Publications by authors named "Michael P Kilgard"

98 Publications

Vagus nerve stimulation enhances fear extinction as an inverted-U function of stimulation intensity.

Exp Neurol 2021 Jul 15;341:113718. Epub 2021 Apr 15.

Texas Biomedical Device Center, The University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080, United States; School of Behavioral Brain Sciences, The University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080, United States.

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. Pairing extinction training with moderate VNS intensity of 0.8 mA produced significant reduction in conditioned fear during extinction retention when rats were tested a week after VNS-paired extinction. High intensity VNS at 1.6 mA failed to enhance extinction. These findings indicate that a narrow range of VNS intensities enhances extinction learning, and suggest that the 0.8 mA VNS intensity used in earlier rodent and human stroke studies may also be the optimal in using VNS as an adjuvant in exposure therapies for PTSD.
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http://dx.doi.org/10.1016/j.expneurol.2021.113718DOI Listing
July 2021

Vagus nerve stimulation promotes extinction generalization across sensory modalities.

Neurobiol Learn Mem 2021 May 23;181:107425. Epub 2021 Mar 23.

Texas Biomedical Device Center, The University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080, United States; School of Behavioral Brain Sciences, The University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080, United States.

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. Male Sprague Dawley rats were implanted with a stimulating cuff on the cervical vagus nerve. Rats then received two days of fear conditioning where olfactory (amyl acetate odor) and auditory (9 kHz tones) stimuli were concomitantly paired with footshock. Twenty-four hours later, rats were given three days of sham or VNS-paired extinction (5 stimulations, 30-sec trains at 0.4 mA) overlapping with presentation of either the olfactory or the auditory stimulus. Two days later, rats were given an extinction retention test where avoidance of the olfactory stimulus or freezing to the auditory stimulus were measured. VNS-paired with exposure to the olfactory stimulus during extinction reduced avoidance of the odor in the retention test. VNS-paired with exposure to the auditory stimulus during extinction also decreased avoidance of the olfactory cue, and VNS paired with exposure to the olfactory stimulus during extinction reduced freezing when the auditory stimulus was presented in the retention test. These results indicate that VNS enhances extinction of olfactory fear and promotes extinction generalization across different sensory modalities. Extinction generalization induced by VNS may therefore improve outcomes of exposure-based therapies.
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http://dx.doi.org/10.1016/j.nlm.2021.107425DOI Listing
May 2021

High intensity VNS disrupts VNS-mediated plasticity in motor cortex.

Brain Res 2021 Apr 1;1756:147332. Epub 2021 Feb 1.

The University of Texas at Dallas, School of Behavioral Brain Sciences, Richardson, TX, United States; The University of Texas at Dallas, Texas Biomedical Device Center, Richardson, TX, United States; The University of Texas at Dallas, Erik Jonsson School of Engineering and Computer Science, Richardson, TX, United States.

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. We tested the interaction of moderate and high intensity VNS trains to probe the mechanisms that may underlie VNS-dependent plasticity. Rats performed a behavioral task where VNS was paired with jaw movement during chewing. For five days, subjects received 100 pairings of moderate intensity VNS (Standard VNS), 100 pairings alternating between moderate and high intensity VNS (Interleaved VNS), or 50 pairings of moderate intensity VNS (Short VNS) approximately every 8 s. After the final behavioral session, intracortical microstimulation (ICMS) was used to evaluate movement representations in motor cortex. 100 pairings of moderate intensity VNS enhanced motor cortex plasticity. Replacing half of moderate intensity stimulation with high intensity VNS blocked this enhancement of plasticity. Removing high intensity stimulation, leaving only 50 pairings of moderate intensity VNS, reinstated plasticity. These results demonstrate that there is a period for at least 8 s after high intensity stimulation in which moderate intensity VNS is not able to engage mechanisms required for synaptic reorganization. More importantly, this study demonstrates that changes in stimulation parameters are a critical determinant of the magnitude of plasticity and likely the efficacy of VNS-enhanced recovery.
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http://dx.doi.org/10.1016/j.brainres.2021.147332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971691PMC
April 2021

Deficits in skilled motor and auditory learning in a rat model of Rett syndrome.

J Neurodev Disord 2020 09 28;12(1):27. Epub 2020 Sep 28.

School of Behavioral and Brain Sciences, The University of Texas at Dallas, 800 West Campbell Road, Richardson, TX, 75080-3021, USA.

Background: 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. Animals were trained to perform a speech discrimination task or a skilled forelimb reaching task.

Results: Our results reveal that Mecp2 rats display slower acquisition and reduced performance on an auditory discrimination task than wild-type (WT) littermates. Similarly, Mecp2 rats exhibit impaired learning rates and worse performance on a skilled forelimb motor task compared to WT.

