Publications & Patents

September 25, 2024
The Journal of Neurophysiology

Pairing Tones with Vagus Nerve Stimulation Improves Brainstem Responses to Speech in the Valproic Acid Model of Autism
Receptive language deficits and aberrant auditory processing are often observed in individuals with autism spectrum disorders (ASD). Symptoms associated with ASD are observed in rodents prenatally exposed to valproic acid (VPA), including deficits in speech sound discrimination ability. These perceptual difficulties are accompanied by changes in neural activity patterns. In both cortical and subcortical levels of the auditory pathway, VPA-exposed rats have impaired responses to speech sounds. Developing a method to improve these neural deficits throughout the auditory pathway is necessary. The purpose of this study was to investigate the ability of vagus nerve stimulation (VNS) paired with sounds to restore degraded inferior colliculus responses in VPA-exposed rats. VNS paired with the speech sound “dad” was presented to a group of VPA-exposed rats 300 times per day for 20 days. Another group of VPA-exposed rats were presented with VNS paired with multiple tone frequencies for 20 days. The inferior colliculus responses were recorded from 19 saline-exposed control rats, 18 VPA-exposed with no VNS, 8 VNS-speech paired VPA-exposed, and 7 VNS-tone paired VPA-exposed female and male rats. Pairing VNS with tones increased the IC response strength to speech sounds by 44% when compared to VPA-exposed rats alone. Contrarily, VNS-speech pairing significantly decreased the IC response to speech compared with VPA-exposed rats by 5%. The current research indicates that pairing VNS with tones improved sound processing in rats exposed to VPA and suggests that auditory processing can be improved through targeted plasticity. Tamaoki Y, Pasapula V, Danaphongse TT, Reyes AR, Chandler CR, Borland MS, Riley JR, Carroll A, Engineer CT.

September 7, 2024
The Journal of Physiology

Vagus nerve stimulation for stroke rehabilitation: Neural substrates, neuromodulatory effects and therapeutic implications
Learning new skills requires neuroplasticity. Vagus nerve stimulation (VNS) during sensory and motor events can increase neuroplasticity in networks related to these events and might therefore serve to facilitate learning on sensory and motor tasks. We tested if VNS could broadly improve learning on a wide variety of tasks across different skill domains in healthy, female adult rats. VNS was paired with presentation of stimuli or on successful trials during training, strategies known to facilitate plasticity and improve recovery in models of neurological disorders. VNS failed to improve either rate of learning or performance for any of the tested tasks, which included skilled forelimb motor control, speech sound discrimination, and paired-associates learning. These results contrast recent findings from multiple labs which found VNS pairing during training produced learning enhancements across motor, auditory, and cognitive domains. We speculate that these contrasting results may be explained by key differences in task designs, training timelines and animal handling approaches, and that while VNS may be able to facilitate rapid and early learning processes in healthy subjects, it does not broadly enhance learning for difficult tasks. Schambra HM, Hays SA.

August 21, 2024
Nature

Neural Mechanisms Responsible for Vagus Nerve Stimulation-Dependent Enhancement of Somatosensory Recovery
Impairments in somatosensory function are a common and often debilitating consequence of neurological injury, with few effective interventions. Building on success in rehabilitation for motor dysfunction, the delivery of vagus nerve stimulation (VNS) combined with tactile rehabilitation has emerged as a potential approach to enhance recovery of somatosensation. In order to maximize the effectiveness of VNS therapy and promote translation to clinical implementation, we sought to optimize the stimulation paradigm and identify neural mechanisms that underlie VNS-dependent recovery. Malley KM, Ruiz AD, Darrow MJ, Danaphongse T, Shiers S, Ahmad FN, Beltran CM, Stanislav BT, Price T, Ii RLR, Kilgard MP, Hays SA.

August 15, 2024
Scientific Reports

Vagus nerve stimulation during training fails to improve learning in healthy rats
Learning new skills requires neuroplasticity. Vagus nerve stimulation (VNS) during sensory and motor events can increase neuroplasticity in networks related to these events and might therefore serve to facilitate learning on sensory and motor tasks. We tested if VNS could broadly improve learning on a wide variety of tasks across different skill domains in healthy, female adult rats. VNS was paired with presentation of stimuli or on successful trials during training, strategies known to facilitate plasticity and improve recovery in models of neurological disorders. VNS failed to improve either rate of learning or performance for any of the tested tasks, which included skilled forelimb motor control, speech sound discrimination, and paired-associates learning. These results contrast recent findings from multiple labs which found VNS pairing during training produced learning enhancements across motor, auditory, and cognitive domains. We speculate that these contrasting results may be explained by key differences in task designs, training timelines and animal handling approaches, and that while VNS may be able to facilitate rapid and early learning processes in healthy subjects, it does not broadly enhance learning for difficult tasks. Carroll AM, Pruitt DT, Riley JR, Danaphongse TT, Rennaker RL, Engineer CT, Hays SA, Kilgard MP

August 5, 2024
IOPScience

Identifying alterations in hand movement coordination from chronic stroke survivors using a wearable high-density EMG sleeve

Non-invasive, high-density electromyography (HD-EMG) has emerged as a useful tool to collect a range of neurophysiological motor information. Recent studies have demonstrated changes in EMG features that occur after stroke, which correlate with functional ability, highlighting their potential use as biomarkers. However, previous studies have largely explored these EMG features in isolation with individual electrodes to assess gross movements, limiting their potential clinical utility. This study aims to predict hand function of stroke survivors by combining interpretable features extracted from a wearable HD-EMG forearm sleeve. Tacca N, Baumgart I, Schlink BR, Kamath A, Dunlap C, Darrow MJ, Colachis Iv S, Putnam P, Branch J, Wengerd L, Friedenberg DA, Meyers EC. J Neural Eng. 2024 Aug 5;21(4).

May 7, 2024
IOPScience

Characterization of an Algorithm for Autonomous, Closed-Loop Neuromodulation During Motor Rehabilitation
Recent evidence demonstrates that manually triggered vagus nerve stimulation (VNS) combined with rehabilitation leads to increased recovery of upper limb motor function after stroke. This approach is premised on studies demonstrating that the timing of stimulation relative to movements is a key determinant in the effectiveness of this approach.Epperson JD, Meyers EC, Pruitt DT, Wright JM, Hudson RA, Adehunoluwa EA, Nguyen-Duong YN, Rennaker RL 2nd, Hays SA, Kilgard MP

April 19, 2024
iScience

Bursts of vagus nerve stimulation paired with auditory rehabilitation fail to improve speech sound perception in rats with hearing loss
Hearing loss can lead to long-lasting effects on the central nervous system, and current therapies, such as auditory training and rehabilitation, show mixed success in improving perception and speech comprehension. Vagus nerve stimulation (VNS) is an adjunctive therapy that can be paired with rehabilitation to facilitate behavioral recovery after neural injury. However, VNS for auditory recovery has not been tested after severe hearing loss or significant damage to peripheral receptors. This study investigated the utility of pairing VNS with passive or active auditory rehabilitation in a rat model of noise-induced hearing loss. Although auditory rehabilitation helped rats improve their frequency discrimination, learn novel speech discrimination tasks, and achieve speech-in-noise performance similar to normal hearing controls, VNS did not enhance recovery of speech sound perception. These results highlight the limitations of VNS as an adjunctive therapy for hearing loss rehabilitation and suggest that optimal benefits from neuromodulation may require restored peripheral signaling. Carroll, Alan M., Riley, Jonathan R., Borland, Michael S., Hays, Seth A., Kilgard, Michael P., Engineer, Crystal T.

Feb. 14, 2024
The Journal of Neuroscience

Frequency specific optogenetic stimulation of the locus coeruleus induces task-relevant plasticity in the motor cortex
The locus ceruleus (LC) is the primary source of neocortical noradrenaline, which is known to be involved in diverse brain functions including sensory perception, attention, and learning. Previous studies have shown that LC stimulation paired with sensory experience can induce task-dependent plasticity in the sensory neocortex and in the hippocampus. However, it remains unknown whether LC activation similarly impacts neural representations in the agranular motor cortical regions that are responsible for movement planning and production. In this study, we test whether optogenetic stimulation of the LC paired with motor performance is sufficient to induce task-relevant plasticity in the somatotopic cortical motor map. Male and female TH-Cre + rats were trained on a skilled reaching lever-pressing task emphasizing the use of the proximal forelimb musculature, and a viral approach was used to selectively express ChR2 in noradrenergic LC neurons. Once animals reached criterial behavioral performance, they received five training sessions in which correct task performance was paired with optogenetic stimulation of the LC delivered at 3, 10, or 30 Hz. After the last stimulation session, motor cortical mapping was performed using intracortical microstimulation. Our results show that lever pressing paired with LC stimulation at 10 Hz, but not at 3 or 30 Hz, drove the expansion of the motor map representation of the task-relevant proximal FL musculature. These findings demonstrate that phasic, training-paired activation of the LC is sufficient to induce experience-dependent plasticity in the agranular motor cortex and that this LC-driven plasticity is highly dependent on the temporal dynamics of LC activation. Tseng CT, Welch HF, Gi AL, Kang EM, Mamidi T, Pydimarri S, Ramesh K, Sandoval A, Ploski JE, Thorn CA.

Jan. 29, 2024
Scientific Reports

Neural Mechanisms Responsible for Vagus Nerve Stimulation-Dependent Enhancement of Somatosensory Recovery
Impairments in somatosensory function are a common and often debilitating consequence of neurological injury, with few effective interventions. Building on success in rehabilitation for motor dysfunction, the delivery of vagus nerve stimulation (VNS) combined with tactile rehabilitation has emerged as a potential approach to enhance recovery of somatosensation. In order to maximize the effectiveness of VNS therapy and promote translation to clinical implementation, we sought to optimize the stimulation paradigm and identify neural mechanisms that underlie VNS-dependent recovery. To do so, we characterized the effect of tactile rehabilitation combined with VNS across a range of stimulation intensities on recovery of somatosensory function in a rat model of chronic sensory loss in the forelimb. Consistent with previous studies in other applications, we find that moderate intensity VNS yields the most effective restoration of somatosensation, and both lower and higher VNS intensities fail to enhance recovery compared to rehabilitation without VNS. We next used the optimized intensity to evaluate the mechanisms that underlie recovery. We find that moderate intensity VNS enhances transcription of Arc, a canonical mediator of synaptic plasticity, in the cortex, and that transcript levels were correlated with the degree of somatosensory recovery. Moreover, we observe that blocking plasticity by depleting acetylcholine in the cortex prevents the VNS-dependent enhancement of somatosensory recovery. Collectively, these findings identify neural mechanisms that subserve VNS-dependent somatosensation recovery and provide a basis for selecting optimal stimulation parameters in order to facilitate translation of this potential intervention. Malley KM, Ruiz AD, Darrow MJ, Danaphongse T, Shiers S, Ahmad FN, Beltran CM, Stanislav BT, Price T, Ii RLR, Kilgard MP, Hays SA.

Jan. 2, 2024
Journal of Neurodevelopmental Disorders

Degraded inferior colliculus responses to complex sounds in prenatally exposed VPA rats. Individuals with autism spectrum disorders (ASD) often exhibit altered sensory processing and deficits in language development. Prenatal exposure to valproic acid (VPA) increases the risk for ASD and impairs both receptive and expressive language. Like individuals with ASD, rodents prenatally exposed to VPA exhibit degraded auditory cortical processing and abnormal neural activity to sounds. Disrupted neuronal morphology has been documented in earlier processing areas of the auditory pathway in VPA-exposed rodents, but there are no studies documenting early auditory pathway physiology. Therefore, the objective of this study is to characterize inferior colliculus (IC) responses to different sounds in rats prenatally exposed to VPA compared to saline-exposed rats. Tamaoki Y, Pasapula V, Chandler C, Borland MS, Olajubutu OI, Tharakan LS, Engineer CT

September 11, 2023
Sage Journals

Effective Delivery of Vagus Nerve Stimulation Requires Many Stimulations Per Session and Many Sessions Per Week Over Many Weeks to Improve Recovery of Somatosensation
Chronic sensory loss is a common and undertreated consequence of many forms of neurological injury. Emerging evidence indicates that vagus nerve stimulation (VNS) delivered during tactile rehabilitation promotes recovery of somatosensation.
Ruiz, Andrea D., Malley, Kaitlyn M., Danaphongse, Tanya T., Ahmad, Fatima N., Beltran, Clareth M., Rennaker, Robert L., Kilgard, Michael, P., Hays, Seth A.,

January 23, 2023
Games for Health Journal

Usage of RePlay as a Take-Home System to Support High-Repetition Motor Rehabilitation After Neurological Injury
Stroke is a leading cause of chronic motor disability. While physical rehabilitation can promote functional recovery, several barriers prevent patients from receiving optimal rehabilitative care. Easy access to at-home rehabilitative tools could increase patients’ ability to participate in rehabilitative exercises, which may lead to improved outcomes. Toward achieving this goal, we developed RePlay: a novel system that facilitates unsupervised rehabilitative exercises at home. RePlay leverages available consumer technology to provide a simple tool that allows users to perform common rehabilitative exercises in a gameplay environment. RePlay collects quantitative time series force and movement data from handheld devices, which provide therapists the ability to quantify gains and individualize rehabilitative regimens. RePlay was developed in C# using Visual Studio. In this feasibility study, we assessed whether participants with neurological injury are capable of using the RePlay system in both a supervised in-office setting and an unsupervised at-home setting, and we assessed their adherence to the unsupervised at-home rehabilitation assignment. All participants were assigned a set of 18 games and exercises to play each day. Participants produced on average 698 ± 36 discrete movements during the initial 1 hour in-office visit. A subset of participants who used the system at home produced 1593 ± 197 discrete movements per day. Participants demonstrated a high degree of engagement while using the system at home, typically completing nearly double the number of assigned exercises per day. These findings indicate that the open-source RePlay system may be a feasible tool to facilitate access to rehabilitative exercises and potentially improve overall patient outcomes.
David T. Pruitt, Y.-Nhy Duong-Nguyen, Eric C. Meyers, Joseph D. Epperson, Joel M. Wright, Rachael A. Hudson, Jane G. Wigginton,
Robert L. Rennaker II, Seth A. Hays, Michael P. Kilgard,

