internal environments. Despite its importance, the mechanisms generating neuronal feature selectivity are incompletely understood. In many cortical microcircuits the integration of two functionally distinct inputs occurs nonlinearly through generation of active dendritic signals that drive burst firing and robust plasticity. To examine the role of this processing in feature selectivity, we recorded CA1 pyramidal neuron membrane potential and local field potential in mice running on a linear treadmill. We found that dendritic plateau potentials were produced by an interaction between properly timed input from entorhinal cortex and hippocampal CA3. These conjunctive signals positively modulated the firing of previously established place fields and rapidly induced new place field formation to produce feature selectivity in CA1 that is a function of both entorhinal cortex and CA3 input. Such selectivity could allow mixed network level representations that support context-dependent spatial maps.
Reward modulates the effect of visual cortical microstimulation on perceptual decisions
Author(s): Cicmil, N; Cumming, BG; Parker, AJ; Krug, K
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Effective perceptual decisions rely upon combining sensory information with knowledge of the rewards available for different choices. However, it is not known where reward signals interact with the multiple stages of the perceptual decision-making pathway and by what mechanisms this may occur. We combined electrical microstimulation of functionally specific groups of neurons in visual area V5/MT with performance-contingent reward manipulation, while monkeys performed a visual discrimination task. Microstimulation was less effective in shifting perceptual choices towards the stimulus preferences of the stimulated neurons when available reward was larger. Psychophysical control experiments showed this result was not explained by a selective change in response strategy on microstimulated trials. A bounded accumulation decision model, applied to analyse behavioural performance, revealed that the interaction of expected reward with microstimulation can be explained if expected reward modulates a sensory representation stage of perceptual decision-making, in addition to the better-known effects at the integration stage.
Large-scale reorganization of the somatosensory cortex following spinal cord injuries is due to brainstem plasticity
Author(s): Kambi, N; Halder, P; Rajan, R; Arora, V; Chand, P; Arora, M; Jain, N
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Adult mammalian brains undergo reorganization following deafferentations due to peripheral nerve, cortical or spinal cord injuries. The largest extent of cortical reorganization is seen in area 3b of the somatosensory cortex of monkeys with chronic transection of the dorsal roots or dorsal columns of the spinal cord. These injuries cause expansion of intact face inputs into the deafferented hand cortex, resulting in a change of representational boundaries by more than 7 mm. Here we show that large-scale reorganization in area 3b following spinal cord injuries is due to changes at the level of the brainstem nuclei and not due to cortical mechanisms. Selective inactivation of the reorganized cuneate nucleus of the brainstem eliminates observed face expansion in area 3b. Thus, the substrate for the observed expanded face representation in area 3b lies in the cuneate nucleus.
Synaptic transmission changes in fear memory circuits underlie key features of an animal model of schizophrenia
Author(s): Pollard, M; Varin, C; Hrupka, B; Pemberton, DJ; Steckler, T; Shaban, H
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Non-competitive antagonists of the N-methyl-d-aspartate receptor (NMDA) such as phencyclidine (PCP) elicit schizophrenia-like symptoms in healthy individuals. Similarly, PCP dosing in rats produces typical behavioral phenotypes that mimic human schizophrenia symptoms. Although schizophrenic behavioral phenotypes of the PCP model have been extensively studied, the underlying alterations of intrinsic neuronal properties and synaptic transmission in relevant limbic brain microcircuits remain elusive. Acute brain slice electrophysiology and immunostaining of inhibitory neurons were used to identify neuronal circuit alterations of the amygdala and hippocampus associated with changes in extinction of fear learning in rats following PCP treatment. Subchronic PCP application led to impaired long-term potentiation (LTP) and marked increases in the ratio of NMDA to 2-amino-3(5-methyl-3-oxo-1,2-oxazol-4-yl)propionic acid (AMPA) receptor-mediated currents at lateral amygdala (LA) principal neurons without alterations in parvalbumin (PV) as well as non-PV, glutamic acid decarboxylase 67 (GAD 67) immunopositive neurons. In addition, LTP was impaired at the Schaffer collateral to CA1 hippocampal pathway coincident with a reduction in colocalized PV and GAD67 immunopositive neurons in the CA3 hippocampal area. These effects occurred without changes in spontaneous events or intrinsic membrane properties of principal cells in the LA. The impairment of LTP at both amygdalar and hippocampal microcircuits, which play a key role in processing relevant survival information such as fear and extinction memory concurred with a disruption of extinction learning of fear conditioned responses. Our results show that subchronic PCP administration in rats impairs synaptic functioning in the amygdala and hippocampus as well as processing of fear-related memories.
Amygdala stimulation evokes time-varying synaptic responses in the gustatory cortex of anesthetized rats
Author(s): Stone, ME; Maffei, A; Fontanini, A
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Gustatory stimuli are characterized by a specific hedonic value; they are either palatable or aversive. Hedonic value, along with other psychological dimensions of tastes, is coded in the time-course of gustatory cortex (GC) neural responses and appears to emerge via top-down modulation by the basolateral amygdala (BLA). While the importance of BLA in modulating gustatory cortical function has been well established, the nature of its input onto GC neurons is largely unknown. Somewhat conflicting results from extracellular recordings point to either excitatory or inhibitory effects. Here, we directly test the hypothesis that BLA can evoke time-varying - excitatory and inhibitory - synaptic responses in GC using in vivo intracellular recording techniques in urethane anesthetized rats. Electrical stimulation of BLA evoked a post-synaptic potential (PSP) in GC neurons that resulted from a combination of short and long latency components: an initial monosynaptic, glutamatergic potential followed by a multisynaptic, GABAergic hyperpolarization. As predicted by the dynamic nature of amygdala evoked potentials, trains of five BLA stimuli at rates that mimic physiological firing rates (5-40 Hz) evoke a combination of excitation and inhibition in GC cells. The magnitude of the different components varies depending on the frequency of stimulation, with summation of excitatory and inhibitory inputs reaching its maximum at higher frequencies. These experiments provide the first description of BLA synaptic inputs to GC and reveal that amygdalar afferents can modulate gustatory cortical network activity and its processing of sensory information via time-varying synaptic dynamics.
Incomplete block of NMDA receptors by intracellular MK-801
Author(s): Sun, W; Wong, JM; Gray, JA; Carter, BC
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NMDA receptors (NMDARs) are essential components in glutamatergic synaptic signaling. The NMDAR antagonist MK-801 has been a valuable pharmacological tool in evaluating NMDAR function because it binds with high affinity to the NMDAR ion channel pore and is non-competitive with ligand binding. MK-801 has also been used to selectively inhibit NMDAR current in only the cell being recorded by including the drug in the intracellular recording solution. Here, we report that intracellular MK-801 (iMK-801) only partially inhibits synaptic NMDAR currents at +40 mV at both cortical layer 4 to layer 2/3 and hippocampal Schaffer collateral to CA1 synapses. Furthermore, iMK-801 incompletely inhibits heterologously expressed NMDAR currents at -60 mV, consistent with a model of iMK-801 having a very slow binding rate and consequently ∼30,000 times lower affinity than MK-801 applied to the extracellular side of the receptor. While iMK-801 can be used as a qualitative tool to study reduced postsynaptic NMDAR function, it cannot be assumed to completely block NMDARs at concentrations typically used in experiments.Copyright © 2018 Elsevier Ltd. All rights reserved.
Persistent sodium current modulates axonal excitability in CA1 pyramidal neurons
Author(s): Müller, P; Draguhn, A; Egorov, AV
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Axonal excitability is an important determinant for the accuracy, direction, and velocity of neuronal signaling. The mechanisms underlying spike generation in the axonal initial segment and transmitter release from presynaptic terminals have been intensely studied and revealed a role for several specific ionic conductances, including the persistent sodium current (INaP ). Recent evidence indicates that action potentials can also be generated at remote locations along the axonal fiber, giving rise to ectopic action potentials during physiological states (e.g., fast network oscillations) or in pathological situations (e.g., following demyelination). Here, we investigated how ectopic axonal excitability of mouse hippocampal CA1 pyramidal neurons is regulated by INaP . Recordings of field potentials and intracellular voltage in brain slices revealed that electrically evoked antidromic spikes were readily suppressed by two different blockers of INaP , riluzole and phenytoin. The effect was mediated by a reduction of the probability of ectopic spike generation while latency was unaffected. Interestingly, the contribution of INaP to excitability was much more pronounced in axonal branches heading toward the entorhinal cortex compared with the opposite fiber direction toward fimbria. Thus, excitability of distal CA1 pyramidal cell axons is affected by persistent sodium currents in a direction-selective manner. This mechanism may be of importance for ectopic spike generation in oscillating network states as well as in pathological situations. © 2018 International Society for Neurochemistry.
Hyperactive Response of Direct Pathway Striatal Projection Neurons to L-dopa and D1 Agonism in Freely Moving Parkinsonian Mice
Author(s): Sagot, B; Li, L; Zhou, FM
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Dopamine (DA) profoundly stimulates motor function as demonstrated by the hypokinetic motor symptoms in Parkinson's disease (PD) and by the hyperkinetic motor side effects during dopaminergic treatment of PD. Dopamine (DA) receptor-bypassing, optogenetics- and chemogenetics-induced spike firing of striatal DA D1 receptor (D1R)-expressing, direct pathway medium spiny neurons (dSPNs or dMSNs) promotes movements. However, the endogenous D1R-mediated effects, let alone those of DA replacement, on dSPN spike activity in freely-moving animals is not established. Here we show that using transcription factor Pitx3 null mutant (Pitx3Null) mice as a model for severe and consistent DA denervation in the dorsal striatum in Parkinson's disease, antidromically identified striatonigral neurons (D1R-expressing dSPNs) had a lower baseline spike firing rate than that in DA-intact normal mice, and these neurons increased their spike firing more strongly in Pitx3Null mice than in WT mice in response to injection of L-dopa or the D1R agonist, SKF81297; the increase in spike firing temporally coincided with the motor-stimulating effects of L-dopa and SKF81297. Taken together, these results provide the first evidence from freely moving animals that in parkinsonian striatum, identified behavior-promoting dSPNs become hyperactive upon the administration of L-dopa or a D1 agonist, likely contributing to the profound dopaminergic motor stimulation in parkinsonian animals and PD patients.
Glutamate Transmission to Ventral Tegmental Area GABA Neurons Is Altered by Acute and Chronic Ethanol
Author(s): Williams, SB; Yorgason, JT; Nelson, AC; Lewis, N; Nufer, TM; Edwards, JG; Steffensen, SC
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Ventral tegmental area (VTA) GABA neurons have been heavily implicated in alcohol reinforcement and reward. In animals that self-administer alcohol, VTA GABA neurons exhibit increased excitability that may contribute to alcohol's rewarding effects. The present study investigated the effects of acute and chronic ethanol exposure on glutamate (GLU) synaptic transmission to VTA GABA neurons. Whole-cell recordings of evoked, spontaneous, and miniature excitatory postsynaptic currents (eEPSCs, sEPSCs, and mEPSCs, respectively) were performed on identified GABA neurons in the VTA of GAD67-GFP+ transgenic mice. Three ethanol exposure paradigms were used: acute ethanol superfusion; a single ethanol injection; and chronic vapor exposure. Acute ethanol superfusion increased the frequency of EPSCs but inhibited mEPSC frequency and amplitude. During withdrawal from a single injection of ethanol, the frequency of sEPSCs was lower than saline controls. There was no difference in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/N-methyl-d-aspartate (NMDA) ratio between neurons following withdrawal from a single exposure to ethanol. However, following withdrawal from chronic ethanol, sEPSCs and mEPSCs had a greater frequency than air controls. There was no difference in AMPA/NMDA ratio following chronic ethanol. These results suggest that presynaptic mechanisms involving local circuit GLU neurons, and not GLU receptors, contribute to adaptations in VTA GABA neuron excitability that accrue to ethanol exposure, which may contribute to the rewarding properties of alcohol via their regulation of mesolimbic dopamine transmission. © 2018 by the Research Society on Alcoholism.
Incomplete block of NMDA receptors by intracellular MK-801
Author(s): Sun, W; Wong, JM; Gray, JA; Carter, BC
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NMDA receptors (NMDARs) are essential components in glutamatergic synaptic signaling. The NMDAR antagonist MK-801 has been a valuable pharmacological tool in evaluating NMDAR function because it binds with high affinity to the NMDAR ion channel pore and is non-competitive with ligand binding. MK-801 has also been used to selectively inhibit NMDAR current in only the cell being recorded by including the drug in the intracellular recording solution. Here, we report that intracellular MK-801 (iMK-801) only partially inhibits synaptic NMDAR currents at +40 mV at both cortical layer 4 to layer 2/3 and hippocampal Schaffer collateral to CA1 synapses. Furthermore, iMK-801 incompletely inhibits heterologously expressed NMDAR currents at -60 mV, consistent with a model of iMK-801 having a very slow binding rate and consequently ∼30,000 times lower affinity than MK-801 applied to the extracellular side of the receptor. While iMK-801 can be used as a qualitative tool to study reduced postsynaptic NMDAR function, it cannot be assumed to completely block NMDARs at concentrations typically used in experiments. Copyright © 2018 Elsevier Ltd. All rights reserved.
Persistent sodium current modulates axonal excitability in CA1 pyramidal neurons
Author(s): Müller, P; Draguhn, A; Egorov, AV
View details Hide details
Axonal excitability is an important determinant for the accuracy, direction, and velocity of neuronal signaling. The mechanisms underlying spike generation in the axonal initial segment and transmitter release from presynaptic terminals have been intensely studied and revealed a role for several specific ionic conductances, including the persistent sodium current (INaP ). Recent evidence indicates that action potentials can also be generated at remote locations along the axonal fiber, giving rise to ectopic action potentials during physiological states (e.g., fast network oscillations) or in pathological situations (e.g., following demyelination). Here, we investigated how ectopic axonal excitability of mouse hippocampal CA1 pyramidal neurons is regulated by INaP . Recordings of field potentials and intracellular voltage in brain slices revealed that electrically evoked antidromic spikes were readily suppressed by two different blockers of INaP , riluzole and phenytoin. The effect was mediated by a reduction of the probability of ectopic spike generation while latency was unaffected. Interestingly, the contribution of INaP to excitability was much more pronounced in axonal branches heading toward the entorhinal cortex compared with the opposite fiber direction toward fimbria. Thus, excitability of distal CA1 pyramidal cell axons is affected by persistent sodium currents in a direction-selective manner. This mechanism may be of importance for ectopic spike generation in oscillating network states as well as in pathological situations. © 2018 International Society for Neurochemistry.
Hyperactive Response of Direct Pathway Striatal Projection Neurons to L-dopa and D1 Agonism in Freely Moving Parkinsonian Mice
Author(s): Sagot, B; Li, L; Zhou, FM
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Dopamine (DA) profoundly stimulates motor function as demonstrated by the hypokinetic motor symptoms in Parkinson's disease (PD) and by the hyperkinetic motor side effects during dopaminergic treatment of PD. Dopamine (DA) receptor-bypassing, optogenetics- and chemogenetics-induced spike firing of striatal DA D1 receptor (D1R)-expressing, direct pathway medium spiny neurons (dSPNs or dMSNs) promotes movements. However, the endogenous D1R-mediated effects, let alone those of DA replacement, on dSPN spike activity in freely-moving animals is not established. Here we show that using transcription factor Pitx3 null mutant (Pitx3Null) mice as a model for severe and consistent DA denervation in the dorsal striatum in Parkinson's disease, antidromically identified striatonigral neurons (D1R-expressing dSPNs) had a lower baseline spike firing rate than that in DA-intact normal mice, and these neurons increased their spike firing more strongly in Pitx3Null mice than in WT mice in response to injection of L-dopa or the D1R agonist, SKF81297; the increase in spike firing temporally coincided with the motor-stimulating effects of L-dopa and SKF81297. Taken together, these results provide the first evidence from freely moving animals that in parkinsonian striatum, identified behavior-promoting dSPNs become hyperactive upon the administration of L-dopa or a D1 agonist, likely contributing to the profound dopaminergic motor stimulation in parkinsonian animals and PD patients.
Glutamate Transmission to Ventral Tegmental Area GABA Neurons Is Altered by Acute and Chronic Ethanol
Author(s): Williams, SB; Yorgason, JT; Nelson, AC; Lewis, N; Nufer, TM; Edwards, JG; Steffensen, SC
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Ventral tegmental area (VTA) GABA neurons have been heavily implicated in alcohol reinforcement and reward. In animals that self-administer alcohol, VTA GABA neurons exhibit increased excitability that may contribute to alcohol's rewarding effects. The present study investigated the effects of acute and chronic ethanol exposure on glutamate (GLU) synaptic transmission to VTA GABA neurons. Whole-cell recordings of evoked, spontaneous, and miniature excitatory postsynaptic currents (eEPSCs, sEPSCs, and mEPSCs, respectively) were performed on identified GABA neurons in the VTA of GAD67-GFP+ transgenic mice. Three ethanol exposure paradigms were used: acute ethanol superfusion; a single ethanol injection; and chronic vapor exposure. Acute ethanol superfusion increased the frequency of EPSCs but inhibited mEPSC frequency and amplitude. During withdrawal from a single injection of ethanol, the frequency of sEPSCs was lower than saline controls. There was no difference in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/N-methyl-d-aspartate (NMDA) ratio between neurons following withdrawal from a single exposure to ethanol. However, following withdrawal from chronic ethanol, sEPSCs and mEPSCs had a greater frequency than air controls. There was no difference in AMPA/NMDA ratio following chronic ethanol. These results suggest that presynaptic mechanisms involving local circuit GLU neurons, and not GLU receptors, contribute to adaptations in VTA GABA neuron excitability that accrue to ethanol exposure, which may contribute to the rewarding properties of alcohol via their regulation of mesolimbic dopamine transmission. © 2018 by the Research Society on Alcoholism.
APP Deletion Accounts for Age-Dependent Changes in the Bioenergetic Metabolism and in Hyperphosphorylated CaMKII at Stimulated Hippocampal Presynaptic Active Zones
Author(s): Laßek, M;Weingarten, J;Wegner, M;Neupärtl, M;Array, TN;Harde, E;Beckert, B;Golghalyani, V;Ackermann, J;Koch, I;Müller, UC;Karas, M;Acker-Palmer, A;Volknandt, W;
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Synaptic release sites are characterized by exocytosis-competent synaptic vesicles tightly anchored to the presynaptic active zone (PAZ) whose proteome orchestrates the fast signaling events involved in synaptic vesicle cycle and plasticity. Allocation of the amyloid precursor protein (APP) to the PAZ proteome implicated a functional impact of APP in neuronal communication. In this study, we combined state-of-the-art proteomics, electrophysiology and bioinformatics to address protein abundance and functional changes at the native hippocampal PAZ in young and old APP-KO mice. We evaluated if APP deletion has an impact on the metabolic activity of presynaptic mitochondria. Furthermore, we quantified differences in the phosphorylation status after long-term-potentiation (LTP) induction at the purified native PAZ. We observed an increase in the phosphorylation of the signaling enzyme calmodulin-dependent kinase II (CaMKII) only in old APP-KO mice. During aging APP deletion is accompanied by a severe decrease in metabolic activity and hyperphosphorylation of CaMKII. This attributes an essential functional role to APP at hippocampal PAZ and putative molecular mechanisms underlying the age-dependent impairments in learning and memory in APP-KO mice.
Selective Silencing of Hippocampal Parvalbumin Interneurons Induces Development of Recurrent Spontaneous Limbic Seizures in Mice
Author(s): Drexel, M;Romanov, RA;Wood, J;Weger, S;Heilbronn, R;Wulff, P;Tasan, RO;Harkany, T;Sperk, G;
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Temporal lobe epilepsy (TLE) is the most frequent form of focal epilepsies and is generally associated with malfunctioning of the hippocampal formation. Recently, a preferential loss of parvalbumin (PV) neurons has been observed in the subiculum of TLE patients and in animal models of TLE. To demonstrate a possible causative role of defunct PV neurons in the generation of TLE, we permanently inhibited GABA release selectively from PV neurons of the ventral subiculum by injecting a viral vector expressing tetanus toxin light chain in male mice. Subsequently, mice were subjected to telemetric EEG recording and video monitoring. Eighty-eight percent of the mice presented clusters of spike-wave discharges (C-SWDs; 40.0 ± 9.07/month), and 64% showed spontaneous recurrent seizures (SRSs; 5.3 ± 0.83/month). Mice injected with a control vector presented with neither C-SWDs nor SRSs. No neurodegeneration was observed due to vector injection or SRS. Interestingly, mice that presented with only C-SWDs but no SRSs, developed SRSs upon injection of a subconvulsive dose of pentylenetetrazole after 6 weeks. The initial frequency of SRSs declined by ∼30% after 5 weeks. In contrast to permanent silencing of PV neurons, transient inhibition of GABA release from PV neurons through the designer receptor hM4Di selectively expressed in PV-containing neurons transiently reduced the seizure threshold of the mice but induced neither acute nor recurrent seizures. Our data demonstrate a critical role for perisomatic inhibition mediated by PV-containing interneurons, suggesting that their sustained silencing could be causally involved in the development of TLE.SIGNIFICANCE STATEMENT Development of temporal lobe epilepsy (TLE) generally takes years after an initial insult during which maladaptation of hippocampal circuitries takes place. In human TLE and in animal models of TLE, parvalbumin neurons are selectively lost in the subiculum, the major output area of the hippocampus. The present experiments demonstrate that specific and sustained inhibition of GABA release from parvalbumin-expressing interneurons (mostly basket cells) in sector CA1/subiculum is sufficient to induce hyperexcitability and spontaneous recurrent seizures in mice. As in patients with nonlesional TLE, these mice developed epilepsy without signs of neurodegeneration. The experiments highlight the importance of the potent inhibitory action mediated by parvalbumin cells in the hippocampus and identify a potential mechanism in the development of TLE.