Conclusions: Together, these findings illustrate novel deficits in skilled learning consistent with clinical manifestation of Rett syndrome and provide a framework for development of therapeutic strategies to improve these complex behaviors.
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http://dx.doi.org/10.1186/s11689-020-09330-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523346PMC
September 2020

The tactile experience paired with vagus nerve stimulation determines the degree of sensory recovery after chronic nerve damage.

Behav Brain Res 2021 01 21;396:112910. Epub 2020 Sep 21.

The University of Texas at Dallas, Texas Biomedical Device Center, 800 West Campbell Road, Richardson, TX 75080-3021, United States; The University of Texas at Dallas, Erik Jonsson School of Engineering and Computer Science, Department of Bioengineering, 800 West Campbell Road, Richardson, TX 75080-3021, United States; The University of Texas at Dallas, School of Behavioral and Brain Sciences, 800 West Campbell Road, Richardson, TX 75080-3021, United States.

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. Here, we tested the hypothesis that a specific component of the tactile rehabilitation paired with VNS is necessary for recovery of somatosensory function. In a second experiment in a separate cohort, we investigated whether VNS paired with tactile rehabilitation could improve skilled forelimb motor function. Elements of the study design, including planned sample size, assessments, and statistical comparisons, were preregistered prior to beginning data collection (https://osf.io/3tm8u/). Animals received a peripheral nerve injury (PNI) causing chronic sensory loss. Eight weeks after injury, animals were given a VNS implant followed by six weeks of tactile rehabilitation sessions consisting of repeated application of one of two distinct mechanical stimuli, a filament or a paintbrush, to the previously denervated forepaw. VNS paired with either filament indentation or brushing of the paw significantly improved recovery of forelimb withdrawal thresholds after PNI compared to tactile rehabilitation without VNS. The effect size was twice as large when VNS was paired with brushing compared to VNS paired with point indentation. An independent replication in a second cohort confirmed that VNS paired with brush restored forelimb withdrawal thresholds to normal. These rats displayed significant improvements in performance on a skilled forelimb task compared to rats that did not receive VNS. These findings support the utility of pairing VNS with tactile rehabilitation to improve recovery of somatosensory and motor function after neurological injury. Additionally, this study demonstrates that the sensory characteristics of the rehabilitation paired with VNS determine the degree of recovery.
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http://dx.doi.org/10.1016/j.bbr.2020.112910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572822PMC
January 2021

Optimizing Dosing of Vagus Nerve Stimulation for Stroke Recovery.

Transl Stroke Res 2021 02 25;12(1):65-71. Epub 2020 Jun 25.

Texas Biomedical Device Center, BSB11 800 W Campbell Rd, Richardson, TX, 75080, USA.

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.
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http://dx.doi.org/10.1007/s12975-020-00829-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759576PMC
February 2021

Corrigendum to "Varying Stimulation Parameters to Improve Cortical Plasticity Generated by VNS-tone Pairing" [Neuroscience 388C (2018) 239-247].

Neuroscience 2020 Aug 12;440:360. Epub 2020 Jun 12.

Texas Biomedical Device Center, Richardson, TX 75080, United States; The University of Texas at Dallas, School of Behavioral Brain Sciences, 800 West Campbell Road, GR 41, Richardson, TX 75080-3021, United States.

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http://dx.doi.org/10.1016/j.neuroscience.2020.05.031DOI Listing
August 2020

A limited range of vagus nerve stimulation intensities produce motor cortex reorganization when delivered during training.

Behav Brain Res 2020 08 28;391:112705. Epub 2020 May 28.

The University of Texas at Dallas, Texas Biomedical Device Center, Richardson, TX, United States; The University of Texas at Dallas, Erik Jonsson School of Engineering and Computer Science, Richardson, TX, United States.

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. However, it is not known whether VNS-dependent enhancement of plasticity is restricted to forelimb training or whether VNS paired with other movements could induce plasticity of other motor representations. We tested the hypothesis that VNS paired with orofacial movements associated with chewing during an unskilled task would drive a specific increase in jaw representation in motor cortex compared to equivalent behavioral experience without VNS. Rats performed a behavioral task in which VNS at a specified intensity between 0 and 1.2 mA was paired with chewing 200 times per day for five days. Intracortical microstimulation (ICMS) was then used to document movement representations in motor cortex. VNS paired with chewing at 0.8 mA significantly increased motor cortex jaw representation compared to equivalent behavioral training without stimulation (Bonferroni-corrected unpaired t-test, p < 0.01). Higher and lower intensities failed to alter cortical plasticity. No changes in other movement representations or total motor cortex area were observed between groups. These results demonstrate that 0.8 mA VNS paired with training drives robust plasticity specific to the paired movement, is not restricted to forelimb representations, and occurs with training on an unskilled task. This suggests that moderate intensity VNS may be a useful adjuvant to enhance plasticity and support benefits of rehabilitative therapies targeting functions beyond upper limb movement.
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http://dx.doi.org/10.1016/j.bbr.2020.112705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413489PMC
August 2020

Vagus Nerve Stimulation Paired With Rehabilitative Training Enhances Motor Recovery After Bilateral Spinal Cord Injury to Cervical Forelimb Motor Pools.