Oct. 3, 2022
Scientific Reports

Timing of vagus nerve stimulation during fear extinction determines efficacy in a rat model of PTSD
Studies have indicated that vagus nerve stimulation (VNS) enhances extinction learning in rodent models. Here, we investigated if pairing VNS with the conditioned stimulus is required for the enhancing effects of VNS. Adult Sprague–Dawley rats were exposed to intense stress followed by fear conditioning training to produce resistant fear. Rats were then implanted with a cuff electrode around the left vagus. After recovery, rats underwent extinction training paired with VNS (0.5 s, 0.8 mA, 100 µs, and 30 Hz) or with Sham VNS (0 mA). VNS rats were randomized into the following subgroups: During VNS (delivered during presentations of the conditioned stimulus, CS), Between VNS (delivered between CS presentations), Continuous VNS (delivered during the entire extinction session), and Dispersed VNS (delivered at longer inter-stimulation intervals across the extinction session).
Rimenez R. Souza, Mark B. Powers, Robert L. Rennaker, Christa K. McIntyre, Seth A. Hays & Michael P. Kilgard 

Aug. 5, 2022
Behavioural Brain Research

Blockade of the mineralocorticoid receptors in the medial prefrontal cortex prevents the acquisition of one-trial tolerance in mice
One-trial tolerance (OTT) is characterized by the lack of anxiolytic-like effects of benzodiazepines in animals submitted to a trial 2 in the elevated plus-maze (EPM) and is described to be influenced by learning mechanisms. Mineralocorticoid receptors (MR) in the infralimbic subregion (IL) of the medial prefrontal cortex (mPFC) are important modulators of emotional learning, but the MR involvement in the establishment of OTT remains unclear.
Kairo Alan, Albernaz-Mariano, Rimenez Rodrigues Souza, Azair Canto-de-Souza

June 11, 2022
Scientific Reports

Vagus nerve stimulation does not improve recovery of forelimb motor or somatosensory function in a model of neuropathic pain
Nerve injury affecting the upper limb is a leading cause of lifelong disability. Damage to the nerves in the arm often causes weakness and somatosensory dysfunction ranging from numbness to pain. Previous studies show that combining brief bursts of electrical vagus nerve stimulation (VNS) with motor or tactile rehabilitation can restore forelimb function after median and ulnar nerve injury, which causes hyposensitivity of the ventral forelimb. Here, we sought to determine whether this approach would be similarly effective in a model of radial nerve injury that produces allodynia in the ventral forelimb.
Katherine S. Adcock, Tanya Danaphongse, Sarah Jacob, Harshini Rallapalli, Miranda Torres, Zainab Haider, Armin Seyedahmadi, Robert A. Morrison, Robert L. Rennaker, Michael P. Kilgard & Seth A. Hays

May 31, 2022
Patent

Stereognosis training system and method for patients with chronic stroke, spinal cord injury or neuropathy
Provided is an effective stereognosis training system that integrates hardware and software to provide a simple, reliable, quantitative system to provide tactile rehabilitation and progress monitoring. The system can include an interactive device including a novel set of objects, that are combined with neuromodulatory systems such as wireless closed-loop vagus nerve stimulation to improve neural plasticity and expedite functional recovery. The system can send updates to therapists or clinicians to monitor progress and encourage compliance with prescribed therapy.
Inventor: Michael P. Kilgard

Feb. 23, 2022
Frontiers in neuroscience

Common Cholinergic, Noradrenergic, and Serotonergic Drugs Do Not Block VNS-Mediated Plasticity
Vagus nerve stimulation (VNS) delivered during motor rehabilitation enhances recovery from a wide array of neurological injuries and was recently approved by the U.S. FDA for chronic stroke. The benefits of VNS result from precisely timed engagement of neuromodulatory networks during rehabilitative training, which promotes synaptic plasticity in networks activated by rehabilitation. Previous studies demonstrate that lesions that deplete these neuromodulatory networks block VNS-mediated plasticity and accompanying enhancement of recovery.
Robert A. Morrison, Stephanie T. Abe, Tanya Danaphongse, Vikram Ezhil, Armaan Somaney, Katherine S. Adcock, Robert L. Rennaker, Michael P. Kilgard, and Seth A. Hays

Jan. 24, 2022
Behavioural Brain Research

The interplay between 5-HT2C and 5-HT3A receptors in the dorsal periaqueductal gray mediates anxiety-like behavior in mice
The monoamine neurotransmitter serotonin (5-HT) modulates anxiety by its activity on 5-HT2C receptors (5-HT2CR) expressed in the dorsal periaqueductal gray (dPAG). Here, we investigated the presence of 5-HT3A receptors (5-HT3AR) in the dPAG, and the interplay between 5-HT2CR and 5-HT3AR in the dPAG in mediating anxiety-like behavior in mice. We found that 5-HT3AR is expressed in the dPAG and the blockade of these receptors using intra-dPAG infusion of ondansetron (5-HT3AR antagonist; 3.0 nmol) induced an anxiogenic-like effect.
Luana Tenorio Lopes, Lucas Canto-de-Souza, Daniela Baptista-de-Souza, Rimenez Rodrigues de Souza, Ricardo L Nunes-de-Souza, Azair Canto-de-Souza

Nov. 21, 2021
Neuroscience

Auditory Brainstem Responses Predict Behavioral Deficits in Rats with Varying Levels of Noise-Induced Hearing Loss
Intense noise exposure is a leading cause of hearing loss, which results in degraded speech sound discrimination ability, particularly in noisy environments. The development of an animal model of speech discrimination deficits due to noise induced hearing loss (NIHL) would enable testing of potential therapies to improve speech sound processing. Rats can accurately detect and discriminate human speech sounds in the presence of quiet and background noise. Further, it is known that profound hearing loss results in functional deafness in rats. In this study, we generated rats with a range of impairments which model the large range of hearing impairments observed in patients with NIHL.
Jonathan R Riley, Michael S Borland, Yuko Tamaoki, Samantha K Skipton, Crystal T Engineer

Nov. 4, 2021
Patent

Systems, methods and devices for paired plasticity
Systems, methods and devices for paired training include timing controls so that training and neural stimulation can be provided simultaneously. Paired trainings may include therapies, rehabilitation and performance enhancement training. Stimulations of nerves such as the vagus nerve that affect subcortical regions such as the nucleus basalis, locus coeruleus or amygdala induce plasticity in the brain, enhancing the effects of a variety of therapies, such as those used to treat tinnitus, stroke, traumatic brain injury, post-traumatic stress disorder, speech deficit or language deficit.
Inventors: Michael P Kilgard, Larry Cauller, Navzer Engineer, Christa McIntyre Rodriguez, Will Rosellini

Nov. 1, 2021
Brain Stimulation

Vagus nerve stimulation paired with sounds improves auditory processing in rat models of neurodevelopmental disorders
Individuals with neurodevelopmental disorders, including autism spectrum disorder and Rett syndrome, often have impaired auditory processing. Expensive, time-consuming behavioral interventions can improve behavioral outcomes, but many individuals undergo these interventions and still experience deficits. The development of adjunctive interventions that can increase the benefit of rehabilitation therapy is essential to improve communication ability.
Crystal Engineer, Katherine Adcock, Yuko Tamaoki

Nov. 1, 2021
Brain Stimulation

Oct. 14, 2021
Patent

Tackling fear memories using vagus nerve stimulation
Exposure-based therapies are considered the first-line, evidence-based psychotherapies used in the treatment of Posttraumatic Stress Disorder (PTSD). These therapies are designed to extinguish conditioned fear through repeated in vivo or imaginal exposure to reminders of the traumatic experiences, reducing the maladaptive fear and other symptoms in PTSD. Unfortunately, large clinical trials have yielded non-response rates that can exceed 50% on some measures, indicating the necessity of improvements. Vagus nerve stimulation (VNS) has emerged as a promising strategy to enhance extinction learning by promoting restorative synaptic plasticity in the fear network. Here we present findings from rodent studies demonstrating that VNS enhances extinction learning and reduces fear return in different models of PTSD.
Rimenez Souza

Vagus nerve stimulation for treating spinal cord injury
Provided herein are methods for the treatment of spinal cord injury in a subject by administering vagus nerve stimulation. In particular, the vagus nerve stimulation is administered in combination with conventional rehabilitation training.
Inventors: II Robert L Rennaker, Michael P Kilgard, D Patrick

Oct. 8, 2021
Neuroscience

Auditory brainstem responses predict behavioral deficits in rats with varying levels of noise-induced hearing loss
Intense noise exposure is a leading cause of hearing loss, which results in degraded speech sound discrimination ability, particularly in noisy environments. The development of an animal model of speech discrimination deficits due to noise induced hearing loss (NIHL) would enable testing of potential therapies to improve speech sound processing.
Jonathan R. Riley, Michael S. Borland, Yuko Tamaoki, Samantha K. Skipton, Crystal T. Engineer

October 2021
Archives of Physical Medicine and Rehabilitation

Characterization of an Algorithm for Autonomous, Closed-Loop Neuromodulation During Stroke Rehabilitation
We sought to leverage sensors and mathematics to design a system that automatically triggers stimulation based on parameters of movement during the rehabilitation exercise. To develop the algorithm, we analyzed data collected from 12 stroke patients with handheld sensors that record compression force, translation, rotation, and touch accuracy.
Joseph Epperson, Eric Meyers, David Pruitt, Joel Wright, Michael Kilgard, Seth Hays

September/October 2021
BASIC SCIENCE

Radial nerve injury causes long-lasting forelimb sensory impairment and motor dysfunction in rats
There is a broad and growing interest in Bioelectronic Medicine, a dynamic field that continues to generate new approaches in disease treatment. The fourth bioelectronic medicine summit “Technology targeting molecular mechanisms” took place on September 23 and 24, 2020. This virtual meeting was hosted by the Feinstein Institutes for Medical Research, Northwell Health. The summit called international attention to Bioelectronic Medicine as a platform for new developments in science, technology, and healthcare.
Adcock, Katherine S.; Hulsey, Daniel R., Danaphongse, Tanya; Haider, Zainab; Morrison, Robert A.; Kilgard, Michael P.; Hays, Seth A.

Sept. 14, 2021
Patent

Systems, methods and devices for paired plasticity
Systems, methods and devices for paired training include timing controls so that training and neural stimulation can be provided simultaneously. Paired trainings may include therapies, rehabilitation and performance enhancement training. Stimulations of nerves such as the vagus nerve that affect subcortical regions such as the nucleus basalis, locus coeruleus or amygdala induce plasticity in the brain, enhancing the effects of a variety of therapies, such as those used to treat tinnitus, stroke, traumatic brain injury and post-traumatic stress disorder.
Inventors: Michael P Kilgard, Larry Cauller, Navzer Engineer, Christa McIntyre Rodriguez, Will Rosellini

August 2021
Journal of Neural Engineering

Validation of a parameterized, open-source model of nerve stimulation
Peripheral nerve stimulation is an effective treatment for various neurological disorders. The method of activation and stimulation parameters used impact the efficacy of the therapy, which emphasizes the need for tools to model this behavior. Computational modeling of nerve stimulation has proven to be a useful tool for estimating stimulation thresholds, optimizing electrode design, and exploring previously untested stimulation methods. Despite their utility, these tools require access to and familiarity with several pieces of specialized software. A simpler, streamlined process would increase accessibility significantly. We developed an open-source, parameterized model with a simple online user interface that allows user to adjust up to 36 different parameters (https://nervestimlab.utdallas.edu).
Jesse E Bucksot, Collin R Chandler, Navaporn M Intharuck, Robert L Rennaker, Michael P Kilgard and Seth A Hays

July 2021
Experimental Neurology

Vagus nerve stimulation enhances fear extinction as an inverted-U function of stimulation intensity
Studies in rodents indicate that pairing vagus nerve stimulation (VNS) with extinction training enhances fear extinction. However, the role of stimulation parameters on the effects of VNS remains largely unknown. Identifying the optimal stimulation intensity is a critical step in clinical translation of neuromodulation-based therapies. Here, we sought to investigate the role of stimulation intensity in rats receiving VNS paired with extinction training in a rat model for Posttraumatic Stress Disorder (PTSD). Male Sprague-Dawley rats underwent single prolonged stress followed by a severe fear conditioning training and were implanted with a VNS device. After recovery, independent groups of rats were exposed to extinction training paired with sham (0 mA) or VNS at different intensities (0.4, 0.8, or 1.6 mA). VNS intensities of 0.4 mA or 0.8 mA decreased conditioned fear during extinction training compared to sham stimulation.
Rimenez R. Souza, Nicole M. Robertson, Christa K. McIntyre, Robert L. Rennaker, Seth A. Hays, Michael P. Kilgard

May 24, 2021
Bioelectronic Medicine

The Fourth Bioelectronic Medicine Summit “Technology Targeting Molecular Mechanisms”: current progress, challenges, and charting the future
There is a broad and growing interest in Bioelectronic Medicine, a dynamic field that continues to generate new approaches in disease treatment. The fourth bioelectronic medicine summit “Technology targeting molecular mechanisms” took place on Sept. 23 and 24, 2020. This virtual meeting was hosted by the Feinstein Institutes for Medical Research, Northwell Health. The summit called international attention to Bioelectronic Medicine as a platform for new developments in science, technology, and healthcare.
Timir Datta-Chaudhuri, Theodoros Zanos, Eric H. Chang, Peder S. Olofsson, Stephan Bickel, Chad Bouton, Daniel Grande, Loren Rieth, Cynthia Aranow, Ona Bloom, Ashesh D. Mehta, Gene Civillico, Molly M. Stevens, Eric Głowacki, Christopher Bettinger, Martin Schüettler, Chris Puleo, Robert Rennaker, Saroj Mohanta, Daniela Carnevale, Silvia V. Conde, Bruno Bonaz, David Chernoff, Suraj Kapa, Magnus Berggren, Kip Ludwig, Stavros Zanos, Larry Miller, Doug Weber, Daniel Yoshor, Lawrence Steinman, Sangeeta S. Chavan, Valentin A. Pavlov, Yousef Al-Abed & Kevin J. Tracey

