Collaborative Projects (CPs)

Active Collaborative Projects

CP1: Stroke BCI-based EEG Rehabilitation (Related to TRD1 and TRD2; Began in 2014)

Collaborators: Dr. D. Reinkensmeyer (UC Irvine) and Dr. E. Wolbrecht (U Idaho, Moscow)

Funding: NIH/NICHD R01-HD095457; UCI NIH CTSA Inst for Clinical & Translational Science UM1-TR004927


Significance and Collaborative Aims


This collaborative project brings together NCAN’s expertise in neurophysiological assessments and integration of realtime feedback of neural features in an EEG-based BCI setup, and UCI’s expertise in robotic technology development and clinical testing. Our initial studies of pre-movement sensorimotor rhythms (McFarland et al., 2015, Norman et al., 2018) developed and tested EEG-based BCI protocols with the UCI FINGER robot. These studies assessed and sought to enhance recovery of finger function after stroke, demonstrating clinical efficacy. Recent NCAN and UCI studies highlighted the important role of somatosensory function in finger movement after brain injury, and its potential to affect recovery (Ingemanson, et al., 2019a, 2019b, Gupta et al., 2017, 2021). Based on these new developments, we collaboratively developed and tested EEG-based procedures to assess neural correlates of proprioception during finger movement, using the UCI FINGER and improved THINGER robots (Farrens et al., 2023, Vall-llosera et al., 2023, Chaisson et al., 2021, Rueda Parra’s PhD (2019-22); Chaisson’s Masters (2020-22). In a recent clinical trial in stroke (NCT04818073, 2022-24, 45 participants), we are seeing evidence that these neural correlates are associated with functional gains from robot-based therapy (Farrens et al., 2023, Rueda Parra, et al., 2024, Gupta et al., 2024). These studies lead to the hypothesis now driving this CP: a BCI that trains people to increase the neural correlates associated with recovery can target beneficial plasticity and can thereby lead to functional recovery. To test this hypothesis, this CP will develop a BCI protocol with the UCI THINGER robot that focuses on the neural correlates of proprioception.


The Collaborative Aims are:


Aim 1. Develop and validate a BCI with the THINGER robot that trains people to increase the neural correlates of proprioception identified in our recent studies.


Aim 2. Assess the ability of this BCI to enhance recovery in chronic stroke survivors. Each person will receive robot-based proprioceptive training with (BCI Group) or without (Control Group) BCI guidance. We expect that recovery will be better in the BCI Group and that these effects will persist.


Publications


• Christopher K. Bitikofer, Sebastian Rueda Parra, Rene Maura, Eric T. Wolbrecht, Joel C. Perry. (2024) BLUE SABINO: Development of a BiLateral Upper-limb Exoskeleton for Simultaneous Assessment of Biomechanical and Neuromuscular Output. (Machines, in press)
• Rueda Parra S, Perry J, Wolbrecht E, Gupta D (2024) Neural correlates of Bilateral Proprioception and Adaptation with Training. PLoS One, 19(3): e0299873. PMID: 38489319
• Rueda Parra S, Perry J, Wolbrecht E, Reinkensmeyer D, Gupta D (2024) Multidimensional feature analysis shows stratification in robotic-motor-training gains based on the level of pre-training motor impairment in stroke. IEEE Engineering in Medicine & Biology Society. Conf. Proc. pp: 1-5.
• Norman SL, Wolpaw JR, Reinkensmeyer DJ (2022) Targeting neuroplasticity to improve motor recovery after
stroke: an artificial neural network model. Brain Communications, 4(6), fcac264. PMID: 36458210
• Norman SL, McFarland DJ, Miner A, Cramer SC, Wolbrecht ET, Wolpaw JR, Reinkensmeyer DJ (2018) Controlling pre-movement sensorimotor rhythm can improve finger extension after stroke. Journal of Neural Engineering, 15(5):056026 PMID: 30063219