Neurorehabil Neural Repair 2020 03 22;34(3):200-209. Epub 2020 Jan 22.

The University of Texas at Dallas, Richardson, TX, USA.

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. While these findings provide initial evidence of the utility of VNS for SCI, the injury model used in these studies spares the majority of alpha motor neurons originating in C7-T1 that innervate distal forelimb muscles. Because the clinical manifestation of SCI in many patients involves damage at these levels, it is important to define whether damage to the distal forelimb motor neuron pools limits VNS-dependent recovery. In this study, we assessed recovery of forelimb function in rats that received a bilateral incomplete contusive SCI at C7/8 and underwent extensive rehabilitative training with or without paired VNS. The study design, including planned sample size, assessments, and statistical comparisons, was preregistered prior to beginning data collection ( https://osf.io/ysvgf/ ). VNS paired with rehabilitative training significantly improved recovery of volitional forelimb strength compared to equivalent rehabilitative training without VNS. Additionally, VNS-dependent enhancement of recovery generalized to 2 similar, but untrained, forelimb tasks. These findings indicate that damage to alpha motor neurons does not prevent VNS-dependent enhancement of recovery and provides additional evidence to support the evaluation of closed-loop VNS paired with rehabilitation in patients with incomplete cervical SCI.
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http://dx.doi.org/10.1177/1545968319895480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080607PMC
March 2020

Correction to: A suite of automated tools to quantify hand and wrist motor function after cervical spinal cord injury.

J Neuroeng Rehabil 2020 01 7;17(1). Epub 2020 Jan 7.

The University of Texas at Dallas, Texas Biomedical Device Center800 West Campbell Road, Richardson, TX, 75080-3021, USA.

The original article [1] contains several errors which the authors would like to rectify.
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http://dx.doi.org/10.1186/s12984-019-0627-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947918PMC
January 2020

Restoration of Somatosensory Function by Pairing Vagus Nerve Stimulation with Tactile Rehabilitation.

Ann Neurol 2020 02 7;87(2):194-205. Epub 2020 Jan 7.

Texas Biomedical Device Center, University of Texas at Dallas, Richardson, TX.

Objective: 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.

Methods: A clinical case report provides initial evidence that a similar implementation of closed-loop VNS paired with a tactile rehabilitation regimen could improve recovery of somatosensory function. Here, we sought to build on these promising initial clinical data and rigorously evaluate the ability of VNS paired with tactile rehabilitation to improve recovery in an animal model of chronic sensory loss. The study design, including planned sample size, assessments, and statistical comparisons, was preregistered prior to beginning data collection (https://osf.io/xsnj5/).

Results: VNS paired with tactile rehabilitation resulted in a significant and nearly complete recovery of mechanosensory withdrawal thresholds. Equivalent tactile rehabilitation without VNS failed to improve sensory function. This VNS-dependent restoration of sensory thresholds was maintained for several months after the cessation of stimulation, illustrating long-term benefits. Moreover, VNS paired with tactile rehabilitation resulted in significant generalized improvements in other measures of sensorimotor forepaw function.

Interpretation: Given the safety and tolerability of VNS therapy, these findings suggest that incorporating VNS paired with sensory retraining into rehabilitative regimens may represent a fundamentally new method to increase recovery of sensory function after neurological injury. ANN NEUROL 2020;87:194-205.
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http://dx.doi.org/10.1002/ana.25664DOI Listing
February 2020

Efficient parameters of vagus nerve stimulation to enhance extinction learning in an extinction-resistant rat model of PTSD.

Prog Neuropsychopharmacol Biol Psychiatry 2020 04 19;99:109848. Epub 2019 Dec 19.

Texas Biomedical Device Center, The University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080, United States of America; School of Behavioral Brain Sciences, The University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080, United States of America.

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. Delivery of the standard LONG VNS trains (30 s) at 0.4 mA enhanced extinction and reduced anxiety but did not prevent fear return. Increasing the intensity of LONG VNS trains to 0.8 mA prevented fear return and attenuated anxiety symptoms. Interestingly, delivering 1, 4 or 16 SHORT VNS bursts (0.5 s) at 0.8 mA during each cue presentation in extinction training also enhanced extinction. LONG VNS trains or multiple SHORT VNS bursts at 0.8 mA attenuated fear renewal and reinstatement, promoted extinction generalization and reduced generalized anxiety. Delivering 16 SHORT VNS bursts also facilitated extinction in fewer trials. This study provides the first evidence that brief bursts of VNS can enhance extinction training, reduce relapse and support symptom remission using much less VNS than previous protocols. These findings suggest that VNS parameters can be adjusted in order to minimize total charge delivery and maximize therapeutic effectiveness.
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http://dx.doi.org/10.1016/j.pnpbp.2019.109848DOI Listing
April 2020

Enhancing plasticity in central networks improves motor and sensory recovery after nerve damage.