April 1, 2021
Brain Research

High intensity VNS disrupts VNS-mediated plasticity in motor cortex
Vagus nerve stimulation (VNS) paired with motor rehabilitation enhances recovery of function after neurological injury in rats and humans. This effect is ascribed to VNS-dependent facilitation of plasticity in motor networks. Previous studies document an inverted-U relationship between VNS intensity and cortical plasticity, such that moderate intensities increase plasticity, while low or high intensity VNS does not.
Robert A. Morrison, Tanya T. Danaphongse, Stephanie T. Abe, Madison E. Stevens, Vikram Ezhil, Armin Seyedahmadi, Katherine S. Adcock, Robert L. Rennaker, Michael P. Kilgard, Seth A. Hays

March 23, 2021
Neurobiology of Learning and Memory

Vagus nerve stimulation promotes extinction generalization across sensory modalities
Traumatic experiences involve complex sensory information, and individuals with trauma-related psychological disorders, such as posttraumatic stress disorder (PTSD), can exhibit abnormal fear to numerous different stimuli that remind them of the trauma. Vagus nerve stimulation (VNS) enhances extinction of auditory fear conditioning in rat models for PTSD. We recently found that VNS-paired extinction can also promote extinction generalization across different auditory cues. Here we tested whether VNS can enhance extinction of olfactory fear and promote extinction generalization across auditory and olfactory sensory modalities.
Rimenez R. Souza, Cecily R. Oleksiak, Michel N. Tabet, Robert L. Rennaker, Seth A. Hays, Michael P. Kilgard, Christa K. McIntyre

November-December 2020
Brain Stimulation

Vagus nerve stimulation paired with tones restores auditory processing in a rat model of Rett syndrome
Rett syndrome is a rare neurological disorder associated with a mutation in the X-linked gene MECP2. This disorder mainly affects females, who typically have seemingly normal early development followed by a regression of acquired skills. The rodent Mecp2 model exhibits many of the classic neural abnormalities and behavioral deficits observed in individuals with Rett syndrome. Similar to individuals with Rett syndrome, both auditory discrimination ability and auditory cortical responses are impaired in heterozygous Mecp2 rats. The development of therapies that can enhance plasticity in auditory networks and improve auditory processing has the potential to impact the lives of individuals with Rett syndrome. Evidence suggests that precisely timed vagus nerve stimulation (VNS) paired with sound presentation can drive robust neuroplasticity in auditory networks and enhance the benefits of auditory therapy.
Katherine S. Adcock, Collin Chandler, Elizabeth P. Buell, Bleyda R. Solorzano, Kristofer W. Loerwald, Michael S. Borland, Crystal T. Engineer

November-December 2020
Brain Stimulation

Vagus nerve stimulation paired with tones restores auditory processing in a rat model of Rett syndrome
Rett syndrome is a rare neurological disorder associated with a mutation in the X-linked gene MECP2. This disorder mainly affects females, who typically have seemingly normal early development followed by a regression of acquired skills. The rodent Mecp2 model exhibits many of the classic neural abnormalities and behavioral deficits observed in individuals with Rett syndrome. Similar to individuals with Rett syndrome, both auditory discrimination ability and auditory cortical responses are impaired in heterozygous Mecp2 rats. The development of therapies that can enhance plasticity in auditory networks and improve auditory processing has the potential to impact the lives of individuals with Rett syndrome. Evidence suggests that precisely timed vagus nerve stimulation (VNS) paired with sound presentation can drive robust neuroplasticity in auditory networks and enhance the benefits of auditory therapy.
Katherine S. Adcock, Collin Chandler, Elizabeth P. Buell, Bleyda R. Solorzano, Kristofer W. Loerwald, Michael S. Borland, Crystal T. Engineer

Sept. 28, 2020
Journal of Neurodevelopmental Disorders

Deficits in skilled motor and auditory learning in a rat model of Rett syndrome
Rett syndrome is an X-linked neurodevelopmental disorder caused by a mutation in the gene MECP2. Individuals with Rett syndrome display developmental regression at an early age, and develop a range of motor, auditory, cognitive, and social impairments. Several studies have successfully modeled some aspects of dysfunction and Rett syndrome-like phenotypes in transgenic mouse and rat models bearing mutations in the MECP2 gene. Here, we sought to extend these findings and characterize skilled learning, a more complex behavior known to be altered in Rett syndrome.
Katherine S. Adcock, Abigail E. Blount, Robert A. Morrison, Amanda Alvarez-Dieppa, Michael P. Kilgard, Crystal T. Engineer & Seth A. Hays

Sept. 21, 2020
Behavioural Brain Research

The tactile experience paired with vagus nerve stimulation determines the degree of sensory recovery after chronic nerve damage
Loss of sensory function is a common consequence of neurological injury. Recent clinical and preclinical evidence indicates vagus nerve stimulation (VNS) paired with tactile rehabilitation, consisting of delivery of a variety of mechanical stimuli to the hyposensitive skin surface, yields substantial and long-lasting recovery of somatosensory function after median and ulnar nerve transection and repair.
Michael J. Darrow, Tabarak M. Mian, Miranda Torres, Zainab Haider, Tanya Danaphongse, Armin Seyedahmadi, Robert L. Rennaker II, Seth A. Hays, Michael P. Kilgard

August 2020
Behavioural Brain Research

A limited range of vagus nerve stimulation intensities produce motor cortex reorganization when delivered during training
Pairing vagus nerve stimulation (VNS) with rehabilitation has emerged as a potential strategy to improve recovery after neurological injury, an effect ascribed to VNS-dependent enhancement of synaptic plasticity. Previous studies demonstrate that pairing VNS with forelimb training increases forelimb movement representations in motor cortex.
Robert A. Morrison, Tanya T. Danaphongse, David T. Pruitt, Katherine S. Adcock, Jobin K. Mathew, Stephanie T. Abe, Dina M. Abdulla, Robert L. Rennaker, Michael P. Kilgard, Seth A. Hays

June 25, 2020
Translational Stroke Research

Optimizing Dosing of Vagus Nerve Stimulation for Stroke Recovery
Vagus nerve stimulation (VNS) paired with rehabilitative training enhances recovery of function in models of stroke and is currently under investigation for use in chronic stroke patients. Dosing is critical in translation of pharmacological therapies, but electrical stimulation therapies often fail to comprehensively explore dosing parameters in preclinical studies. Varying VNS parameters has non-monotonic effects on plasticity in the central nervous system, which may directly impact efficacy for stroke. We sought to optimize stimulation intensity to maximize recovery of motor function in a model of ischemic stroke. The study design was preregistered prior to beginning data collection (DOI: https://doi.org/10.17605/OSF.IO/BMJEK). After training on an automated assessment of forelimb function and receiving an ischemic lesion in motor cortex, rats were separated into groups that received rehabilitative training paired with VNS at distinct stimulation intensities (sham, 0.4 mA, 0.8 mA, or 1.6 mA). Moderate-intensity VNS at 0.8 mA enhanced recovery of function compared with all other groups. Neither 0.4 mA nor 1.6 mA VNS was sufficient to improve functional recovery compared with equivalent rehabilitation without VNS. These results demonstrate that moderate-intensity VNS delivered during rehabilitation improves recovery and defines an optimized intensity paradigm for clinical implementation of VNS therapy.
David T. Pruitt, Tanya T. Danaphongse, Megan Lutchman, Nishi Patel, Priyanka Reddy, Vanesse Wang, Anjana Parashar, Robert L. Rennaker II, Michael P. Kilgard & Seth A. Hays 

June 2020
Europe PMC

Deficits in Skilled Motor and Auditory Learning in a Rat Model of Rett Syndrome
Rett Syndrome is an X-linked neurodevelopmental disorder caused by a mutation in the gene MECP2. Individuals with Rett Syndrome display developmental regression at an early age, and develop a range of motor, auditory, cognitive and social impairments. Several studies have successfully modeled some aspects of dysfunction and Rett Syndrome-like phenotypes in transgenic mouse and rat models bearing mutations in the MECP2 gene. Here, we sought to extend these findings and characterize skilled learning, a more complex behavior known to be altered in Rett syndrome. Methods We evaluated the acquisition and performance of auditory and motor function on two complex tasks in heterozygous female Mecp2 rats.
Adcock KS, Blount AE, Morrison RA, Alvarez-Dieppa A, Kilgard MP, Engineer CT, Hays SA

May 2020
Experimental Neurology

Parametric characterization of the rat Hering-Breuer reflex evoked with implanted and non-invasive vagus nerve stimulation
Vagus nerve stimulation (VNS) has rapidly gained interest as a treatment for a variety of disorders. A number of methods have been employed to stimulate the vagus nerve, but the most common relies on a cuff electrode implanted around the cervical branch of the nerve.
Jesse E. Bucksot, Karen Morales Castelan, Samantha K. Skipton, Seth A. Hays

April 4, 2020
Progress in Neuro-Psychopharmacology and Biological Psychiatry

Efficient parameters of vagus nerve stimulation to enhance extinction learning in an extinction-resistant rat model of PTSD
Vagus nerve stimulation (VNS) has shown promise as an adjuvant treatment for posttraumatic stress disorder (PTSD), as it enhances fear extinction and reduces anxiety symptoms in multiple rat models of this condition. Yet, identification of the optimal stimulation paradigm is needed to facilitate clinical translation of this potential therapy. Using an extinction-resistant rat model of PTSD, we tested whether varying VNS intensity and duration could maximize extinction learning while minimizing the total amount of stimulation. We confirmed that sham rats failed to extinguish after a week of extinction training.
Rimenez R Souza, Nicole M Robertson, Ezek Mathew, Michel N Tabet, Jesse E Bucksot, David T Pruitt, Robert L Rennaker, Seth A Hays, Christa K McIntyre, Michael P Kilgard

Jan. 22, 2020
Neurorehabilitation and Neural Repair

Vagus Nerve Stimulation Paired With Rehabilitative Training Enhances Motor Recovery After Bilateral Spinal Cord Injury to Cervical Forelimb Motor Pools
Closed-loop vagus nerve stimulation (VNS) paired with rehabilitative training has emerged as a strategy to enhance recovery after neurological injury. Previous studies demonstrate that brief bursts of closed-loop VNS paired with rehabilitative training substantially improve recovery of forelimb motor function in models of unilateral and bilateral contusive spinal cord injury (SCI) at spinal level C5/6.
Michael J. Darrow, PhD, Miranda Torres, Maria J. Sosa, Tanya T. Danaphongse, Zainab Haider, Robert L. Rennaker, PhD, Michael P. Kilgard, PhD, Seth A. Hays, PhD
Interview with Dr. Michael Darrow

Jan. 1, 2020
Journal of Neurotrauma

Acute Cardiovascular Responses to Vagus Nerve Stimulation Following Experimental Spinal Cord Injury
Pairing vagus nerve stimulation (VNS) with rehabilitation has emerged as a potential strategy to enhance plasticity and improve recovery in a range of neurological disorders. A recent study highlights the therapeutic promise of VNS in promoting motor recovery after spinal cord injury (SCI). Here we investigate the safety of acute VNS in a rat model of chronic SCI. We measured the cardiovascular response to various VNS paradigms following chronic high-thoracic SCI that is known to deleteriously impact cardiovascular control.
Dr. Rahul Sachdeva, Dr. Andrei V Krassioukov, Mr. Jesse E Bucksot, and Dr. Seth A Hays

Dec. 25, 2019
Annals of Neurology

Restoration of somatosensory function by pairing vagus nerve stimulation with tactile rehabilitation
Sensory dysfunction is a common consequence of many forms of neurological injury, including stroke and nerve damage. Rehabilitative paradigms that incorporate sensory retraining can provide modest benefits, but the majority of patients are left with lasting sensory loss. We have developed a novel strategy that uses closed-loop vagus nerve stimulation (VNS) paired with tactile rehabilitation to enhance synaptic plasticity and facilitate recovery of sensory function.
Darrow MJ, Mian TM, Torres M, Haider Z, Danaphongse T, Rennaker RL 2nd, Kilgard MP, Hays SA
Interview with Dr. Michael Darrow

Dec. 19, 2019
Nature Communications

Enhancing plasticity in central networks improves motor and sensory recovery after nerve damage
Vagus nerve stimulation (VNS) has shown promise as an adjuvant treatment for posttraumatic stress disorder (PTSD), as it enhances fear extinction and reduces anxiety symptoms in multiple rat models of this condition. Yet, identification of the optimal stimulation paradigm is needed to facilitate clinical translation of this potential therapy. Using an extinction-resistant rat model of PTSD, we tested whether varying VNS intensity and duration could maximize extinction learning while minimizing the total amount of stimulation.
Meyers EC, Kasliwal N, Solorzano BR, Lai E, Bendale G, Berry A, Ganzer PD, Romero-Ortega M, Rennaker RL 2nd, Kilgard MP, Hays SA

Dec. 19, 2019
Progress in Neuropsychopharmacology & Biological Psychiatry

Efficient parameters of vagus nerve stimulation to enhance extinction learning in an extinction-resistant rat model of PTSD
Vagus nerve stimulation (VNS) has shown promise as an adjuvant treatment for posttraumatic stress disorder (PTSD), as it enhances fear extinction and reduces anxiety symptoms in multiple rat models of this condition. Yet, identification of the optimal stimulation paradigm is needed to facilitate clinical translation of this potential therapy. Using an extinction-resistant rat model of PTSD, we tested whether varying VNS intensity and duration could maximize extinction learning while minimizing the total amount of stimulation.
Souza RR, Robertson NM, Mathew E, Tabet MN, Bucksot JE, Pruitt DT, Rennaker RL, Hays SA, McIntyre CK, Kilgard MP