Resistance to action potential depression of a rat axon terminal in vivo
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The shape of the presynaptic action potential (AP) has a strong impact on neurotransmitter release. Because of the small size of most terminals in the central nervous system, little is known about the regulation of their AP shape during natural firing patterns in vivo. The calyx of Held is a giant axosomatic terminal in the auditory brainstem, whose biophysical properties have been well studied in slices. Here, we made whole-cell recordings from calyceal terminals in newborn rat pups. The calyx showed a characteristic burst firing pattern, which has previously been shown to originate from the cochlea. Surprisingly, even for frequencies over 200 Hz, the AP showed little or no depression. Current injections showed that the rate of rise of the AP depended strongly on its onset potential, and that the membrane potential after the AP (Vafter) was close to the value at which no depression would occur during high-frequency activity. Immunolabeling revealed that Nav1.6 is already present at the calyx shortly after its formation, which was in line with the fast recovery from AP depression that we observed in slice recordings. Our findings thus indicate that fast recovery from depression and an inter-AP membrane potential that minimizes changes on the next AP in vivo, together enable high timing precision of the calyx of Held already shortly after its formation.
Altered Expression of Reorganized Inputs as They Ascend From the Cuneate Nucleus to Cortical Area 3b in Monkeys With Long-Term Spinal Cord Injuries.
Author(s): Halder, P;Kambi, N;Chand, P;Jain, N;
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Chronic deafferentations in adult mammals result in reorganization of the brain. Lesions of the dorsal columns of the spinal cord at cervical levels in monkeys result in expansion of the intact chin inputs into the deafferented hand representation in area 3b, second somatosensory (S2) and parietal ventral (PV) areas of the somatosensory cortex, ventroposterior lateral nucleus (VPL) of the thalamus, and cuneate nucleus of the brainstem. Here, we describe the extent and nature of reorganization of the cuneate and gracile nuclei of adult macaque monkeys with chronic unilateral lesions of the dorsal columns, and compare it with the reorganization of area 3b in the same monkeys. In both, area 3b and the cuneate nucleus chin inputs expand to reactivate the deafferented neurons. However, unlike area 3b, neurons in the cuneate nucleus also acquire receptive fields on the shoulder, neck, and occiput. A comparison with the previously published results shows that reorganization in the cuneate nucleus is similar to that in VPL. Thus, the emergent topography following deafferentations by spinal cord injuries undergoes transformation as the reorganized inputs ascend from subcortical nuclei to area 3b. The results help us understand mechanisms of the brain plasticity following spinal cord injuries.
Giant modulation of the electronic band gap of carbon nanotubes by dielectric screening.
Author(s): Aspitarte, L;McCulley, DR;Bertoni, A;Island, JO;Ostermann, M;Rontani, M;Steele, GA;Minot, ED;
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Carbon nanotubes (CNTs) are a promising material for high-performance electronics beyond silicon. But unlike silicon, the nature of the transport band gap in CNTs is not fully understood. The transport gap in CNTs is predicted to be strongly driven by electron-electron (e-e) interactions and correlations, even at room temperature. Here, we use dielectric liquids to screen e-e interactions in individual suspended ultra-clean CNTs. Using multiple techniques, the transport gap is measured as dielectric screening is increased. Changing the dielectric environment from air to isopropanol, we observe a 25% reduction in the transport gap of semiconducting CNTs, and a 32% reduction in the band gap of narrow-gap CNTs. Additional measurements are reported in dielectric oils. Our results elucidate the nature of the transport gap in CNTs, and show that dielectric environment offers a mechanism for significant control over the transport band gap.
Downstream effects of hippocampal sharp wave ripple oscillations on medial entorhinal cortex layer V neurons in vitro
Author(s): Roth, FC;Beyer, KM;Both, M;Draguhn, A;Egorov, AV;
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The entorhinal cortex (EC) is a critical component of the medial temporal lobe (MTL) memory system. Local networks within the MTL express a variety of state-dependent network oscillations that are believed to organize neuronal activity during memory formation. The peculiar pattern of sharp wave-ripple complexes (SPW-R) entrains neurons by a very fast oscillation at ∼200 Hz in the hippocampal areas CA3 and CA1 and then propagates through the output loop into the EC. The precise mechanisms of SPW-R propagation and the resulting cellular input patterns in the mEC are, however, largely unknown. We therefore investigated the activity of layer V (LV) principal neurons of the medial EC (mEC) during SPW-R oscillations in horizontal mouse brain slices. Intracellular recordings in the mEC were combined with extracellular monitoring of propagating network activity. SPW-R in CA1 were regularly followed by negative field potential deflections in the mEC. Propagation of SPW-R activity from CA1 to the mEC was mostly monosynaptic and excitatory, such that synaptic input to mEC LV neurons directly reflected unit activity in CA1. Comparison with propagating network activity from CA3 to CA1 revealed a similar role of excitatory long-range connections for both regions. However, SPW-R-induced activity in CA1 involved strong recruitment of rhythmic synaptic inhibition and corresponding fast field oscillations, in contrast to the mEC. These differences between features of propagating SPW-R emphasize the differential processing of network activity by each local network of the hippocampal output loop. © 2016 Wiley Periodicals, Inc.
Short- and long-term dopamine depletion causes enhanced beta oscillations in the cortico-basal ganglia loop of parkinsonian rats
Author(s): Beck, MH;Haumesser, JK;Kühn, J;Altschüler, J;Kühn, AA;van Riesen, C;
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Abnormally enhanced beta oscillations have been found in deep brain recordings from human Parkinson's disease (PD) patients and in animal models of PD. Recent correlative evidence suggests that beta oscillations are related to disease-specific symptoms such as akinesia and rigidity. However, this hypothesis has also been repeatedly questioned by studies showing no changes in beta power in animal models using an acute pharmacologic dopamine blockade. To further investigate the temporal dynamics of exaggerated beta synchrony in PD, we investigated the reserpine model, which is characterized by an acute and stable disruption of dopamine transmission, and compared it to the chronic progressive 6-hydroxydopamine (6-OHDA) model. Using simultaneous electrophysiological recordings in urethane anesthetized rats from the primary motor cortex, the subthalamic nucleus and the reticulate part of the substantia, we found evidence for enhanced beta oscillations in the basal ganglia of both animal models during the activated network state. In contrast to 6-OHDA, reserpine treated animals showed no involvement of primary motor cortex. Notably, beta coherence levels between primary motor cortex and basal ganglia nuclei were elevated in both models. Although both models exhibited elevated beta power and coherence levels, they differed substantially in respect to their mean peak frequency: while the 6-OHDA peak was located in the low beta range (17Hz), the reserpine peak was centered at higher beta frequencies (27Hz). Our results further support the hypothesis of an important pathophysiological relation between enhanced beta activity and akinesia in parkinsonism.
Evaluation of Drug Concentrations Delivered by Microiontophoresis
Author(s): Kirkpatrick, DC;Wightman, RM;
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Microiontophoresis uses an electric current to eject a drug solution from a glass capillary and is often utilized for targeted delivery in neurochemical investigations. The amount of drug ejected, and its effective concentration at the tip, has historically been difficult to determine, which has precluded its use in quantitative studies. To address this, a method called controlled iontophoresis was developed which employs a carbon-fiber microelectrode incorporated into a multibarreled iontophoretic probe to detect the ejection of electroactive species. Here, we evaluate the accuracy of this method. To do this, we eject different concentrations of quinpirole, a D2 receptor agonist, into a brain slice containing the dorsal striatum, a brain region with a high density of dopamine terminals. Local electrical stimulation was used to evoke dopamine release, and inhibitory actions of quinpirole on this release were examined. The amount of drug ejected was estimated by detection of a coejected electrochemical marker. Dose response curves generated in this manner were compared to curves generated by conventional perfusion of quinpirole through the slice. We find several experimental conditions must be optimized for accurate results. First, selection of a marker with an identical charge was necessary to mimic the ejection of the cationic agonist. Next, evoked responses were more precise following longer periods between the end of the ejection and stimulation. Lastly, the accuracy of concentration evaluations was improved by longer ejections. Incorporation of these factors into existing protocols allows for greater certainty of concentrations delivered by controlled iontophoresis.
Representation of egomotion in rat's trident and E-row whisker cortices
Author(s): Chorev, E;Preston-Ferrer, P;Brecht, M;
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The whisker trident, a three-whisker array on the rat's chin, has been implicated in egomotion sensing and might function as a tactile speedometer. Here we study the cortical representation of trident whiskers and E-row whiskers in barrel cortex. Neurons identified in trident cortex of anesthetized animals showed sustained velocity-sensitive responses to ground motion. In freely moving animals, about two-thirds of the units in the trident and E-row whisker cortices were tuned to locomotion speed, a larger fraction of speed-tuned cells than in the somatosensory dysgranular zone. Similarly, more units were tuned to acceleration and showed sensitivity to turning in trident and E-row whisker cortices than in the dysgranular zone. Microstimulation in locomoting animals evoked small but significant speed changes, and such changes were larger in the trident and E-row whisker representations than in the dysgranular zone. Thus, activity in trident and E-row cortices represents egomotion information and influences locomotion behavior.
Rett syndrome like phenotypes in the R255X Mecp2 mutant mouse are rescued by MECP2 transgene
Author(s): Pitcher, MR;Herrera, JA;Buffington, SA;Kochukov, MY;Merritt, JK;Fisher, AR;Schanen, NC;Costa-Mattioli, M;Neul, JL;
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Rett syndrome (RTT) is a severe neurodevelopmental disorder that is usually caused by mutations in Methyl-CpG-binding Protein 2 (MECP2). Four of the eight common disease causing mutations in MECP2 are nonsense mutations and are responsible for over 35% of all cases of RTT. A strategy to overcome disease-causing nonsense mutations is treatment with nonsense mutation suppressing drugs that allow expression of full-length proteins from mutated genes with premature in-frame stop codons. To determine if this strategy is useful in RTT, we characterized a new mouse model containing a knock-in nonsense mutation (p.R255X) in the Mecp2 locus (Mecp2(R255X)). To determine whether the truncated gene product acts as a dominant negative allele and if RTT-like phenotypes could be rescued by expression of wild-type protein, we genetically introduced an extra copy of MECP2 via an MECP2 transgene. The addition of MECP2 transgene to Mecp2(R255X) mice abolished the phenotypic abnormalities and resulted in near complete rescue. Expression of MECP2 transgene Mecp2(R255X) allele also rescued mTORC1 signaling abnormalities discovered in mice with loss of function and overexpression of Mecp2. Finally, we treated Mecp2(R255X) embryonic fibroblasts with the nonsense mutation suppressing drug gentamicin and we were able to induce expression of full-length MeCP2 from the mutant p.R255X allele. These data provide proof of concept that the p.R255X mutation of MECP2 is amenable to the nonsense suppression therapeutic strategy and provide guidelines for the extent of rescue that can be expected by re-expressing MeCP2 protein.
Inhibition of presynaptic calcium transients in cortical inputs to the dorsolateral striatum by metabotropic GABA(B) and mGlu2/3 receptors
Author(s): Kupferschmidt, DA;Lovinger, DM;
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Cortical inputs to the dorsolateral striatum (DLS) are dynamically regulated during skill learning and habit formation, and are dysregulated in disorders characterized by impaired action control. Therefore, a mechanistic investigation of the processes regulating corticostriatal transmission is key to understanding DLS-associated circuit function, behaviour and pathology. Presynaptic GABA(B) and group II metabotropic glutamate (mGlu2/3) receptors exert marked inhibitory control over corticostriatal glutamate release in the DLS, yet the signalling pathways through which they do so are unclear. We developed a novel approach using the genetically encoded calcium (Ca(2+) ) indicator GCaMP6 to assess presynaptic Ca(2+) in corticostriatal projections to the DLS. Using simultaneous photometric presynaptic Ca(2+) and striatal field potential recordings, we report that relative to P/Q-type Ca(2+) channels, N-type channels preferentially contributed to evoked presynaptic Ca(2+) influx in motor cortex projections to, and excitatory transmission in, the DLS. Activation of GABA(B) or mGlu2/3 receptors inhibited both evoked presynaptic Ca(2+) transients and striatal field potentials. mGlu2/3 receptor-mediated depression did not require functional N-type Ca(2+) channels, but was attenuated by blockade of P/Q-type channels. These findings reveal presynaptic mechanisms of inhibitory modulation of corticostriatal function that probably contribute to the selection and shaping of behavioural repertoires.
Appearance of fast astrocytic component in voltage-sensitive dye imaging of neural activity
Author(s): Pál, I;Kardos, J;Dobolyi, Á;Héja, L;
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Voltage-sensitive dye (VSD) imaging and intrinsic optical signals (IOS) are widely used methods for monitoring spatiotemporal neural activity in extensive networks. In spite of that, identification of their major cellular and molecular components has not been concluded so far. We addressed these issues by imaging spatiotemporal spreading of IOS and VSD transients initiated by Schaffer collateral stimulation in rat hippocampal slices with temporal resolution comparable to standard field potential recordings using a 464-element photodiode array. By exploring the potential neuronal and astroglial molecular players in VSD and IOS generation, we identified multiple astrocytic mechanisms that significantly contribute to the VSD signal, in addition to the expected neuronal targets. Glutamate clearance through the astroglial glutamate transporter EAAT2 has been shown to be a significant player in VSD generation within a very short (
Propranolol, but not naloxone, enhances spinal reflex bladder activity and reduces pudendal inhibition in cats
Author(s): Rogers, MJ;Xiao, Z;Shen, B;Wang, J;Schwen, Z;Roppolo, JR;de Groat, WC;Tai, C;
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This study examined the role of β-adrenergic and opioid receptors in spinal reflex bladder activity and in the inhibition induced by pudendal nerve stimulation (PNS) or tibial nerve stimulation (TNS). Spinal reflex bladder contractions were induced by intravesical infusion of 0.25% acetic acid in α-chloralose-anesthetized cats after an acute spinal cord transection (SCT) at the thoracic T9/T10 level. PNS or TNS at 5 Hz was applied to inhibit these spinal reflex contractions at 2 and 4 times the threshold intensity (T) for inducing anal or toe twitch, respectively. During a cystrometrogram (CMG), PNS at 2T and 4T significantly (P < 0.05) increased bladder capacity from 58.0 ± 4.7% to 85.8 ± 10.3% and 96.5 ± 10.7%, respectively, of saline control capacity, while TNS failed to inhibit spinal reflex bladder contractions. After administering propranolol (3 mg/kg iv, a β₁/β₂-adrenergic receptor antagonist), the effects of 2T and 4T PNS on bladder capacity were significantly (P < 0.05) reduced to 64.5 ± 9.5% and 64.7 ± 7.3%, respectively, of the saline control capacity. However, the residual PNS inhibition (about 10% increase in capacity) was still statistically significant (P < 0.05). Propranolol treatment also significantly (P = 0.0019) increased the amplitude of bladder contractions but did not change the control bladder capacity. Naloxone (1 mg/kg iv, an opioid receptor antagonist) had no effect on either spinal reflex bladder contractions or PNS inhibition. At the end of experiments, hexamethonium (10 mg/kg iv, a ganglionic blocker) significantly (P < 0.05) reduced the amplitude of the reflex bladder contractions. This study indicates an important role of β₁/β₂-adrenergic receptors in pudendal inhibition and spinal reflex bladder activity.
Potentiation of NMDA receptor-mediated transmission in striatal cholinergic interneurons
Author(s): Oswald, MJ;Schulz, JM;Kelsch, W;Oorschot, DE;Reynolds, JN;
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Pauses in the tonic firing of striatal cholinergic interneurons (CINs) emerge during reward-related learning in response to conditioning of a neutral cue. We have previously reported that augmenting the postsynaptic response to cortical afferents in CINs is coupled to the emergence of a cell-intrinsic afterhyperpolarization (AHP) underlying pauses in tonic activity. Here we investigated in a bihemispheric rat-brain slice preparation the mechanisms of synaptic plasticity of excitatory afferents to CINs and the association with changes in the AHP. We found that high frequency stimulation (HFS) of commissural corticostriatal afferents from the contralateral hemisphere induced a robust long-term depression (LTD) of postsynaptic potentials (PSP) in CINs. Depression of the PSP of smaller magnitude and duration was observed in response to HFS of the ipsilateral white matter or cerebral cortex. In Mg(2+)-free solution HFS induced NMDA receptor-dependent potentiation of the PSP, evident in both the maximal slope and amplitude of the PSP. The increase in maximal slope corroborates previous findings, and was blocked by antagonism of either D1-like dopamine receptors with SCH23390 or D2-like dopamine receptors with sulpiride during HFS in Mg(2+)-free solution. Potentiation of the slower PSP amplitude component was due to augmentation of the NMDA receptor-mediated potential as this was completely reversed on subsequent application of the NMDA receptor antagonist AP5. HFS similarly potentiated NMDA receptor currents isolated by blockade of AMPA/kainate receptors with CNQX. The plasticity-induced increase in the slow PSP component was directly associated with an increase in the subsequent AHP. Thus plasticity of cortical afferent synapses is ideally suited to influence the cue-induced firing dynamics of CINs, particularly through potentiation of NMDA receptor-mediated synaptic transmission.
Conjunctive input processing drives feature selectivity in hippocampal CA1 neurons
Author(s): Bittner, KC;Grienberger, C;Vaidya, SP;Milstein, AD;Macklin, JJ;Suh, J;Tonegawa, S;Magee, JC;
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Feature-selective firing allows networks to produce representations of the external and internal environments. Despite its importance, the mechanisms generating neuronal feature selectivity are incompletely understood. In many cortical microcircuits the integration of two functionally distinct inputs occurs nonlinearly through generation of active dendritic signals that drive burst firing and robust plasticity. To examine the role of this processing in feature selectivity, we recorded CA1 pyramidal neuron membrane potential and local field potential in mice running on a linear treadmill. We found that dendritic plateau potentials were produced by an interaction between properly timed input from entorhinal cortex and hippocampal CA3. These conjunctive signals positively modulated the firing of previously established place fields and rapidly induced new place field formation to produce feature selectivity in CA1 that is a function of both entorhinal cortex and CA3 input. Such selectivity could allow mixed network level representations that support context-dependent spatial maps.
Reward modulates the effect of visual cortical microstimulation on perceptual decisions
Author(s): Cicmil, N;Cumming, BG;Parker, AJ;Krug, K;
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Effective perceptual decisions rely upon combining sensory information with knowledge of the rewards available for different choices. However, it is not known where reward signals interact with the multiple stages of the perceptual decision-making pathway and by what mechanisms this may occur. We combined electrical microstimulation of functionally specific groups of neurons in visual area V5/MT with performance-contingent reward manipulation, while monkeys performed a visual discrimination task. Microstimulation was less effective in shifting perceptual choices towards the stimulus preferences of the stimulated neurons when available reward was larger. Psychophysical control experiments showed this result was not explained by a selective change in response strategy on microstimulated trials. A bounded accumulation decision model, applied to analyse behavioural performance, revealed that the interaction of expected reward with microstimulation can be explained if expected reward modulates a sensory representation stage of perceptual decision-making, in addition to the better-known effects at the integration stage.
Evaluating the tongue-hold maneuver using high-resolution manometry and electromyography
Author(s): Hammer, MJ;Jones, CA;Jones, CA;Mielens, JD;Kim, CH;McCulloch, TM;
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The tongue-hold maneuver is a widely used clinical technique designed to increase posterior pharyngeal wall movement in individuals with dysphagia. It is hypothesized that the tongue-hold maneuver results in increased contraction of the superior pharyngeal constrictor. However, an electromyographic study of the pharynx and tongue during the tongue-hold is still needed to understand whether and how swallow muscle activity and pressure may change with this maneuver. We tested eight healthy young participants using simultaneous intramuscular electromyography with high-resolution manometry during three task conditions including (a) saliva swallow without maneuver, (b) saliva swallow with the tongue tip at the lip, and (c) saliva swallow during the tongue-hold maneuver. We tested the hypothesis that tongue and pharyngeal muscle activity would increase during the experimental tasks, but that pharyngeal pressure would remain relatively unchanged. We found that the pre-swallow magnitude of tongue, pharyngeal constrictor, and cricopharyngeus muscle activity increased. During the swallow, the magnitude and duration of tongue and pharyngeal constrictor muscle activity each increased. However, manometric pressures and durations remained unchanged. These results suggest that increased superior pharyngeal constrictor activity may serve to maintain relatively stable pharyngeal pressures in the absence of posterior tongue movement. Thus, the tongue-hold maneuver may be a relatively simple but robust example of how the medullary swallow center is equipped to dynamically coordinate actions between tongue and pharynx. Our findings emphasize the need for combined modality swallow assessment to include high-resolution manometry and intramuscular electromyography to evaluate the potential benefit of the tongue-hold maneuver for clinical populations.
Choline-mediated modulation of hippocampal sharp wave-ripple complexes in vitro
Author(s): Fischer, V;Both, M;Draguhn, A;Egorov, AV;
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The cholinergic system is critically involved in the modulation of cognitive functions, including learning and memory. Acetylcholine acts through muscarinic (mAChRs) and nicotinic receptors (nAChRs), which are both abundantly expressed in the hippocampus. Previous evidence indicates that choline, the precursor and degradation product of Acetylcholine, can itself activate nAChRs and thereby affects intrinsic and synaptic neuronal functions. Here, we asked whether the cellular actions of choline directly affect hippocampal network activity. Using mouse hippocampal slices we found that choline efficiently suppresses spontaneously occurring sharp wave-ripple complexes (SPW-R) and can induce gamma oscillations. In addition, choline reduces synaptic transmission between hippocampal subfields CA3 and CA1. Surprisingly, these effects are mediated by activation of both mAChRs and α7-containing nAChRs. Most nicotinic effects became only apparent after local, fast application of choline, indicating rapid desensitization kinetics of nAChRs. Effects were still present following block of choline uptake and are, therefore, likely because of direct actions of choline at the respective receptors. Together, choline turns out to be a potent regulator of patterned network activity within the hippocampus. These actions may be of importance for understanding state transitions in normal and pathologically altered neuronal networks. In this study we asked whether choline, the precursor and degradation product of acetylcholine, directly affects hippocampal network activity. Using mouse hippocampal slices we found that choline efficiently suppresses spontaneously occurring sharp wave-ripple complexes (SPW-R). In addition, choline reduces synaptic transmission between hippocampal subfields. These effects are mediated by direct activation of muscarinic as well as nicotinic cholinergic pathways. Together, choline turns out to be a potent regulator of patterned activity within hippocampal networks.