References


• McFarland DJ, Sarnacki WA, Wolpaw JR (2015) Effects of training pre-movement sensorimotor rhythms on behavioral performance. Journal of Neuroengineering, 12: 066021 (11pp). PMID:26529119
• Ingemanson ML, Rowe JR, Chan V, Riley J, Wolbrecht E, Reinkensmeyer D, Cramer S (2019a) Neural Correlates of Passive Position Finger Sense After Stroke. Neurorehabil Neural Repair. 33(9):740-750.
• Ingemanson ML, Rowe JR, Chan V, Wolbrecht ET, Reinkensmeyer DJ, Cramer SC (2019b). Somatosensory system integrity explains differences in treatment response after stroke. Neurology. 92(10):e1098-e1108.
• Gupta D, Barachant A, Gordon A, Ferre C, Kuo H-C, Carmel J, Kathleen F (2017) Effect of sensory and motor connectivity on hand function in hemiplegic children, Annals of Neurology, 82(5).
• Gupta D, Barachant A, Carmel J, Friel K (2021) A new method for extracting neural correlates of movement in people with movement disorders: A study of ipsilateral control for bimanual function in pediatric hemiplegia, ASNR Annual Meeting.
•Wolpaw J, Thompson A, Perez M, Norman S, Oudega M, Winstein C, (2024).Neurorehabilitation in the 21st century: new science, new strategies, new expectations. (In Revision.)


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Reinkensmeyer People page
Wolbrecht People page

CP2: Attention, Orientation and the Human Prefrontal Cortex (Part of TRD1 and TRD3)

Collaborator: Dr. Robert T. Knight, University of California, Berkeley (UCB)

Collaborator Funding: NIH/NINDS R01-NS021135 (9/9/1985-1/31/2027), “Attention, Orientation and the Human Prefrontal Cortex”

Significance and Collaborative Aims


The long-term goal of this ongoing collaborative project is to improve the understanding of prefrontal cortex (PFC) function by combining NCAN’s unique BCI2000-based technologies to characterize cortical function and
behavior with UCB’s sophisticated neuroscientific understanding of the PFC. Over the past cycle of this project, we have, together with UCB developed gamified BCI2000-based experiments that can induce anxiety and stressor
(Gorenstein et al., 2024; Staveland et al. 2023, 2024). We have also developed better approaches to detecting neural oscillations (Cho et al. 2023) and directly decoding perception from neural signals (Bellier et al., 2023). In
accordance with the aims of the UCB NIH grant, we will further develop our BCI2000-based experiments to social interactions in pairs of intracranially monitored patients (Alnes et al., 2024). We will use the psychometric and
neurometric functions developed in TRD3 to determine the relationship between the induced stressors, autonomic nervous system functions and behavior.


The Collaborative Aims are:


Aim 1. Develop BCI2000-based experiments that facilitate induction of anxiety and other stressors in the interactions between pairs of intracranially-monitored human subjects.


Aim 2. Develop psychometric and neurometric functions to determine the relationship between induced stressors, autonomic nervous system functions and behavior.


Publications


• Blenkmann AO, Leske SL, Llorens A, Lin JJ, Chang EF, Brunner P, Schalk G, Ivanovic J, Larsson PG, Knight RT, Endestad T, Solbakk AK. Anatomical registration of intracranial electrodes. Robust modelbased localization and deformable smooth brain-shift compensation methods. J Neurosci Methods. 2024. 404:110056. PMID: 38224783.
• Bellier L, Llorens A, Marciano D, Gunduz A, Schalk G, Brunner P, Knight RT. Music can be reconstructed from human auditory cortex activity using nonlinear decoding models. PLoS Biol. 2023. 21(8):e3002176. PMCID: PMC10427021.
• Cho H, Fonken YM, Adamek M, Jimenez R, Lin JJ, Schalk G, Knight RT, Brunner P. Unexpected sound omissions are signaled in human posterior superior temporal gyrus: an intracranial study. Cereb Cortex. 2023. 33(14):8837-8848. PMCID: PMC10350817.


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Knight People page

CP3: Electrical stimulation to control feedback modulation of perception (Part of TRD1 and TRD3)

Collaborators: Drs. Dora Hermes and Kai Miller, Mayo Clinic

Collaborator Funding: NIH/NEI R01-EY035533 (9/1/2023-6/30/2027), “Electrical stimulation to control feedback modulation of perception.”