Nov. 18, 2019
PLOS

Flat electrode contacts for vagus nerve stimulation
The majority of available systems for vagus nerve stimulation use helical stimulation electrodes, which cover the majority of the circumference of the nerve and produce largely uniform current density within the nerve. Flat stimulation electrodes that contact only one side of the nerve may provide advantages, including ease of fabrication. However, it is possible that the flat configuration will yield inefficient fiber recruitment due to a less uniform current distribution within the nerve. Here we tested the hypothesis that flat electrodes will require higher current amplitude to activate all large-diameter fibers throughout the whole cross-section of a nerve than circumferential designs.
Jesse E. Bucksot, Andrew J. Wells, Kimiya C. Rahebi, Vishnoukumaar Sivaji, Mario Romero-Ortega, Michael P. Kilgard, Robert L. Rennaker II, Seth A. Hays
Interview with Jesse Bucksot

Nov. 13, 2019
Journal of Affective Disorders

Vagus nerve stimulation produces immediate dose-dependent anxiolytic effect in rats
Chronic vagus nerve stimulation (VNS) attenuates anxiety in rats and humans. However, it is unclear whether VNS can promote acute anxiolytic effects. Here we examined short-term anxiolytic effects of VNS using single or multiple trains in rats submitted to a battery of tests.
Ezek Mathew, Michel N. Tabet, Nicole M. Robertson, Seth A. Hays, Robert L Rennaker, Michael P. Kilgard, Christa K. McIntyre, Rimenez R. Souza
Interview with Dr. Rimenez R. Souza

July 4, 2019
Experimental Brain Research

Quantitative assessment of cortical somatosensory digit representations after median and ulnar nerve injury in rats
Incomplete recovery of sensory function is common after peripheral nerve injury (PNI). Despite reinnervation following injury, disorganized cortical representations persist and may contribute to functional deficits. There is a dearth of literature characterizing cortical responses after PNI in rodent models. Here we develop a quantitative electrophysiological method for mapping forepaw digit responses in primary somatosensory cortex (S1) of rats. We tested the hypothesis that PNI in the forelimb would generate significant, long lasting sensory deficits, and corresponding disorganization in S1.
Daniel R. Hulsey, Tabarak M. Mian, Michael J. Darrow, Seth A. Hays

June 19, 2019
Journal of Neurophysiology

Pairing vagus nerve stimulation with tones drives plasticity across the auditory pathway
Previous studies have demonstrated that pairing vagus nerve stimulation (VNS) with sounds can enhance the primary auditory cortex (A1) response to the paired sound. The neural response to sounds following VNS-sound pairing in other subcortical and cortical auditory fields has not been documented. We predicted that VNS-tone pairing would increase neural responses to the paired tone frequency across the auditory pathway. In this study, we paired VNS with the presentation of a 9 kHz tone 300 times a day for 20 days.
Michael Borland, Will A Vrana, Nicole A Moreno, Elizabeth A Fogarty, Elizabeth P Buell, Sven Vanneste, Michael P. Kilgard, and Crystal T Engineer

June 7, 2019
Experimental Neurology

Norepinephrine and serotonin are required for vagus nerve stimulation directed cortical plasticity
Vagus nerve stimulation (VNS) paired with forelimb training drives robust, specific reorganization of movement representations in the motor cortex. This effect is hypothesized to be mediated by VNS-dependent engagement of neuromodulatory networks. VNS influences activity in the locus coeruleus (LC) and dorsal raphe nucleus (DRN), but the involvement of these neuromodulatory networks in VNS-directed plasticity is unknown. We tested the hypothesis that cortical norepinephrine and serotonin are required for VNS-dependent enhancement of motor cortex plasticity. Rats were trained on a lever pressing task emphasizing proximal forelimb use.
Daniel R. Hulsey, Christine M. Shedd, Sadmaan F. Sarker, Michael P. Kilgard, Seth A. Hays

April 23, 2019
The International Journal on the Biology of Stress

Vagus nerve stimulation reverses the extinction impairments in a model of PTSD with prolonged and repeated trauma
We have shown that vagus nerve stimulation (VNS) enhances extinction of conditioned fear and reduces anxiety in rat models of PTSD using moderate stress. However, it is still unclear if VNS can be effective in enhancing extinction of severe fear after prolonged and repeated trauma. Severe fear was induced in adult male rats by combining single prolonged stress (SPS) and protracted aversive conditioning (PAC). After SPS and PAC procedures, rats were implanted with stimulating cuff electrodes, exposed to five days of extinction training with or without VNS, and then tested for extinction retention, return of fear in a new context and reinstatement.
Rimenez R. Souza, Nicole M. Robertson, David T. Pruitt, Phillip A. Gonzales, Seth A. Hays, Robert L. Rennaker, Michael P. Kilgard & Christa K. McIntyre

April 11, 2019
Journal of NeuroEngineering and Rehabilitation

A suite of automated tools to quantify hand and wrist motor function after cervical spinal cord injury
Cervical spinal cord injury (cSCI) often causes chronic upper extremity disability. Reliable measurement of arm function is critical for development of therapies to improve recovery after cSCI. In this study, we report a suite of automated rehabilitative tools to allow simple, quantitative assessment of hand and wrist motor function.
We measured range of motion and force production using these devices in cSCI participants with a range of upper limb disability and in neurologically intact participants at two time points separated by approximately 4 months. Additionally, we determined whether measures collected with the rehabilitative tools correlated with standard upper limb assessments, including the Graded Redefined Assessment of Strength, Sensibility, and Prehension (GRASSP) and the Jebsen Hand Function Test (JHFT).
Katelyn M. Grasse, Seth A. Hays, Kimiya C. Rahebi, Victoria S. Warren, Elizabeth A. Garcia, Jane G. Wigginton, Michael P. Kilgard and Robert L. Rennaker II

March 21, 2019
Neuroscience

Vagus Nerve Stimulation Rate and Duration Determine whether Sensory Pairing Produces Neural Plasticity
Repeatedly pairing a brief train of vagus nerve stimulation (VNS) with an auditory stimulus drives reorganization of primary auditory cortex (A1), and the magnitude of this VNS-dependent plasticity is dependent on the stimulation parameters, including intensity and pulse rate. However, there is currently little data to guide the selection of VNS train durations, an easily adjusted parameter that could influence the effect of VNS-based therapies. Here, we tested the effect of varying the duration of the VNS train on the extent of VNS-dependent cortical plasticity.
Elizabeth P. Buell, Michael S. Borland, Kristofer W. Loerwald, Collin Chandler, Seth A. Hays, Crystal T. Engineer, Michael P. Kilgard

Patent
Methods for enhancing exposure therapy using pairing with vagus nerve stimulation

March 8, 2019
Frontiers in Neuroscience

Targeted Vagus Nerve Stimulation for Rehabilitation After Stroke
Stroke is a leading cause of disability worldwide. In approximately 60% of individuals, upper limb deficits persist six months after stroke. These deficits adversely affect functional use of the upper limb and restrict participation in day to day activities. An important goal of stroke rehabilitation is to improve the quality of life by restoring functional independence and participation in activities. Since upper limb deficits are one of the best predictors of quality of life after stroke, effective interventions targeting upper limb deficits may represent a means to improve quality of life.
Navzer D. Engineer, Teresa J. Kimberley, PhD, PT, Cecília N. Prudente, Jesse Dawson, Brent Tarver and Seth A. Hays

March 5, 2019
Journal of Neuroscience Methods

ReStore: a wireless peripheral nerve stimulation system
The present study describes the ReStore system, a miniature, implantable wireless nerve stimulator system that has no battery or leads and is constructed using commercial components and processes. The implant can be programmed wirelessly to deliver charge-balanced, biphasic current pulses of varying amplitudes, pulse widths, frequencies, and train durations. Here, we describe bench and in vivo testing to evaluate the operational performance and efficacy of nerve recruitment. Additionally, we also provide results from a large-animal chronic active stimulation study assessing the long-term biocompatibility of the device.
Vishnoukumaar Sivaji, Dane W. Grasse, Seth A. Hays, Jesse E. Bucksot, Rahul Saini, Michael P Kilgard, Robert L. Rennaker II

Feb. 15, 2019
Methods and Protocols

Protocol for Construction of Rat Nerve Stimulation Cuff Electrodes
Peripheral nerve stimulation has emerged as a platform therapy to treat a wide range of disorders. Continued development and translation of these strategies requires that researchers have access to reliable, customizable electrodes for nerve stimulation. Here, we detail procedures to build three different configurations of cuff electrodes with varying numbers and orientations of contacts for nerve stimulation in rats.
Manolo U. Rios, Jesse E. Bucksot, Kimiya C. Rahebi, Crystal T. Engineer, Michael P. Kilgard and Seth A. Hays

March-April 2019
Brain Stimulation

Vagus Nerve Stimulation as a Strategy to Augment Auditory Rehabilitation
Many individuals with auditory processing disorders undergo expensive, time-consuming behavioral interventions that often yield only modest improvements. The development of adjunctive interventions that can increase the benefit of rehabilitation therapies is necessary. Previous studies have shown that pairing a specific sound with neuromodulator release results in an expansion of the primary auditory cortex (A1) region that responds to the paired sound.
C. Engineer

March-April 2019
Brain Stimulation

Vagus Nerve Stimulation as a Strategy to Augment Stroke Rehabilitation
Neural plasticity supports recovery after neurological injury. Strategies that enhance adaptive neural plasticity in conjunction with rehabilitation hold promise to substantially improve recovery of motor and sensory function after neurological damage. We have developed an innovative method using brief bursts of vagus nerve stimulation (VNS) paired with rehabilitative training to enhance plasticity in motor circuits. VNS drives phasic activation of plasticity-enhancing neuromodulatory systems which augment rehabilitation-dependent plasticity. Our studies demonstrate that VNS paired with rehabilitative training improves recovery of forelimb function in multiple animal models of neurological injury, including spinal cord injury (SCI), traumatic brain injury (TBI), intracerebral hemorrhage, and ischemic stroke.
S. Hays

November 2018
Stroke

Vagus Nerve Stimulation Paired With Upper Limb Rehabilitation After Chronic Stroke
We assessed safety, feasibility, and potential effects of vagus nerve stimulation (VNS) paired with rehabilitation for improving arm function after chronic stroke.
Teresa J. Kimberley, David Pierce, Cecília N. Prudente, Gerard E. Francisco, Nuray Yozbatiran, Patricia Smith, Brent Tarver, Navzer D. Engineer, David Alexander Dickie, Danielle K. Kline, Jane G. Wigginton, Steven C. Cramer, and Jesse Dawson

Nov. 3, 2018
Brain Stimulation

Vagus nerve stimulation intensity influences motor cortex plasticity
Vagus nerve stimulation (VNS) paired with forelimb motor training enhances reorganization of movement representations in the motor cortex. Previous studies have shown an inverted-U relationship between VNS intensity and plasticity in other brain areas, such that moderate intensity VNS yields greater cortical plasticity than low or high intensity VNS. However, the relationship between VNS intensity and plasticity in the motor cortex is unknown. In this study we sought to test the hypothesis that VNS intensity exhibits an inverted-U relationship with the degree of motor cortex plasticity in rats.
Robert A. Morrison, Daniel R. Hulsey, Katherine S. Adcock, Robert L. Rennaker II, Michael P. Kilgard, Seth A. Hays

Sept. 21, 2018
Brain Stimulation

Vagus nerve stimulation promotes generalization of conditioned fear extinction and reduces anxiety in rats
Exposure-based therapies are used to treat a variety of trauma- and anxiety-related disorders by generating successful extinction following cue exposure during treatment. The development of adjuvant strategies that accelerate extinction learning, improve tolerability, and increase efficiency of treatment could increase the efficacy of exposure-based therapies. Vagus nerve stimulation (VNS) paired with exposure can enhance fear extinction, in rat models of psychiatric disorders, and chronic administration of VNS reduces anxiety in rats and humans.
Lindsey J. Noble, Venkat B. Meruva, Seth A. Hays, Robert L. Rennaker, Michael P. Kilgard, Christa K. McIntyre

Patent
Systems and methods for optimizing targeted neuroplasticity

Sept. 14, 2018
Neuroscience Letters

Functional brain changes in auditory phantom perception evoked by different stimulus frequencies
Bayesian models of brain function such as active inference and predictive coding offer a general theoretical framework with which to explain several aspects of normal and disordered brain function. Of particular interest to the present study is the potential for such models to explain the pathology of auditory phantom perception, i.e. tinnitus. To test this framework empirically, we perform an fMRI experiment on a large clinical sample (n = 75) of the human chronic tinnitus population.
Jeffrey Hullfish, Ian Abenes, Silvia Kovacs, Stefan Sunaert, Dirk De Ridder, Sven Vanneste

Aug. 22, 2018
Progress in Neuro-Psychopharmacology and Biological Psychiatry

Tinnitus and neuropathic pain share a common neural substrate in the form of specific brain connectivity and microstate profiles
Tinnitus and neuropathic pain share similar pathophysiological, clinical, and treatment characteristics. In this EEG study, a group of tinnitus (n = 100) and neuropathic pain (n = 100) patients are compared to each other and to a healthy control group (n = 100). Spectral analysis demonstrates gamma band activity within the primary auditory and somatosensory cortices in patients with tinnitus and neuropathic pain, respectively.
Sven Vanneste, Wing Ting To, Dirk De Ridder

July 29, 2018
Neuroscience

Varying Stimulation Parameters to Improve Cortical Plasticity Generated by VNS-tone Pairing
Pairing vagus nerve stimulation (VNS) with movements or sounds can direct robust plasticity in motor or auditory cortex, respectively. The degree of map plasticity is influenced by the intensity and pulse width of VNS, number of VNS-event pairings, and the interval between each pairing. It is likely that these parameters interact, influencing optimal implementation of VNS pairing protocols. We varied VNS intensity, number of stimulations, and inter-stimulation interval (ISI) to test for interactions among these parameters.
Kristofer W. Loerwald, Elizabeth P. Buell, Michael S. Borland, Robert L. Rennaker II, Seth A. Hays, Michael P. Kilgard