Human chromosome 21 orthologous region on mouse chromosome 17 is a major determinant of Down syndrome-related developmental cognitive deficits
Author(s): Zhang, L;Meng, K;Jiang, X;Liu, C;Pao, A;Belichenko, PV;Kleschevnikov, AM;Josselyn, S;Liang, P;Ye, P;Mobley, WC;Yu, YE;
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Trisomy 21 (Down syndrome, DS) is the most common genetic cause of developmental cognitive deficits, and the so-called Down syndrome critical region (DSCR) has been proposed as a major determinant of this phenotype. The regions on human chromosome 21 (Hsa21) are syntenically conserved on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. DSCR is conserved between the Cbr1 and Fam3b genes on Mmu16. Ts65Dn mice carry three copies of ∼100 Hsa21 gene orthologs on Mmu16 and exhibited impairments in the Morris water maze and hippocampal long-term potentiation (LTP). Converting the Cbr1-Fam3b region back to two copies in Ts65Dn mice rescued these phenotypes. In this study, we performed similar conversion of the Cbr1-Fam3b region in Dp(16)1Yey/+ mice that is triplicated for all ∼115 Hsa21 gene orthologs on Mmu16, which also resulted in the restoration of the wild-type phenotypes in the Morris water maze and hippocampal LTP. However, converting the Cbr1-Fam3b region back to two copies in a complete model, Dp(10)1Yey/+;Dp(16)1Yey/+;Dp(17)1Yey/+, failed to yield the similar phenotypic restorations. But, surprisingly, converting both the Cbr1-Fam3b region and the Hsa21 orthologous region on Mmu17 back to two copies in the complete model did completely restore these phenotypes to the wild-type levels. Our results demonstrated that the Hsa21 orthologous region on Mmu17 is a major determinant of DS-related developmental cognitive deficits. Therefore, the inclusion of the three copies of this Hsa21 orthologous region in mouse models is necessary for unraveling the mechanism underlying DS-associated developmental cognitive deficits and for developing effective interventions for this clinical manifestation.
Lactational anovulation in mice results from a selective loss of kisspeptin input to GnRH neurons
Author(s): Liu, X;Brown, RS;Herbison, AE;Grattan, DR;
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In mammals, lactation is associated with a period of infertility characterized by the loss of pulsatile secretion of GnRH and cessation of ovulatory cycles. Despite the importance of lactational infertility in determining overall fecundity of a species, the mechanisms by which the suckling stimulus suppresses GnRH secretion remain unclear. Because kisspeptin neurons are critical for fertility, the aim of this study was to test the hypothesis that reduced kisspeptin expression might mediate the lactation-induced suppression of fertility, using mouse models. In the rostral periventricular area of the third ventricle (RP3V), a progressive decrease in RP3V Kiss1 mRNA levels was observed during pregnancy culminating in a 10-fold reduction during lactation compared with diestrous controls. This was associated with approximately 60% reduction in the numbers of kisspeptin-immunoreactive neurons in the RP3V detected during lactation. Similarly, in the arcuate nucleus there was also a significant decrease in Kiss1 mRNA levels during late pregnancy and midlactation, and a notable decrease in kisspeptin fiber density during lactation. The functional characteristics of the RP3V kisspeptin input to GnRH neurons were assessed using electrophysiological approaches in an acute brain slice preparation. Although endogenous RP3V kisspeptin neurons were found to activate GnRH neurons in diestrous mice, this was never observed during lactation. This did not result from an absence of kisspeptin receptors because GnRH neurons responded normally to 100 nM exogenous kisspeptin during lactation. The kisspeptin deficit in lactating mice was selective, because GnRH neurons responded normally to RP3V gamma aminobutryic acid inputs during lactation. These data demonstrate that a selective loss of RP3V kisspeptin inputs to GnRH neurons during lactation is the likely mechanism causing lactational anovulation in the mouse.
Large-scale reorganization of the somatosensory cortex following spinal cord injuries is due to brainstem plasticity
Author(s): Kambi, N;Halder, P;Rajan, R;Arora, V;Chand, P;Arora, M;Jain, N;
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Adult mammalian brains undergo reorganization following deafferentations due to peripheral nerve, cortical or spinal cord injuries. The largest extent of cortical reorganization is seen in area 3b of the somatosensory cortex of monkeys with chronic transection of the dorsal roots or dorsal columns of the spinal cord. These injuries cause expansion of intact face inputs into the deafferented hand cortex, resulting in a change of representational boundaries by more than 7 mm. Here we show that large-scale reorganization in area 3b following spinal cord injuries is due to changes at the level of the brainstem nuclei and not due to cortical mechanisms. Selective inactivation of the reorganized cuneate nucleus of the brainstem eliminates observed face expansion in area 3b. Thus, the substrate for the observed expanded face representation in area 3b lies in the cuneate nucleus.
Thalamocortical oscillations during sleep and general anaesthesia
Author(s): Baker, RH;
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The tungsten bipolar electrodes (Microprobes, USA) were placed according to the co - ordinates of Paxinos and Watson (1986) (see Table 2.1) with all measurements taken using Bregma as the reference point.
DBS of nucleus accumbens on heroin seeking behaviors in self-administering rats
Author(s): Guo, L;Zhou, H;Wang, R;Xu, J;Zhou, W;Zhang, F;Tang, S;Liu, H;Jiang, J;
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Surgical ablation of select brain areas has been frequently used to alleviate psychological dependence on opiate drugs in certain countries. However, ablative brain surgery was stopped in China in 2004 due to the related ethical controversy and possible side effects. Deep brain stimulation (DBS), a less invasive, reversible and adjustable process of neuromodulation, was adopted to attenuate relapses in studies of drug addiction. Preclinical experiments were designed to assess the long-term effects of DBS of the nucleus accumbens (NAc) on cue- and heroin-induced reinstatement of drug seeking behaviors. After a rat self-administration model of heroin relapse was established, DBS was administered bilaterally or unilaterally to the NAc core through concentric bipolar electrodes. A 1-h long continuous stimulation (130 Hz, 100 μs, 0-150 μA) was given daily for 7 days during the abstinence session. Drug seeking behaviors were elicited by conditioned cues or a small dose of heroin. 75 μA and 150 μA bilateral NAc DBS attenuated cue- and heroin-induced reinstatement of drug seeking, and unilateral DBS of the right NAc achieved effects almost equivalent to bilateral DBS. Additional experiments showed that DBS had no long-term influence on locomotor activity and spatial learning and retention capabilities in Morris water maze tasks. Subsequent immunohistochemistry measurements revealed that the behavioral consequences were associated with a significant increase in the expression of pCREB and a reduction in the expression of ΔFosB in the NAc. These findings indicate that the NAc DBS could be an effective and safe therapeutic option for preventing relapse to heroin addiction.
Dopamine regulation of gonadotropin-releasing hormone neuron excitability in male and female mice
Author(s): Liu, X;Herbison, AE;
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Numerous in vivo studies have shown that dopamine is involved in the regulation of LH secretion in mammals. However, the mechanisms through which this occurs are not known. In this study, we used green fluorescent protein-tagged GnRH neurons to examine whether and how dopamine may modulate the activity of adult GnRH neurons in the mouse. Bath-applied dopamine (10-80 μm) potently inhibited the firing of approximately 50% of GnRH neurons. This resulted from direct postsynaptic inhibitory actions through D1-like, D2-like, or both receptors. Further, one third of GnRH neurons exhibited an increase in their basal firing rate after administration of SCH23390 (D1-like antagonist) and/or raclopride (D2-like antagonist) indicating tonic inhibition by endogenous dopamine in the brain slice. The role of dopamine in presynaptic modulation of the anteroventral periventricular nucleus (AVPV) γ-aminobutyric acid/glutamate input to GnRH neurons was examined. Exogenous dopamine was found to presynaptically inhibit AVPV-evoked γ-aminobutyric acid /glutamate postsynaptic currents in about 50% of GnRH neurons. These effects were, again, mediated by both D1- and D2-like receptors. Neither postsynaptic nor presynaptic actions of dopamine were found to be different between diestrous, proestrous, and estrous females, or males. Approximately 20% of GnRH neurons were shown to receive a dopaminergic input from AVPV neurons in male and female mice. Together, these observations show that dopamine is one of the most potent inhibitors of GnRH neuron excitability and that this is achieved through complex pre- and postsynaptic actions that each involve D1- and D2-like receptor activation.
Parallel dopamine D1 receptor activity dependence of l-Dopa-induced normal movement and dyskinesia in mice
Author(s): Li, L;Zhou, FM;
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l-3,4-Dihydroxyphenylalanine (l-Dopa)-induced dyskinesia (LID) in Parkinson's disease (PD) is a major clinical problem. The prevailing view is that in PD patients and animal PD models dyskinesia develops after repeated l-dopa use or priming, independent of l-dopa's anti-PD therapeutic effect that occurs immediately. Here we show that in mice with severe and consistent dopamine (DA) loss in the dorsal striatum, rendered by transcription factor Pitx3 null mutation, the very first injection of l-dopa or D1-like agonist SKF81297 induced both normal ambulatory and dyskinetic movements. Furthermore, the robust stimulating effects on normal and dyskinetic movements had an identical time course and parallel dose-response curves. In contrast, D2-like agonist ropinirole stimulated normal and dyskinetic movements relatively modestly. These results demonstrate that severe DA loss in the dorsal striatum sets the stage for dyskinesia to occur on the first exposure to l-dopa or a D1 agonist without any priming. These results also indicate that l-dopa stimulated both normal and dyskinetic movements primarily via D1 receptor activation and that proper D1 agonism is potentially an efficacious therapy for PD motor deficits.
Rapid and continuous modulation of hippocampal network state during exploration of new places
Author(s): Kemere, C;Carr, MF;Karlsson, MP;Frank, LM;
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Hippocampal information processing is often described as two-state, with a place cell state during movement and a reactivation state during stillness. Relatively little is known about how the network transitions between these different patterns of activity during exploration. Here we show that hippocampal network changes quickly and continuously as animals explore and become familiar with initially novel places. We measured the relationship between moment-by-moment changes in behavior and information flow through hippocampal output area CA1 in rats. We examined local field potential (LFP) patterns, evoked potentials and ensemble spiking and found evidence suggestive of a smooth transition from strong CA3 drive of CA1 activity at low speeds to entorhinal cortical drive of CA1 activity at higher speeds. These changes occurred with changes in behavior on a timescale of less than a second, suggesting a continuous modulation of information processing in the hippocampal circuit as a function of behavioral state.
Temporal dynamics of neuromodulator release in motor cortex revealed by cell-based optically-active probes
Author(s): Joseph, VT;
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… Additionally, a 0.1 M tungsten bipolar stimulating electrodes with a tip separation of 500 m (Microprobes Inc.) was implanted into either substantia nigra (-3.2 mm A/P, -1.3 mm M/L, -4.4 mm D/V) or locus coeruleus (-5.3 mm A/P, -0.9 mm M/L, -3.4 mm D/V). After a day of recovery …
Developmental changes in short-term plasticity at the rat calyx of Held synapse
Author(s): Crins, TT;Rusu, SI;Rodríguez-Contreras, A;Borst, JG;
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The calyx of Held synapse of the medial nucleus of the trapezoid body functions as a relay synapse in the auditory brainstem. In vivo recordings have shown that this synapse displays low release probability and that the average size of synaptic potentials does not depend on recent history. We used a ventral approach to make in vivo extracellular recordings from the calyx of Held synapse in rats aged postnatal day 4 (P4) to P29 to study the developmental changes that allow this synapse to function as a relay. Between P4 and P8, we observed evidence for the presence of large short-term depression, which was counteracted by short-term facilitation at short intervals. Major changes occurred in the last few days before the onset of hearing for air-borne sounds, which happened at P13. The bursting pattern changed into a primary-like pattern, the amount of depression and facilitation decreased strongly, and the decay of facilitation became much faster. Whereas short-term plasticity was the most important cause of variability in the size of the synaptic potentials in immature animals, its role became minor around hearing onset and afterward. Similar developmental changes were observed during stimulation experiments both in brain slices and in vivo following cochlear ablation. Our data suggest that the strong reduction in release probability and the speedup of the decay of synaptic facilitation that happen just before hearing onset are important events in the transformation of the calyx of Held synapse into an auditory relay synapse.
Estrous cycle- and sex-dependent changes in pre- and postsynaptic GABAB control of GnRH neuron excitability
Author(s): Liu, X;Herbison, AE;
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The GnRH neurons are the key neurons controlling fertility in mammals. Although γ-aminobutyric acid (GABA) plays an important role in the regulation of GnRH neurons, the role of GABA(B) receptors is poorly understood. Using GnRH-green fluorescent protein transgenic mice and a parahorizontal brain slice preparation, we have undertaken a series of electrophysiological experiments to examine 1) postsynaptic GABA(B) receptors expressed by GnRH neurons, and 2) presynaptic GABA(B) receptors located on the terminals of an important neural input to GnRH neurons originating from the anteroventral periventricular nucleus (AVPV). The GABA(B) receptor agonist baclofen induced a direct postsynaptic hyperpolarization of GnRH neurons through induction of an outward current blocked by barium. Baclofen also acted presynaptically to suppress AVPV-activated GABA- and glutamate-evoked postsynaptic currents in GnRH neurons. The number of GnRH neurons exhibiting postsynaptic GABA(B) receptors was significantly (P < 0.05) different in males (22%) and females (70%), whereas presynaptic GABA(B) modulation of AVPV afferents was the same in the two sexes. Across the estrous cycle, a striking approximately 70% reduction (P < 0.05) in presynaptic GABA(B) modulation of AVPV afferents to GnRH neurons was found on proestrus compared with diestrus and estrus. In contrast, postsynaptic GABA(B) receptors did not change. Together, these findings show that GABA(B) receptors are active at both pre- and postsynaptic sites to modulate the excitability of GnRH neurons. The balance of this pre- and postsynaptic activity is different between the sexes and changes in a dynamic manner across the estrous cycle.
Amygdala stimulation evokes time-varying synaptic responses in the gustatory cortex of anesthetized rats
Author(s): Stone, ME;Maffei, A;Fontanini, A;
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Gustatory stimuli are characterized by a specific hedonic value; they are either palatable or aversive. Hedonic value, along with other psychological dimensions of tastes, is coded in the time-course of gustatory cortex (GC) neural responses and appears to emerge via top-down modulation by the basolateral amygdala (BLA). While the importance of BLA in modulating gustatory cortical function has been well established, the nature of its input onto GC neurons is largely unknown. Somewhat conflicting results from extracellular recordings point to either excitatory or inhibitory effects. Here, we directly test the hypothesis that BLA can evoke time-varying - excitatory and inhibitory - synaptic responses in GC using in vivo intracellular recording techniques in urethane anesthetized rats. Electrical stimulation of BLA evoked a post-synaptic potential (PSP) in GC neurons that resulted from a combination of short and long latency components: an initial monosynaptic, glutamatergic potential followed by a multisynaptic, GABAergic hyperpolarization. As predicted by the dynamic nature of amygdala evoked potentials, trains of five BLA stimuli at rates that mimic physiological firing rates (5-40 Hz) evoke a combination of excitation and inhibition in GC cells. The magnitude of the different components varies depending on the frequency of stimulation, with summation of excitatory and inhibitory inputs reaching its maximum at higher frequencies. These experiments provide the first description of BLA synaptic inputs to GC and reveal that amygdalar afferents can modulate gustatory cortical network activity and its processing of sensory information via time-varying synaptic dynamics.
Role of PKMz in morphological and synaptic development of optic tectal neurons in Xenopus laevis tadpoles in vivo
Author(s): Liu, X;
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In order to record evoked synaptic currents, tadpole brains w ere sectioned along the dorsal midline and a bipolar stimulating electrode ( MicroProbes for Life Science, MD ) was placed at the optic chiasm to stimulate the optic nerve using stimulus parameters as described previously (Wu et al., 1996).
Simulation of the role of vibration on Scanning Vibrating Electrode Technique measurements close to a disc in plane
Author(s): Dolgikh, O;Demeter, A;Lamaka, SV;Taryb, M;Bastos, AC;CQuevedo, M;Deconinck, J
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An elegant and accessible way to account for the local stirring created by the vibration of the SVET tip by adding a new diffusion–like term into the molar flux expression is proposed, in order to avoid solving the fluid flow. This term is maximal in the point of vibration and rapidly decreases with the distance. It is shown that the local mixing leads to a substantial increase of the migration current density in the vicinity of the probe with simultaneous decrease of the diffusion current contribution. This local mixing has no effect on the pH distribution, regardless the applied polarization, and increases under cathodic polarization the oxygen concentration only when the probe is close to the electrode surface which is confirmed by experimental observations. The proposed model is compared with the analytical current density distributions obtained from potential model and experimental data. All this indicates that local mixing might explain why the SVET technique, although based on the measurement of an ohmic current density, measures always the total current density.
Active and passive protection of AA2024-T3 by a hybrid inhibitor doped mesoporous sol–gel and top coating system
Author(s): Recloux, I;Gonzalez-Garcia, Y;Druart, M;FKhelifa, ;Dubois, P;Mol, J;Olivier, M
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In the present investigation, a two-layer coating system was developed in order to protect 2024 aluminium alloy against corrosion. At the metal interface, a silica mesoporous thin film was used to offer storage and release functionalities for benzotriazole inhibitive molecules (active protection). An acrylic top coat was then applied as a barrier layer against corrosive species (passive protection). Various electrochemical techniques were employed to evaluate the anticorrosion performance of the coating system. Amongst them, the scanning vibrating electrode technique (SVET) and the scanning electrochemical microscopy (SECM) showed a slowdown of corrosion processes occurring within the damaged coating area. The acquisition of anodic polarization curves inside the scratch through the use of an electrochemical micro-cell allowed to correlate this enhancement in the corrosion protection with the formation of an inhibitive film. Upon a through-coating damage, the mesoporous reservoir comes into contact with the aggressive electrolyte and benzotriazole molecules are able to be released and to inhibit corrosion of the bare metal exposed in the scratch. The work demonstrates the potential of mesoporous films as reservoir for inhibitive species and its efficiency for controlled release of the inhibitor. Furthermore, the work demonstrates the added value of electrochemical micro-cell measurements to highlight active corrosion protection in coating defects due to inhibitor doped coating systems.
Determination of current maps by SVET of hot-dip galvanized steel under simultaneous straining
Author(s): Manhabosco, SM;Batista, RJC;da Silva, SN;Dick, LFP
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A new experimental procedure was used to analyse the corrosion behaviour of hot-dip Zn coated steel based on the association of the scanning vibrating electrode technique (SVET) and uniaxial tensile strain applied up to 3.1% in 0.01 M NaCl solutions without release of the elastic strain during the test. The nucleation of localized corrosion sites on the coating occurs at very low strain values around the yield point and the maximum current densities increase continuously with the increase of the applied strain. The nucleation of localized corrosion on the Zn surface was favoured by the rupture of the passive film in contact with the solution by the action of slip steps and fine intergranular cracks, rather than by the exposure of the steel substrate. Straining of the Zn coating immersed in the solution was comparatively a much more aggressive condition than straining the sample in air before the corrosion tests.
Comparative study of the corrosion behavior of galvanized, galvannealed and Zn55Al coated interstitial free steels
Author(s): dos Santos, AP;Manhabosco, S;JSRodrigues, ;Dick, L
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In the present work, we comparatively studied the corrosion attack of Zn-based coatings on interstitial free steel. For this, the electrochemical behavior of industrially coated hot-dip galvanized (GI), galvanneal (GA) and galvalume (Zn55Al) interstitial free (IF) steels was analyzed by cyclic voltammetry in quiescent and stirred 0.1 mol/L NaCl solution and by scanning vibrating electrode technique (SVET). All three coatings protect the steel substrate by their localized corrosion leading to final coating perforation. However, Zn55Al corrodes more homogenously due to a well-distributed interdendritic η phase and the barrier effect of interfacial Al–Fe intermetallics. Due to its surface cracks, GA presents the opposite behavior, suffering a substrate attack with only 70% of the charge density expected for GI.
Influence of Inclusions on Early Corrosion Development of Ultra-Low Carbon Bainitic Steel in NaCl Solution
Author(s): Wei, J;Dong, JH;Ke, W;He, XY
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The early corrosion development of ultra-low carbon bainitic (ULCB) low alloy steel in NaCl solution was studied by ex situ imaging of corrosion morphology and in situ monitoring of microarea current density and potential, and the corrosion mechanism from initial localized corrosion to uniform corrosion was interpreted. The results indicate that the corrosion development of ULCB steel from initial localized corrosion around inclusions to the uniform corrosion on the whole steel surface is controlled by the galvanic couple effect between different phases resulting from their electrode potential difference in electrolyte solution. The early localized corrosion of steel matrix is initiated and accelerated by the galvanic couple effect between MnS inclusions and steel matrix to form the initial corrosion gaps and the circular corrosion spots around inclusions. The ohmic drop caused by solution resistance influences the acceleration effect of the galvanic couple. With the separation of inclusion from steel matrix, this galvanic couple effect becomes invalid, which results in the expansion from localized corrosion to uniform corrosion. The microgalvanic couple between martensite/residual austenite (M/A) islands and bainite ferrite also accelerates the anodic dissolution of bainite ferrite phase; however, its acceleration corrosion effect is much weaker than that caused by MnS inclusion.
Encapsulation of aliphatic amines into nanoparticles for self-healing corrosion protection of steel sheets
Author(s): Choi, H;Kim, KY;Park, JM
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A noble approach based on the encapsulation of corrosion inhibitors has been presented, which are capable of improving the active corrosion protection without negatively influencing the barrier properties of the coating layers. Polymeric nanocapsules loaded with six types of amine corrosion inhibitors were synthesized by multi-stage emulsion polymerization. Depending on the basicity and water solubility of amines, different amounts of releasable corrosion inhibitors were encapsulated into the polymer capsules. Encapsulated organic amines were generally well released under alkaline conditions, and linear amines were more easily released from inside capsules than branched ones. The nanocapsules were incorporated into the coating resin and were coated on cold-rolled steel sheets to investigate corrosion protection efficiencies. The corrosion inhibitive efficiencies of the nanocapsule-containing coating layers were evaluated by electrochemical impedance spectroscopy (EIS) and scanning vibrating electrode technique (SVET). In this study, it was revealed that the intrinsic properties of the amines as well as their encapsulation/release behaviors determined the barrier property and self-healing protection capability of the coating layer.