Significance and Collaborative Aims


Over the past cycle of this project, we have, together with Mayo Clinic, developed a custom BCI2000-based system for closed-loop paired sensory and electrical stimulation in intracranially monitored patients. In accordance with the Mayo Clinic grant, we will combine this BCI2000-based system with the neurometric and psychometric functions developed in TRD3 to determine the neuromodulatory-effect of paired sensory and electrical stimulation on visual perception. This work is really suited to drive and refine the conceptual work in TRD1 and the technology development in TRD3 and will improve the understanding of visual perception by combining NCAN’s unique technologies with Mayo Clinic’s sophisticated understanding of the visual pathway and unique access to intracranially monitored patients with electrodes implanted within the visual pathways.


The Collaborative Aims are:


Aim 1. Develop BCI2000-based experiments that facilitate paired sensory and electrical stimulation of intracranially-monitored human subjects.


Aim 2. Develop psychometric and neurometric functions to determine the interactions between electrical stimulation and visual perception, and their effect on the underlying neural function.


Publications


• Schalk G, Brunner P, Allison BZ, Soekadar SR, Guan C, Denison T, Rickert J, Miller KJ. Translation of neurotechnologies. Nature Reviews Bioengineering 2024. 2(8):637–652. ISSN 2731-6092.
• Jensen MA, Huang H, Valencia GO, Klassen BT, van den Boom MA, Kaufmann TJ, Schalk G, Brunner P, Worrell GA, Hermes D, Miller KJ. A motor association area in the depths of the central sulcus. Nat Neurosci. 2023. 26(7):1165-1169. PMCID: PMC10322697.
• Adamek M, Rockhill AP, Ince NF, Brunner P, Hermes D. Dynamic Visualization of Gyral and Sulcal Stereoelectroencephalographic Contacts in Humans. Annu Int Conf IEEE Eng Med Biol Soc. 2023. 2023:1-4. PMCID: PMC10760314.
• Schalk G, Worrell S, Mivalt F, Belsten A, Kim I, Morris JM, Hermes D, Klassen BT, Staff NP, Messina S, Kaufmann T, Rickert J, Brunner P, Worrell GA, Miller KJ. Toward a fully implantable ecosystem for adaptive neuromodulation in humans: Preliminary experience with the CorTec BrainInterchange device in a canine model. Front Neurosci. 2022. 16:932782. PMCID: PMC9806357.


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Hermes People page
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CP4: Neurometric and Psychometric Functions of Traumatic Brain Injury (Part of TRD1 and TRD3)

Collaborator: Dr. Sudhin Shah, Weill Cornell Medicine (WCU)

Collaborator Funding: NIH/NIA R01-AG077576 (9/30/2023-6/30/2028), “Brain fluid clearance and misfolded protein dynamics following traumatic brain injury.”

Significance and Collaborative Aims


Over the past year of this new project, we have, together with Weill Cornell Medicine, started to develop a custom BCI2000-based system for simultaneous EEG monitoring and closed-loop paired sensory and transcranial electrical stimulation during testing of visuospatial attention. In accordance with the Weill Cornell Medicine grant, we will combine this BCI2000-based system with the neurometric and psychometric functions developed in TRD3 to track neurorehabilitation after traumatic brain injury. This work is ideally suited to drive and refine the conceptual work in TRD1 and the technology development in TRD3 and will improve the understanding of transcranial electrical stimulation in patients recovering from traumatic brain injury by combining NCAN’s unique technologies with Weill Cornell’s unique access and longitudinal monitoring of patients recovering from traumatic brain injury.


The Collaborative Aims are:


Aim 1. Develop BCI2000-based experiments that facilitate paired sensory and transcranial electrical stimulation.


Aim 2. Develop psychometric and neurometric functions to determine the interactions between transcranial electrical stimulation and attention to sensory perception, and their effect on the underlying neural function.