July 8, 2018
Brain Stimulation

Cortical map plasticity as a function of vagus nerve stimulation rate
Repeatedly pairing a brief train of vagus nerve stimulation (VNS) with an external event can reorganize the sensory or motor cortex. A 30 Hz train of sixteen VNS pulses paired with a tone significantly increases the number of neurons in primary auditory cortex (A1) that respond to tones near the paired tone frequency. The effective range of VNS pulse rates for driving cortical map plasticity has not been defined. This project investigated the effects of VNS rate on cortical plasticity. We expected that VNS pulse rate would affect the degree of plasticity caused by VNS-tone pairing.
E.P. Buell, K.W. Loerwald, C.T. Engineer, M.S. Borland, J.M. Buell, C.A. Kelly, I.I. Khan, S.A. Hays, M.P. Kilgard

Patent
Vagus nerve stimulation for treating spinal cord injury

March 13, 2018
eLIFE

Closed-loop neuromodulation restores network connectivity and motor control after spinal cord injury
Recovery from serious neurological injury requires substantial rewiring of neural circuits. Precisely-timed electrical stimulation could be used to restore corrective feedback mechanisms and promote adaptive plasticity after neurological insult, such as spinal cord injury (SCI) or stroke. This study provides the first evidence that closed-loop vagus nerve stimulation (CLV) based on the synaptic eligibility trace leads to dramatic recovery from the most common forms of SCI.
Patrick D Ganzer, Michael J Darrow, Eric C Meyers, Bleyda R Solorzano, Andrea D Ruiz, Nicole M Robertson, Katherine S Adcock, Justin T James, Han S Jeong, April M Becker, Mark P Goldberg, David T Pruitt, Seth A Hays, Michael P Kilgard, Robert L Rennaker II 

March 12, 2018
NeuroRehabilitation

Vagus nerve stimulation paired with tactile training improved sensory function in a chronic stroke patient
Recent studies indicate that vagus nerve stimulation (VNS) paired with rehabilitation can enhance neural plasticity in the primary sensory and motor cortices, improve forelimb function after stroke in animal models and improve motor function in patients with arm weakness after stroke. To gain “first-in-man” experience of VNS paired with tactile training in a patient with severe sensory impairment after stroke.
Michael P. Kilgard, Robert L. Rennaker, Jen Alexander, Jesse Dawson 

March-April 2018
Brain Stimulation

The interaction of pulse width and current intensity on the extent of cortical plasticity evoked by vagus nerve stimulation
Repeatedly pairing a tone with a brief burst of vagus nerve stimulation (VNS) results in a reorganization of primary auditory cortex (A1). The plasticity-enhancing and memory-enhancing effects of VNS follow an inverted-U response to stimulation intensity, in which moderate intensity currents yield greater effects than low or high intensity currents. It is not known how other stimulation parameters effect the plasticity-enhancing effects of VNS.
Kristofer W. Loerwald, Michael S. Borland, Robert L. Rennaker II, Seth A. Hays, Michael P. Kilgard

March 15, 2018
Journal of Neuroscience Methods

The M-Maze task: An automated method for studying fear memory in rats exposed to protracted aversive conditioning
We introduce the M-Maze task, a system that measures extinction of conditioned fear using suppression of operant behavior. The apparatus consists of an M-shaped maze where rats are trained to alternate nose poking at two pellet dispensers. Proximity sensors measure the animal’s locomotion, as well as the latencies and number of operant behaviors. Here we also describe the protracted aversive conditioning (PAC), a rat model of severe fear that induces resistant extinction following a 4-day conditioning protocol that combines delay, unpredictable, and short- and long-trace conditioning.
Rimenez R. Souza, Nicole M. Robertson, David T. Pruitt, Lindsey Noble, Eric C. Meyers, Phillip A. Gonzales, Nathaniel P. Bleker, Holle L. Carey, Seth A. Hays, Michael P. Kilgard, Christa K. McIntyre, Robert L. Rennaker

Jan. 25, 2018
Stroke

Vagus Nerve Stimulation Enhances Stable Plasticity and Generalization of Stroke Recovery
Chronic impairment of the arm and hand is a common consequence of stroke. Animal and human studies indicate that brief bursts of vagus nerve stimulation (VNS) in conjunction with rehabilitative training improve recovery of motor function after stroke. In this study, we tested whether VNS could promote generalization, long-lasting recovery, and structural plasticity in motor networks.
Eric C. Meyers, Bleyda R. Solorzano, Justin James, Patrick D. Ganzer, Elaine S. Lai, Robert L. Rennaker, Michael P. Kilgard, Seth A. Hays

Jan. 15, 2018
Neuroscience

The Interval Between VNS-Tone Pairings Determines the Extent of Cortical Map Plasticity
Repeatedly pairing vagus nerve stimulation (VNS) with a tone or movement drives highly specific and long-lasting plasticity in auditory or motor cortex, respectively. Based on this robust enhancement of plasticity, VNS paired with rehabilitative training has emerged as a potential therapy to improve recovery, even when delivered long after the neurological insult. Development of VNS delivery paradigms that reduce therapy duration and maximize efficacy would facilitate clinical translation. The goal of the current study was to determine whether primary auditory cortex (A1) plasticity can be generated more quickly by shortening the interval between VNS-tone pairing events or by delivering fewer VNS-tone pairing events.
Michael S. Borland, Crystal T. Engineer, William A. Vrana, Nicole A. Moreno, Navzer D. Engineer, Sven Vanneste, Pryanka Sharma, Meghan C. Pantalia, Mark C. Lane, Robert L. Rennaker, Michael P. Kilgard

Dec. 11, 2017
Scientific Reports

Pairing sound with vagus nerve stimulation modulates cortical synchrony and phase coherence in tinnitus: An exploratory retrospective study
Recent research has shown that vagus nerve stimulation (VNS) paired with tones or with rehabilitative training can help patients to achieve reductions in tinnitus perception or to expedite motor rehabilitation after suffering an ischemic stroke. The rationale behind this treatment is that VNS paired with experience can drive neural plasticity in a controlled and therapeutic direction.
Sven Vanneste, Jeffrey Martin, Robert L. Rennaker II, Michael P. Kilgard

Nov. 10, 2017
Neuroscience

The Interval Between VNS-Tone Pairings Determines the Extent of Cortical Map Plasticity
Repeatedly pairing vagus nerve stimulation (VNS) with a tone or movement drives highly specific and long-lasting plasticity in auditory or motor cortex, respectively. Based on this robust enhancement of plasticity, VNS paired with rehabilitative training has emerged as a potential therapy to improve recovery, even when delivered long after the neurological insult.
Michael S. Borland, Crystal T. Engineer, William A. Vrana, Nicole A. Moreno, Navzer D. Engineer, Sven Vanneste, Pryanka Sharma, Meghan C. Pantalia, Mark C. Lane, Robert L. Rennaker, Michael P. Kilgard

Oct. 20, 2017
Autism Research

Shank3-deficient rats exhibit degraded cortical responses to sound
Individuals with SHANK3 mutations have severely impaired receptive and expressive language abilities. While brain responses are known to be abnormal in these individuals, the auditory cortex response to sound has remained largely understudied. In this study, we document the auditory cortex response to speech and non-speech sounds in the novel Shank3-deficient rat model.
Crystal T. Engineer, Kimiya C. Rahebi, Michael S. Borland, Elizabeth P. Buell, Kwok W. Im, Linda G. Wilson, Pryanka Sharma, Sven Vanneste, Hala Harony-Nicolas, Joseph D. Buxbaum, Michael P. Kilgard

Sept. 20, 2017
Scientific Reports

Vagus Nerve Stimulation Paired with Tones for the Treatment of Tinnitus: A Prospective Randomized Double-blind Controlled Pilot Study in Humans
The aim of the pilot study was to evaluate the effect of Vagus Nerve Stimulation (VNS) paired with sounds in chronic tinnitus patients. All participants were implanted and randomized to a paired VNS (n = 16) or control (n = 14) group. After 6 weeks of home therapy, all participants received paired VNS. The device was used on 96% of days with good compliance.
Tyler R, Cacace A, Stocking C, Tarver B, Engineer N, Martin J, Deshpande A, Stecker N, Pereira M, Kilgard M, Burress C, Pierce D, Rennaker R, Vanneste S

Aug. 22, 2017
Translational Psychiatry

Effects of vagus nerve stimulation on extinction of conditioned fear and post-traumatic stress disorder symptoms in rats
Exposure-based therapies help patients with post-traumatic stress disorder (PTSD) to extinguish conditioned fear of trauma reminders. However, controlled laboratory studies indicate that PTSD patients do not extinguish conditioned fear as well as healthy controls, and exposure therapy has high failure and dropout rates.
Noble LJ, Gonzalez IJ, Meruva VB, Callahan KA, Belfort BD, Ramanathan KR, Meyers E, Kilgard MP, Rennaker RL, McIntyre CK

July 4, 2017
Journal of Neurodevelopmental Disorders

Vagus nerve stimulation as a potential adjuvant to behavioral therapy for autism and other neurodevelopmental disorders
Vagus nerve stimulation (VNS) is an FDA approved therapy that is safe and effective in reducing seizure frequency and duration in individuals with epilepsy. Individuals with neurodevelopmental disorders often exhibit decreased vagal tone, and studies indicate that VNS can be used to overcome an insufficient vagal response. Multiple studies have also documented significant improvements in quality of life after VNS therapy in individuals with neurodevelopmental disorders. Moreover, recent findings indicate that VNS significantly enhances the benefits of rehabilitative training in animal models and patients, leading to greater recovery in a variety of neurological diseases. Here, we review these findings and provide a discussion of how VNS paired with rehabilitation may yield benefits in the context of neurodevelopmental disorders.
Crystal T. Engineer, Seth A. Hays and Michael P. Kilgard

June 13, 2017
Journal of Neuroscience Research

Cerebrolysin prevents deficits in social behavior, repetitive conduct, and synaptic inhibition in a rat model of autism
Autism spectrum disorder (ASD) is a syndrome of diverse neuropsychiatric diseases of growing incidence characterized by repetitive conduct and impaired social behavior and communication for which effective pharmacological treatment is still unavailable.
Cuevas-Olguin R, Roychowdhury S, Banerjee A, Garcia-Oscos F, Esquivel-Rendon E, Bringas ME, Kilgard MP, Flores G, Atzori M

May 2, 2017
Journal of Neurotrauma

Traumatic brain injury occludes training-dependent cortical reorganization in the contralesional hemisphere
Rehabilitative training drives plasticity in the ipsilesional (injured) motor cortex that is believed to support recovery of motor function after either stroke or TBI.  In addition, adaptive plasticity in the contralesional (uninjured) motor cortex has been well‐ characterized in the context of stroke. While similar rehabilitation‐dependent plasticity in the intact hemisphere may occur after TBI, this has yet to be thoroughly explored.    In this study, we investigated the effects of TBI and forelimb training on reorganization of movement representations in the intact motor cortex.  Rats were trained to proficiency on the isometric pull task and then received a controlled‐cortical impact (CCI) in the left motor cortex to impair function of the trained right forelimb.  After TBI, animals underwent forelimb training on the pull task for two months. At the end of training, intracortical microstimulation (ICMS) was used to document the organization of the intact motor cortex (the contralesional hemisphere).  TBI significantly decreased the cortical area eliciting movements of the impaired forelimb in untrained animals.  In the absence of TBI, training significantly increased forelimb map area compared to untrained controls.   However, training of the impaired forelimb after TBI was insufficient to increase forelimb map area.  These findings are consistent with other studies showing impaired rehabilitation‐dependent plasticity after TBI and provide a novel characterization of TBI on rehabilitation‐dependent plasticity in contralesional motor circuits.    
Mr. David Pruitt, Miss Tanya Danaphongse, Ms. Ariel Schmid, Mr. Robert Morrison, Dr. Michael Kilgard, Dr. Robert L Rennaker II, and Dr. Seth Hays.

March 21, 2017
Muscle and Nerve

Median and ulnar nerve injuries reduce volitional forelimb strength in rats
Peripheral nerve injuries (PNI) are among the leading causes of physical disability in the United States. The majority of injuries occur in the upper extremities, and functional recovery is often limited. Robust animal models are critical first steps for developing effective therapies to restore function after PNI.
Eric C. Meyers MS, Rafael Granja MD, Bleyda R. Solorzano BS, Mario Romero-Ortega PhD, Michael P. Kilgard PhD, Robert L. Rennaker II PhD, Seth Hays PhD

March 2017
Experimental Neurology

Parametric characterization of neural activity in the locus coeruleus in response to vagus nerve stimulation
In this study, we recorded neural activity in the LC and the mesencephalic trigeminal nucleus (Me5) in response to VNS over a broad range of current amplitudes, pulse frequencies, train durations, inter-train intervals, and pulse widths. Brief 0.5 s trains of VNS drive rapid, phasic firing of LC neurons at 0.1 mA. Higher current intensities and longer pulse widths drive greater increases in LC firing rate. Varying the pulse frequency substantially affects the timing, but not the total amount, of phasic LC activity. VNS drives pulse-locked neural activity in the Me5 at current levels above 1.2 mA. These results provide insight into VNS-evoked phasic neural activity in multiple neural structures and may be useful in guiding the selection of VNS parameters to enhance clinical efficacy.
Daniel R. Hulsey, Jonathan R. Riley, Kristofer W. Loerwald, Robert L. Rennaker II, Michael P. Kilgarda, Seth A. Hays

Jan. 30, 2017
JAMA Neurology

Retinal Architecture and Melanopsin-Mediated Pupillary Response Characteristics: A Putative Pathophysiologic Signature for the Retino-Hypothalamic Tract in Multiple Sclerosis
In this case-control study, attenuation of the melanopsin-mediated sustained pupillary constriction response was significantly associated with thinning of the GCL + IPL sector of the retina in the eyes of patients with MS, particularly those with a history of acute optic neuritis. Melanopsin-containing ganglion cells in the retina represent, at least in part, the composition of the retinohypothalamic tract. As such, our findings may signify the ability to elucidate a putative surrogate neurophysiologic signature that correlates with a constellation of homeostatic mechanisms in both health and illness.
Ethan Meltzer, Peter V. Sguigna, Adnan Subei,  Shin Beh, Eric Kildebeck, Darrel Conger1, Amy Conger, Marlen Lucero, Benjamin S. Frohman, Ashley N. Frohman, Shiv Saidha, Steven Galetta, Peter A. Calabresi, Robert Rennaker, Teresa C. Frohman, Randy H. Kardon, Laura J. Balcer, Elliot M. Frohman