FLOATING MICROELECTRODE ARRAYLINEAR MICROELECTRODE ARRAYMICROELECTRODE ARRAYMICROWIRE ARRAY
Long-term stability of neural signals from microwire arrays implanted in common marmoset motor cortex and striatum
Author(s): Debnath, S; Prins, N; Pohlmeyer, E; Mylavarapu, R; Geng, S; Sanchez, J; Prasad, A
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Current neuroprosthetics rely on stable, high quality recordings from chronically implanted microelectrode arrays (MEAs) in neural tissue. While chronic electrophysiological recordings and electrode failure modes have been reported from rodent and larger non-human primate (NHP) models, chronic recordings from the marmoset model have not been previously described. The common marmoset is a New World primate that is easier to breed and handle compared to larger NHPs and has a similarly organized brain, making it a potentially useful smaller NHP model for neuroscience studies. This study reports recording stability and signal quality of MEAs chronically implanted in behaving marmosets. Six adult male marmosets, trained for reaching tasks, were implanted with either a 16-channel tungsten microwire array (five animals) or a Pt-Ir floating MEA (one animal) in the hand-arm region of the primary motor cortex (M1) and another MEA in the striatum targeting the nucleus accumbens (NAcc). Signal stability and quality was quantified as a function of array yield (active electrodes that recorded action potentials), neuronal yield (isolated single units during a recording session), and signal-to-noise ratio (SNR). Out of 11 implanted MEAs, nine provided functional recordings for at least three months, with two arrays functional for 10 months. In general, implants had high yield, which remained stable for up to several months. However, mechanical failure attributed to MEA connector was the most common failure mode. In the longest implants, signal degradation occurred, which was characterized by gradual decline in array yield, reduced number of isolated single units, and changes in waveform shape of action potentials. This work demonstrates the feasibility of long-term recordings from MEAs implanted in cortical and deep brain structures in the marmoset model. The ability to chronically record cortical signals for neural prosthetics applications in the common marmoset extends the potential of this model in neural interface research.
Neural dynamics of variable grasp movement preparation in the macaque fronto-parietal network
Author(s): Michaels, JA; Dann, B; Intveld, RW; Scherberger, H
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Our voluntary grasping actions lie on a continuum between immediate action and waiting for the right moment, depending on the context. Therefore, studying grasping requires investigating how preparation time affects this process. Two macaque monkeys (Macaca mulatta) performed a grasping task with a short instruction followed by an immediate or delayed go cue (0-1300 ms) while we recorded in parallel from neurons in the hand area (F5) of the ventral premotor cortex and the anterior intraparietal area (AIP). Initial population dynamics followed a fixed trajectory in the neural state space unique to each grip type, reflecting unavoidable preparation, then diverged depending on the delay. Although similar types of single unit responses were present in both areas, population activity in AIP stabilized within a unique memory state while F5 activity continued to evolve, tracking subjective anticipation of the go cue. Intriguingly, activity during movement initiation clustered into two trajectory clusters, corresponding to movements that were either 'as fast as possible' or withheld movements, demonstrating a widespread state shift in the frontoparietal grasping network when movements must be withheld. Our results reveal how dissociation between static and dynamic components of movement preparation as well as differentiation between cortical areas is possible through population level analysis.
Mixed selectivity morphs population codes in prefrontal cortex
Author(s): Parthasarathy, Aw; Herikstad, R; Bong, JH; Medina, FS; Libedinsky, C; n, SY
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The prefrontal cortex maintains working memory information in the presence of distracting stimuli. It has long been thought that sustained activity in individual neurons or groups of neurons was responsible for maintaining information in the form of a persistent, stable code. Here we show that, upon the presentation of a distractor, information in the lateral prefrontal cortex was reorganized into a different pattern of activity to create a morphed stable code without losing information. In contrast, the code in the frontal eye fields persisted across different delay periods but exhibited substantial instability and information loss after the presentation of a distractor. We found that neurons with mixed-selective responses were necessary and sufficient for the morphing of code and that these neurons were more abundant in the lateral prefrontal cortex than the frontal eye fields. This suggests that mixed selectivity provides populations with code-morphing capability, a property that may underlie cognitive flexibility.
Rodent model for assessing the long term safety and performance of peripheral nerve recording electrodes.
Author(s): Vasudevan, S; Patel, K; Welle, C
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In the US alone, there are approximately 185 000 cases of limb amputation annually, which can reduce the quality of life for those individuals. Current prosthesis technology could be improved by access to signals from the nervous system for intuitive prosthesis control. After amputation, residual peripheral nerves continue to convey motor signals and electrical stimulation of these nerves can elicit sensory percepts. However, current technology for extracting information directly from peripheral nerves has limited chronic reliability, and novel approaches must be vetted to ensure safe long-term use. The present study aims to optimize methods to establish a test platform using rodent model to assess the long term safety and performance of electrode interfaces implanted in the peripheral nerves.
METHODOLOGICAL CONSIDERATIONS FOR A CHRONIC NEURAL INTERFACE WITH THE CUNEATE NUCLEUS OF MACAQUES
Author(s): Suresh, AK; Winberry, J; Versteeg, C; Chowdhury, RH; Tomlinson, T; Rosenow, JM; Miller, LE; Bensmaia, SJ
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While the response properties of neurons in the somatosensory nerves and anterior parietal cortex have been extensively studied, little is known about the encoding of tactile and proprioceptive information in the cuneate nucleus (CN) or external cuneate nucleus (ECN), the first recipients of upper limb somatosensory afferent signals. The major challenge in characterizing neural coding in CN/ECN has been to record from these tiny, difficult to access brainstem structures. Most previous investigations of CN response properties have been carried out in decerebrate or anesthetized animals, thereby eliminating the well-documented top-down signals from cortex, which likely exert a strong influence on CN responses. Seeking to fill this gap in our understanding of somatosensory processing, we describe an approach to chronically implant arrays of electrodes in the upper limb representation in the brain stem in primates. First, we describe the topography of CN/ECN in Rhesus macaques, including its somatotopic organization and the layout of its submodalities (touch and proprioception). Second, we describe the design of electrode arrays and the implantation strategy to obtain stable recordings. Third, we show sample responses of CN/ECN neurons in brainstem obtained from awake, behaving monkeys. With this method, we are in a position to characterize, for the first time, somatosensory representations in CN and ECN of primates.
Independent Mobility Achieved through a Wireless Brain-Machine Interface
Author(s): Libedinsky, C; So, R; Xu, Z; Kyar, TK; Ho, D; Lim, C; Chan, L; Chua, Y; Yao, L; Cheong, JH; Lee, JH; Vishal, KV; Guo, Y; Chen, ZN; Lim, LK; Li, P; Liu, L; Zou, X; Ang, KK; Gao, Y; Ng, WH; Han, BS; Chng, K; Guan, C; Je, M; Yen, SC
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Individuals with tetraplegia lack independent mobility, making them highly dependent on others to move from one place to another. Here, we describe how two macaques were able to use a wireless integrated system to control a robotic platform, over which they were sitting, to achieve independent mobility using the neuronal activity in their motor cortices. The activity of populations of single neurons was recorded using multiple electrode arrays implanted in the arm region of primary motor cortex, and decoded to achieve brain control of the platform. We found that free-running brain control of the platform (which was not equipped with any machine intelligence) was fast and accurate, resembling the performance achieved using joystick control. The decoding algorithms can be trained in the absence of joystick movements, as would be required for use by tetraplegic individuals, demonstrating that the non-human primate model is a good pre-clinical model for developing such a cortically-controlled movement prosthetic. Interestingly, we found that the response properties of some neurons differed greatly depending on the mode of control (joystick or brain control), suggesting different roles for these neurons in encoding movement intention and movement execution. These results demonstrate that independent mobility can be achieved without first training on prescribed motor movements, opening the door for the implementation of this technology in persons with tetraplegia.
A four-dimensional virtual hand brain-machine interface using active dimension selection.
Author(s): Rouse, AG
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Brain-machine interfaces (BMI) traditionally rely on a fixed, linear transformation from neural signals to an output state-space. In this study, the assumption that a BMI must control a fixed, orthogonal basis set was challenged and a novel active dimension selection (ADS) decoder was explored.
Parallel electrochemical measurements of implanted neural recording microelectrodes
Author(s): Hu, Z; Troyk, P; DeMichele, G
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An electrochemical instrument capable of parallel measurement of 16 microelectrodes was used, for the first time, for evaluating 32 implanted microelectrodes in-vivo. The result reveals the inadequacy of traditional single-frequency impedance measurements as an assessment of microelectrodes. The combinational measurements of cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) provide more comprehensive information of the “health” of implanted microelectrodes. Parallel measurements allow investigators to gather this information for a large number of electrodes at much faster speed than have been traditionally available.
A bidirectional peripheral neural interface for restoring sensorimotor function of non-human primates
Author(s): Zhang, P; Ma, X; He, J
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Upper limb loss is a big disaster and markedly affects the quality of life. Bidirectional peripheral neural interface (PNI) is a feasible way to restore the sensorimotor functions of amputees. Bidirectional interface includes motor commands decoding and sensory feedback restoring. In this paper, we presented two neurobehavioral platforms for studying bidirectional PNI in the monkey. In the first platform, the monkey was guided to do reaching and grasping tasks meanwhile cortical and peripheral neural signals were recorded, motor commands can be decoded. In the other platform, the monkey was guided to express tactile sensation into motor action; sensory feedback restoring can be seen from the action of the monkey. We designed a bidirectional PNI and tried to achieve it, many substantial challenges still remains.
Brain-computer interface control with small motor cortex ensembles
Author(s): Law, AJ
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… 10. Using general anesthesia and aseptic technique, two male rhesus macaques, monkey M and monkey V, were implanted with four floating microelectrode arrays (FMAs, MicroProbes, Gaithersburg, MD) in the primary motor cortex (M1) of the left hemisphere  …
Regenerative Peripheral Nerve Interfacing Of Sensory Modalities
Author(s): Dutta, NT
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Figure 2.1: Shows (A) Arrangement of 18 electrodes with dimensions of the Floating Multielectrode array as in REMI design (Array dimensions 2.5mmX1.95mm)(Courtesy Microprobes Inc., MD)
Object vision to hand action in macaque parietal, premotor, and motor cortices
Author(s): Schaffelhofer, S; Scherberger, H
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Grasping requires translating object geometries into appropriate hand shapes. How the brain computes these transformations is currently unclear. We investigated three key areas of the macaque cortical grasping circuit with microelectrode arrays and found cooperative but anatomically separated visual and motor processes. The parietal area AIP operated primarily in a visual mode. Its neuronal population revealed a specialization for shape processing, even for abstract geometries, and processed object features ultimately important for grasping. Premotor area F5 acted as a hub that shared the visual coding of AIP only temporarily and switched to highly dominant motor signals towards movement planning and execution. We visualize these non-discrete premotor signals that drive the primary motor cortex M1 to reflect the movement of the grasping hand. Our results reveal visual and motor features encoded in the grasping circuit and their communication to achieve transformation for grasping.
A chronic neural interface to the macaque dorsal column nuclei
Author(s): Richardson, AG; Weigand, PK; Sritharan, SY; Lucas, TH
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The dorsal column nuclei (DCN) of the brain stem contain secondary afferent neurons, which process ascending somatosensory information. Most of the known physiology of the DCN in primates has been acquired in acute experiments with anesthetized animals. Here, we developed a technique to implant a multielectrode array (MEA) chronically in the DCN of macaque monkeys to enable experiments with the animals awake. Two monkeys were implanted with brain-stem MEAs for 2-5 mo with no major adverse effects. Responses of the cuneate and gracile nuclei were quantified at the level of both field potentials and single units. Tactile receptive fields (RFs) were identified for 315 single units. A subset of these units had very regular spiking patterns with spike frequencies predominantly in the alpha band (8-14 Hz). The stability of the neuronal recordings was assessed with a novel analysis that identified units by their mean spike waveform and by the spike-triggered average of activity on all other electrodes in the array. Fifty-six identified neurons were observed over two or more sessions and in a few cases for as long as 1 mo. RFs of stable neurons were largely consistent across days. The results demonstrate that a chronic DCN implant in a macaque can be safe and effective, yielding high-quality unit recording for several months. The unprecedented access to these nuclei in awake primates should lead to a better understanding of their role in sensorimotor behavior.
Somatosensory encoding with cuneate nucleus microstimulation: Detection of artificial stimuli
Author(s): Sritharan, SY; Richardson, AG; Weigand, PK; Planell-Mendez, I; Xilin Liu, ; Hongjie Zhu, ; Milin Zhang, ; Van der Spiegel, J; Lucas, TH
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The sense of touch and proprioception are critical to movement control. After spinal cord injury, these senses may be restored with direct, electrical microstimulation of the brain as part of a complete sensorimotor neuroprosthesis. The present study was designed to test, in part, the hypothesis that the cuneate nucleus (CN) of the brainstem is a suitable site to encode somatosensory information. Two rhesus macaques were implanted with microelectrode arrays providing chronic access to the CN. The monkeys were trained on an active touch oddity task to detect vibrotactile stimuli. When the vibrotactile stimuli were replaced with electrical stimuli delivered to the CN, initial detection probabilities were near chance. Detection performance improved over time, reaching a plateau after about 10 daily sessions. At plateau performance, the monkeys exhibited detection probabilities that were 68-80% higher than the chance probability. Finally, detection probability was quantified as a function of stimulus amplitude. The resulting psychometric curve showed a detection threshold of 45 μA for 100-Hz stimulus trains. These behavioral data are the first to show that artificial CN activation is sufficient for perception. The results are consistent with our hypothesis and motivate future tests of the CN as a somatosensory encoding site.
Implantation and testing of WFMA stimulators in macaque
Author(s): Trovk, PR; Frim, D; Roitberg, B; Towle, VL; Takahashi, K; Suh, S; Bak, M; Bredeson, S; Zhe Hu
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Our on-going work to develop an intracortical visual prosthesis has motivated the design, fabrication, and testing of a Wireless Floating Microelectrode Array (WFMA) stimulator. This implantable device can be used for an electrical stimulation interface in the peripheral and the central nervous system. Previously, its use in a sciatic nerve rodent model was described. Here implantation of two WFMAs in motor cortex of two NHP (macaque - two devices/animal) is presented. Preliminary functional tests show the implanted devices to be fully functional with stimulation-induced motor movements obtained. Functional testing is on-going.
Decoding a wide range of hand configurations from macaque motor, premotor, and parietal cortices
Author(s): Schaffelhofer, S; Agudelo-Toro, A; Scherberger, H
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Despite recent advances in decoding cortical activity for motor control, the development of hand prosthetics remains a major challenge. To reduce the complexity of such applications, higher cortical areas that also represent motor plans rather than just the individual movements might be advantageous. We investigated the decoding of many grip types using spiking activity from the anterior intraparietal (AIP), ventral premotor (F5), and primary motor (M1) cortices. Two rhesus monkeys were trained to grasp 50 objects in a delayed task while hand kinematics and spiking activity from six implanted electrode arrays (total of 192 electrodes) were recorded. Offline, we determined 20 grip types from the kinematic data and decoded these hand configurations and the grasped objects with a simple Bayesian classifier. When decoding from AIP, F5, and M1 combined, the mean accuracy was 50% (using planning activity) and 62% (during motor execution) for predicting the 50 objects (chance level, 2%) and substantially larger when predicting the 20 grip types (planning, 74%; execution, 86%; chance level, 5%). When decoding from individual arrays, objects and grip types could be predicted well during movement planning from AIP (medial array) and F5 (lateral array), whereas M1 predictions were poor. In contrast, predictions during movement execution were best from M1, whereas F5 performed only slightly worse. These results demonstrate for the first time that a large number of grip types can be decoded from higher cortical areas during movement preparation and execution, which could be relevant for future neuroprosthetic devices that decode motor plans.
Representation of continuous hand and arm movements in macaque areas M1, F5, and AIP: a comparative decoding study.
Author(s): Menz, VK; Schaffelhofer, S; Scherberger, H
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In the last decade, multiple brain areas have been investigated with respect to their decoding capability of continuous arm or hand movements. So far, these studies have mainly focused on motor or premotor areas like M1 and F5. However, there is accumulating evidence that anterior intraparietal area (AIP) in the parietal cortex also contains information about continuous movement.
Smoothness as a failure mode of Bayesian mixture models in brain-machine interfaces
Author(s): Yousefi, S; Wein, A; Kowalski, KC; Richardson, AG; Srinivasan, L
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Various recursive Bayesian filters based on reach state equations (RSE) have been proposed to convert neural signals into reaching movements in brain-machine interfaces. When the target is known, RSE produce exquisitely smooth trajectories relative to the random walk prior in the basic Kalman filter. More realistically, the target is unknown, and gaze analysis or other side information is expected to provide a discrete set of potential targets. In anticipation of this scenario, various groups have implemented RSE-based mixture (hybrid) models, which define a discrete random variable to represent target identity. While principled, this approach sacrifices the smoothness of RSE with known targets. This paper combines empirical spiking data from primary motor cortex and mathematical analysis to explain this loss in performance. We focus on angular velocity as a meaningful and convenient measure of smoothness. Our results demonstrate that angular velocity in the trajectory is approximately proportional to change in target probability. The constant of proportionality equals the difference in heading between parallel filters from the two most probable targets, suggesting a smoothness benefit to more narrowly spaced targets. Simulation confirms that measures to smooth the data likelihood also improve the smoothness of hybrid trajectories, including increased ensemble size and uniformity in preferred directions. We speculate that closed-loop training or neuronal subset selection could be used to shape the user's tuning curves towards this end.
Chronic and low charge injection wireless intraneural stimulation in vivo
Author(s): Romero-Ortega, M; Kanneganti, A; Bendale, G; Seifert, J; Bredeson, S; Troyk, P; Deku, F; Cogan, S
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Functional stability and in-vivo reliability are significant factors determining the longevity of a neural interface. In this ongoing study, we test the performance of a wireless floating microelectrode array (WFMA) over a period of 143 days. The topography of the microelectrodes has allowed for selective stimulation of different fascicles of the rat sciatic nerve. We confirmed that motor evoked thresholds remain stable over time and that the nerve stimulation charges were within tissue safety limits. Importantly, motor evoked responses were elicited at threshold currents in fully awake animals without causing pain or discomfort. These data validate the use of the WFMA system for intraneural interfacing of peripheral nerves for neuroprosthetic and bioelectronics medical applications.
In Vivo Electrochemical Analysis of a PEDOT/MWCNT Neural Electrode Coating
Author(s): Alba, NA; Du, ZJ; Catt, KA; Kozai, TD; Cui, XT
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Neural electrodes hold tremendous potential for improving understanding of brain function and restoring lost neurological functions. Multi-walled carbon nanotube (MWCNT) and dexamethasone (Dex)-doped poly(3,4-ethylenedioxythiophene) (PEDOT) coatings have shown promise to improve chronic neural electrode performance. Here, we employ electrochemical techniques to characterize the coating in vivo. Coated and uncoated electrode arrays were implanted into rat visual cortex and subjected to daily cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) for 11 days. Coated electrodes experienced a significant decrease in 1 kHz impedance within the first two days of implantation followed by an increase between days 4 and 7. Equivalent circuit analysis showed that the impedance increase is the result of surface capacitance reduction, likely due to protein and cellular processes encapsulating the porous coating. Coating's charge storage capacity remained consistently higher than uncoated electrodes, demonstrating its in vivo electrochemical stability. To decouple the PEDOT/MWCNT material property changes from the tissue response, in vitro characterization was conducted by soaking the coated electrodes in PBS for 11 days. Some coated electrodes exhibited steady impedance while others exhibiting large increases associated with large decreases in charge storage capacity suggesting delamination in PBS. This was not observed in vivo, as scanning electron microscopy of explants verified the integrity of the coating with no sign of delamination or cracking. Despite the impedance increase, coated electrodes successfully recorded neural activity throughout the implantation period.
Sensitivity to microstimulation of somatosensory cortex distributed over multiple electrodes
Author(s): Kim, S; Callier, T; Tabot, GA; Tenore, FV; Bensmaia, SJ
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Meaningful and repeatable tactile sensations can be evoked by electrically stimulating primary somatosensory cortex. Intracortical microstimulation (ICMS) may thus be a viable approach to restore the sense of touch in individuals who have lost it, for example tetraplegic patients. One of the potential limitations of this approach, however, is that high levels of current can damage the neuronal tissue if the resulting current densities are too high. The limited range of safe ICMS amplitudes thus limits the dynamic range of ICMS-evoked sensations. One way to get around this limitation would be to distribute the ICMS over multiple electrodes in the hopes of intensifying the resulting percept without increasing the current density experienced by the neuronal tissue. Here, we test whether stimulating through multiple electrodes is a viable solution to increase the dynamic range of ICMS-elicited sensations without increasing the peak current density. To this end, we compare the ability of non-human primates to detect ICMS delivered through one vs. multiple electrodes. We also compare their ability to discriminate pulse trains differing in amplitude when these are delivered through one or more electrodes. We find that increasing the number of electrodes through which ICMS is delivered only has a marginal effect on detectability or discriminability despite the fact that 2-4 times more current is delivered overall. Furthermore, the impact of multielectrode stimulation (or lack thereof) is found whether pulses are delivered synchronously or asynchronously, whether the leading phase of the pulses is cathodic or anodic, and regardless of the spatial configuration of the electrode groups.