Publications


• Alkhoury L, Scanavini G, Swissler P, Shah SA, Gupta D, Hill NJ. SyncGenie: A Programmable Event Synchronization Device for Neuroscience Research. HardwareX. 2025. 21:e00619. doi:10.1016/j.ohx.2024.e00619
• Schiff ND, Diringer M, Diserens K, Edlow BL, Gosseries O, Hill NJ, Hochberg LR, Ismail FY, Meyer IA, Mikell CB, Mofakham S, Molteni E, Polizzotto L, Shah SA, Stevens RD, Thengone D; and the Curing Coma Campaign and its Contributing Members. Brain-Computer Interfaces for Communication in Patients with Disorders of Consciousness: A Gap Analysis and Scientific Roadmap. Neurocrit Care. 2024. 41(1):129-145. PMCID: PMC11284251.
• Kim N, Jamison K, Jaywant A, Garetti J, Blunt E, RoyChoudhury A, Butler T, Dams-O’Connor K, Khedr S, Chen CC, Shetty T, Winchell R, Hill NJ, Schiff ND, Kuceyeski A, Shah SA. Comparisons of electrophysiological markers of impaired executive attention after traumatic brain injury and in healthy aging. Neuroimage. 2023. 1;274:120126. PMCID: PMC10286242.
• Kim N, O’Sullivan J, Olafson E, Caliendo E, Nowak S, Voss HU, Lowder R, Watson WD, Ivanidze J, Fins JJ, Schiff ND, Hill NJ, Shah SA. Cognitive-Motor Dissociation Following Pediatric Brain Injury: What About the Children? Neurol Clin Pract. 2022. 12(3):248-257. PMCID: PMC9208423.
• Kim N, Watson W, Caliendo E, Nowak S, Schiff ND, Shah SA, Hill NJ. Objective Neurophysiologic Markers of Cognition After Pediatric Brain Injury. Neurol Clin Pract. 2022. 12(5):352-364. PMCID: PMC9647802.


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Shah People page

CP5: Optimizing Patient-Specific Deep Brain Stimulation Models Using Electrophysiology (Part of TRD2 and TRD3)

Collaborator: Dr. Svjetlana Miocinovic, Emory University, and Dr. Enrico Opri, University of Michigan

Collaborator Funding: NIH/NINDS R01-NS125143 (1/1/2022-12/31/2026), “Optimizing Patient-Specific Deep Brain Stimulation Models Using Electrophysiology.”

Significance and Collaborative Aims


Over the past cycle of this project, we have, together with Emory University and the University of Michigan, developed a BCI2000-based closed-loop recording and stimulation system based on the FDA-approved Neuro-Omega system, which is used clinically for DBS recording and stimulation within the operating room. In accordance with the Emory University grant, we will combine this BCI2000-based system with the neurometric and psychometric functions developed in TRD3 to optimize patient-specific deep brain stimulation models. This work is ideally suited to drive and refine the conceptual work in TRD1 and the technology development in TRD3 and will improve the understanding of deep-brain stimulation parameter optimization in patients undergoing deep-brain stimulation by combining NCAN’s unique technologies with Emory University’s and University of Michigan’s unique access to patients undergoing implantation of deep brain stimulators.


Publications


• Block CK, Patel M, Risk BB, Staikova E, Loring D, Esper CD, Scorr L, Higginbotham L, Aia P, DeLong MR, Wichmann T, Factor SA, Au Yong N, Willie JT, Boulis NM, Gross RE, Buetefisch C, Miocinovic S. Patients with Cognitive Impairment in Parkinson’s Disease Benefit from Deep Brain Stimulation: A Case-Control Study. Mov Disord Clin Pract. 2023. 10(3):382-391. PMCID: PMC10026300.
• Connolly MJ, Cole ER, Isbaine F, de Hemptinne C, Starr PA, Willie JT, Gross RE, Miocinovic S. Multi-objective data-driven optimization for improving deep brain stimulation in Parkinson’s disease. J Neural Eng. 2021. 18(4). PMCID: PMC9638882.


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Opri People page
Miocinovic People page

CP6: Clinical System for Reflex Operant Conditioning (Related to TRD1; Began in 2021)

Collaborators: Drs. M. McKinnon and I. Clements (BioCircuit Technologies, Atlanta, GA)

Collaborator Funding: NIH/NINDS U44-NS114420 (9/30/2020-3/31/2026 NCE), “Spinal Reflex Conditioning System for Enhancing Motor Function Recovery after Incomplete Spinal Cord Injury.”

Significance and Collaborative Aims


Prior to this extremely effective collaboration with BioCircuit Technologies (BCT), spinal reflex operant conditioning (ROC) was implemented by a cumbersome and demanding lab system, and was therefore confined to use by researchers with highly specialized training. This CP has developed and is validating a robust highly automated ROC system suitable for dissemination to and use by physical therapists and other clinicians. This translational trajectory will continue along two parallel tracks, reflected by the following two Collaborative Aims.