Jan. 11, 2017
Brain Stimulations

Temporal plasticity in auditory cortex improves neural discrimination of speech sounds
Many individuals with language learning impairments exhibit temporal processing deficits and degraded neural responses to speech sounds. Auditory training can improve both the neural and behavioral deficits, though significant deficits remain. Recent evidence suggests that vagus nerve stimulation (VNS) paired with rehabilitative therapies enhances both cortical plasticity and recovery of normal function.
Crystal T. Engineer, Jai A. Shetake, Navzer D. Engineer, Will A. Vrana, Jordan T. Wolf, Michael P. Kilgard

Jan. 3, 2017

Patent
Methods, systems, and devices for pairing vagus nerve stimulation with motor therapy in stroke patients

Nov. 9, 2016
Neural Plasticity

Vagus Nerve Stimulation Enhances Extinction of Conditioned Fear in Rats and Modulates Arc Protein, CaMKII, and GluN2B-Containing NMDA Receptors in the Basolateral Amygdala.
Vagus nerve stimulation (VNS) enhances the consolidation of extinction of conditioned fear. High frequency stimulation of the infralimbic cortex (IL) produces long-term potentiation in the basolateral amygdala (BLA) in rats given VNS-paired extinction training, whereas the same stimulation produces long-term depression in sham-treated rats.
Alvarez-Dieppa AC, Griffin K, Cavalier S, McIntyre CK

Oct. 15, 2016
Behavioural Brain Research

Forelimb training drives transient map reorganization in ipsilateral motor cortex
Skilled motor training results in reorganization of contralateral motor cortex movement representations. The ipsilateral motor cortex is believed to play a role in skilled motor control, but little is known about how training influences reorganization of ipsilateral motor representations of the trained limb.
Pruitt DT, Schmid AN, Danaphongse TT, Flanagan KE, Morrison RA, Kilgard MP, Rennaker RL 2nd, Hays SA

Sept. 29, 2016

Patent
Methods and systems for improving speech recognition

Sept. 21, 2016
Journal of Biomedical Materials Research

Design and demonstration of an intracortical probe technology with tunable modulus
Intracortical probe technology, consisting of arrays of microelectrodes, offers a means of recording the bioelectrical activity from neural tissue. A major limitation of existing intracortical probe technology pertains to limited lifetime of 6 months to a year of recording after implantation. A major contributor to device failure is widely believed to be the interfacial mechanical mismatch of conventional stiff intracortical devices and the surrounding brain tissue. We describe the design, development, and demonstration of a novel functional intracortical probe technology that has a tunable Young’s modulus from ∼2 GPa to ∼50 MPa.
Dustin M. Simon, Hamid Charkhkar, Conan St. John, Sakthi Rajendran, Tong Kang, Radu Reit, David Arreaga-Salas, Daniel G. McHail, Gretchen L. Knaack, Andrew Sloan, Dane Grasse, Theodore C. Dumas, Robert L. Rennaker, Joseph J. Pancrazio, Walter E. Voit

Aug. 30, 2016
Neurorehabilitation and Neural Repair

Vagus Nerve Stimulation During Rehabilitative Training Improves Forelimb Recovery After Chronic Ischemic Stroke in Rats
Stroke is a leading cause of long-term disability. Currently, there are no consistently effective rehabilitative treatments for chronic stroke patients. Our recent studies demonstrate that vagus nerve stimulation (VNS) paired with rehabilitative training improves recovery of function in multiple models of stroke.
Khodaparast N, Kilgard MP, Casavant R, Ruiz A, Qureshi I, Ganzer PD, Rennaker RL 2nd, Hays SA

July 1, 2016
Behavioural Brain Research

Awake behaving electrophysiological correlates of forelimb hyperreflexia, weakness and disrupted muscular synchronization following cervical spinal cord injury in the rat
Spinal cord injury usually occurs at the level of the cervical spine and results in profound impairment of forelimb function. In this study, we recorded awake behaving intramuscular electromyography (EMG) from the biceps and triceps muscles of the impaired forelimb during volitional and reflexive forelimb movements before and after unilateral cervical spinal cord injury (cSCI) in rats.
Ganzer PD, Meyers EC, Sloan AM, Maliakkal R, Ruiz A, Kilgard MP, Robert LR 2nd

July 2016
Neurobiology of Aging

Vagus nerve stimulation during rehabilitative training enhances recovery of forelimb function after ischemic stroke in aged rats
Advanced age is associated with a higher incidence of stroke and worse functional outcomes. Vagus nerve stimulation (VNS) paired with rehabilitative training has emerged* as a potential method to improve recovery after brain injury but to date has only been evaluated in young rats.
Hays SA, Ruiz A, Bethea T, Khodaparast N, Carmel JB, Rennaker RL 2nd, Kilgard MP

June 15, 2016
Journal of Neuroscience Methods

The supination assessment task: An automated method for quantifying forelimb rotational function in rats
Neurological injuries or disease can impair the function of motor circuitry controlling forearm supination, and recovery is often limited. Preclinical animal models are essential tools for developing therapeutic interventions to improve motor function after neurological damage.
Meyers E, Sindhurakar A, Choi R, Solorzano R, Martinez T, Sloan A, Carmel J, Kilgard MP, Rennaker RL 2nd, Hays S

May 26, 2016

Patent
Methods and systems for therapy of multiple sclerosis

May 1, 2016
Journal of Neurotrauma

Vagus Nerve Stimulation Delivered with Motor Training Enhances Recovery of Function after Traumatic Brain Injury
Traumatic Brain Injury (TBI) is one of the largest health problems in the United States, and affects nearly 2 million people every year. The effects of TBI, including weakness and loss of coordination, can be debilitating and last years after the initial injury.
Pruitt DT, Schmid AN, Kim LJ, Abe CM, Trieu JL, Choua C, Hays SA, Kilgard MP, Rennaker RL

April 27, 2016
The Journal of Neuroscience

Knockdown of Dyslexia-Gene Dcdc2 Interferes with Speech Sound Discrimination in Continuous Streams
Dyslexia is the most common developmental language disorder and is marked by deficits in reading and phonological awareness. One theory of dyslexia suggests that the phonological awareness deficit is due to abnormal auditory processing of speech sounds.
Centanni TM, Booker AB, Chen F, Sloan AM, Carraway RS, Rennaker RL, LoTurco JJ, Kilgard MP

April 13, 2016
Neurotherapeutics

Enhancing Rehabilitative Therapies with Vagus Nerve Stimulation
Pathological neural activity could be treated by directing specific plasticity to renormalize circuits and restore function. Rehabilitative therapies aim to promote adaptive circuit changes after neurological disease or injury, but insufficient or maladaptive plasticity often prevents a full recovery.
Hays SA

April 2016
Brain Stimulation

Reorganization of Motor Cortex by Vagus Nerve Stimulation Requires Cholinergic Innervation
Vagus nerve stimulation (VNS) paired with forelimb training drives robust, specific reorganization of movement representations in the motor cortex. The mechanisms that underlie VNS-dependent enhancement of map plasticity are largely unknown.
Hulsey DR, Hays SA, Khodaparast N, Ruiz A, Das P, Rennaker RL 2nd, Kilgard MP

Feb. 23, 2016

Patent
Methods, systems, and devices for treating tinnitus with VNS pairing

Feb. 17, 2016
The Journal of Neuroscience

Selective Disruption of Metabotropic Glutamate Receptor 5-Homer Interactions Mimics Phenotypes of Fragile X Syndrome in Mice
Altered function of the Gq-coupled, Group 1 metabotropic glutamate receptors, specifically mGlu5, is implicated in multiple mouse models of autism and intellectual disability. mGlu5 dysfunction has been most well characterized in the fragile X syndrome mouse model, the Fmr1 knock-out (KO) mouse, where pharmacological and genetic reduction of mGlu5 reverses many phenotypes. mGlu5 is less associated with its scaffolding protein Homer in Fmr1 KO mice, and restoration of mGlu5-Homer interactions by genetic deletion of a short, dominant negative of Homer, H1a, rescues many phenotypes of Fmr1 KO mice.
Guo W, Molinaro G, Collins KA, Hays SA, Paylor R, Worley PF, Szumlinski KK, Huber KM

Jan. 30, 2016
Journal of Neuroscience Methods

An Automated Task for the Training and Assessment of Distal Forelimb Function in a Mouse Model of Ischemic Stroke
Behavioral models relevant to stroke research seek to capture important aspects of motor skills typically impaired in human patients, such as coordination of distal musculature. Such models may focus on mice since many genetic tools are available for use only in that species, and since the training and behavioral demands of mice can differ from rats even for superficially similar behavioral readouts.
April M. Becker, Eric Meyers, Andrew Sloan, Robert Rennaker, Michael Kilgard, Mark P. Goldberg

January 2016
Brain Stimulation

Cortical Map Plasticity as a Function of Vagus Nerve Stimulation Intensity
The primary goal of this study was to determine the range of VNS intensities that can be used to direct cortical map plasticity.
Borland MS, Vrana WA, Moreno NA, Fogarty EA, Buell EP, Sharma P, Engineer CT, Kilgard MP

January 2016
Stroke

Safety, Feasibility, and Efficacy of Vagus Nerve Stimulation Paired With Upper-Limb Rehabilitation After Ischemic Stroke
Recent animal studies demonstrate that vagus nerve stimulation (VNS) paired with movement induces movement-specific plasticity in motor cortex and improves forelimb function after stroke.
Jesse Dawson, David Pierce, Anand Dixit, Teresa J. Kimberley, Michele Robertson, Brent Tarver, Omar Hilmi, John McLean, Kirsten Forbes, Michael P. Kilgard, Robert L. Rennaker, Steven C. Cramer, Matthew Walters and Navzer Engineer

Dec. 17, 2015

Patent
A helmet having an outer shell and an inner shell placed within the outer shell. The inner shell attached to the outer shell by a plurality of elastomeric elements to isolate the inner shell from impacts and rotational forces applied to the outer shell.

Nov. 17, 2015

Integration of High-Charge-Injection-Capacity Electrodes onto Polymer Softening Neural Interfaces
Softening neural interfaces are implanted stiff to enable precise insertion, and they soften in physiological conditions to minimize modulus mismatch with tissue. In this work, a high-charge-injection-capacity iridium electrode fabrication process is detailed.
David E. Arreaga-Salas, Adrian Avendaño-Bolívar, Dustin Simon, Radu Reit, Aldo Garcia-Sandoval, Robert L. Rennaker, and Walter Voit

Nov. 4, 2015
Neurorehabilitation and Neural Repair

Vagus Nerve Stimulation During Rehabilitative Training Improves Forelimb Recovery After Chronic Ischemic Stroke in Rats
Stroke is a leading cause of long-term disability. Currently, there are no consistently effective rehabilitative treatments for chronic stroke patients. Our recent studies demonstrate that vagus nerve stimulation (VNS) paired with rehabilitative training improves recovery of function in multiple models of stroke.
Navid Khodaparast, Michael P. Kilgard, Reema Casavant, Andrea Ruiz, Iqra Qureshi, Patrick D. Ganzer, Robert L. Rennaker II, Seth A. Hays

November 2015
Neurobiology of Disease

Degraded neural and behavioral processing of speech sounds in a rat model of Rett syndrome
Individuals with Rett syndrome have greatly impaired speech and language abilities. Auditory brainstem responses to sounds are normal, but cortical responses are highly abnormal.
Crystal T. Engineer, Kimiya C. Rahebi, Michael S. Borland, Elizabeth P. Buell, Tracy M. Centanni, Melyssa K. Fink, Kwok W. Im, Linda G. Wilson, Michael P. Kilgard

Oct. 27, 2015

A Within-Animal Comparison of Skilled Forelimb Assessments in Rats
A variety of skilled reaching tasks have been developed to evaluate forelimb function in rodent models. The single pellet skilled reaching task and pasta matrix task have provided valuable insight into recovery of forelimb function in models of neurological injury and disease. Recently, several automated measures have been developed to reduce the cost and time burden of forelimb assessment in rodents.
Andrew M. Sloan, Melyssa K. Fink, Amber J. Rodriguez, Adam M. Lovitz, Navid Khodaparast, Robert L. Rennaker, Seth A. Hays

Oct. 17, 2015
Journal of Neuroscience Methods

An Automated Task for the Training and Assessment of Distal Forelimb Function in a Mouse Model of Ischemic Stroke
Behavioral models relevant to stroke research seek to capture important aspects of motor skill typically impaired in human patients, such as coordination of distal musculature. Such models may focus on mice since many genetic tools are available for use only in that species, and since the training and behavioral demands of mice can differ from rats even for superficially similar behavioral readouts.
Andrew M. Sloan, Melyssa K. Fink, Amber J. Rodriguez, Adam M. Lovitz, Navid Khodaparast, Robert L. Rennaker, Seth A. Hays

Sept. 23, 2015

Retinal oximetry: a novel visual biomarker of retinal metabolic dysfunction in MS
Optic neuropathy occurs very commonly in multiple sclerosis (MS) patients. Optical coherence tomography (OCT) has been shown to be a sensitive, and precise method of quantifying structural retinal changes that occur in MS. It is very likely, however, that metabolic dysfunction precedes such structural changes in the retina; therefore, a method of detecting and measuring these metabolic changes (for example, retinal oxygen utilization) would result in a more sensitive visual biomarker of MS disease activity.
S.C. Beh, M. Lucero, D. Conger, A. Conger, V. Stokes, T.C. Frohman, P.A. Calabresi, R. Rennaker, L.J. Balcer, E.M. Frohman

Sept. 15, 2015
Nature Reviews Neurology

Ocular motor signatures of cognitive dysfunction in multiple sclerosis
The anatomical and functional overlap between ocular motor command circuitry and the higher-order networks that form the scaffolding for cognition makes for a compelling hypothesis that measures of ocular motility could provide a means to sensitively interrogate cognitive dysfunction in people with multiple sclerosis (MS).
Joanne Fielding, Meaghan Clough, Shin Beh, Lynette Millist, Derek Sears, Ashley N. Frohman, Nathaniel Lizak, Jayne Lim, Scott Kolbe, Robert L. Rennaker II, Teresa C. Frohman, Owen B. White & Elliot M. Frohman

Sept. 3, 2015

Patent
System for acceleration measurements and traumatic brain injury detection

Sept. 3, 2015

Patent
System for traumatic brain injury detection using oculomotor tests

July 28, 2015

Patent
Methods for enhancing exposure therapy using vagus nerve stimulation

July 28, 2015

Patent
Systems, methods and devices for paired plasticity

July 1, 2015
Behavioural Brain Research

Speech training alters consonant and vowel responses in multiple auditory cortex fields
Speech sounds evoke unique neural activity patterns in primary auditory cortex (A1). Extensive speech sound discrimination training alters A1 responses. While the neighboring auditory cortical fields each contain information about speech sound identity, each field processes speech sounds differently.
Engineer CT, Rahebi KC, Buell EP, Fink MK, Kilgard MP

June 2015
Journal of Neuroscience Research

Activation of the anti-inflammatory reflex blocks lipopolysaccharide-induced decrease in synaptic inhibition in the temporal cortex of the rat
Stress is a potential trigger for a number of neuropsychiatric conditions, including anxiety syndromes and schizophrenic psychoses. The temporal neocortex is a stress-sensitive area involved in the development of such conditions.
Garcia-Oscos F, Peña D, Housini M, Cheng D, Lopez D, Cuevas-Olguin R, Saderi N, Salgado Delgado R, Galindo Charles L, Salgado Burgos H, Rose-John S, Flores G, Kilgard MP, Atzori M.