Experimental validation of a primary afferent based somatosensory neuroprosthesis
Author(s): Ayers, CA
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… Floating microelectrode arrays. 38. (Microprobes for Life Science, Gaithersburg, MD, USA) were implanted chronically in the L6 and L7 DRG of four cats and the stability and selectivity of the response to stimulation was monitored for up to six months after implantation  …
Predicting Reaction Time from the Neural State Space of the Premotor and Parietal Grasping Network
Author(s): Michaels, JA; Dann, B; Intveld, RW; Scherberger, H
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Neural networks of the brain involved in the planning and execution of grasping movements are not fully understood. The network formed by macaque anterior intraparietal area (AIP) and hand area (F5) of the ventral premotor cortex is implicated strongly in the generation of grasping movements. However, the differential role of each area in this frontoparietal network is unclear. We recorded spiking activity from many electrodes in parallel in AIP and F5 while three macaque monkeys (Macaca mulatta) performed a delayed grasping task. By analyzing neural population activity during action preparation, we found that state space analysis of simultaneously recorded units is significantly more predictive of subsequent reaction times (RTs) than traditional methods. Furthermore, because we observed a wide variety of individual unit characteristics, we developed the sign-corrected average rate (SCAR) method of neural population averaging. The SCAR method was able to explain at least as much variance in RT overall as state space methods. Overall, F5 activity predicted RT (18% variance explained) significantly better than AIP (6%). The SCAR methods provides a straightforward interpretation of population activity, although other state space methods could provide richer descriptions of population dynamics. Together, these results lend support to the differential role of the parietal and frontal cortices in preparation for grasping, suggesting that variability in preparatory activity in F5 has a more potent effect on trial-to-trial RT variability than AIP. Grasping movements are planned before they are executed, but how is the preparatory activity in a population of neurons related to the subsequent reaction time (RT)? A population analysis of the activity of many neurons recorded in parallel in macaque premotor (F5) and parietal (AIP) cortices during a delayed grasping task revealed that preparatory activity in F5 could explain a threefold larger fraction of variability in trial-to-trial RT than AIP. These striking differences lend additional support to a differential role of the parietal and premotor cortices in grasp movement preparation, suggesting that F5 has a more direct influence on trial-to-trial variability and movement timing, whereas AIP might be more closely linked to overall movement intentions.
Behavioral assessment of sensitivity to intracortical microstimulation of primate somatosensory cortex
Author(s): Kim, S; Callier, T; Tabot, GA; Gaunt, RA; Tenore, FV; Bensmaia, SJ
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Intracortical microstimulation (ICMS) is a powerful tool to investigate the functional role of neural circuits and may provide a means to restore sensation for patients for whom peripheral stimulation is not an option. In a series of psychophysical experiments with nonhuman primates, we investigate how stimulation parameters affect behavioral sensitivity to ICMS. Specifically, we deliver ICMS to primary somatosensory cortex through chronically implanted electrode arrays across a wide range of stimulation regimes. First, we investigate how the detectability of ICMS depends on stimulation parameters, including pulse width, frequency, amplitude, and pulse train duration. Then, we characterize the degree to which ICMS pulse trains that differ in amplitude lead to discriminable percepts across the range of perceptible and safe amplitudes. We also investigate how discriminability of pulse amplitude is modulated by other stimulation parameters-namely, frequency and duration. Perceptual judgments obtained across these various conditions will inform the design of stimulation regimes for neuroscience and neuroengineering applications.
Generalized analog thresholding for spike acquisition at ultralow sampling rates
Author(s): He, BD; Wein, A; Varshney, LR; Kusuma, J; Richardson, AG; Srinivasan, L
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Efficient spike acquisition techniques are needed to bridge the divide from creating large multielectrode arrays (MEA) to achieving whole-cortex electrophysiology. In this paper, we introduce generalized analog thresholding (gAT), which achieves millisecond temporal resolution with sampling rates as low as 10 Hz. Consider the torrent of data from a single 1,000-channel MEA, which would generate more than 3 GB/min using standard 30-kHz Nyquist sampling. Recent neural signal processing methods based on compressive sensing still require Nyquist sampling as a first step and use iterative methods to reconstruct spikes. Analog thresholding (AT) remains the best existing alternative, where spike waveforms are passed through an analog comparator and sampled at 1 kHz, with instant spike reconstruction. By generalizing AT, the new method reduces sampling rates another order of magnitude, detects more than one spike per interval, and reconstructs spike width. Unlike compressive sensing, the new method reveals a simple closed-form solution to achieve instant (noniterative) spike reconstruction. The base method is already robust to hardware nonidealities, including realistic quantization error and integration noise. Because it achieves these considerable specifications using hardware-friendly components like integrators and comparators, generalized AT could translate large-scale MEAs into implantable devices for scientific investigation and medical technology.
Chronic recruitment of primary afferent neurons by microstimulation in the feline dorsal root ganglia.
Author(s): Fisher, LE; Ayers, CA; Ciollaro, M; Ventura, V; Weber, DJ; Gaunt, RA
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This study describes results of primary afferent neural microstimulation experiments using microelectrode arrays implanted chronically in the lumbar dorsal root ganglia (DRG) of four cats. The goal was to test the stability and selectivity of these microelectrode arrays as a potential interface for restoration of somatosensory feedback after damage to the nervous system such as amputation.
Principal components of hand kinematics and neurophysiological signals in motor cortex during reach to grasp movements
Author(s): Mollazadeh, M; Aggarwal, V; Thakor, NV; Schieber, MH
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A few kinematic synergies identified by principal component analysis (PCA) account for most of the variance in the coordinated joint rotations of the fingers and wrist used for a wide variety of hand movements. To examine the possibility that motor cortex might control the hand through such synergies, we collected simultaneous kinematic and neurophysiological data from monkeys performing a reach-to-grasp task. We used PCA, jPCA and isomap to extract kinematic synergies from 18 joint angles in the fingers and wrist and analyzed the relationships of both single-unit and multiunit spike recordings, as well as local field potentials (LFPs), to these synergies. For most spike recordings, the maximal absolute cross-correlations of firing rates were somewhat stronger with an individual joint angle than with any principal component (PC), any jPC or any isomap dimension. In decoding analyses, where spikes and LFP power in the 100- to 170-Hz band each provided better decoding than other LFP-based signals, the first PC was decoded as well as the best decoded joint angle. But the remaining PCs and jPCs were predicted with lower accuracy than individual joint angles. Although PCs, jPCs or isomap dimensions might provide a more parsimonious description of kinematics, our findings indicate that the kinematic synergies identified with these techniques are not represented in motor cortex more strongly than the original joint angles. We suggest that the motor cortex might act to sculpt the synergies generated by subcortical centers, superimposing an ability to individuate finger movements and adapt the hand to grasp a wide variety of objects.
Rapid acquisition of novel interface control by small ensembles of arbitrarily selected primary motor cortex neurons
Author(s): Law, AJ; Rivlis, G; Schieber, MH
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Pioneering studies demonstrated that novel degrees of freedom could be controlled individually by directly encoding the firing rate of single motor cortex neurons, without regard to each neuron's role in controlling movement of the native limb. In contrast, recent brain-computer interface work has emphasized decoding outputs from large ensembles that include substantially more neurons than the number of degrees of freedom being controlled. To bridge the gap between direct encoding by single neurons and decoding output from large ensembles, we studied monkeys controlling one degree of freedom by comodulating up to four arbitrarily selected motor cortex neurons. Performance typically exceeded random quite early in single sessions and then continued to improve to different degrees in different sessions. We therefore examined factors that might affect performance. Performance improved with larger ensembles. In contrast, other factors that might have reflected preexisting synaptic architecture-such as the similarity of preferred directions-had little if any effect on performance. Patterns of comodulation among ensemble neurons became more consistent across trials as performance improved over single sessions. Compared with the ensemble neurons, other simultaneously recorded neurons showed less modulation. Patterns of voluntarily comodulated firing among small numbers of arbitrarily selected primary motor cortex (M1) neurons thus can be found and improved rapidly, with little constraint based on the normal relationships of the individual neurons to native limb movement. This rapid flexibility in relationships among M1 neurons may in part underlie our ability to learn new movements and improve motor skill.
Predicting hand orientation in reach-to-grasp tasks using neural activities from primary motor cortex
Author(s): Zhang, P; Ma, X; Huang, H; He, J
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Hand orientation is an important control parameter during reach-to-grasp task. In this paper, we presented a study for predicting hand orientation of non-human primate by decoding neural activities from primary motor cortex (M1). A non-human primate subject was guided to do reaching and grasping tasks meanwhile neural activities were acquired by chronically implanted microelectrode arrays. A Support Vector Machines (SVMs) classifier has been trained for predicting three different hand orientations using these M1 neural activities. Different number of neurons were selected and analyzed; the classifying accuracy was 94.1% with 2 neurons and was 100% with 8 neurons. Data from highly event related neuron units contribute a lot to the accuracy of hand orientation prediction. These results indicate that three different hand orientations can be predicted accurately and effectively before the actual movements occurring with a small number of related neurons in M1.
On the asynchronously continuous control of mobile robot movement by motor cortical spiking activity
Author(s): Xu, Z; So, RQ; Toe, KK; Ang, KK; Guan, C
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This paper presents an asynchronously intracortical brain-computer interface (BCI) which allows the subject to continuously drive a mobile robot. This system has a great implication for disabled patients to move around. By carefully designing a multiclass support vector machine (SVM), the subject's self-paced instantaneous movement intents are continuously decoded to control the mobile robot. In particular, we studied the stability of the neural representation of the movement directions. Experimental results on the nonhuman primate showed that the overt movement directions were stably represented in ensemble of recorded units, and our SVM classifier could successfully decode such movements continuously along the desired movement path. However, the neural representation of the stop state for the self-paced control was not stably represented and could drift.
A study of predicting movement intentions in various spatial reaching tasks from M1 neural activities
Author(s): Ma, X; Zhang, P; Huang, H; He, J
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Understanding how M1 neurons innervate flexible coordinated upper limb reaching and grasping is important for BMI systems that attempt to reproduce the same actions. In this paper, we presented a study for exploring M1 neuronal activities while a non-human primate subject was guided to finish different visual cued spatial reaching and grasping tasks. By applying various configurations of target objects in the experiment paradigm, we can make thorough investigations on how neural ensemble activities represented subjects' intentions in different task-related time stages when target objects' properties, including shape, position, orientation, varied. Extracted neuron units were categorized according to their event related attributes. The prediction of subjects' movement intentions was completed with a support vector machine (SVM) based method and a simulated on-line test was performed to illustrate the validation of the proposed method. The results showed that, by M1 neural ensemble spike train signals, correct prediction of subject's intentions can be generated in certain time intervals before the movements were actually executed.
Chronic sensory-motor activity in behaving animals using regenerative multi-electrode interfaces
Author(s): Desai, VH; Anand, S; Tran, M; Kanneganti, A; Vasudevan, S; Seifert, JL; Cheng, J; Keefer, EW; Romero-Ortega, MI
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Regenerative peripheral nerve interfaces have been proposed as viable alternatives for the natural control and feel of robotic prosthetic limbs. We have developed a Regenerative Multi-electrode Interface (REMI) that guides re-growing axons through an electrode array deployed in the lumen of a nerve guide. While acute studies have shown the use of the REMI in the rat sciatic nerve, the quality of chronic signal recording has not been reported. Here we show that implantation of this interface in the sciatic nerve is stable with high quality recordings up to 120 days and failures mainly attributable to abiotic factors related to pedestal detachment and wire breakage. We further tested the interfacing of REMI with fascicles of the sciatic nerve that primarily innervate muscles (tibial) and skin (sural). When implanted into the tibial nerve, bursting activity was observed synchronous to stepping. However, implantation of REMI into the sural nerve failed due to its small size. While fascicles smaller than 300 μm are a challenge for regenerative interfacing, we show that a modified REMI can be used in an insertion mode to record sensory signals from skin. In summary, the REMI represents an effective tool for recording firing patterns of specific axon types during voluntary movement, which may be used to improve the motor control and sensory feedback in closed loop control systems for robotic prosthesis.
Abiotic-biotic characterization of Pt/Ir microelectrode arrays in chronic implants
Author(s): Prasad, A; Xue, QS; Dieme, R; Sankar, V; Mayrand, RC; Nishida, T; Streit, WJ; Sanchez, JC
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Pt/Ir electrodes have been extensively used in neurophysiology research in recent years as they provide a more inert recording surface as compared to tungsten or stainless steel. While floating microelectrode arrays (FMA) consisting of Pt/Ir electrodes are an option for neuroprosthetic applications, long-term in vivo functional performance characterization of these FMAs is lacking. In this study, we have performed comprehensive abiotic-biotic characterization of Pt/Ir arrays in 12 rats with implant periods ranging from 1 week up to 6 months. Each of the FMAs consisted of 16-channel, 1.5 mm long, and 75 μm diameter microwires with tapered tips that were implanted into the somatosensory cortex. Abiotic characterization included (1) pre-implant and post-explant scanning electron microscopy (SEM) to study recording site changes, insulation delamination and cracking, and (2) chronic in vivo electrode impedance spectroscopy. Biotic characterization included study of microglial responses using a panel of antibodies, such as Iba1, ED1, and anti-ferritin, the latter being indicative of blood-brain barrier (BBB) disruption. Significant structural variation was observed pre-implantation among the arrays in the form of irregular insulation, cracks in insulation/recording surface, and insulation delamination. We observed delamination and cracking of insulation in almost all electrodes post-implantation. These changes altered the electrochemical surface area of the electrodes and resulted in declining impedance over the long-term due to formation of electrical leakage pathways. In general, the decline in impedance corresponded with poor electrode functional performance, which was quantified via electrode yield. Our abiotic results suggest that manufacturing variability and insulation material as an important factor contributing to electrode failure. Biotic results show that electrode performance was not correlated with microglial activation (neuroinflammation) as we were able to observe poor performance in the absence of neuroinflammation, as well as good performance in the presence of neuroinflammation. One biotic change that correlated well with poor electrode performance was intraparenchymal bleeding, which was evident macroscopically in some rats and presented microscopically by intense ferritin immunoreactivity in microglia/macrophages. Thus, we currently consider intraparenchymal bleeding, suboptimal electrode fabrication, and insulation delamination as the major factors contributing toward electrode failure.
Microelectrode array recordings from the ventral roots in chronically implanted cats
Author(s): Debnath, S; Bauman, MJ; Fisher, LE; Weber, DJ; Gaunt, RA
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The ventral spinal roots contain the axons of spinal motoneurons and provide the only location in the peripheral nervous system where recorded neural activity can be assured to be motor rather than sensory. This study demonstrates recordings of single unit activity from these ventral root axons using floating microelectrode arrays (FMAs). Ventral root recordings were characterized by examining single unit yield and signal-to-noise ratios (SNR) with 32-channel FMAs implanted chronically in the L6 and L7 spinal roots of nine cats. Single unit recordings were performed for implant periods of up to 12 weeks. Motor units were identified based on active discharge during locomotion and inactivity under anesthesia. Motor unit yield and SNR were calculated for each electrode, and results were grouped by electrode site size, which were varied systematically between 25 and 160 μm to determine effects on signal quality. The unit yields and SNR did not differ significantly across this wide range of electrode sizes. Both SNR and yield decayed over time, but electrodes were able to record spikes with SNR > 2 up to 12 weeks post-implant. These results demonstrate that it is feasible to record single unit activity from multiple isolated motor units with penetrating microelectrode arrays implanted chronically in the ventral spinal roots. This approach could be useful for creating a spinal nerve interface for advanced neural prostheses, and results of this study will be used to improve design of microelectrodes for chronic neural recording in the ventral spinal roots.
Mathematical and Experimental Models for Studying Somatosensory Feedback via Primary Afferent Microstimulation
Author(s): Hokanson, JA
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For cat 2, both L6 and L7 were implanted with 32-channel floating microelectrode arrays (FMA, Microprobes Inc., Gaithersburg , MD).
Evaluation and use of regenerative multi electrode interfaces in peripheral nerves
Author(s): Desai, V
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… (a) Ceramic Base holding 18 Platinum electrodes of FMA. (b) REMI consisting of 18 pin Floating Micro-electrode Array (FMA) in a polyurethane conduit; Image source- Microprobes Inc. (c) (d) Utah Slanted Electrode Array (USEA) Scale Bar = 1mm  …
Evaluation Of Tissue Response From The Regenerative Multielectrode Array (REMI) Implant Using ATF-3 And cJun
Author(s): Bhetawal, S
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FMA were cust om made having the dimension of 2.45mm X 1.95 mm X 0.45 mm (Microprobes Inc. MD) and each FMA consists of 18 Platinum / Iridium (70 / 30 %) electrodes separated by 400 μm and height range from 0.7 mm to 1 mm to maximize the neuronal contacts at different p lanes.
Restoring the sense of touch with a prosthetic hand through a brain interface
Author(s): Tabot, GA; Dammann, JF; Berg, JA; Tenore, FV; Boback, JL; Vogelstein, RJ; Bensmaia, SJ
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Our ability to manipulate objects dexterously relies fundamentally on sensory signals originating from the hand. To restore motor function with upper-limb neuroprostheses requires that somatosensory feedback be provided to the tetraplegic patient or amputee. Given the complexity of state-of-the-art prosthetic limbs and, thus, the huge state space they can traverse, it is desirable to minimize the need for the patient to learn associations between events impinging on the limb and arbitrary sensations. Accordingly, we have developed approaches to intuitively convey sensory information that is critical for object manipulation--information about contact location, pressure, and timing--through intracortical microstimulation of primary somatosensory cortex. In experiments with nonhuman primates, we show that we can elicit percepts that are projected to a localized patch of skin and that track the pressure exerted on the skin. In a real-time application, we demonstrate that animals can perform a tactile discrimination task equally well whether mechanical stimuli are delivered to their native fingers or to a prosthetic one. Finally, we propose that the timing of contact events can be signaled through phasic intracortical microstimulation at the onset and offset of object contact that mimics the ubiquitous on and off responses observed in primary somatosensory cortex to complement slowly varying pressure-related feedback. We anticipate that the proposed biomimetic feedback will considerably increase the dexterity and embodiment of upper-limb neuroprostheses and will constitute an important step in restoring touch to individuals who have lost it.
State-based decoding of hand and finger kinematics using neuronal ensemble and LFP activity during dexterous reach-to-grasp movements.
Author(s): Aggarwal, V; Mollazadeh, M; Davidson, AG; Schieber, MH; Thakor, NV
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The performance of brain-machine interfaces (BMIs) that continuously control upper limb neuroprostheses may benefit from distinguishing periods of posture and movement so as to prevent inappropriate movement of the prosthesis. Few studies, however, have investigated how decoding behavioral states and detecting the transitions between posture and movement could be used autonomously to trigger a kinematic decoder. We recorded simultaneous neuronal ensemble and local field potential (LFP) activity from microelectrode arrays in primary motor cortex (M1) and dorsal (PMd) and ventral (PMv) premotor areas of two male rhesus monkeys performing a center-out reach-and-grasp task, while upper limb kinematics were tracked with a motion capture system with markers on the dorsal aspect of the forearm, hand, and fingers. A state decoder was trained to distinguish four behavioral states (baseline, reaction, movement, hold), while a kinematic decoder was trained to continuously decode hand end point position and 18 joint angles of the wrist and fingers. LFP amplitude most accurately predicted transition into the reaction (62%) and movement (73%) states, while spikes most accurately decoded arm, hand, and finger kinematics during movement. Using an LFP-based state decoder to trigger a spike-based kinematic decoder [r = 0.72, root mean squared error (RMSE) = 0.15] significantly improved decoding of reach-to-grasp movements from baseline to final hold, compared with either a spike-based state decoder combined with a spike-based kinematic decoder (r = 0.70, RMSE = 0.17) or a spike-based kinematic decoder alone (r = 0.67, RMSE = 0.17). Combining LFP-based state decoding with spike-based kinematic decoding may be a valuable step toward the realization of BMI control of a multifingered neuroprosthesis performing dexterous manipulation.
Neuroprosthetic technology for individuals with spinal cord injury
Author(s): Collinger, JL; Foldes, S; Bruns, TM; Wodlinger, B; Gaunt, R; Weber, DJ
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Spinal cord injury (SCI) results in a loss of function and sensation below the level of the lesion. Neuroprosthetic technology has been developed to help restore motor and autonomic functions as well as to provide sensory feedback. This paper provides an overview of neuroprosthetic technology that aims to address the priorities for functional restoration as defined by individuals with SCI. We describe neuroprostheses that are in various stages of preclinical development, clinical testing, and commercialization including functional electrical stimulators, epidural and intraspinal microstimulation, bladder neuroprosthesis, and cortical stimulation for restoring sensation. We also discuss neural recording technologies that may provide command or feedback signals for neuroprosthetic devices. Neuroprostheses have begun to address the priorities of individuals with SCI, although there remains room for improvement. In addition to continued technological improvements, closing the loop between the technology and the user may help provide intuitive device control with high levels of performance.
Comparison of Abiotic-Biotic Responses of Tungsten Microwires, Pt/Ir Floating Arrays, and Utah Arrays in Chronic Neural Implants
Author(s): Nishida, T; Shaw, G; Streit, W; Sanchez, JC
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Chronically implanted electrodes in the nervous syst em undergo temporal degradation in signal quality o ver time as they can be affected by both biotic and abiotic factors ultimately resulting in electrode failure [1]. An i nterplay of these time varying factors affect the functional performance o f implanted electrodes on different time scales ran ging from hours and days following implantation surgery [2, 3]. We have been studying this time-varying relationship of th e various electrode failure modes for three electrode types commonly us ed in humans, primates and rodents in a well -contro lled surgical and testing environment designed for chronic electrode evaluation [4, 5]. In this study, we provide a comp rehensive comparison between the electrodes to serve as an aid for choos ing electrode types and materials in neuroprostheti c research. In this work, we focused on detailed abiotic and biotic character ization of tungsten microwires (Tucker Davis Techno logies, Alachua FL) in 25 rats, Pt/Ir floating microelectrode arrays (Mic roProbe, Gaithersburg MD) in 15 rats, and silicon sh ank arrays (Blackroc k Microsystems, UT) in 10 rats. Abiotic characterizat ion was performed via evaluation of pre-implant and post-explant scanning electron microscope (SEM) images of electr ode recording sites to evaluate morphological chang es at the electrode recording sites, corrosion, and insulation delamina tion for all electrodes. Electrical characterization was performed through daily electrode impedance spectroscopy before each recording session to provide insights into the dyna mic nature of the electrode-tissue interface. Biotic characterization was performed via post-mortem histopathology to as sess blood brain barrier (BBB) disruption, and microglial activation and deg eneration. Finally, we coupled the chronic electrod e functional performance (array yield, signal-to-noise ratio) wi th the abiotic and biotic responses to provide a mo re complete understanding of these interactions during the chro nic lifetime of an electrode in the neural tissue. Comprehensive electrode characterization suggested that electrode recording characteristics are related to changes in impedanc e spectra and future electrode performance can be predicted using given impedance values. Abiotic analysis indicated progres sive increases in electrode impedance in the first 2-3 weeks followin g implant where large changes in complex impedance spectra corresponded with poor electrode performance during this period. The Pt/Ir arrays exhibited greater dai ly variation in electrode impedance as compared to both the Utah ar rays and the tungsten microwires. Post-explant SEM i maging indicated tungsten microwires were more prone to corrosion an d insulation damage even on short-time scales of fe w weeks as compared to Pt/Ir arrays which indicated reduced cor rosion and insulation damage even for the longest-t erm animals (6- months). Histopathology indicated that in general, there was reduced expression of microglial markers (Iba1, ED1) and ferritin (marker for BBB disruption) for the Pt/Ir a rrays as compared to the tungsten microwire arrays. Functional performance for the Utah arrays was poor (70% yield) and compar able among animals for both tungsten microwires and Pt/Ir arrays .