Aim 1. Development of a Reflex Operant Conditioning (ROC) System for Home Use. Building on the successful collaboration between NCAN and BCT that resulted in a clinically deployable ROC system for use in outpatient therapeutic settings, this project aims to adapt the ROC system for home use. After initial set-up and patient training by the therapist, the home-based ROC system will enable patients to self-administer therapy with periodic remote oversight by the therapist. This new ROC system should greatly reduce the need for clinic visits, reduce costs, enable more use of the system and thereby increase its efficacy, and increase the numbers of patients who can benefit from it.


Aim 2. Adaptation of the ROC System for Conditioning Reflexes During Specific Phases of Movement. The second collaborative aim focuses on enhancing the existing ROC system to condition reflexes during specific phases of functional movements, such as walking. Current ROC therapy has shown efficacy when administered during quiet standing. By integrating the ROC system with locomotor practice, the therapy’s impact on walking speed, distance, and symmetry can be magnified (Thompson & Wolpaw 2021). The CP will develop a system that can synchronize ROC therapy with a specific phase of the gait cycle during treadmill walking (e.g., the swing phase). By delivering conditioning stimuli at a precise moment in the step cycle, the new protocol aims to enhance the rapidity and magnitude of improvement in locomotion in people with chronic spinal cord injury (SCI) or other disorders.


Publications


• McKinnon ML, Hill NJ, Carp JS, Dellenbach B & Thompson AK (2023). Methods for automated delineation and assessment of EMG responses evoked by peripheral nerve stimulation in diagnostic and closed-loop therapeutic applications. Journal of Neural Engineering 20(4):046012. doi:10.1088/1741-2552/ace6fb PMID: 37437593. PMCID: PMC10445400.
• Hill NJ, Gupta D, Eftekhar A, Brangaccio JA, Norton JJ, McLeod M, Fake T, Wolpaw JR & Thompson AK (2022). The evoked potential operant conditioning system (EPOCS): a research tool and an emerging therapy for chronic neuromuscular disorders. Journal of Visualized Experiments Aug 25(186):e63736. doi:10.3791/63736. PMID: 36094287. PMCID: 9948679.


References
• Thompson AK, Wolpaw JR. H-reflex conditioning during locomotion in people with spinal cord injury. J Physiol. 2021; 599(9):2453-2469.


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McKinnon People page
Clements People page

CP7: Locating the Neural Substrates for the Flexor Synergy after Stroke (Related to TRD1 and TRD2; New CP)

Collaborator: Dr. Stuart Baker (Newcastle University)

Funding: NIH/NINDS R01-NS119319 (3/15/2021-2/28/2026), “Locating the neural substrates for the flexor synergy after stroke.”

Significance and Collaborative Aims


Evidence supports the view that targeted neurostimulation benefits rehabilitation. It is superior to stimulating neural pathways nonspecifically (e.g., repetitive transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS)). We use the known physiology and anatomy of CNS pathways to engage the system. Protocols using this concept include paired associative stimulation (PAS) in which precisely synchronized stimuli engage plasticity . PAS protocols have been shown to accelerate and enhance functional recovery (e.g., Jo & Perez, 2020). PAS studies to date have focused primarily on strengthening the corticospinal tract (CST). Recent joint work of Dr. Baker’s and Dr. Perez’s groups shows that the reticulospinal tract (RST) also contributes to movement control in primates, including humans (Choudbury et al., 2019; Baker & Perez 2017). This supports the hypothesis that therapies that strengthen the RST as well as the CST can further enhance functional recovery. This CP will test this hypothesis.


Our two Collaborative Aims are:


Aim 1. Develop PAS of the RST in humans and incorporate it into a combined-therapy protocol that administers PAS to both the CST and the RST.


Aim 2. Apply this combined therapy in pilot studies of people with chronic stroke or spinal cord injury (SCI) and determine whether it produces functional recovery greater than either therapy alone.