May/June 2015
Brain Stimulation

Pairing Speech Sounds With Vagus Nerve Stimulation Drives Stimulus-specific Cortical Plasticity
Individuals with communication disorders, such as aphasia, exhibit weak auditory cortex responses to speech sounds and language impairments. Previous studies have demonstrated that pairing vagus nerve stimulation (VNS) with tones or tone trains can enhance both the spectral and temporal processing of sounds in auditory cortex, and can be used to reverse pathological primary auditory cortex (A1) plasticity in a rodent model of chronic tinnitus.
Engineer CT, Engineer ND, Riley JR, Seale JD, Kilgard MP

April 21, 2015
Otology & Neurotology

Placebo-Controlled Vagus Nerve Stimulation Paired With Tones in a Patient With Refractory Tinnitus: A Case Report
Classical neuromodulation consists of applying electrical or magnetic stimuli to the nervous system to modulate ongoing activity and connectivity. However, recently, an exciting novel neuromodulation technique was developed in which stimulation of the vagal nerve was paired with simultaneous presentation of tones, demonstrating that it reverses a tinnitus percept in noise-exposed rats.
De Ridder D, Kilgard M, Engineer N, Vanneste S

April 2015
Otology & Neurotology

Vagus Nerve Stimulation and Rehabilitation Improves Recovery of A Motor Task after Neurological Injury
Ischemic stroke and spinal cord injury are neurological injuries that produce persisting motor deficits. Additionally, the majority of those suffering from impairments due to ischemic stroke or spinal cord injury rarely fully recover complete function with current treatment options. Here, we investigate the use of vagus nerve stimulation (VNS), which facilitates specific and long-lasting plasticity after injury.
Rachel Choi, Eric Meyers, Patrick Ganzer, Seth Hays, Michael Kilgard, Robert Rennaker

Feb. 1, 2015
Stroke

Vagus Nerve Stimulation Improves Motor Function After Chronic Stroke in Adult Rats
Stroke is the leading cause of serious long-term disability. Currently, there is no effective treatment for chronic stroke patients. Neuroplasticity within motor circuitry is believed to support recovery of function after stroke. We have developed a method using vagus nerve stimulation (VNS) paired with motor training to drive robust, specific plasticity in the motor cortex.
Navid Khodaparast, Reema Casavant, Andrea Ruiz, Robert L Rennaker and Michael P Kilgard

Feb. 1, 2015
Stroke

Vagus Nerve Stimulation Enhances Neuroplasticity and Forelimb Recovery after Stroke in Aged Rats
Advanced age is a leading risk factor for stroke and is associated with worse recovery. The goal of post-stroke rehabilitative therapies is to enhance neuroplasticity to support the recovery of motor function. Recent studies indicate that vagus nerve stimulation (VNS) paired with rehabilitative training drives robust plasticity and results in significantly enhanced recovery of forelimb function in multiple models of brain injury in young rats.
Seth A Hays, Andrea Ruiz, Daniel R Hulsey, Navid Khodaparast, Thelma Bethea, Jason B Carmel, Robert L Rennaker and Michael P Kilgard

Jan. 13, 2015

Patent
Systems, methods and devices for treating tinnitus

January 2015
Brain, Behavior, and Immunity

Vagal nerve stimulation blocks interleukin 6-dependent synaptic hyperexcitability induced by lipopolysaccharide-induced acute stress in the rodent prefrontal cortex
The ratio between synaptic inhibition and excitation (sI/E) is a critical factor in the pathophysiology of neuropsychiatric disease. We recently described a stress-induced interleukin-6 dependent mechanism leading to a decrease in sI/E in the rodent temporal cortex. The aim of the present study was to determine whether a similar mechanism takes place in the prefrontal cortex, and to elaborate strategies to prevent or attenuate it.
Garcia-Oscos F, Peña D, Housini M, Cheng D, Lopez D, Borland MS, Salgado-Delgado R, Salgado H, D’Mello S, Kilgard MP, Rose-John S, Atzori M

2014

A 700mV low power low noise implantable neural recording system design
A low power, low noise implantable neural recording interface for use in a Radio-Frequency Identification (RFID) is presented in this paper. A two stage neural amplifier and 8 bit Pipelined Analog to Digital Converter (ADC) are integrated in this system.
An G, Hutchens C, Rennaker RL 2nd

Nov. 18, 2014
Neuroscience 2014

Pairing vagus nerve stimulation with rehabilitative training enhances functional recovery after traumatic brain injury
Traumatic Brain Injury (TBI) is one of the largest health problems in the United States, and affects nearly two million people every year. The effects of TBI, including weakness and loss of coordination, can be observed years after the initial injury. We have developed a method by which we drive cortical plasticity through stimulation of the vagus nerve during rehabilitative therapy to enhance recovery from TBI.
D. Pruitt, A. Schmid, C. Choua, L. Kim, J. Trieu, C. Abe, K. Flanagan, M. Kilgard, R. L. Rennaker, II;

Nov. 12, 2014
Frontiers in Behavioral Neuroscience

Abnormal emotional learning in a rat model of autism exposed to valproic acid in utero
Autism Spectrum Disorders (ASD) are complex neurodevelopmental disorders characterized by repetitive behavior and impaired social communication and interactions. Apart from these core symptoms, a significant number of ASD individuals display higher levels of anxiety and some ASD individuals exhibit impaired emotional learning.
Banerjee A, Engineer CT, Sauls BL, Morales AA, Kilgard MP, Ploski JE

Sept. 25, 2014
Frontiers in Behavioral Neuroscience

An analog front-end circuit with spike detection for implantable neural recording system design
A low power, low noise implantable neural recording interface for use in a power harvested inductive coupling system is presented in this paper. A two stage neural amplifier, selective reference thresholder and a serial communication interface form the neural data logger.
Guanglei An, De Kanishka, Cheng Hao, Rehan Ahmed, Chriswell Hutchens, Robert L. Rennaker

Sept. 18, 2014
Frontiers in Behavioral Neuroscience

Vagus nerve stimulation enhances extinction of conditioned fear and modulates plasticity in the pathway from the ventromedial prefrontal cortex to the amygdala
Fearful experiences can produce long-lasting and debilitating memories. Extinction of the fear response requires consolidation of new memories that compete with fearful associations.
Peña DF, Childs JE, Willett S, Vital A, McIntyre CK, Kroener S

Aug. 14, 2014

Patent
Methods, systems, and devices for pairing vagus nerve stimulation with motor therapy in stroke patients

Aug. 21, 2014
Stroke

Vagus Nerve Stimulation During Rehabilitative Training Improves Functional Recovery After Intracerebral Hemorrhage
VNS paired with rehabilitative training significantly improved recovery of forelimb function when compared with rehabilitative training without VNS.
Seth A. Hays, Navid Khodaparast, Daniel R. Hulsey, Andrea Ruiz, Andrew M. Sloan, Robert L. Rennaker and Michael P. Kilgard

Aug. 5, 2014
Frontiers in Systems Neuroscience

Speech sound discrimination training improves auditory cortex responses in a rat model of autism
Children with autism often have language impairments and degraded cortical responses to speech. Extensive behavioral interventions can improve language outcomes and cortical responses.
Engineer CT, Centanni TM, Im KW, Kilgard MP

Aug. 1, 2014
Brain Research

Controlled-cortical impact reduces volitional forelimb strength in rats
Traumatic brain injury (TBI) is one of the largest health problems in the United States and affects both cognitive and motor function. Although weakness is common in TBI patients, few studies have demonstrated a reduction in strength in models of brain injury.
David Pruitt, Seth Hays, Ariel Schmid, Connie Choua, Lily Kim, Jenny Trieu, Michael P. Kilgard, Robert L. Rennaker II

July 31, 2014

Implanted Miniaturized Antenna for Brain Computer Interface Applications: Analysis and Design
Implantable Brain Computer Interfaces (BCIs) are designed to provide real-time control signals for prosthetic devices, study brain function, and/or restore sensory information lost as a result of injury or disease.
Yujuan Zhao, Robert L. Rennaker, Chris Hutchens, Tamer S. Ibrahim

July 28, 2014
Ear and Hearing

Behavioral and Neural Discrimination of Speech Sounds After Moderate or Intense Noise Exposure in Rats
Hearing loss is a commonly experienced disability in a variety of populations including veterans and the elderly and can often cause significant impairment in the ability to understand spoken language. In this study, we tested the hypothesis that neural and behavioral responses to speech will be differentially impaired in an animal model after two forms of hearing loss.
Reed AC, Centanni TM, Borland MS, Matney CJ, Engineer CT, Kilgard MP

June 18, 2014
NeuroReport

The timing and amount of vagus nerve stimulation during rehabilitative training affect post-stroke recovery of forelimb strength
Loss of upper arm strength after stroke is a leading cause of disability. Strategies that can enhance the benefits of rehabilitation training could improve motor function after stroke.
Hays, Seth A.; Khodaparast, Navid; Ruiz, Andrea; Sloan, Andrew M.; Hulsey, Daniel R.; Rennaker, Robert L. II; Kilgard, Michael P.

June 17, 2014
Journal of Neurotrauma

Controlled-Cortical Impact Reduces Rats Ability to Sustain Application of Submaximal Force
Traumatic brain injury (TBI) is an increasingly large health risk in the United States and often results in a severe lack of motor control and weakness. We have recently reported that experimental TBI in rats induces a chronic impairment in maximal volitional forelimb strength. Many activities of daily living, however, require consistent application of controlled submaximal force rather than maximal force.
C. Choua, A. Schmid, L. Kim, J. Trieu, D. Machuca, S. Sterling, S. Shah, S. Khan, D. Pruitt, R.L. Rennaker II

June 17, 2014
Journal of Neurotrauma

Vagus Nerve Stimulation and Nonparetic Limb Training Modify Stroke Recovery
Vagus nerve stimulation (VNS) is a safe, tolerable treatment that has been shown to drive powerful, long-lasting plasticity especially when paired with somatosensory inputs. VNS paired with rehabilitative training has been shown to improve functional recovery beyond what can be achieved by rehabilitative training alone in models of stroke.
A. Nguyen, N. Khodaparast, S.A. Hays, M.P. Kilgard, R.L. Rennaker

May 28, 2014

Speech Sound Processing Deficits and Training-Induced Neural Plasticity in Rats with Dyslexia Gene Knockdown
In utero RNAi of the dyslexia-associated gene Kiaa0319 in rats (KIA-) degrades cortical responses to speech sounds and increases trial-by-trial variability in onset latency.
Tracy M. Centanni, Fuyi Chen, Anne M. Booker, Crystal T. Engineer, Andrew M. Sloan, Robert L. Rennaker, Joseph J. LoTurco, Michael P. Kilgard

April 16, 2014
The Journal of Neuroscience

Environmental Acoustic Enrichment Promotes Recovery from Developmentally Degraded Auditory Cortical Processing
It has previously been shown that environmental enrichment can enhance structural plasticity in the brain and thereby improve cognitive and behavioral function. In this study, we reared developmentally noise-exposed rats in an acoustic-enriched environment for ∼4 weeks to investigate whether or not enrichment could restore developmentally degraded behavioral and neuronal processing of sound frequency.
Xiaoqing Zhu, Fang Wang, Huifang Hu, Xinde Sun, Michael P. Kilgard, Michael M. Merzenich, and Xiaoming Zhou

April 5, 2014
Brain Research

Degraded speech sound processing in a rat model of fragile X syndrome
Fragile X syndrome is the most common inherited form of intellectual disability and the leading genetic cause of autism. Impaired phonological processing in fragile X syndrome interferes with the development of language skills. 
Crystal T. Engineer, Tracy M. Centanni, Kwok W. Im, Kimiya C. Rahebi, Elizabeth P. Buell, Michael P. Kilgard

April 4, 2014
Developmental Neurobiology

Degraded auditory processing in a rat model of autism limits the speech representation in non-primary auditory cortex
Although individuals with autism are known to have significant communication problems, the cellular mechanisms responsible for impaired communication are poorly understood.
Engineer CT, Centanni TM, Im KW, Borland MS, Moreno NA, Carraway RS, Wilson LG, Kilgard MP

Feb. 20, 2014
Encyclopedia of Computational Neuroscience

Neural Coding of Speech Sounds
Speech sounds are composed of both rapid spectrotemporal changes and slow steady-state portions. The neural coding of speech sounds involves the representation of precise action potential timing across many cortical areas. Behavioral speech sound discrimination accuracy is well predicted by quantifying the similarity between the spatiotemporal response patterns evoked by two sounds.
Michael Kilgard

Feb. 18, 2014
Neurorehabilitation and Neural Repair

Vagus Nerve Stimulation Delivered During Motor Rehabilitation Improves Recovery in a Rat Model of Stroke
Neural plasticity is widely believed to support functional recovery following brain damage.
Navid Khodaparast, PhD, Seth A. Hays, PhD, Andrew M. Sloan, PhD, Tabbassum Fayyaz, Daniel R. Hulsey, Robert L. Rennaker II, PhD, Michael P. Kilgard, PhD

Feb. 1, 2014
Stroke

A Novel Means of Augmenting Motor Recovery After Ischemic Stroke; Vagus Nerve Stimulation (VNS) Paired with Intensive Upper Limb Rehabilitation
Chronic upper limb impairment is a major predictor of poor functional outcome after stroke. We have developed a rehabilitation intervention to address this issue. It pairs VNS with intensive upper limb training. Our hypothesis is that short bursts of VNS, specifically timed during therapy, will drive cortical plasticity and improve clinical outcomes via timely release of neuromodulators such as acetylcholine and norepinephrine.