A new method of accurate hand- and arm-tracking for small primates.
Author(s): Schaffelhofer, S; Scherberger, H
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The investigation of grasping movements in cortical motor areas depends heavily on the measurement of hand kinematics. Currently used methods for small primates need either a large number of sensors or provide insufficient accuracy. Here, we present both a novel glove based on electromagnetic tracking sensors that can operate at a rate of 100 Hz and a new modeling method that allows to monitor 27 degrees of freedom (DOF) of the hand and arm using only seven sensors. A rhesus macaque was trained to wear the glove while performing precision and power grips during a delayed grasping task in the dark without noticeable hindrance. During five recording sessions all 27 joint angles and their positions could be tracked reliably. Furthermore, the field generator did not interfere with electrophysiological recordings below 1 kHz and did not affect single-cell separation. Measurements with the glove proved to be accurate during static and dynamic testing (mean absolute error below 2° and 3°, respectively). This makes the glove a suitable solution for characterizing electrophysiological signals with respect to hand grasping and in particular for brain-machine interface applications.
Activity of the same motor cortex neurons during repeated experience with perturbed movement dynamics.
Author(s): Richardson, AG; Borghi, T; Bizzi, E
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Neurons in the primary motor cortex (M1) have been shown to have persistent, memory-like activity following adaptation to altered movement dynamics. However, the techniques used to study these memory traces limited recordings to only single sessions lasting no more than a few hours. Here, chronically implanted microelectrode arrays were used to study the long-term neuronal responses to repeated experience with perturbing, velocity-dependent force fields. Force-field-related neuronal activity within each session was similar to that found previously. That is, the directional tuning curves of the M1 neurons shifted in a manner appropriate to compensate for the forces. Next, the across-session behavior was examined. Long-term learning was evident in the performance improvements across multiple force-field sessions. Correlated with this change, the neuronal population had smaller within-session spike rate changes as experience with the force field increased. The smaller within-session changes were a result of persistent across-session shifts in directional tuning. The results extend the observation of memory traces of newly learned dynamics and provide further evidence for the role of M1 in early motor memory formation.
Normal molecular repair mechanisms in regenerative peripheral nerve interfaces allow recording of early spike activity despite immature myelination
Author(s): Seifert, JL; Desai, V; Watson, RC; Musa, T; Kim, YT; Keefer, EW; Romero, MI
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Clinical use of neurally controlled prosthetics has advanced in recent years, but limitations still remain, including lacking fine motor control and sensory feedback. Indwelling multi-electrode arrays, cuff electrodes, and regenerative sieve electrodes have been reported to serve as peripheral neural interfaces, though long-term stability of the nerve-electrode interface has remained a formidable challenge. We recently developed a regenerative multi-electrode interface (REMI) that is able to record neural activity as early as seven days post-implantation. While this activity might represent normal neural depolarization during axonal regrowth, it can also be the result of altered nerve regeneration around the REMI. This study evaluated high-throughput expression levels of 84 genes involved in nerve injury and repair, and the histological changes that occur in parallel to this early neural activity. Animals exhibiting spike activity increased from 29% to 57% from 7 to 14 days following REMI implantation with a corresponding increase in firing rate of 113%. Two weeks after implantation, numbers of neurofilament-positive axons in the control and REMI implanted nerves were comparable, and in both cases the number of myelinated axons was low. During this time, expression levels of genes related to nerve injury and repair were similar in regenerated nerves, both in the presence or absence of the electrode array. Together, these results indicate that the early neural activity is intrinsic to the regenerating axons, and not induced by the REMI neurointerface.
A real time brain machine interface for hand grasping via signals from higher order cortical areas
Author(s): SubaÅ, E
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After recovery from this procedure, and subsequent training of the task in the head-fixed condition, each animal was implanted with floating microelectrode arrays (FMAs, Microprobe Inc, Gaithersburg, MD, USA) in a separate procedure.
Cortical control of intraspinal microstimulation to restore motor function after paralysis
Author(s): Zimmermann, JB
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Additionally, a Ęoating microelectrode array (FMA; MicroProbes, Gaithersburg, MD, USA) – consisting of  platinum/iridium electrodes, im- pedance ∼  kΩ, array size . × . mm  , electrode length – mm, diameter  μm – was implanted into the cords of monkeys Ti and X (cf. section ..). ISMS was delivered ac- cording to three stimulation sequences:
A floating 3D silicon microprobe array for neural drug delivery compatible with electrical recording
Author(s): Spieth, S; Brett, O; Seidl, K; Aarts, AA; Erismis, MA; Herwik, S; Trenkle, F; Tätzner, S; Auber, J; Daub, M
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This paper reports on the design, fabrication, assembly and characterization of a three-dimensional silicon-based floating microprobe array for localized drug delivery to be applied in neuroscience research. The microprobe array is composed of a silicon platform into which up to four silicon probe combs with needle-like probe shafts can be inserted. Two dedicated positions in the array allow the integration of combs for drug delivery. The implemented comb variants feature 8 mm long probe shafts with two individually addressable microchannels incorporated in a single shaft or distributed to two shafts. Liquid supply to the array is realized by a highly flexible 250 µm thick multi-lumen microfluidic cable made from polydimethylsiloxane (PDMS). The specific design concept of the slim-base platform enables floating implantation of the array in the small space between brain and skull. In turn, the flexible cable mechanically decouples the array from any microfluidic interface rigidly fixed to the skull. After assembly of the array, full functionality is demonstrated and characterized at infusion rates from 1 to 5 µL min−1. Further, the effect of a parylene-C coating on the water vapour and osmotic liquid water transport through the PDMS cable walls is experimentally evaluated by determining the respective transmission rates including the water vapour permeability of the used PDMS type.
Integrated neural systems and algorithms for analysis of population activity during dexterous hand movements
Author(s): Mollazadeh, M
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… 2.2.2 Microelectrode Array Implantation. Using sterile technique and isoflorane anesthesia, each monkey was implanted withmultiple floating microelectrode arrays (FMAs, MicroProbes, Gaithersburg, MD) in corti¬cal motor areas of the left hemisphere  …
An information transmission measure for the analysis of effective connectivity among cortical neurons
Author(s): Law, AJ; Sharma, G; Schieber, MH
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We present a methodology for detecting effective connections between simultaneously recorded neurons using an information transmission measure to identify the presence and direction of information flow from one neuron to another. Using simulated and experimentally-measured data, we evaluate the performance of our proposed method and compare it to the traditional transfer entropy approach. In simulations, our measure of information transmission outperforms transfer entropy in identifying the effective connectivity structure of a neuron ensemble. For experimentally recorded data, where ground truth is unavailable, the proposed method also yields a more plausible effective connectivity structure than transfer entropy.
In search of more robust decoding algorithms for neural prostheses, a data driven approach
Author(s): Subasi, E; Townsend, B; Scherberger, H
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In the past decade the field of neural interface systems has enjoyed an increase in attention from the scientific community and the general public, in part due to the enormous potential that such systems have to increase the quality of life for paralyzed patients. While significant progress has been made, serious challenges remain to be addressed from both biological and engineering perspectives. A key issue is how to optimize the decoding of neural information, such that neural signals are correctly mapped to effectors that interact with the outside world - like robotic hands and limbs or the patient's own muscles. Here we present some recent progress on tackling this problem by applying the latest developments in machine learning. Neural data was collected from macaque monkeys performing a real-time hand grasp decoding task. Signals were recorded via chronically implanted electrodes in the anterior intraparietal cortex (AIP) and ventral premotor cortex (F5), brain areas that are known to be involved in the transformation of visual signals into hand grasping instructions. We present a comparative study of different classical machine learning methods with an application of decoding of hand postures, as well as a new approach for more robust decoding. Results suggests that combining data-driven algorithmic approaches with well-known parametric methods could lead to better performing and more robust learners, which may have direct implications for future clinical devices.
Quantification of Chronic Microelectrode Signal Quality over Time
Author(s): Sleight, TW
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… obtained from microelectrode arrays (16-channel, NeuroNexus, Inc, 16-channel, MicroProbes for Life Science) implanted chronically in the barrel cortex of adult rats. Signal to noise ratio of unit  … (A) Floating Microelectrode Array (MicroProbes for Life Science, Gaithersburg, MD)  …
Modulation of excitation on parvalbumin interneurons by neuroligin-3 regulates the hippocampal network
Author(s): Polepalli, JS; Wu, H; Goswami, D; Halpern, CH; Südhof, TC; Malenka, RC
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Hippocampal network activity is generated by a complex interplay between excitatory pyramidal cells and inhibitory interneurons. Although much is known about the molecular properties of excitatory synapses on pyramidal cells, comparatively little is known about excitatory synapses on interneurons. Here we show that conditional deletion of the postsynaptic cell adhesion molecule neuroligin-3 in parvalbumin interneurons causes a decrease in NMDA-receptor-mediated postsynaptic currents and an increase in presynaptic glutamate release probability by selectively impairing the inhibition of glutamate release by presynaptic Group III metabotropic glutamate receptors. As a result, the neuroligin-3 deletion altered network activity by reducing gamma oscillations and sharp wave ripples, changes associated with a decrease in extinction of contextual fear memories. These results demonstrate that neuroligin-3 specifies the properties of excitatory synapses on parvalbumin-containing interneurons by a retrograde trans-synaptic mechanism and suggest a molecular pathway whereby neuroligin-3 mutations contribute to neuropsychiatric disorders.
Refinement of learned skilled movement representation in motor cortex deep output layer
Author(s): Li, Q; Ko, H; Qian, ZM; Yan, LYC; Chan, DCW; Arbuthnott, G; Ke, Y; Yung, WH
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The mechanisms underlying the emergence of learned motor skill representation in primary motor cortex (M1) are not well understood. Specifically, how motor representation in the deep output layer 5b (L5b) is shaped by motor learning remains virtually unknown. In rats undergoing motor skill training, we detect a subpopulation of task-recruited L5b neurons that not only become more movement-encoding, but their activities are also more structured and temporally aligned to motor execution with a timescale of refinement in tens-of-milliseconds. Field potentials evoked at L5b in vivo exhibit persistent long-term potentiation (LTP) that parallels motor performance. Intracortical dopamine denervation impairs motor learning, and disrupts the LTP profile as well as the emergent neurodynamical properties of task-recruited L5b neurons. Thus, dopamine-dependent recruitment of L5b neuronal ensembles via synaptic reorganization may allow the motor cortex to generate more temporally structured, movement-encoding output signal from M1 to downstream circuitry that drives increased uniformity and precision of movement during motor learning.
An investigation of sub-cortical contributions to self-motion perception
Author(s): Paez, AD
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Dale and Cullen, 2013) was recorded using a linear microelectrode array (LMA; MicroProbes, Gaithersburg, MD) with eight 12.5μm - diameter recording sites (~1Mohm impedance) spaced 50μm apart (Figs. 3. 1A1, 3. 1B1).
Analysis of intrinsic cardiac neuron activity in relation to neurogenic atrial fibrillation and vagal stimulation
Author(s): Salavatian, S
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Following a transthoracic thoracotomy (T4), a pe ricardial cradle was formed. The activity generated by neurons located in the right atri al ganglionated plexus (RAGP) was recorded in situ by means of a multichannel linear microelectrode arra y (MicroProbes Inc., Guithersberg, MD).
Myocardial infarction induces structural and functional remodelling of the intrinsic cardiac nervous system
Author(s): Rajendran, PS; Nakamura, K; Ajijola, OA; Vaseghi, M; Armour, JA; Ardell, JL; Shivkumar, K
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Intrinsic cardiac (IC) neurons undergo differential morphological and phenotypic remodelling that reflects the site of myocardial infarction (MI). Afferent neural signals from the infarcted region to IC neurons are attenuated, while those from border and remote regions are preserved post-MI, giving rise to a 'neural sensory border zone'. Convergent IC local circuit (processing) neurons have enhanced transduction capacity following MI. Functional network connectivity within the intrinsic cardiac nervous system is reduced post-MI. MI reduces the response and alters the characteristics of IC neurons to ventricular pacing. Autonomic dysregulation following myocardial infarction (MI) is an important pathogenic event. The intrinsic cardiac nervous system (ICNS) is a neural network located on the heart that is critically involved in autonomic regulation. The aims of this study were to characterize structural and functional remodelling of the ICNS post-MI in a porcine model (control (n  =  16) vs. healed anteroapical MI (n  =  16)). In vivo  microelectrode recordings of basal activity, as well as responses to afferent and efferent stimuli, were recorded from intrinsic cardiac neurons. From control 118 neurons and from MI animals 102 neurons were functionally classified as afferent, efferent, or convergent (receiving both afferent and efferent inputs). In control and MI, convergent neurons represented the largest subpopulation (47% and 48%, respectively) and had enhanced transduction capacity following MI. Efferent inputs to neurons were maintained post-MI. Afferent inputs were attenuated from the infarcted region (19% in control vs. 7% in MI; P  =  0.03), creating a 'neural sensory border zone', or heterogeneity in afferent information. MI reduced transduction of changes in preload (54% in control vs. 41% in MI; P  =  0.05). The overall functional network connectivity, or the ability of neurons to respond to independent pairs of stimuli, within the ICNS was reduced following MI. The neuronal response was differentially decreased to ventricular vs. atrial pacing post-MI (63% in control vs. 44% in MI to ventricular pacing; P < 0. 01 ) . MI induced morphological and phenotypic changes within the ICNS. The alteration of afferent neural signals, and remodelling of convergent neurons, represents a 'neural signature' of ischaemic heart disease.
Vagal stimulation targets select populations of intrinsic cardiac neurons to control neurally induced atrial fibrillation
Author(s): Salavatian, S; Beaumont, E; Longpré, JP; Armour, JA; Vinet, A; Jacquemet, V; Shivkumar, K; Ardell, JL
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Mediastinal nerve stimulation (MNS) reproducibly evokes atrial fibrillation (AF) by excessive and heterogeneous activation of intrinsic cardiac (IC) neurons. This study evaluated whether preemptive vagus nerve stimulation (VNS) impacts MNS-induced evoked changes in IC neural network activity to thereby alter susceptibility to AF. IC neuronal activity in the right atrial ganglionated plexus was directly recorded in anesthetized canines (n = 8) using a linear microelectrode array concomitant with right atrial electrical activity in response to: 1) epicardial touch or great vessel occlusion vs. 2) stellate or vagal stimulation. From these stressors, post hoc analysis (based on the Skellam distribution) defined IC neurons so recorded as afferent, efferent, or convergent (afferent and efferent inputs) local circuit neurons (LCN). The capacity of right-sided MNS to modify IC activity in the induction of AF was determined before and after preemptive right (RCV)- vs. left (LCV)-sided VNS (15 Hz, 500 μs; 1.2× bradycardia threshold). Neuronal (n = 89) activity at baseline (0.11 ± 0.29 Hz) increased during MNS-induced AF (0.51 ± 1.30 Hz; P < 0.001). Convergent LCNs were preferentially activated by MNS. Preemptive RCV reduced MNS-induced changes in LCN activity (by 70%) while mitigating MNS-induced AF (by 75%). Preemptive LCV reduced LCN activity by 60% while mitigating AF potential by 40%. IC neuronal synchrony increased during neurally induced AF, a local neural network response mitigated by preemptive VNS. These antiarrhythmic effects persisted post-VNS for, on average, 26 min. In conclusion, VNS preferentially targets convergent LCNs and their interactive coherence to mitigate the potential for neurally induced AF. The antiarrhythmic properties imposed by VNS exhibit memory.
Gating of tactile information through gamma band during passive arm movement in awake primates
Author(s): Song, W; Francis, JT
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To make precise and prompt action in a dynamic environment, the sensorimotor system needs to integrate all related information. The inflow of somatosensory information to the cerebral cortex is regulated and mostly suppressed by movement, which is commonly referred to as sensory gating or gating. Sensory gating plays an important role in preventing redundant information from reaching the cortex, which should be considered when designing somatosensory neuroprosthetics. Gating can occur at several levels within the sensorimotor pathway, while the underlying mechanism is not yet fully understood. The average sensory evoked potential is commonly used to assess sensory information processing, however the assumption of a stereotyped response to each stimulus is still an open question. Event related spectral perturbation (ERSP), which is the power spectrum after time-frequency decomposition on single trial evoked potentials (total power), could overcome this limitation of averaging and provide additional information for understanding the underlying mechanism. To this aim, neural activities in primary somatosensory cortex (S1), primary motor cortex (M1), and ventral posterolateral (VPL) nucleus of thalamus were recorded simultaneously in two areas (S1 and M1 or S1 and VPL) during passive arm movement and rest in awake monkeys. Our results showed that neural activity at different recording areas demonstrated specific and unique response frequency characteristics. Tactile input induced early high frequency responses followed by low frequency oscillations within sensorimotor circuits, and passive movement suppressed these oscillations either in a phase-locked or non-phase-locked manner. Sensory gating by movement was non-phase-locked in M1, and complex in sensory areas. VPL showed gating of non-phase-locked at gamma band and mix of phase-locked and non-phase-locked at low frequency, while S1 showed gating of phase-locked and non-phase-locked at gamma band and an early phase-locked elevation followed by non-phase-locked gating at low frequency. Granger causality (GC) analysis showed bidirectional coupling between VPL and S1, while GC between M1 and S1 was not responsive to tactile input. Thus, these results suggest that tactile input is dominantly transmitted along the ascending direction from VPL to S1, and the sensory input is suppressed during movement through a bottom-up strategy within the gamma-band during passive movement.
Measure of synchrony in the activity of intrinsic cardiac neurons.
Author(s): Longpré, JP; Salavatian, S; Beaumont, E; Armour, JA; Ardell, JL; Jacquemet, V
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Recent multielectrode array recordings in ganglionated plexi of canine atria have opened the way to the study of population dynamics of intrinsic cardiac neurons. These data provide critical insights into the role of local processing that these ganglia play in the regulation of cardiac function. Low firing rates, marked non-stationarity, interplay with the cardiovascular and pulmonary systems and artifacts generated by myocardial activity create new constraints not present in brain recordings for which almost all neuronal analysis techniques have been developed. We adapted and extended the jitter-based synchrony index (SI) to (1) provide a robust and computationally efficient tool for assessing the level and statistical significance of SI between cardiac neurons, (2) estimate the bias on SI resulting from neuronal activity possibly hidden in myocardial artifacts, (3) quantify the synchrony or anti-synchrony between neuronal activity and the phase in the cardiac and respiratory cycles. The method was validated on firing time series from a total of 98 individual neurons identified in 8 dog experiments. SI ranged from -0.14 to 0.66, with 23 pairs of neurons with SI > 0.1. The estimated bias due to artifacts was typically < 1%. Strongly cardiovascular- and pulmonary-related neurons (SI > 0.5) were found. Results support the use of jitter-based SI in the context of intrinsic cardiac neurons.
Network interactions within the canine intrinsic cardiac nervous system: implications for reflex control of regional cardiac function
Author(s): Beaumont, E; Salavatian, S; Southerland, EM; Vinet, A; Jacquemet, V; Armour, JA; Ardell, JL
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The aims of the study were to determine how aggregates of intrinsic cardiac (IC) neurons transduce the cardiovascular milieu versus responding to changes in central neuronal drive and to determine IC network interactions subsequent to induced neural imbalances in the genesis of atrial fibrillation (AF). Activity from multiple IC neurons in the right atrial ganglionated plexus was recorded in eight anaesthetized canines using a 16-channel linear microelectrode array. Induced changes in IC neuronal activity were evaluated in response to: (1) focal cardiac mechanical distortion; (2) electrical activation of cervical vagi or stellate ganglia; (3) occlusion of the inferior vena cava or thoracic aorta; (4) transient ventricular ischaemia, and (5) neurally induced AF. Low level activity (ranging from 0 to 2.7 Hz) generated by 92 neurons was identified in basal states, activities that displayed functional interconnectivity. The majority (56%) of IC neurons so identified received indirect central inputs (vagus alone: 25%; stellate ganglion alone: 27%; both: 48%). Fifty per cent transduced the cardiac milieu responding to multimodal stressors applied to the great vessels or heart. Fifty per cent of IC neurons exhibited cardiac cycle periodicity, with activity occurring primarily in late diastole into isovolumetric contraction. Cardiac-related activity in IC neurons was primarily related to direct cardiac mechano-sensory inputs and indirect autonomic efferent inputs. In response to mediastinal nerve stimulation, most IC neurons became excessively activated; such network behaviour preceded and persisted throughout AF. It was concluded that stochastic interactions occur among IC local circuit neuronal populations in the control of regional cardiac function. Modulation of IC local circuit neuronal recruitment may represent a novel approach for the treatment of cardiac disease, including atrial arrhythmias.
Recording and identification of cardiac neuron activity in the right atrium ganglionated plexus
Author(s): Salavatian, S; Vinet, A; Beaumont, E; Armour, JA; Ardell, JL; Jacquemet, V
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Recent multichannel electrode array technology has enabled the simultaneous recording of multiple cardiac neurons located in ganglia on a beating heart. These new bioelectric signals are contaminated by the electrical activity of the atrial muscle just underneath. These atrial waveforms may mask relevant neuronal activity. In this paper, we evaluate the application of a principal component analysis technique to suppress atrial activity (AA) and reveal hidden neuronal activity. Neuronal signals were recorded in situ using a 16-channel electrode in an open-chest, anesthetized dog in sinus rhythm. Validation of AA cancellation was performed by comparing neuron spike waveforms extracted from within AA with those found in AA-free time intervals. Results showed that consistent neuronal waveforms can be identified within AA in order to improve the detection of neuron firings.