Publications


• Baker, Stuart N., and Monica A. Perez. "Reticulospinal contributions to gross hand function after human spinal cord injury." Journal of Neuroscience 37.40 (2017): 9778-9784.
• Choudhury S, Shobhana A, Singh R, Sen D, Anand SS, Shubham S, Baker MR, Kumar H, Baker SN. The Relationship Between Enhanced Reticulospinal Outflow and Upper Limb Function in Chronic Stroke Patients. Neurorehabil Neural Repair. 2019 May;33(5):375-383. doi: 10.1177/1545968319836233. Epub 2019 Mar 27. PMID: 30913964.
• Jo HJ, Perez MA. Corticospinal-motor neuronal plasticity promotes exercise-mediated recovery in humans with spinal cord injury. Brain. 2020; 143(5):1368-1382.
• Perez MA, Soteropoulos DS, Baker SN. Corticomuscular coherence during bilateral isometric arm voluntary activity in healthy humans. J Neurophysiol. 2012 Apr;107(8):2154-62. doi: 10.1152/jn.00722.2011. Epub 2012 Jan 25. PMID: 22279195; PMCID: PMC3331598.


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CP8: Enhancing Recovery of Lower Limb Function after Spinal Cord Injury (Related to TRD1 and TRD2; New CP)

Collaborators: E Meyers and RL Rennaker (UT Dallas, TX)

Funding: NIH/NINDS UG3-NS131971 (7/1/2024-6/30/2029) Enhancing recovery of lower limb function after spinal cord injury.”

Significance and Collaborative Aims


Spinal cord injuries (SCIs) affect about 350,000 Americans, with 17,000 new injuries occurring each year. Based on the principles of directing and increasing plasticity, the goal of this CP is to combine H-reflex operant conditioning (HROC) and vagal nerve stimulation (VNS) to enhance recovery after SCI. In this approach, HROC drives targeted plasticity through the modification of specific spinal circuits contributing to spasticity, and VNS increases the plasticity effects of HROC by synchronizing the timed release of neuromodulators. We hypothesize that VNS can enhance the spinal conditioning effects of HROC to improve functional recovery after SCI. We will first use HROC paired with VNS to suppress hyperactive reflexes that prevent effective gait practice, and then promote recovery of normal gait patterns through gait training (and/or associated exercises) paired with VNS. We hypothesize that this combined therapy will both accelerate and enhance functional recovery for individuals with SCI. To accomplish this, we have the following Collaborative Aims:


Aim 1. Develop and test a combined system. We will develop and test a system that combines NCAN’s HROC software with UTD’s wireless implantable VNS device. We will use advice from key stakeholders – people with SCI, their caregivers, therapists, and researchers – to guide system design for ease of use.


Aim 2. Evaluate the safety, feasibility, and efficacy of the system in people with SCI. We will test a subset of people with SCI who have already been implanted with the VNS device for a previous clinical trial at UTD. Using a double-blind randomized controlled design, we will assess the effect of combined HROC-VNS therapy (vs. HROC-Sham VNS therapy) in individuals with impaired gait due to chronic (>6 months) SCI.


Aim 3. Assess home use of the HROC-VNS system. In final testing, participants will take the system home for an additional 12 weeks of home therapy. Participants (and their aides as needed) will receive training in system use with follow-up evaluations of participant compliance, ability to use the system, and system efficacy.


Publications


• Ganzer PD, Darrow MJ, Meyers EC, Solorzano BR, Ruiz AD, Robertson NM, Adcock KS, James JT, Jeong HS, Becker AM, Goldberg MP, Pruitt DT, Hays SA, Kilgard MP, Rennaker RL 2nd. Closed-loop neuromodulation restores network connectivity and motor control after spinal cord injury. Elife. 2018. 7:e32058. PMCID: PMC5849415.
• Epperson JD, Meyers EC, Pruitt DT, Wright JM, Hudson RA, Adehunoluwa EA, Nguyen-Duong YN, Rennaker RL 2nd, Hays SA, Kilgard MP. Characterization of an Algorithm for Autonomous, Closed-Loop Neuromodulation During Motor Rehabilitation. Neurorehabil Neural Repair. 2024. 38(7):493-505. PMCID: PMC11179975.


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Meyers People page
Rennaker People page

CP9: Supercomputer-based Models of Motoneurons for Estimating Their Synaptic Inputs in Humans (Related to TRD1 and TRD2; New CP)

Collaborator: Dr. Charles J. Heckman (Northwestern University)

Funding: NIH/NINDS R01-NS125863 (5/1/2022-2/28/2027), “Supercomputer-based Models of Motoneurons for Estimating Their Synaptic Inputs in Humans.”