Nat Commun 2019 12 19;10(1):5782. Epub 2019 Dec 19.

Texas Biomedical Device Center, The University of Texas at Dallas, 800 West Campbell Road, Richardson, TX, 75080-3021, USA.

Nerve damage can cause chronic, debilitating problems including loss of motor control and paresthesia, and generates maladaptive neuroplasticity as central networks attempt to compensate for the loss of peripheral connectivity. However, it remains unclear if this is a critical feature responsible for the expression of symptoms. Here, we use brief bursts of closed-loop vagus nerve stimulation (CL-VNS) delivered during rehabilitation to reverse the aberrant central plasticity resulting from forelimb nerve transection. CL-VNS therapy drives extensive synaptic reorganization in central networks paralleled by improved sensorimotor recovery without any observable changes in the nerve or muscle. Depleting cortical acetylcholine blocks the plasticity-enhancing effects of CL-VNS and consequently eliminates recovery, indicating a critical role for brain circuits in recovery. These findings demonstrate that manipulations to enhance central plasticity can improve sensorimotor recovery and define CL-VNS as a readily translatable therapy to restore function after nerve damage.
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http://dx.doi.org/10.1038/s41467-019-13695-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923364PMC
December 2019

Vagus nerve stimulation produces immediate dose-dependent anxiolytic effect in rats.

J Affect Disord 2020 03 13;265:552-557. Epub 2019 Nov 13.

Texas Biomedical Device Center, The University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080, United States; School of Behavioral Brain Sciences, The University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080, United States. Electronic address:

Background: 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.

Methods: Three groups of rats were implanted with VNS cuffs and tested for anxiety using the elevated plus maze (EPM), novelty suppressed feeding (NSF), and acoustic startle response (ASR), after receiving either one or five VNS trains (0.4 mA/30 Hz/30‑sec), or sham stimulation.

Results: Both single and multiple VNS trains reduced state anxiety as measured using the EPM, but only multiple trains reduced anxiety in the EPM and NSF. VNS did not decrease arousal as measured using the ASR.

Limitations: The anxiolytic effects of VNS may be differently influenced by test order or prior-exposure to stress. VNS did not affect startle responses in naïve rats but the present findings do not determine whether VNS would affect startle responses that are potentiated by fear or anxiety.

Conclusion: A single VNS train can produce an anxiolytic-like effect in the EPM minutes later, an effect that is not observed in the NSF. Delivering 5 VNS trains restores the immediate effects across tests of anxiety, indicating that more trains produce a more robust anxiolytic effect. The lack of effects on ASR suggests that VNS affects state anxiety but not baseline arousal in naïve rats. We suggest that the anxiolytic effect of VNS can increase tolerability and reduce dropout in exposure-based therapies.
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http://dx.doi.org/10.1016/j.jad.2019.11.090DOI Listing
March 2020

Flat electrode contacts for vagus nerve stimulation.

PLoS One 2019 18;14(11):e0215191. Epub 2019 Nov 18.

The University of Texas at Dallas, Erik Jonsson School of Engineering and Computer Science, Richardson, Texas, United States of America.

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. Computational modeling and in vivo experiments were performed to evaluate fiber recruitment in different nerves and different species using a variety of electrode designs. Initial results demonstrated similar fiber recruitment in the rat vagus and sciatic nerves with a standard circumferential cuff electrode and a cuff electrode modified to approximate a flat configuration. Follow up experiments comparing true flat electrodes to circumferential electrodes on the rabbit sciatic nerve confirmed that fiber recruitment was equivalent between the two designs. These findings demonstrate that flat electrodes represent a viable design for nerve stimulation that may provide advantages over the current circumferential designs for applications in which the goal is uniform activation of all fascicles within the nerve.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215191PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862926PMC
March 2020

Pairing vagus nerve stimulation with tones drives plasticity across the auditory pathway.

J Neurophysiol 2019 08 19;122(2):659-671. Epub 2019 Jun 19.

The University of Texas at Dallas, Texas Biomedical Device Center, Richardson, Texas.