Oophorectomy Reduces Estradiol Levels and Long-Term Spontaneous Neurovascular Recovery in a Female Rat Model of Focal Ischemic Stroke
Author(s): Bazzigaluppi, P; Adams, C; Koletar, MM; Dorr, A; Pikula, A; Carlen, PL; Stefanovic, B
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Although epidemiological evidence suggests significant sex and gender-based differences in stroke risk and recovery, females have been widely under-represented in preclinical stroke research. The neurovascular sequelae of brain ischemia in females, in particular, are largely uncertain. We set out to address this gap by a multimodal in vivo study of neurovascular recovery from endothelin-1 model of cortical focal-stroke in sham vs. ovariectomized female rats. Three weeks post ischemic insult, sham operated females recapitulated the phenotype previously reported in male rats in this model, of normalized resting perfusion but sustained peri-lesional cerebrovascular hyperreactivity. In contrast, ovariectomized (Ovx) females showed reduced peri-lesional resting blood flow, and elevated cerebrovascular responsivity to hypercapnia in the peri-lesional and contra-lateral cortices. Electrophysiological recordings showed an attenuation of theta to low-gamma phase-amplitude coupling in the peri-lesional tissue of Ovx animals, despite relative preservation of neuronal power. Further, this chronic stage neuronal network dysfunction was inversely correlated with serum estradiol concentration. Our pioneering data demonstrate dramatic differences in spontaneous recovery in the neurovascular unit between Ovx and Sham females in the chronic stage of stroke, underscoring the importance of considering hormonal-dependent aspects of the ischemic sequelae in the development of novel therapeutic approaches and patient recruitment in clinical trials.
Long-term stability of neural signals from microwire arrays implanted in common marmoset motor cortex and striatum
Author(s): Debnath, S; Prins, N; Pohlmeyer, E; Mylavarapu, R; Geng, S; Sanchez, J; Prasad, A
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Current neuroprosthetics rely on stable, high quality recordings from chronically implanted microelectrode arrays (MEAs) in neural tissue. While chronic electrophysiological recordings and electrode failure modes have been reported from rodent and larger non-human primate (NHP) models, chronic recordings from the marmoset model have not been previously described. The common marmoset is a New World primate that is easier to breed and handle compared to larger NHPs and has a similarly organized brain, making it a potentially useful smaller NHP model for neuroscience studies. This study reports recording stability and signal quality of MEAs chronically implanted in behaving marmosets. Six adult male marmosets, trained for reaching tasks, were implanted with either a 16-channel tungsten microwire array (five animals) or a Pt-Ir floating MEA (one animal) in the hand-arm region of the primary motor cortex (M1) and another MEA in the striatum targeting the nucleus accumbens (NAcc). Signal stability and quality was quantified as a function of array yield (active electrodes that recorded action potentials), neuronal yield (isolated single units during a recording session), and signal-to-noise ratio (SNR). Out of 11 implanted MEAs, nine provided functional recordings for at least three months, with two arrays functional for 10 months. In general, implants had high yield, which remained stable for up to several months. However, mechanical failure attributed to MEA connector was the most common failure mode. In the longest implants, signal degradation occurred, which was characterized by gradual decline in array yield, reduced number of isolated single units, and changes in waveform shape of action potentials. This work demonstrates the feasibility of long-term recordings from MEAs implanted in cortical and deep brain structures in the marmoset model. The ability to chronically record cortical signals for neural prosthetics applications in the common marmoset extends the potential of this model in neural interface research.
Neonatal brain injury causes cerebellar learning deficits and Purkinje cell dysfunction
Author(s): Sathyanesan, A; Kundu, S; Abbah, J; Gallo, V
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Premature infants are more likely to develop locomotor disorders than term infants. In a chronic sub-lethal hypoxia (Hx) mouse model of neonatal brain injury, we recently demonstrated the presence of cellular and physiological changes in the cerebellar white matter. We also observed Hx-induced delay in Purkinje cell (PC) arborization. However, the behavioral consequences of these cellular alterations remain unexplored. Using the Erasmus Ladder to study cerebellar behavior, we report the presence of locomotor malperformance and long-term cerebellar learning deficits in Hx mice. Optogenetics experiments in Hx mice reveal a profound reduction in spontaneous and photoevoked PC firing frequency. Finally, treatment with a gamma-aminobutyric acid (GABA) reuptake inhibitor partially rescues locomotor performance and improves PC firing. Our results demonstrate a long-term miscoordination phenotype characterized by locomotor malperformance and cerebellar learning deficits in a mouse model of neonatal brain injury. Our findings also implicate the developing GABA network as a potential therapeutic target for prematurity-related locomotor deficits.
Model-based deconstruction of cortical evoked potentials generated by subthalamic nucleus deep brain stimulation
Author(s): Kumaravelu, K; Oza, CS; Behrend, CE; Grill, WM
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Parkinson's disease is associated with altered neural activity in the motor cortex. Chronic high-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective in suppressing parkinsonian motor symptoms and modulates cortical activity. However, the anatomical pathways responsible for STN DBS-mediated cortical modulation remain unclear. Cortical evoked potentials (cEP) generated by STN DBS reflect the response of cortex to subcortical stimulation, and the goal of this study was to determine the neural origin of STN DBS-generated cEP using a two-step approach. First, we recorded cEP over ipsilateral primary motor cortex during different frequencies of STN DBS in awake healthy and unilateral 6-OHDA-lesioned parkinsonian rats. Second, we used a detailed, biophysically based model of the thalamocortical network to deconstruct the neural origin of the recorded cEP. The in vivo cEP included short (R1)-, intermediate (R2)-, and long-latency (R3) responses. Model-based cortical responses to simulated STN DBS matched remarkably well the in vivo responses. The short-latency response was generated by antidromic activation of layer 5 pyramidal neurons, whereas recurrent activation of layer 5 pyramidal neurons via excitatory axon collaterals reproduced the intermediate-latency response. The long-latency response was generated by polysynaptic activation of layer 2/3 pyramidal neurons via the cortico-thalamic-cortical pathway. Antidromic activation of the hyperdirect pathway and subsequent intracortical and cortico-thalamo-cortical synaptic interactions were sufficient to generate cortical potential evoked by STN DBS, and orthodromic activation through basal ganglia-thalamus-cortex pathways was not required. These results demonstrate the utility of cEP to determine the neural elements activated by STN DBS that might modulate cortical activity and contribute to the suppression of parkinsonian symptoms. NEW & NOTEWORTHY Subthalamic nucleus (STN) deep brain stimulation (DBS) is increasingly used to treat Parkinson's disease (PD). Cortical potentials evoked by STN DBS in patients with PD exhibit consistent short-latency (1-3 ms), intermediate-latency (5-15 ms), and long-latency (18-25 ms) responses. The short-latency response occurs as a result of antidromic activation of the hyperdirect pathway comprising corticosubthalamic axons. However, the neural origins of intermediate- and long-latency responses remain elusive, and the dominant view is that these are produced through the orthodromic pathway (basal ganglia-thalamus-cortex). By combining in vivo electrophysiology with computational modeling, we demonstrate that antidromic activation of the cortico-thalamic-cortical pathway is sufficient to generate the intermediate- and long-latency cortical responses to STN DBS.
Patterned low frequency deep brain stimulation induces motor deficits and modulates cortex-basal ganglia neural activity in healthy rats
Author(s): Oza, CS; Brocker, DT; Behrend, CE
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Deep brain stimulation (DBS) is an effective therapy for movement disorders, including Parkinson’s disease (PD), although the mechanisms of action remain unclear. Abnormal oscillatory neural activity is correlated with motor symptoms, and pharmacological or DBS treatment that alleviates motor symptoms appears to suppress abnormal oscillations. However, whether such oscillatory activity is causal of motor deficits such as tremor remains unclear. Our goal was to generate abnormal oscillatory activity in the cortex-basal ganglia loop using patterned subthalamic nucleus DBS and to quantify motor behavior in awake healthy rats. Stimulation patterns were designed via model-based optimization to increase power in the low-frequency (7–11 Hz) band because these oscillations are associated with the emergence of motor symptoms in the 6-hydroxydopamine lesioned rat model of parkinsonism. We measured motor activity using a head-mounted accelerometer, as well as quantified neural activity in cortex and globus pallidus (GP), in response to 5 stimulation patterns that generated a range of 7- to 11-Hz spectral power. Stimulation patterns induced oscillatory activity in the low-frequency band in the cortex and GP and caused tremor, whereas control patterns and regular 50-Hz DBS did not generate any such effects. Neural and motor-evoked responses observed during stimulation were synchronous and time-locked to stimulation bursts within the patterns. These results identified elements of irregular patterns of stimulation that were correlated with tremor and tremor-related neural activity in the cortex and basal ganglia and may lead to the identification of the oscillatory activity and structures associated with the generation of tremor activity. NEW & NOTEWORTHY Subthalamic nucleus deep brain stimulation is a promising therapy for movement disorders such as Parkinson’s disease. Several groups reported correlation between suppression of abnormal oscillatory activity in the cortex-basal ganglia and motor symptoms, but it remains unclear whether such oscillations play a causal role in the emergence of motor symptoms. We demonstrate generation of tremor and pathological oscillatory activity in otherwise healthy rats by stimulation with patterns that produced increases in low-frequency oscillatory activity.
Arousal Dependent Modulation Of Thalamo-Cortical Functional Interaction
Author(s): Stitt, I; Zhou, ZC; Radtke-Schuller, S; Frohlich, F
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Cognition and behavior emerge from the dynamic interaction of widely distributed, but functionally specialized brain networks. However, it remains unclear how network-level interactions dynamically reorganize to support ever-shifting cognitive and behavioral demands. Here, we investigate how the interaction between posterior parietal cortex (PPC) and lateral posterior (LP)/Pulvinar is shaped by ongoing fluctuations in pupil-linked arousal, which is a non-invasive measure related to neuromodulatory tone in the brain. We found that fluctuations in pupil-linked arousal tracked the dynamic interaction between PPC and LP/Pulvinar characterized by changes in the direction and carrier frequency of oscillatory interaction. Active visual exploration by saccadic eye movements elicited similar transitions in thalamo-cortical interaction. These findings suggest a common network substrate of both spontaneous activity and active vision. Thus, neuromodulators may play a role in dynamically sculpting the patterns of thalamo-cortical functional interaction that underlie visual processing.
Theta Oscillations Organize Spiking Activity in Higher-Order Visual Thalamus during Sustained Attention
Author(s): Yu, C; Stitt, I; Li, Y; Zhou, ZC; Sellers, K; Frohlich, F
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Higher-order visual thalamus plays a fundamental but poorly understood role in attention-demanding tasks. To investigate how neuronal dynamics in higher-order visual thalamus are modulated by sustained attention, we performed multichannel electrophysiological recordings in the lateral posterior-pulvinar complex (LP/pulvinar) in the ferret (Mustela putorius furo). We recorded single unit activity and local field potential during the performance of the 5-choice serial reaction time task (5-CSRTT) that is used in both humans and animals as an assay of sustained attention. We found that half of the units exhibited an increasing firing rate during the delay period before stimulus onset (attention-modulated units). In contrast, the non-attention-modulated units responded to the stimulus, but not during the delay period. Spike-field coherence of only the attention-modulated neurons significantly increased from the start of the delay period until screen touch, predominantly in the theta frequency band. In addition, theta power and theta-gamma phase-amplitude coupling were elevated throughout the delay period. Our findings suggest that the theta oscillation plays a central role in orchestrating thalamic signaling during sustained attention.
Midbrain Synchrony to Envelope Structure Supports Behavioral Sensitivity to Single-Formant Vowel-Like Sounds in Noise
Author(s): Henry, KS; Abrams, KS; Forst, J; Mender, MJ; Neilans, EG; Idrobo, F; Carney, LH
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Vowels make a strong contribution to speech perception under natural conditions. Vowels are encoded in the auditory nerve primarily through neural synchrony to temporal fine structure and to envelope fluctuations rather than through average discharge rate. Neural synchrony is thought to contribute less to vowel coding in central auditory nuclei, consistent with more limited synchronization to fine structure and the emergence of average-rate coding of envelope fluctuations. However, this hypothesis is largely unexplored, especially in background noise. The present study examined coding mechanisms at the level of the midbrain that support behavioral sensitivity to simple vowel-like sounds using neurophysiological recordings and matched behavioral experiments in the budgerigar. Stimuli were harmonic tone complexes with energy concentrated at one spectral peak, or formant frequency, presented in quiet and in noise. Behavioral thresholds for formant-frequency discrimination decreased with increasing amplitude of stimulus envelope fluctuations, increased in noise, and were similar between budgerigars and humans. Multiunit recordings in awake birds showed that the midbrain encodes vowel-like sounds both through response synchrony to envelope structure and through average rate. Whereas neural discrimination thresholds based on either coding scheme were sufficient to support behavioral thresholds in quiet, only synchrony-based neural thresholds could account for behavioral thresholds in background noise. These results reveal an incomplete transformation to average-rate coding of vowel-like sounds in the midbrain. Model simulations suggest that this transformation emerges due to modulation tuning, which is shared between birds and mammals. Furthermore, the results underscore the behavioral relevance of envelope synchrony in the midbrain for detection of small differences in vowel formant frequency under real-world listening conditions.
Individual Differences in Human Auditory Processing: Insights From Single-Trial Auditory Midbrain Activity in an Animal Model.
Author(s): White-Schwoch, T; Nicol, T; Warrier, CM; Abrams, DA; Kraus, N
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Auditory-evoked potentials are classically defined as the summations of synchronous firing along the auditory neuraxis. Converging evidence supports a model whereby timing jitter in neural coding compromises listening and causes variable scalp-recorded potentials. Yet the intrinsic noise of human scalp recordings precludes a full understanding of the biological origins of individual differences in listening skills. To delineate the mechanisms contributing to these phenomena, in vivo extracellular activity was recorded from inferior colliculus in guinea pigs to speech in quiet and noise. Here we show that trial-by-trial timing jitter is a mechanism contributing to auditory response variability. Identical variability patterns were observed in scalp recordings in human children, implicating jittered timing as a factor underlying reduced coding of dynamic speech features and speech in noise. Moreover, intertrial variability in human listeners is tied to language development. Together, these findings suggest that variable timing in inferior colliculus blurs the neural coding of speech in noise, and propose a consequence of this timing jitter for human behavior. These results hint both at the mechanisms underlying speech processing in general, and at what may go awry in individuals with listening difficulties.
Age-related changes in the spatiotemporal responses to electrical stimulation in the visual cortex of rats with progressive vision loss
Author(s): Miyamoto, S; Suematsu, N; Umehira, Y; Hayashida, Y; Yagi, T
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The Royal College of Surgeons (RCS) rat gradually loses vision due to retinal degeneration. Previous physiological studies have depicted the progressive loss of optical responses in the visual pathway, including the primary visual cortex (V1), over the course of retinal degeneration in the RCS rat. However, little is known about how the excitability of the V1 circuit changes during over the course of the gradual loss of visual signal input from the retina. We elucidated the properties of responses to electrical stimulations directly applied to V1 at different stages of vision input loss in the RCS rat in reference to those of the Long-Evans (LE) rat, using in vivo voltage-sensitive dye imaging. The V1 neuronal network of the RCS rat exhibited an excitatory response comparable to the LE rat. The excitatory response was maintained even long after total loss of the visual signal input from the retina. However, the response time-course suggested that the suppressive response was somewhat debilitated in the RCS rat. This is the first experiment demonstrating the long-term effect of retinal degeneration on cortical activities. Our findings provide the physiological fundamentals to enhance the preclinical research of cortical prostheses with the use of the RCS rat.
Characterization of neurons in the primate medial intraparietal area reveals a joint representation of intended reach direction and amplitude
Author(s): Rajalingham, R; Musallam, S
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To support accurate memory-guided reaching, the brain must represent both the direction and amplitude of reaches in a movement plan. Several cortical areas have been shown to represent the direction of a planned reaching movement, but the neuronal representation of reach amplitude is still unclear, especially in sensory-motor integration areas. To investigate this, we recorded from neurons in the medial intraparietal area (MIP) of monkeys performing a variable amplitude memory reach task. In one monkey, we additionally recorded from the dorsal premotor cortex (PMd) for direct cross-area comparisons. In both areas, we found modest but significant proportions of neurons with movement-planning activity sensitive to reach amplitude. However, reach amplitude was under-represented relative to direction in the neuronal population, with approximately one third as many selective neurons. We observed an interaction between neuronal selectivity for amplitude and direction; neurons in both areas exhibited significant modulation of neuronal activity by reach amplitude in some but not all directions. Consistent with an encoding of reach goals as a position in visual space, the response patterns of MIP/PMd neurons were best predicted by 2D Gaussian position encoding model, in contrast to a number of alternative direction and amplitude tuning models. Taken together, these results suggest that amplitude and direction jointly modulate activity in MIP, as in PMd, to form representations of intended reach position.
Robust tactile sensory responses in finger area of primate motor cortex relevant to prosthetic control.
Author(s): Schroeder, KE; Irwin, ZT; Bullard, AJ; Thompson, DE; Bentley, JN; Stacey, WC; Patil, PG; Chestek, CA
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Challenges in improving the performance of dexterous upper-limb brain-machine interfaces (BMIs) have prompted renewed interest in quantifying the amount and type of sensory information naturally encoded in the primary motor cortex (M1). Previous single unit studies in monkeys showed M1 is responsive to tactile stimulation, as well as passive and active movement of the limbs. However, recent work in this area has focused primarily on proprioception. Here we examined instead how tactile somatosensation of the hand and fingers is represented in M1.
Selective Stimulation of Facial Muscles Following Chronic Intraneural Electrode Array Implantation and Facial Nerve Injury in the Feline Model.
Author(s): Sahyouni, R; Haidar, YM; Moshtaghi, O; Wang, BY; Djalilian, HR; Middlebrooks, JC; Lin, HW
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Our group has previously shown that activation of specific facial nerve (FN) fiber populations and selective activation of facial musculature can be achieved through acute intraneural multichannel microelectrode array (MEA) implantation in the feline model.
Failure to suppress low-frequency neuronal oscillatory activity underlies the reduced effectiveness of random patterns of deep brain stimulation
Author(s): McConnell, GC; So, RQ; Grill, WM
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Subthalamic nucleus (STN) deep brain stimulation (DBS) is an established treatment for the motor symptoms of Parkinson's disease (PD). However, the mechanisms of action of DBS are unknown. Random temporal patterns of DBS are less effective than regular DBS, but the neuronal basis for this dependence on temporal pattern of stimulation is unclear. Using a rat model of PD, we quantified the changes in behavior and single-unit activity in globus pallidus externa and substantia nigra pars reticulata during high-frequency STN DBS with different degrees of irregularity. Although all stimulus trains had the same average rate, 130-Hz regular DBS more effectively reversed motor symptoms, including circling and akinesia, than 130-Hz irregular DBS. A mixture of excitatory and inhibitory neuronal responses was present during all stimulation patterns, and mean firing rate did not change during DBS. Low-frequency (7-10 Hz) oscillations of single-unit firing times present in hemiparkinsonian rats were suppressed by regular DBS, and neuronal firing patterns were entrained to 130 Hz. Irregular patterns of DBS less effectively suppressed 7- to 10-Hz oscillations and did not regularize firing patterns. Random DBS resulted in a larger proportion of neuron pairs with increased coherence at 7-10 Hz compared with regular 130-Hz DBS, which suggested that long pauses (interpulse interval > 50 ms) during random DBS facilitated abnormal low-frequency oscillations in the basal ganglia. These results suggest that the efficacy of high-frequency DBS stems from its ability to regularize patterns of neuronal firing and thereby suppress abnormal oscillatory neural activity within the basal ganglia.
Deep brain stimulation exacerbates hypokinetic dysarthria in a rat model of Parkinson's disease
Author(s): King, NO; Anderson, CJ; Dorval, AD
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Motor symptoms of Parkinson's disease (PD) follow the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Deep brain stimulation (DBS) treats some parkinsonian symptoms, such as tremor, rigidity, and bradykinesia, but may worsen certain medial motor symptoms, including hypokinetic dysarthria. The mechanisms by which DBS exacerbates dysarthria while improving other symptoms are unclear and difficult to study in human patients. This study proposes an animal model of DBS-exacerbated dysarthria. We use the unilateral, 6-hydroxydopamine (6-OHDA) rat model of PD to test the hypothesis that DBS exacerbates quantifiable aspects of vocalization. Mating calls were recorded from sexually experienced male rats under healthy and parkinsonian conditions and during DBS of the subthalamic nucleus. Relative to healthy rats, parkinsonian animals made fewer calls with shorter and less complex vocalizations. In the parkinsonian rats, putatively therapeutic DBS further reduced call frequency, duration, and complexity. The individual utterances of parkinsonian rats spanned a greater bandwidth than those of healthy rats, potentially reducing the effectiveness of the vocal signal. This utterance bandwidth was further increased by DBS. We propose that the parkinsonism-associated changes in call frequency, duration, complexity, and dynamic range combine to constitute a rat analog of parkinsonian dysarthria. Because DBS exacerbates the parkinsonism-associated changes in each of these metrics, the subthalamic stimulated 6-OHDA rat is a good model of DBS-induced hypokinetic dysarthria in PD. This model will help researchers examine how DBS alleviates many motor symptoms of PD while exacerbating parkinsonian speech deficits that can greatly diminish patient quality of life.
Neural Circuit Mechanisms Underlying Skill Learning, Adaptation, and Maintenance
Author(s): Otchy, TM
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" A custom recording array (4 channels, ~250 um spacing) of 100 kOhm tungsten or platinum electrodes (Microprobes, Inc.) was implanted within the boundaries of HVC and a silver ground reference placed outside of HVC between the dura and the surface of the brain. "
Neural and behavioral responses to deep brain stimulation of the subthalamic nucleus
Author(s): Anderson, C
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… A four-channel micro-stimulating array 22 grid of 75 m platinum-iridium electrodes (~100 k @ 1 kHz) with 400 m spacing (Microprobes for Life Science, Inc., Gaithersburg, MD) was implanted vertically into the STN (3.6 mm posterior, 2.6 mm lateral, and 7.8 mm ventral)  …
Eliciting naturalistic cortical responses with a sensory prosthesis via optimized microstimulation
Author(s): Choi, JS; Brockmeier, AJ; McNiel, DB; Kraus, LM; Príncipe, JC; Francis, JT
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Lost sensations, such as touch, could one day be restored by electrical stimulation along the sensory neural pathways. Such stimulation, when informed by electronic sensors, could provide naturalistic cutaneous and proprioceptive feedback to the user. Perceptually, microstimulation of somatosensory brain regions produces localized, modality-specific sensations, and several spatiotemporal parameters have been studied for their discernibility. However, systematic methods for encoding a wide array of naturally occurring stimuli into biomimetic percepts via multi-channel microstimulation are lacking. More specifically, generating spatiotemporal patterns for explicitly evoking naturalistic neural activation has not yet been explored. We address this problem by first modeling the dynamical input-output relationship between multichannel microstimulation and downstream neural responses, and then optimizing the input pattern to reproduce naturally occurring touch responses as closely as possible. Here we show that such optimization produces responses in the S1 cortex of the anesthetized rat that are highly similar to natural, tactile-stimulus-evoked counterparts. Furthermore, information on both pressure and location of the touch stimulus was found to be highly preserved. Our results suggest that the currently presented stimulus optimization approach holds great promise for restoring naturalistic levels of sensation.