Significance and Collaborative Aims


In this Collaborative Project, we propose that a striking form of neuroplasticity that occurs in spinal motoneurons (SMNs) after spinal cord injury (SCI) is an important target for therapies that enhance functional recovery in people with SCI. Normally, SMN excitability depends on brainstem neuromodulatory input, particularly from the raphespinal tract (RaST). RaST axons densely innervate SMNs and release serotonin (5HT). The most important effect of 5HT on SMNs is facilitation of a key set of voltage-sensitive channels that mediate persistent inward currents (PICs). Remarkably, in the weeks and months after SCI, PIC amplitudes increase greatly and contribute to maladaptive symptoms such as spasticity and spasms that interfere with voluntary motor output. PICs can be suppressed by reciprocal inhibition from antagonistic muscles. Based on this knowledge (Heckman et al. 2005; Murray et al. 2010; Tysseling et al. 2017), we hypothesize that paired associative stimulation (PAS) that strengthens corticospinal (CST) pathways that upregulate reciprocal inhibitory circuits will reduce PICs in people with SCI and thereby enhance functional recovery. To test this hypothesis, we have three collaborative Aims:


Aim 1. Develop, optimize, and validate a PAS protocol that strengthens CST and increases reciprocal inhibition (RI) from antagonist muscles.


Aim 2. Establish the safety of this PAS-RI protocol and its efficacy for reducing spasticity and muscle spasms) in people with chronic SCI and thereby enhancing recovery of function.


Aim 3. Combine this PAS-RI therapy with concurrent exercise and show that this combined-therapy protocol further enhances efficacy for reducing spasticity and muscle spasms and thereby further improves recovery effective voluntary movement in people with chronic SCI.


Publications


• Chen B, Gaikwad S, Powell RH, Jo HJ, Kessler A, Chen D, Heckman CJ, Linda Jones, Guest J, Wolpaw J, Oudega M, Blight AR, Perez MA. Combinatorial approaches targeting synaptic transmission accelerate recovery in humans with spinal cord injury. Under review 2024.


References


• Heckman, C.J. et al. (2005) Persistent inward currents in motoneuron dendrites: Implications for motor output. Muscle Nerve 31, 135–156
• Murray, K.C. et al. (2010) Recovery of motoneuron and locomotor function after spinal cord injury depends on constitutive activity in 5-HT2C receptors. Nat Med 16, 694–700.
• Tysseling, V.M. et al. (2017) Constitutive activity of 5-HT 2C receptors is present after incomplete spinal cord injury but is not modified after chronic SSRI or baclofen treatment. J. Neurophysiol. 118, 2944–2952


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CP10: User-Friendly, Noninvasive Neuro-Orthosis that Restores Volitionally Controlled Grasp Functions for SCI Survivors with Tetraplegia (Related to TRD1; New CP)

Collaborators: Drs. Lauren Wengerd (OSU, Columbus, OH) and Eric Meyers (UT Dallas, Dallas, TX)

Funding: Wengerd: DOD/SCIRP W81XWH-22-1-1083 (9/1/2021-8/31/2025), “A User-Friendly, Noninvasive Neuro-Orthosis That Restores Volitionally Controlled Grasp Functions for SCI Survivors with Tetraplegia.” Meyers: NIH/NIBIB, U54-EB033664 (2/1/2024-6/30/2027), “Discovery and Applied Research for Technological Innovations to improve Human Health.”

Significance and Collaborative Aims


Each year, >500,000 Americans experience their first stroke (Tsao, 2023); and about 3,500,000 stroke survivors struggle with functional limitations in their arms and hands (Albishi,2024). Inability to perform voluntary movements and activities of daily living greatly reduce quality of life and cost billions in medical costs and lost productivity (Feigin, 2022). Current therapies focus on repeated practice of motor skills. The possible benefits of reflex operant conditioning protocols have received relatively little attention.