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. We recorded neural responses to tones from 2,950 sites in the inferior colliculus (IC), A1, anterior auditory field (AAF), and posterior auditory field (PAF) 24 h after the last pairing session in anesthetized rats. We found that VNS-tone pairing increased the percentage of IC, A1, AAF, and PAF that responds to the paired tone frequency. Across all tested auditory fields, the response strength to tones was strengthened in VNS-tone paired rats compared with control rats. VNS-tone pairing reduced spontaneous activity, frequency selectivity, and response threshold across the auditory pathway. This is the first study to document both cortical and subcortical plasticity following VNS-sound pairing. Our findings suggest that VNS paired with sound presentation is an effective method to enhance auditory processing. Previous studies have reported primary auditory cortex plasticity following vagus nerve stimulation (VNS) paired with a sound. This study extends previous findings by documenting that fields across the auditory pathway are altered by VNS-tone pairing. VNS-tone pairing increases the percentage of each field that responds to the paired tone frequency. This is the first study to document both cortical and subcortical plasticity following VNS-sound pairing.
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http://dx.doi.org/10.1152/jn.00832.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734404PMC
August 2019

Norepinephrine and serotonin are required for vagus nerve stimulation directed cortical plasticity.

Exp Neurol 2019 10 7;320:112975. Epub 2019 Jun 7.

The University of Texas at Dallas, Texas Biomedical Device Center, 800 West Campbell Road, Richardson, TX 75080-3021, United States of America; The University of Texas at Dallas, Erik Jonsson School of Engineering and Computer Science, 800 West Campbell Road, Richardson, TX 75080-3021, United States of America.

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. Once proficient, all rats received a surgically implanted vagus nerve cuff and cortical injections of either immunotoxins to deplete serotonin or norepinephrine, or vehicle control. Following surgical recovery, rats received half second bursts of 0.8 mA or sham VNS after successful trials. After five days of pairing intracortical microstimulation (ICMS) was performed in the motor cortex contralateral to the trained limb. VNS paired with training more than doubled cortical representations of proximal forelimb movements. Depletion of either cortical norepinephrine or serotonin prevented this effect. The requirement of multiple neuromodulators is consistent with earlier studies showing that these neuromodulators regulate synaptic plasticity in a complimentary fashion.
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http://dx.doi.org/10.1016/j.expneurol.2019.112975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708444PMC
October 2019

Vagus nerve stimulation reverses the extinction impairments in a model of PTSD with prolonged and repeated trauma.

Stress 2019 07 23;22(4):509-520. Epub 2019 Apr 23.

a Texas Biomedical Device Center , The University of Texas at Dallas , Richardson , TX , USA.

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. The elevated plus maze, open field and startle were used to test anxiety. Sham rats showed no reduction of fear during extensive extinction training. VNS-paired with extinction training reduced freezing at the last extinction session by 70% compared to sham rats. VNS rats exhibited half as much fear as shams, as well as less fear renewal. Sham rats exhibited significantly more anxiety than naive controls, whereas VNS rats did not. These results demonstrate that VNS enhances extinction and reduces anxiety in a severe model of PTSD that combined SPS and a conditioning procedure that is 30 times more intense than the conditioning procedures in previous VNS studies. The broad utility of VNS in enhancing extinction learning in rats and the strong clinical safety record of VNS suggest that VNS holds promise as an adjuvant to exposure-based therapy in people with PTSD and other complex forms of this condition.
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http://dx.doi.org/10.1080/10253890.2019.1602604DOI Listing
July 2019

A suite of automated tools to quantify hand and wrist motor function after cervical spinal cord injury.

J Neuroeng Rehabil 2019 04 11;16(1):48. Epub 2019 Apr 11.

The University of Texas at Dallas, Texas Biomedical Device Center800 West Campbell Road, Richardson, TX, 75080-3021, USA.

Background: 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.

Methods: 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).

Results: We find that the rehabilitative devices are useful to provide assessment of upper limb function in physical units over time in SCI participants and are well-correlated with standard assessments.

Conclusions: These results indicate that these tools represent a reliable system for longitudinal evaluation of upper extremity function after cSCI and may provide a framework to assess the efficacy of strategies aimed at improving recovery of upper limb function.
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http://dx.doi.org/10.1186/s12984-019-0518-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458684PMC
April 2019

Protocol for Construction of Rat Nerve Stimulation Cuff Electrodes.

Methods Protoc 2019 Mar 15;2(1). Epub 2019 Feb 15.

School of Brain and Behavioral Sciences, The University of Texas at Dallas, Richardson, TX 75080-3021, USA; (M.U.R.); (M.P.K.), (S.A.H.).

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. These designs are built with simple, widely available materials, using platinum-iridium electrodes assembled into polyurethane tubing. Moreover, the designs can easily be customized to increase versatility and individualize for specific stimulation applications. This protocol provides a resource to facilitate the construction and customization of stimulation cuffs to support preclinical nerve stimulation research.
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http://dx.doi.org/10.3390/mps2010019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448795PMC
March 2019

Vagus Nerve Stimulation Rate and Duration Determine whether Sensory Pairing Produces Neural Plasticity.

Neuroscience 2019 05 21;406:290-299. Epub 2019 Mar 21.

Texas Biomedical Device Center, Richardson, TX 75080, USA; The University of Texas at Dallas, School of Behavioral Brain Sciences, 800 West Campbell Road, GR 41, Richardson, TX 75080-3021, USA.