Blocking central pathways in the primate motor system using high-frequency sinusoidal current
Author(s): Fisher, KM; Jillani, NE; Oluoch, GO; Baker, SN
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Electrical stimulation with high-frequency (2-10 kHz) sinusoidal currents has previously been shown to produce a transient and complete nerve block in the peripheral nervous system. Modeling and in vitro studies suggest that this is due to a prolonged local depolarization across a broad section of membrane underlying the blocking electrode. Previous work has used cuff electrodes wrapped around the peripheral nerve to deliver the blocking stimulus. We extended this technique to central motor pathways, using a single metal microelectrode to deliver focal sinusoidal currents to the corticospinal tract at the cervical spinal cord in anesthetized adult baboons. The extent of conduction block was assessed by stimulating a second electrode caudal to the blocking site and recording the antidromic field potential over contralateral primary motor cortex. The maximal block achieved was 99.6%, similar to findings of previous work in peripheral fibers, and the optimal frequency for blocking was 2 kHz. Block had a rapid onset, being complete as soon as the transient activation associated with the start of the sinusoidal current was over. High-frequency block was also successfully applied to the pyramidal tract at the medulla, ascending sensory pathways in the dorsal columns, and the descending systems of the medial longitudinal fasciculus. High-frequency sinusoidal stimulation produces transient, reversible lesions in specific target locations and therefore could be a useful alternative to permanent tissue transection in some experimental paradigms. It also could help to control or prevent some of the hyperactivity associated with chronic neurological disorders.
Combining firing rate and spike-train synchrony features in the decoding of motor cortical activity
Author(s): Chew, G; Kai Keng Ang, ; So, RQ; Zhiming Xu, ; Cuntai Guan,
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Decoding of directional information in the motor cortex traditionally utilizes only firing rate information. However, information from other features could be extracted and combined with firing rate in order to increase classification accuracy. This study proposes the combination of firing rate and spike-train synchrony information in the decoding of motor cortical activity. Synchrony measures used are Event Synchronization (ES), SPIKE-Distance, and ISI-Distance. All data used for analyses were obtained from implanted electrode recordings of the primary motor cortex of a monkey that was trained to manipulate a motorized vehicle with 4 degrees of freedom (left, right, front and stop) via joystick control. Firstly, synchrony features could decode time periods, which were otherwise incorrectly decoded by firing rate alone, above chance levels. Secondly, using an ensemble classifier design for offline analysis, combining firing rate and ISI-distance information increases overall decoding accuracy by 1.1%. These results show that synchrony features in spike-trains do contain information not carried in firing rate. In addition, these results also demonstrate the feasibility of combining synchrony and firing rate for improving the classification accuracy of invasive brain-machine interface (BMI) in the control of neural prosthetics.
Cortical neural excitations in rats in vivo with using a prototype of a wireless multi-channel microstimulation system
Author(s): Hayashida, Y; Umehira, Y; Takatani, K; Futami, S; Kameda, S; Kamata, T; Khan, AU; Takeuchi, Y; Imai, M; Yagi, T
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Understanding neural responses to multi-site electrical stimuli would be of essential importance for developing cortical neural prostheses. In order to provide a tool for such studies in experimental animals, we recently constructed a prototype of a wireless multi-channel microstimulation system, consisting of a stimulator chip, wireless data/power transmitters and receivers, and microcomputers. The proper operations of the system in cortical neural excitations were examined in anesthetized rats in vivo, with utilizing the voltage-sensitive dye imaging technique.
Reach and Saccade Movement Direction Decoding from Monkey Local Field Potential Recordings
Author(s): Lu, VZY
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… Both monkeys are right-handed. The monkeys were implanted with head fixation posts (MRI Chair by Rogue Research). Then microelectrode arrays (MicroProbe, Gaithersburg, MD) were implanted in the left medial intraparietal (MIP) and left dorsal premotor cortex (PMd)  …
Generalized analog thresholding for spike acquisition at ultralow sampling rates
Author(s): He, BD; Wein, A; Varshney, LR; Kusuma, J; Richardson, AG; Srinivasan, L
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Efficient spike acquisition techniques are needed to bridge the divide from creating large multielectrode arrays (MEA) to achieving whole-cortex electrophysiology. In this paper, we introduce generalized analog thresholding (gAT), which achieves millisecond temporal resolution with sampling rates as low as 10 Hz. Consider the torrent of data from a single 1,000-channel MEA, which would generate more than 3 GB/min using standard 30-kHz Nyquist sampling. Recent neural signal processing methods based on compressive sensing still require Nyquist sampling as a first step and use iterative methods to reconstruct spikes. Analog thresholding (AT) remains the best existing alternative, where spike waveforms are passed through an analog comparator and sampled at 1 kHz, with instant spike reconstruction. By generalizing AT, the new method reduces sampling rates another order of magnitude, detects more than one spike per interval, and reconstructs spike width. Unlike compressive sensing, the new method reveals a simple closed-form solution to achieve instant (noniterative) spike reconstruction. The base method is already robust to hardware nonidealities, including realistic quantization error and integration noise. Because it achieves these considerable specifications using hardware-friendly components like integrators and comparators, generalized AT could translate large-scale MEAs into implantable devices for scientific investigation and medical technology.
Large-scale reorganization of the somatosensory cortex following spinal cord injuries is due to brainstem plasticity
Author(s): Kambi, N; Halder, P; Rajan, R; Arora, V; Chand, P; Arora, M; Jain, N
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Adult mammalian brains undergo reorganization following deafferentations due to peripheral nerve, cortical or spinal cord injuries. The largest extent of cortical reorganization is seen in area 3b of the somatosensory cortex of monkeys with chronic transection of the dorsal roots or dorsal columns of the spinal cord. These injuries cause expansion of intact face inputs into the deafferented hand cortex, resulting in a change of representational boundaries by more than 7 mm. Here we show that large-scale reorganization in area 3b following spinal cord injuries is due to changes at the level of the brainstem nuclei and not due to cortical mechanisms. Selective inactivation of the reorganized cuneate nucleus of the brainstem eliminates observed face expansion in area 3b. Thus, the substrate for the observed expanded face representation in area 3b lies in the cuneate nucleus.
MANTA--an open-source, high density electrophysiology recording suite for MATLAB.
Author(s): Englitz, B; David, SV; Sorenson, MD; Shamma, SA
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The distributed nature of nervous systems makes it necessary to record from a large number of sites in order to decipher the neural code, whether single cell, local field potential (LFP), micro-electrocorticograms (μECoG), electroencephalographic (EEG), magnetoencephalographic (MEG) or in vitro micro-electrode array (MEA) data are considered. High channel-count recordings also optimize the yield of a preparation and the efficiency of time invested by the researcher. Currently, data acquisition (DAQ) systems with high channel counts (> 100) can be purchased from a limited number of companies at considerable prices. These systems are typically closed-source and thus prohibit custom extensions or improvements by end users. We have developed MANTA, an open-source MATLAB-based DAQ system, as an alternative to existing options. MANTA combines high channel counts (up to 1440 channels/PC), usage of analog or digital headstages, low per channel cost ( < $ 90 /channel), feature-rich display and filtering, a user-friendly interface, and a modular design permitting easy addition of new features. MANTA is licensed under the GPL and free of charge. The system has been tested by daily use in multiple setups for > 1 year, recording reliably from 128 channels. It offers a growing list of features, including integrated spike sorting, PSTH and CSD display and fully customizable electrode array geometry (including 3D arrays), some of which are not available in commercial systems. MANTA runs on a typical PC and communicates via TCP/IP and can thus be easily integrated with existing stimulus generation/control systems in a lab at a fraction of the cost of commercial systems. With modern neuroscience developing rapidly, MANTA provides a flexible platform that can be rapidly adapted to the needs of new analyses and questions. Being open-source, the development of MANTA can outpace commercial solutions in functionality, while maintaining a low price-point.
Stimulation location within the substantia nigra pars reticulata differentially modulates gait in hemiparkinsonian rats
Author(s): McConnell, GC; Grill, WM
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Deep brain stimulation (DBS) improves the distal motor symptoms of Parkinson's disease, but long-term improvements in gait and postural disturbances are less pronounced. The effects of stimulation location, within the large nuclear region of the substantia nigra pars reticulata (SNr), and stimulation parameters on improvement in gait are unclear, and this lack of foundational knowledge hinders the application and optimization of SNr DBS. We quantified the effects of medial vs. lateral SNr DBS on methamphetamine-induced circling in hemiparkinsonian rats to test the hypothesis that stimulation location differentially modulates axial symptoms. The frequency tuning curves showed opposite trends with stimulation frequency; during high frequency stimulation, medial SNr DBS decreased ipsilateral circling, while lateral SNr DBS had no effect on circling. As well, we quantified the effects of 130 Hz SNr DBS on gait to test the hypothesis that SNr DBS location differentially modulates gait. High frequency DBS of the medial SNr, but not lateral SNr, improved the rat's ability to maintain walking speed. The therapeutic effects of medial SNr DBS appeared to improve with time on the same order as clinical studies (> 10 min). These results suggest that improvement in gait depends on the location of the electrodes (medial vs. lateral SNr) with a time course for improvement reminiscent of human data and provide a rational basis for the appropriate selection of implant site and stimulation parameters for SNr DBS.
Electrostimulation as a prosthesis for repair of information flow in a computer model of neocortex
Author(s): Kerr, CC; Neymotin, SA; Chadderdon, GL; Fietkiewicz, CT; Francis, JT; Lytton, WW
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Damage to a cortical area reduces not only information transmitted to other cortical areas, but also activation of these areas. This phenomenon, whereby the dynamics of a follower area are dramatically altered, is typically manifested as a marked reduction in activity. Ideally, neuroprosthetic stimulation would replace both information and activation. However, replacement of activation alone may be valuable as a means of restoring dynamics and information processing of other signals in this multiplexing system. We used neuroprosthetic stimulation in a computer model of the cortex to repair activation dynamics, using a simple repetitive stimulation to replace the more complex, naturalistic stimulation that had been removed. We found that we were able to restore activity in terms of neuronal firing rates. Additionally, we were able to restore information processing, measured as a restoration of causality between an experimentally recorded signal fed into the in silico brain and a cortical output. These results indicate that even simple neuroprosthetics that do not restore lost information may nonetheless be effective in improving the functionality of surrounding areas of cortex.
Characterizing effects of subthalamic nucleus deep brain stimulation on methamphetamine-induced circling behavior in hemi-Parkinsonian rats
Author(s): So, RQ; McConnell, GC; August, AT; Grill, WM
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The unilateral 6-hydroxydopamine (6-OHDA) lesioned rat model is frequently used to study the effects of subthalamic nucleus (STN) deep brain stimulation (DBS) for the treatment of Parkinson's disease. However, systematic knowledge of the effects of DBS parameters on behavior in this animal model is lacking. The goal of this study was to characterize the effects of DBS on methamphetamine-induced circling in the unilateral 6-OHDA lesioned rat. DBS parameters tested include stimulation amplitude, stimulation frequency, methamphetamine dose, stimulation polarity, and anatomical location of the electrode. When an appropriate stimulation amplitude and dose of methamphetamine were applied, high-frequency stimulation (> 130 Hz), but not low frequency stimulation (< 10 Hz), reversed the bias in ipsilateral circling without inhibiting movement. This characteristic frequency tuning profile was only generated when at least one electrode used during bipolar stimulation was located within the STN. No difference was found between bipolar stimulation and monopolar stimulation when the most effective electrode contact was selected, indicating that monopolar stimulation could be used in future experiments. Methamphetamine-induced circling is a simple, reliable, and sensitive behavioral test and holds potential for high-throughput study of the effects of STN DBS in unilaterally lesioned rats.
Functional connectivity and tuning curves in populations of simultaneously recorded neurons
Author(s): Stevenson, IH; London, BM; Oby, ER; Sachs, NA; Reimer, J; Englitz, B; David, SV; Shamma, SA; Blanche, TJ; Mizuseki, K; Zandvakili, A; Hatsopoulos, NG; Miller, LE; Kording, KP
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How interactions between neurons relate to tuned neural responses is a longstanding question in systems neuroscience. Here we use statistical modeling and simultaneous multi-electrode recordings to explore the relationship between these interactions and tuning curves in six different brain areas. We find that, in most cases, functional interactions between neurons provide an explanation of spiking that complements and, in some cases, surpasses the influence of canonical tuning curves. Modeling functional interactions improves both encoding and decoding accuracy by accounting for noise correlations and features of the external world that tuning curves fail to capture. In cortex, modeling coupling alone allows spikes to be predicted more accurately than tuning curve models based on external variables. These results suggest that statistical models of functional interactions between even relatively small numbers of neurons may provide a useful framework for examining neural coding.
Encapsulation of triethanolamine as organic corrosion inhibitor into nanoparticles and its active corrosion protection for steel sheets
Author(s): Choi, H; Song, YK; Kim, KY; Park, JM
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Triethanolamine (TEA), a corrosion inhibitor for zinc and steel, was introduced into nano-sized particles as nanoreservoirs to increase longevity of inhibitive property and prevent degradation caused by direct addition of corrosion inhibitor into coating layer. TEA-incorporated nanoparticles with average particle size around 400–450 nm were successfully synthesized by sequential emulsion polymerization, occupying around 5% of total solid weight of particles during a neutralization process. Encapsulated TEA was released from the capsule inside when the pH level of environment became acidic or alkaline due to an acid–base interaction or ionization of seed material in specific conditions. In the corrosion tests, the encapsulated TEA decreased the corrosion rate of steel substrate owing to its adsorption on steel surface and the resistance of coating layer against corrosive environment was much higher and remained its resistance as immersion time increased when TEA was incorporated in coating layer in the encapsulated form. Based on the scanning vibrating electrode technique (SVET) result, anticorrosive ability of the encapsulated TEA seemed to improve due to the spontaneous passivation of exposed metal on the defected region of coated steel.
Opioid-senstive brainstem neurons seperately modulate pain and respiration
Author(s): Cleary, DR
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Stainless - steel microelectrodes (Microprobe, Gaithersburg, MD) with gold - and plati num - plated tips were used for all recordings. Signals were amplified 10,000 - fold, sampled at 20 kHz, bandpass filtered (150 Hz to 15 kHz), and displayed on an oscilloscope. The signal was simultaneously digitized and stored for off - line analysis
Irregular high frequency patterns decrease the effectiveness of deep brain stimulation in a rat model of Parkinson's disease
Author(s): Grill, RQ; McConnell, GC; McConnell, GC
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Deep brain stimulation (DBS) is an effective treatment of Parkinson's disease, but its mechanisms are still unclear. To test the hypothesis that DBS alleviates motor symptoms by regularizing neuronal firing, we applied regular frequency stimulation between 5-260 Hz as well as irregular high frequency stimulation with an average rate of 130Hz to rats with unilateral 6-hydroxydopamine (6-OHDA) lesions. We found that high frequency regular stimulation above 130Hz was more effective than both low frequency stimulation and high frequency irregular stimulation at normalizing pathological circling behavior. Our results support the hypothesis that DBS is effective because it is able to mask pathological firing patterns within the basal ganglia, and highlight the importance of the temporal pattern in addition to the rate of stimulation.
Preparation and electrochemical characterization of amoxicillin-doped cellulose acetate films for AA2024-T3 aluminum alloy coatings
Author(s): Tamborim, S; Dias, S; Silva, S; Dick, L; Azambuja, D
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Cellulose acetate films doped with amoxicillin were deposited onto AA2024-T3 aluminum alloy and the corrosion protection in 0.05 M NaCl was evaluated by Electrochemical Impedance Spectroscopy (EIS) and the Scanning Vibrating Electrode Technique (SVET). The doping of the cellulose acetate film with amoxicillin resulted in a significant increase in the high frequency resistance and a decrease in the capacitance of the material. The protective effect could be observed under anodic polarization by way of a marked decrease in the anodic current. These results show the promising potential for the deposition of cellulose acetate films doped with amoxicillin onto AA2024-T3.
Revolutionizing prosthetics: Devices for neural integration
Author(s): Tenore, FV; Vogelstein, RJ
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Interfacing with the human body to extract signals that capture a subject’s intent can be done in many ways but can in general be categorized into three different approaches that relate to how the signals are extracted: invasively, non- invasively, and minimally invasively. Over the course of three phases, the Revolutionizing Prosthetics team has explored a wide variety of devices capable of acquiring electri - cal signals at their source locations: nerves and neuronal cells. To accomplish this, we investigated invasive devices, which are intended to be implanted within the human body. Specifically, the Revolutionizing Prosthetics program focused much of its efforts on evaluating the state of these devices as well as advancing the state of the art of a select few that were found to have the best chance of being transitioned for human use. This article provides a summary of our efforts to identify optimal devices for neural signal acquisition.
Afferents integration and neural adaptive control of breathing
Author(s): Tin, C
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Two different layouts of microelectrode arrays (2x8 or 4x4) were used to record neuronal signals from the dorsolateral pons (Microprobes, Inc., Gaithersburg, MD). Each electrode in the array was spaced by 250 pm in rows and columns.
Using primary afferent neural activity for predicting limb kinematics in cat
Author(s): Wagenaar, JB
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Microwire arrays, fabricated by TDT (Tucker Davis Technologies, Alachua, USA) and MircroProbes (MicroProbes for Life Science, Gaithersburg, USA), are the third type of MEAs currently available and have been used for recording and stimulation studies in both acute and chronic experiments [99, 124]
Structural and functional neuroprotection in glaucoma: role of galantamine-mediated activation of muscarinic acetylcholine receptors
Author(s): Almasieh, M; Zhou, Y; Kelly, ME; Casanova, C; Di Polo, A
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Glaucoma is the leading cause of irreversible blindness worldwide. Loss of vision due to glaucoma is caused by the selective death of retinal ganglion cells (RGCs). Treatments for glaucoma, limited to drugs or surgery to lower intraocular pressure (IOP), are insufficient. Therefore, a pressing medical need exists for more effective therapies to prevent vision loss in glaucoma patients. In this in vivo study, we demonstrate that systemic administration of galantamine, an acetylcholinesterase inhibitor, promotes protection of RGC soma and axons in a rat glaucoma model. Functional deficits caused by high IOP, assessed by recording visual evoked potentials from the superior colliculus, were improved by galantamine. These effects were not related to a reduction in IOP because galantamine did not change the pressure in glaucomatous eyes and it promoted neuronal survival after optic nerve axotomy, a pressure-independent model of RGC death. Importantly, we demonstrate that galantamine-induced ganglion cell survival occurred by activation of types M1 and M4 muscarinic acetylcholine receptors, while nicotinic receptors were not involved. These data provide the first evidence of the clinical potential of galantamine as neuroprotectant for glaucoma and other optic neuropathies, and identify muscarinic receptors as potential therapeutic targets for preventing vision loss in these blinding diseases.
Neural basis for improgan antinociception
Author(s): Heinricher, MM; Martenson, ME; Nalwalk, JW; Hough, LB
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Improgan, the prototype compound of a novel class of non-opioid analgesic drugs derived from histamine antagonists, attenuates thermal and mechanical nociception in rodents following intracerebroventricular (i.c.v.) administration. Improgan does not bind to known opioid, histamine or cannabinoid receptors, and its molecular target has not been identified. It is known however, that improgan acts directly in the periaqueductal gray and the rostral ventromedial medulla to produce its antinociceptive effects, and that inactivation of the rostral ventromedial medulla prevents the antinociceptive effect of improgan given i.c.v. Here we used in vivo single-cell recording in lightly anesthetized rats to show that improgan engages pain-modulating neurons in the medulla to produce antinociception. Following improgan administration, OFF-cells, which inhibit nociception, became continuously active and no longer paused during noxious stimulation. The increase in OFF-cell firing does not represent a non-specific neuroexcitant effect of this drug, since ON-cell discharge, associated with net nociceptive facilitation, was depressed. NEUTRAL-cell firing was unaffected by improgan. The net response of rostral ventromedial medulla (RVM) neurons to improgan is thus comparable to that evoked by mu-opioids and cannabinoids, well known RVM-active analgesic drugs. This common basis for improgan, opioid, and cannabinoid antinociception in the RVM supports the idea that improgan functions as a specific analgesic agent.
Localised measurements of pH and dissolved oxygen as complements to SVET in the investigation of corrosion at defects in coated aluminum alloy
Author(s): Bastos, AC; Karavai, OV; Zheludkevich, ML; Yasakau, KA; Ferreira, MG
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This paper presents measurements of local pH and local oxygen reduction current performed to complement SVET (Scanning Vibrating Electrode Technique) in the characterization of the chemical environment near artificial defects on coated 2024-T3 aluminum alloy during corrosion and inhibition. The main purpose is to give examples on how micropotentiometry and microamperometry can add supplementary information to SVET, providing important insights for the understanding of corrosion mechanisms and inhibition processes necessary to develop effective self- healing coatings.
Ghrelin regulates phasic dopamine and nucleus accumbens signaling evoked by food-predictive stimuli
Author(s): Cone, JJ; Roitman, JD; Roitman, MF
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Environmental stimuli that signal food availability hold powerful sway over motivated behavior and promote feeding, in part, by activating the mesolimbic system. These food-predictive cues evoke brief (phasic) changes in nucleus accumbens (NAc) dopamine concentration and in the activity of individual NAc neurons. Phasic fluctuations in mesolimbic signaling have been directly linked to goal-directed behaviors, including behaviors elicited by food-predictive cues. Food-seeking behavior is also strongly influenced by physiologi