Publications by authors named "David T Pruitt"

9 Publications

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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

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

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

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

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

Traumatic Brain Injury Occludes Training-Dependent Cortical Reorganization in the Contralesional Hemisphere.

J Neurotrauma 2017 09 19;34(17):2495-2503. Epub 2017 Jul 19.

2 Erik Jonsson School of Engineering and Computer Science University of Texas at Dallas , Richardson, Texas.

Rehabilitative training drives plasticity in the ipsilesional (injured) motor cortex that is believed to support recovery of motor function after either stroke or traumatic brain injury (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 2 months. At the end of training, intracortical microstimulation 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 with in 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.
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http://dx.doi.org/10.1089/neu.2016.4796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576212PMC
September 2017

Forelimb training drives transient map reorganization in ipsilateral motor cortex.

Behav Brain Res 2016 10 5;313:10-16. Epub 2016 Jul 5.

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

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. To determine whether training results in reorganization of ipsilateral motor cortex maps, rats were trained to perform the isometric pull task, an automated motor task that requires skilled forelimb use. After either 3 or 6 months of training, intracortical microstimulation (ICMS) mapping was performed to document motor representations of the trained forelimb in the hemisphere ipsilateral to that limb. Motor training for 3 months resulted in a robust expansion of right forelimb representation in the right motor cortex, demonstrating that skilled motor training drives map plasticity ipsilateral to the trained limb. After 6 months of training, the right forelimb representation in the right motor cortex was significantly smaller than the representation observed in rats trained for 3 months and similar to untrained controls, consistent with a normalization of motor cortex maps. Forelimb map area was not correlated with performance on the trained task, suggesting that task performance is maintained despite normalization of cortical maps. This study provides new insights into how the ipsilateral cortex changes in response to skilled learning and may inform rehabilitative strategies to enhance cortical plasticity to support recovery after brain injury.
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http://dx.doi.org/10.1016/j.bbr.2016.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987250PMC
October 2016

Vagus Nerve Stimulation Delivered with Motor Training Enhances Recovery of Function after Traumatic Brain Injury.

J Neurotrauma 2016 05 5;33(9):871-9. Epub 2015 Aug 5.

1 The, School of Behavioral Brain Sciences, The University of Texas at Dallas , Richardson, Texas.

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. Recovery of motor function is often incomplete. We have developed a method using electrical stimulation of the vagus nerve paired with forelimb use by which we have demonstrated enhanced recovery from ischemic and hemorrhagic stroke. Here we have tested the hypothesis that vagus nerve stimulation (VNS) paired with physical rehabilitation could enhance functional recovery after TBI. We trained rats to pull on a handle to receive a food reward. Following training, they received a controlled-cortical impact (CCI) in the forelimb area of motor cortex opposite the trained forelimb, and were then randomized into two treatment groups. One group of animals received VNS paired with rehabilitative therapy, whereas another group received rehabilitative therapy without VNS. Following CCI, volitional forelimb strength and task success rate in all animals were significantly reduced. VNS paired with rehabilitative therapy over a period of 5 weeks significantly increased recovery of both forelimb strength and success rate on the isometric pull task compared with rehabilitative training without VNS. No significant improvement was observed in the Rehab group. Our findings indicate that VNS paired with rehabilitative therapy enhances functional motor recovery after TBI.
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http://dx.doi.org/10.1089/neu.2015.3972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860663PMC
May 2016