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. Rats were exposed to a 9 kHz tone 300 times per day for 20 days. Coincident with tone presentation, groups received trains of 4, 16, or 64 pulses of VNS delivered at 30 Hz, corresponding to train durations of 0.125 s, 0.5 s, and 2.0 s, respectively. High-density microelectrode mapping of A1 revealed that 0.5 s duration VNS trains significantly increased the number of neurons in A1 that responded to tones near the paired tone frequency. Trains lasting 0.125 or 2.0 s failed to alter A1 responses, indicating that both shorter and longer stimulation durations are less effective at enhancing plasticity. A second set of experiments evaluating the effect of delivering 4 or 64 pulses in a fixed 0.5 s VNS train duration paired with tone presentation reveal that both slower and faster stimulation rates are less effective at enhancing plasticity. We incorporated these results with previous findings describing the effect of stimulation parameters on VNS-dependent plasticity and activation of neuromodulatory networks to generate a model of synaptic activation by VNS.
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http://dx.doi.org/10.1016/j.neuroscience.2019.03.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511481PMC
May 2019

ReStore: A wireless peripheral nerve stimulation system.

J Neurosci Methods 2019 05 5;320:26-36. Epub 2019 Mar 5.

The University of Texas at Dallas, Erik Jonsson School of Engineering and Computer Science, Department of Bioengineering, 800 West Campbell Road, Richardson, TX 75080-3021, United States; The University of Texas at Dallas, Texas Biomedical Device Center, 800 West Campbell Road, Richardson, TX 75080-3021, United States; The University of Texas at Dallas, School of Behavioral Brain Sciences, 800 West Campbell Road, GR41, Richardson, TX 75080-3021, United States. Electronic address:

Background: The growing use of neuromodulation techniques to treat neurological disorders has motivated efforts to improve on the safety and reliability of implantable nerve stimulators.

New Method: 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.

Results: The results show that the system can reliably deliver accurate stimulation pulses through a range of different loads. Tests of nerve recruitment demonstrate that the implant can effectively activate peripheral nerves, even after accelerated aging and post-chronic implantation. Biocompatibility and hermeticity tests provide an initial indication that the implant will be safe for use in humans.

Comparison With Existing Method(s): Most commercially available nerve stimulators include a battery and wire leads which often require subsequent surgeries to address failures in these components. Though miniaturized battery-less stimulators have been prototyped in academic labs, they are often constructed using custom components and processes that hinder clinical translation.

Conclusions: The results from testing the performance and safety of the ReStore system establish its potential to advance the field of peripheral neuromodulation.
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http://dx.doi.org/10.1016/j.jneumeth.2019.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529940PMC
May 2019

Vagus nerve stimulation intensity influences motor cortex plasticity.

Brain Stimul 2019 Mar - Apr;12(2):256-262. Epub 2018 Nov 3.

The University of Texas at Dallas, School of Behavioral Brain Sciences, Richardson, TX, USA; The University of Texas at Dallas, Texas Biomedical Device Center, Richardson, TX, USA; The University of Texas at Dallas, Erik Jonsson School of Engineering and Computer Science, Richardson, TX, USA.

Background: 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.

Objective: 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.

Methods: Rats were taught to perform a lever pressing task emphasizing use of the proximal forelimb musculature. Once proficient, rats underwent five additional days of behavioral training in which low intensity VNS (0.4 mA), moderate intensity VNS (0.8 mA), high intensity VNS (1.6 mA), or sham stimulation was paired with forelimb movement. 24 h after the completion of behavioral training, intracortical microstimulation (ICMS) was used to document movement representations in the motor cortex.

Results: VNS delivered at 0.8 mA caused a significant increase in motor cortex proximal forelimb representation compared to training alone. VNS delivered at 0.4 mA and 1.6 mA failed to cause a significant expansion of proximal forelimb representation.

Conclusion: Moderate intensity 0.8 mA VNS optimally enhances motor cortex plasticity while low intensity 0.4 mA and high intensity 1.6 mA VNS fail to enhance plasticity. Plasticity in the motor cortex exhibits an inverted-U function of VNS intensity similar to previous findings in auditory cortex.
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http://dx.doi.org/10.1016/j.brs.2018.10.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347516PMC
June 2019

Vagus nerve stimulation promotes generalization of conditioned fear extinction and reduces anxiety in rats.

Brain Stimul 2019 Jan - Feb;12(1):9-18. Epub 2018 Sep 21.

The University of Texas at Dallas, School of Behavior and Brain Sciences, 800 West Campbell Road, Richardson, TX, 75080-3021, United States; The University of Texas at Dallas, Texas Biomedical Device Center, 800 West Campbell Road, Richardson, TX, 75080-3021, United States. Electronic address:

Background: 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.