Dr. Wengerd’s laboratory identifies and implements evidence-based interventions to maximize sensorimotor recovery after neurological injury. Encouraged by promising results in the lower limb (Thompson et al. 2022), the overall aim of this CP is to thoroughly investigate and optimize H-reflex down-conditioning in the upper limbs of adult stroke survivors, and to assess its effects on functional recovery. We will use high-density electromyography (EMG) arrays (BioCircuit) with up to 40 electrodes per patch to record high-density EMG across the forearm muscles. This will allow us to explore NCAN targeted-plasticity protocols in detail through analysis of high-density EMG data. We will characterize the impact of muscle size, electrode positioning, and other factors on H-reflex conditioning in the upper extremity.


We will integrate NCAN’s BCI2000-based EPOCS software with the high-density EMG signals. This will allow us to analyze data across multiple forearm muscles and capture motor unit data within muscles. We can record this data while participants are actively engaged in upper extremity task-oriented training, which we hypothesize can be used to enhance the effects of H-reflex down-conditioning (e.g., Thompson & Wolpaw, 2021). We will use motion capture and accelerometers to detect and characterize different phases of grasp and release. Our goal is to down-condition hyperactive forearm flexor H-reflexes and thereby improve functional grasp and release. To accomplish this, we have the following Collaborative Aims:


Aim 1. Hardware/Software Development: Integrate EPOCS with high-density EMG, accelerometers, and motion capture systems to objectively characterize muscle/motor unit activity and phases of grasp and release.


Aim 2. Protocol Development: Use the results of Aim 1 to develop and optimize a therapeutic protocol that down-conditions forearm flexor H-reflexes during task performance and thereby reduces spasticity in adults with chronic stroke.


Aim 3. System Testing: Collaborative Aim 3: Test the efficacy of the therapeutic protocol developed in Aim 2 for improving upper extremity function (e.g., grasp and release) in people with chronic stroke.


Publications


• Ganzer PD, Darrow MJ, Meyers EC, Solorzano BR, Ruiz AD, Robertson NM, Adcock KS, James JT, Jeong HS, Becker AM, Goldberg MP, Pruitt DT, Hays SA, Kilgard MP, Rennaker RL. (2018) Closed-loop neuromodulation restores network connectivity and motor control after spinal cord injury. eLife 7:e32058 DOI:https://doi.org/10.7554/eLife.32058.
• Juckett LA, Banhos M, Howard ML ... Wengerd, L. Bundling implementation strategies supports outcome measure adoption in stroke rehabilitation: preliminary findings. Implement Sci Commun 5, 102 (2024). https://doi.org/10.1186/s43058-024-00643-3
• 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. Identifying alterations in hand movement coordination from chronic stroke survivors using a wearable high-density EMG sleeve. J Neural Eng. 2024 Aug 5;21(4). doi: 10.1088/1741-2552/ad634d. PMID: 39008975.
• Wengerd L, Friedenberg DA, Meyers EC. Identifying alterations in hand movement coordination from chronic stroke survivors using a wearable high-density EMG sleeve. J Neural Eng. 2024 Aug 5;21(4). doi: 10.1088/1741-2552/ad634d. PMID: 39008975.


References


• Albishi AM. How does combining physical therapy with transcranial direct stimulation improve upper-limb motor functions in patients with stroke? A theory perspective. Ann Med Surg (Lond). 2024 Jun 19;86(8):4601-4607. doi: 10.1097/MS9.0000000000002287. PMID: 39118708; PMCID: PMC11305811.
• Feigin VL,Brainin M, Norrving B, Martins S, Sacco RL, Hacke W, Fisher M, Pandian J, Lindsay P. World Stroke Organization (WSO): Global Stroke Fact Sheet 2022. Int J Stroke. 2022 Jan;17(1):18-29. doi: 10.1177/17474930211065917. Erratum in: Int J Stroke. 2022 Apr;17(4):478. doi: 10.1177/17474930221080343.
PMID: 34986727.• Thompson AK, Gill CR, Feng W, Segal RL. Operant down-conditioning of the soleus H-reflex in people after stroke. Front Rehabil Sci. 2022; 3:859724.
• Thompson AK, Wolpaw JR. H-reflex conditioning during locomotion in people with spinal cord injury. J Physiol. 2021; 599(9):2453-2469.
• Tsao CW, Aday AW, Almarz ZI, et al. Heart disease and stroke statistics—2023 update: a report from the American Heart Association. Circulation. 2023;147: e93–e621.)


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