February 2014
Neuromodulation

Safety and efficacy of vagus nerve stimulation paired with tones for the treatment of tinnitus: a case series
Classical neuromodulation applies current to the nervous system in an attempt to alter ongoing activity. However, classical neuromodulation interferes with activity but does not drive it in a controlled way. Recently, an animal study demonstrated it is possible to drive plasticity in a controlled way by using stimulation of the vagus nerve paired with tones. This reversed the tinnitus percept and pathological neural plasticity in noise-exposed rats with behavioral characteristics of tinnitus. The aim of the current study was to translate this innovative neuromodulation method to humans suffering from tinnitus.
De Ridder D, Vanneste S, Engineer ND, Kilgard MP

Jan. 31, 2014
Neuroscience

Detection and identification of speech sounds using cortical activity patterns
We have developed a classifier capable of locating and identifying speech sounds using activity from rat auditory cortex with an accuracy equivalent to behavioral performance and without the need to specify the onset time of the speech sounds.
T.M. Centanni, A.M. Sloan, A.C. Reed, C.T. Engineer, R.L. Rennaker II, M.P. Kilgard

January 2014
Behavioural Brain Research

Speech training alters tone frequency tuning in rat primary auditory cortex
Previous studies in both humans and animals have documented improved performance following discrimination training.
Crystal T. Engineer, Claudia A. Perez, Ryan S. Carraway, Kevin Q. Chang, Jarod L. Roland, Michael P. Kilgard

2013

Targeting Plasticity with Vagus Nerve Stimulation to Treat Neurological Disease
Pathological neural activity in a variety of neurological disorders could be treated by directing plasticity to specifically renormalize aberrant neural circuits, thereby restoring normal function.
Seth A. Hays, Robert L. Rennaker, Michael P. Kilgard

December 2013

Vagus nerve stimulation during rehabilitative training improves forelimb strength following ischemic stroke
Upper limb impairment is a common debilitating consequence of ischemic stroke. Physical rehabilitation after stroke enhances neuroplasticity and improves limb function, but does not typically restore normal movement.
Khodaparast N, Hays SA, Sloan AM, Hulsey DR, Ruiz A, Pantoja M, Rennaker RL 2nd, Kilgard MP

Nov. 12, 2013

Increasing diversity of neural responses to speech sounds across the central auditory pathway
Neurons at higher stations of each sensory system are responsive to feature combinations not present at lower levels. As a result, the activity of these neurons becomes less redundant than lower levels.
Ranasinghe KG, Vrana WA, Matney CJ, Kilgard MP

Nov. 6, 2013

Studies in RF Power Communication, SAR, and Temperature Elevation in Wireless Implantable Neural Interfaces
Implantable neural interfaces are designed to provide a high spatial and temporal precision control signal implementing high degree of freedom real-time prosthetic systems.
Yujuan Zhao, Lin Tang, Robert Rennaker, Chris Hutchens, Tamer S. Ibrahim

Oct. 16, 2013

Similarity of Cortical Activity Patterns Predicts generalization Behavior
Humans and animals readily generalize previously learned knowledge to new situations. Determining similarity is critical for assigning category membership to a novel stimulus.
Crystal T. Engineer, Claudia A. Perez, Ryan S. Carraway, Kevin Q. Chang, Jarod L. Roland, Andrew M. Sloan, Michael P. Kilgard

Oct. 7, 2013

Enabling energy efficient protocol processing for passive RFID sensors using sub/near-threshold circuit
Recent research trend of passive RFID based sensors has posed stringent low power requirement for energy efficient communication, which can be addressed by sub/near-Vt operation with standard CMOS process. This paper discusses new design challenges under scaled voltages and presents critical building blocks for low power protocol processing.
R. Liao, R. Ahmed, C. G. Hutchens, R. L. Rennaker

Oct. 4, 2013

Investigating the structure and function of the retinohypothalamic tract in multiple sclerosis by optical coherence tomography (OCT) and pupillometry
Objective: To characterize the retinohypothalamic tract in the setting of multiple sclerosis and a history of optic neuritis by directly interrogating the functional output of the hypothalamus via body temperature, early morning melatonin suppression, and sleep, fatigue, and depression questionnaires.

Aug. 7, 2013

Fear conditioning alters neuron-specific hippocampal place field stability via the basolateral amygdala
It is well established that physical changes to an environment result in plasticity of hippocampal place cell activity, while in the absence of changes, place fields are remarkably stable.
Donzis EJ, Rennaker RL, Thompson LT

July 16, 2013

Impairment of cortical GABAergic synaptic transmission in an environmental rat model of autism
The biological mechanisms of autism spectrum disorders (ASDs) are largely unknown in spite of extensive research.
Banerjee A, García-Oscos F, Roychowdhury S, Galindo LC, Hall S, Kilgard MP, Atzori M

July 16, 2013

Patent
Timing control for paired plasticity

July 2013

Cortical speech-evoked response patterns in multiple auditory fields are correlated with behavioral discrimination ability
Different speech sounds evoke unique patterns of activity in primary auditory cortex (A1).
Centanni TM, Engineer CT, Kilgard MP

July 2013

A comparison of polymer substrates for photolithographic processing of flexible bioelectronics
Flexible bioelectronics encompass a new generation of sensing devices, in which controlled interactions with tissue enhance understanding of biological processes in vivo.
Dustin Simon, Taylor Ware, Ryan Marcotte, Benjamin R. Lund, Dennis W. Smith Jr., Matthew Di Prima, Robert L. Rennaker, Walter Voit

June 13, 2013

Rapid remission of conditioned fear expression with extinction training paired with vagus nerve stimulation
Fearful experiences can produce long-lasting and debilitating memories. Extinction of conditioned fear requires consolidation of new memories that compete with fearful associations.
Peña DF, Engineer ND, McIntyre CK

June 11, 2013

Mechanical cycling stability of organic thin film transistors on shape memory polymers
Organic thin film transistors on shape memory polymers are fabricated by full photolithography.
Avendano-Bolivar A, Ware T, Arreaga-Salas D, Simon D, Voit W

June 2013

A Two Stage Power Optimized Implantable Neural Amplifier Based on Cascoded Structures
Hutchens, Chris, Renneker, Robert L, II

May 19, 2013

A 2μW digital baseband core for wireless Micro-Neural-Interface in 0.18μm CMOS
This paper presents the design of a low power digital baseband core with a custom-tailored protocol for wirelessly powered Micro-Neural-Interface (MNI) system on a chip (SoC) to be implanted within the skull to record cortical neural activities.
Ran Liao, Chriswell Hutchens, Robert. L. Rennaker

May 13, 2013

Thiol-ene/acrylate substrates for softening intracortical electrodes
Neural interfaces have traditionally been fabricated on rigid and planar substrates, including silicon and engineering thermoplastics.
Taylor Ware, Dustin Simon, Clive Liu, Tabassum Musa, Srikanth Vasudevan, Andrew Sloan, Edward W. Keefer, Robert L. Rennaker II, Walter Voit

March 30, 2013

The bradykinesia assessment task: An automated method to measure forelimb speed in rodents
Bradykinesia in upper extremities is associated with a wide variety of motor disorders; however, there are few tasks that assay forelimb movement speed in rodent models.
Seth A. Hays, Navid Khodaparast, Andrew M. Sloan, Tabbassum Fayyaz, Daniel R. Hulsey, Andrea D. Ruiz, Maritza Pantoja, Michael P. Kilgard, Robert L. Rennaker II

March 2013

Different timescales for the neural coding of consonant and vowel sounds
Psychophysical, clinical, and imaging evidence suggests that consonant and vowel sounds have distinct neural representations. This study tests the hypothesis that consonant and vowel sounds are represented on different timescales within the same population of neurons by comparing behavioral discrimination with neural discrimination based on activity recorded in rat inferior colliculus and primary auditory cortex.
Perez CA, Engineer CT, Jakkamsetti V, Carraway RS, Perry MS, Kilgard MP

Feb. 8, 2013

Knockdown of the Dyslexia-Associated Gene Kiaa0319 Impairs Temporal Responses to Speech Stimuli in Rat Primary Auditory Cortex
One in 15 school age children have dyslexia, which is characterized by phoneme-processing problems and difficulty learning to read. Dyslexia is associated with mutations in the gene KIAA0319.
T. M. Centanni, A. B. Booker, A. M. Sloan, F. Chen, B. J. Maher, R. S. Carraway, N. Khodaparast, R. Rennaker, J. J. LoTurco and M. P. Kilgard

Feb. 6, 2013

A target cell-specific role for presynaptic Fmr1 in regulating glutamate release onto neocortical fast-spiking inhibitory neurons
In the mouse model of Fragile X syndrome, the Fmr1 knock-out, local excitation of layer 4 fast-spiking (FS) inhibitory neurons is robustly decreased by 50%, but the mechanisms mediating this change are unknown. Here, we performed recordings in acutely prepared slices obtained from Fmr1 “mosaic” mice, where Fmr1 is deleted in about half of all neurons, and we found that loss of presynaptic, but not postsynaptic, Fmr1 fully recapitulates the deficit.
Patel AB, Hays SA, Bureau I, Huber KM, Gibson JR

Feb. 4, 2013

Smart Polymers for Neural Interfaces
Thermomechanical properties of smart polymers can be specifically tuned to address critical problems in neural interfaces. A compilation of materials and approaches is presented from each of three often overlapping research communities: shape memory polymers, hydrogels, and neural interfaces.
Taylor Ware, Dustin Simon, Robert L. Rennaker II & Walter Voit

Jan. 30, 2013

The isometric pull task: A novel automated method for quantifying forelimb force generation in rats
Reach-to-grasp tasks are commonly used to assess forelimb function in rodent models. While these tasks have been useful for investigating several facets of forelimb function, they are typically labor-intensive and do not directly quantify physiological parameters.
Seth A. Hays, Navid Khodaparast, Andrew M. Sloan, Daniel R. Hulsey, Maritza Pantoja, Andrea D. Ruiz, Michael P. Kilgard, Robert L. Rennaker II

Jan. 28, 2013

Sub-meninges implantation reduces immune response to neural implants
One in 15 school age children have dyslexia, which is characterized by phoneme-processing problems and difficulty learning to read. Dyslexia is associated with mutations in the gene KIAA0319.
Neil T. Markwardt, Jodi Stokol, Robert L. Rennaker II

January 2013

Directing neural plasticity to understand and treat tinnitus
The functional organization of cortical and subcortical networks can be altered by sensory experience. Sensory deprivation destabilizes neural networks resulting in increased excitability, greater neural synchronization and increased spontaneous firing in cortical and subcortical neurons.
Navzer D. Engineer, Aage R. Møller, Michael P. Kilgard

December 2012

Harnessing plasticity to understand learning and treat disease
A large body of evidence suggests that neural plasticity contributes to learning and disease. Recent studies suggest that cortical map plasticity is typically a transient phase that improves learning by increasing the pool of task-relevant responses.

Nov. 20, 2012

Three-Dimensional Flexible Electronics Enabled by Shape Memory Polymer Substrates for Responsive Neural Interfaces
Planar electronics processing methods have enabled neural interfaces to become more precise and deliver more information. However, this processing paradigm is inherently 2D and rigid.

Aug. 13, 2012

Neural mechanisms supporting robust discrimination of spectrally and temporally degraded speech
Cochlear implants provide good speech discrimination ability despite highly limited amount of information they transmit compared with normal cochlea.

July 28, 2012

Experience-Dependent Plasticity and Auditory Cortex
Throughout their lifetimes, individuals are constantly engaged by acoustic environments that leave lasting impressions, such as the sound of a familiar voice or the rhythm of a catchy tune. A fundamental question in auditory neuroscience concerns how and where such acoustic knowledge is acquired and stored in the brain.
Kathryn N. Shepard, Michael P. Kilgard, Robert C. Liu

July 2012

Speech discrimination after early exposure to pulsed-noise or speech
Early experience of structured inputs and complex sound features generate lasting changes in tonotopy and receptive field properties of primary auditory cortex (A1).

May 2, 2012

Fabrication of Responsive, Softening Neural Interfaces
A novel processing method is described using photolithography to pattern thin-film flexible electronics on shape memory polymer substrates with mechanical properties tailored to improve biocompatability and enhance adhesion between the polymer substrate and metal layers.

Feb. 21, 2012

Complex Mixture Discrimination and the Role of Contaminants
Rats were trained in a 2-alternative odor choice task to discriminate between a 10-component odor mixture and the same mixture with one component removed and replaced with 1 of 3 concentrations of a different monomolecular odor (contaminant).