Objective: We tested whether VNS, like other cognitive enhancers, could produce generalization of extinction for stimuli that are not presented during the extinction sessions, but are associated with the fear event.

Methods: Male Sprague Dawley rats underwent auditory fear conditioning with two easily discriminable auditory stimuli. Following fear conditioning, extinction training consisted of exposure to only one of the conditioned sounds. Half of the rats received VNS and half received sham stimulation during with sound presentations. VNS effects on anxiety were examined in a separate study where VNS was administered prior to testing on the elevated plus maze.

Results: Sham stimulated rats given 20 presentations of a conditioned stimulus (CS) during the extinction session showed performance that was matched to VNS-treated rats given only 4 presentations of the CS. Despite comparable levels of freezing to the presented CS, only the VNS-treated rats showed a significant decrease in freezing to the CS that was not presented. VNS-induced generalization of extinction was observed only when the two sounds were paired with footshock within the same fear conditioning session; VNS did not promote generalization of extinction when the two sounds were conditioned on different days or in different contexts. On the anxiety test, VNS administration significantly increased time spent in the open arms of the elevated plus maze.

Conclusion: These results provide evidence that VNS can promote generalization of extinction to other stimuli associated with a specific fear experience. Furthermore, non-contingent VNS appears to reduce anxiety. The ability to generalize extinction and reduce anxiety makes VNS a potential candidate for use as an adjunctive strategy to improve the efficacy and tolerability of exposure-based therapies.
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http://dx.doi.org/10.1016/j.brs.2018.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301121PMC
May 2019

Varying Stimulation Parameters to Improve Cortical Plasticity Generated by VNS-tone Pairing.

Neuroscience 2018 09 29;388:239-247. Epub 2018 Jul 29.

Texas Biomedical Device Center, Richardson, TX 75080, United States; The University of Texas at Dallas, School of Behavioral Brain Sciences, 800 West Campbell Road, GR 41, Richardson, TX 75080-3021, United States.

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. Rats were implanted with a vagus nerve stimulating cuff and randomly assigned to one of three treatment groups to receive 20 days of VNS paired with a 9-kHz tone: (1) Fast VNS: 50 daily pairings of 400-µA VNS with a 30-s ISI; (2) Dispersed VNS: 50 daily pairings of 400-µA VNS with a 180-s ISI; and (3) Standard VNS: 300 daily pairings of 800-µA VNS with a 30-s ISI. Following 20 days of VNS-tone pairing, multi-unit recordings were conducted in primary auditory cortex (A1) and receptive field properties were analyzed. Increasing ISI (Dispersed VNS) did not lead to an enhancement of cortical plasticity. Reducing the current intensity and number of stimulations (Fast VNS) resulted in robust cortical plasticity, using 6 times fewer VNS pairings than the Standard protocol. These findings reveal an interaction between current intensity, stimulation number, and ISI and identify a novel VNS paradigm that is substantially more efficient than the previous standard paradigm.
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http://dx.doi.org/10.1016/j.neuroscience.2018.07.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460466PMC
September 2018

Vagus nerve stimulation paired with tactile training improved sensory function in a chronic stroke patient.

NeuroRehabilitation 2018 ;42(2):159-165

Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Western Infirmary, Glasgow, UK.

Background: 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.

Objective: To gain "first-in-man" experience of VNS paired with tactile training in a patient with severe sensory impairment after stroke.

Methods: During the long-term follow-up phase of a clinical trial of VNS paired with motor rehabilitation, a 71-year-old man who had made good motor recovery had ongoing severe sensory loss in his left hand and arm. He received VNS paired with tactile therapy in an attempt to improve his sensory function. During twenty 2-hour sessions, each passive and active tactile event was paired with a 0.5 second burst of 0.8 mA VNS. Sensory function was measured before, halfway through, and after this therapy.

Results: The patient did not report any side effects during or following VNS+Tactile therapy. Quantitative measures revealed lasting and clinically meaningful improvements in tactile threshold, proprioception, and stereognosis. After VNS+Tactile therapy, the patient was able to detect tactile stimulation to his affected hand that was eight times less intense, identify the joint position of his fingers in the affected hand three times more often, and identify everyday objects using his affected hand seven times more often, compared to baseline.

Conclusions: Sensory function significantly improved in this man following VNS paired with tactile stimulation. This approach merits further study in controlled clinical trials.
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http://dx.doi.org/10.3233/NRE-172273DOI Listing
July 2018

Closed-loop neuromodulation restores network connectivity and motor control after spinal cord injury.

Elife 2018 03 13;7. Epub 2018 Mar 13.

Erik Jonsson School of Engineering and Computer Science, The University of Texas at Dallas, Richardson, United States.

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. The addition of CLV to rehabilitation promoted substantially more recovery of forelimb function compared to rehabilitation alone following chronic unilateral or bilateral cervical SCI in a rat model. Triggering stimulation on the most successful movements is critical to maximize recovery. CLV enhances recovery by strengthening synaptic connectivity from remaining motor networks to the grasping muscles in the forelimb. The benefits of CLV persist long after the end of stimulation because connectivity in critical neural circuits has been restored.
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http://dx.doi.org/10.7554/eLife.32058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849415PMC
March 2018

The M-Maze task: An automated method for studying fear memory in rats exposed to protracted aversive conditioning.

J Neurosci Methods 2018 03 13;298:54-65. Epub 2018 Feb 13.

Texas Biomedical Device Center, The University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080, United States; School of Behavioral Brain Sciences, The University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080, United States; Erik Jonsson School of Engineering and Computer Science. The University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080, United States.

Background: Fear conditioning (FC) in rodents is the most used animal model to investigate the neurobiology of posttraumatic stress disorder (PTSD). Although research using FC has generated a better understanding of fear memories, studies often rely on mild or moderate FC training and behavioral analysis generally focuses on measuring freezing responses within few test sessions.

New Method: 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.

Results: An intense one-day auditory FC protocol induced a sharp elevation in transit time and suppression of nose pokes by conditioned cues, but in contrast to what is found in PTSD patients, fear extinction was rapidly observed. On the other hand, PAC alone or in combination with exposure to single prolonged stress induced persistent extinction impairments in M-Maze tests, as well as enhanced anxiety, and social withdrawal.

Comparison With Other Existing Methods: The M-Maze task is fully automated and allows multiple animals to be tested simultaneously in long-term experiments. Moreover, PAC training can be an alternative approach to study extinction-resistant fear.

Conclusions: The M-Maze task allows rapid and unbiased measurements of fear-induced suppression. We suggest that long-term assessment of extinction impairments would lead to a better understanding of the neurobiology of persistent fear and the screening for new therapies.
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http://dx.doi.org/10.1016/j.jneumeth.2018.02.004DOI Listing
March 2018

Vagus Nerve Stimulation Enhances Stable Plasticity and Generalization of Stroke Recovery.

Stroke 2018 03 25;49(3):710-717. Epub 2018 Jan 25.

From the Texas Biomedical Device Center (E.C.M., B.R.S., J.J., P.D.G., E.S.L., R.L.R., M.P.K., S.A.H.), Erik Jonsson School of Engineering and Computer Science (E.C.M., P.D.G., E.S.L., R.L.R., M.P.K., S.A.H.), and School of Behavioral Brain Sciences (J.J., R.L.R., M.P.K.), University of Texas at Dallas, Richardson.

Background And Purpose: 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.

Methods: Rats were trained on a fully automated, quantitative task that measures forelimb supination. On task proficiency, unilateral cortical and subcortical ischemic lesions were administered. One week after ischemic lesion, rats were randomly assigned to receive 6 weeks of rehabilitative training on the supination task with or without VNS. Rats then underwent 4 weeks of testing on a task assessing forelimb strength to test generalization of recovery. Finally, the durability of VNS benefits was tested on the supination task 2 months after the cessation of VNS. After the conclusion of behavioral testing, viral tracing was performed to assess synaptic connectivity in motor networks.

Results: VNS enhances plasticity in corticospinal motor networks to increase synaptic connectivity to musculature of the rehabilitated forelimb. Adding VNS more than doubled the benefit of rehabilitative training, and the improvements lasted months after the end of VNS. Pairing VNS with supination training also significantly improved performance on a similar, but untrained task that emphasized volitional forelimb strength, suggesting generalization of forelimb recovery.

Conclusions: This study provides the first evidence that VNS paired with rehabilitative training after stroke (1) doubles long-lasting recovery on a complex task involving forelimb supination, (2) doubles recovery on a simple motor task that was not paired with VNS, and (3) enhances structural plasticity in motor networks.
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http://dx.doi.org/10.1161/STROKEAHA.117.019202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454573PMC
March 2018

Pairing sound with vagus nerve stimulation modulates cortical synchrony and phase coherence in tinnitus: An exploratory retrospective study.

Sci Rep 2017 12 11;7(1):17345. Epub 2017 Dec 11.

Texas Biomedical Device Center, University of Texas at Dallas, Richardson, TX, USA.

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. Since previous studies observed that gamma activity in the auditory cortex is correlated with tinnitus loudness, we assessed resting-state source-localized EEG before and after one to three months of VNS-tone pairing in chronic tinnitus patients. VNS-tone pairing reduced gamma band activity in left auditory cortex. VNS-tone pairing also reduced the phase coherence between the auditory cortex and areas associated with tinnitus distress, including the cingulate cortex. These results support the hypothesis that VNS-tone pairing can direct therapeutic neural plasticity. Targeted plasticity therapy might also be adapted to treat other conditions characterized by hypersynchronous neural activity.
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http://dx.doi.org/10.1038/s41598-017-17750-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725594PMC
December 2017