Neuro-Intermuscular Coordination Enhancement (NICE) Rehabilitation Through Human-Machine Interaction in Chronic Stroke

Stroke is the leading cause of severe long-term disability, affecting 9.4 million Americans. Each year around 800,000 people suffer a stroke even in the USA. Chronic upper extremity motor impairment is a major contributing factor to disability; functional use of the affected UE in daily life is a key factor for increased independence, return to work, and overall quality of life. Thus, effective and innovative treatment to address long-term disability is both a major public health need and an economic necessity.

This study is an early-stage, randomized controlled rehabilitation trial designed to evaluate the clinical effects, feasibility, transfer of therapeutic gains, and exploratory neurophysiological correlates of Neuro-Intermuscular Coordination Enhancement (NICE) in individuals with chronic stroke and upper-extremity hemiparesis.

Forty-eight participants will be enrolled to obtain a target analyzable sample of 40 participants. Eligible participants will be randomized to either: (1) NICE, a motor module-guided rehabilitation intervention using isometric human-machine interaction and real-time EMG-based visual feedback to retrain impaired intermuscular coordination patterns; or (2) an active comparator consisting of dose-matched EMG amplitude biofeedback exercise. Both interventions will be delivered three times per week for six weeks (18 total sessions). Participants will complete assessments at baseline, immediately post-intervention, and at 10- and 18-week follow-up time points.

Outcomes will include standardized clinical measures of upper-extremity motor impairment and function, measures of intermuscular coordination derived from surface electromyography, kinematic measures obtained during untrained dynamic motor tasks, and EEG-based measures of brain activity and connectivity.

The primary objective is to determine whether NICE improves upper-extremity motor impairment relative to the active comparator. Secondary objectives are to evaluate intervention-related changes in intermuscular coordination and transfer of therapeutic gains to untrained motor behaviors. Exploratory objectives are to characterize rehabilitation-associated neurophysiological changes and examine relationships among EEG-derived biomarkers, intermuscular coordination, and clinical recovery outcomes.

• Neuromuscular coordination enhancement (NICE) intervention (Other): Neuro-Intermuscular Coordination Enhancement (NICE) is a motor module-guided rehabilitation intervention designed to improve upper-extremity motor recovery after stroke by retraining impaired intermuscular coordination patterns. Participants perform isometric upper-extremity force-generation tasks using a human-machine interface while receiving real-time visual feedback derived from motor module recruitment signals calculated from surface electromyography (EMG). Individualized motor module targets are derived from the participant's less-affected upper extremity and used to guide selective recruitment of impaired coordination patterns in the more-affected upper extremity. Participants will complete 18 one-hour training sessions over six weeks (3 sessions/week). During training, participants perform repetitive target-matching tasks that require preferential recruitment of specific motor modules while minimizing unintended activation of non-target modules.
• EMG Amplitude Biofeedback Exercise (Other): EMG Amplitude Biofeedback Exercise is an active comparator rehabilitation intervention designed to improve upper-extremity motor function after stroke through targeted muscle activation training. Participants perform isometric upper-extremity exercises using a human-machine interface with real-time EMG amplitude-based visual feedback. Individualized muscle activation targets derived from the less-affected upper extremity guide training of the more-affected upper extremity. Participants will complete 18 one-hour sessions over 6 weeks (3 sessions/week).

Primary outcomes

• Fugl-Meyer Assessment (FMA) score [Baseline, six- week, 10-week, and 18-week follow-ups.]: Motor impairment after stroke will be measured by upper extremity FMA (UE-FMA). The maximum UE-FMA motor score is 66 (i.e., 0: complete motor impairment; 66: normal motor performance). Each item is scored on a 3-point scale (0 = cannot perform, 1 = performs partially, 2 = performs fully). The FMA score reflects the level of upper extremity motor impairment.

Secondary outcomes

• Similarity Score of Intermuscular Coordination Patterns (or Motor Modules) [Baseline, six- week, 10-week, and 18-week follow-ups.]: Surface EMGs will be recorded from 8 key arm muscles during a 54-target isometric force generation task. A dimensionality reduction method (non-negative matrix factorization (NNMF)) will be applied to identify intermuscular coordination patterns - operational definition of motor modules in the field of motor neuroscience. They are mathematically 8-dimensional unit vectors. Similarity score is the scalar product (or dot product) between a pair of intermuscular coordination patterns in comparison (i.e., motor modules). We compute the similarity score between the less-affected and the more-affected arms. Also, surface EMGs will be recorded from 8 key arm muscles during 3D dynamic reaching tasks. NNMF will be applied to EMGs to identify and compare intermuscular coordination patterns. Similarity score is the scalar product between motor modules (i.e., intermuscular coordination patters) of the more-affected arm in stroke group and dominant arm in healthy group.
• Kinematic Synergy Similarity Score [Baseline, six-week, 10-week, and 18-week follow-ups.]: Kinematic synergies are a representation of multi-joint coordination. It will be identified using NNMF algorithm applied to the joint kinematic data obtained from 3D dynamic point-to-point reaching tasks. Kinematic synergy similarity between stroke and healthy will be calculated using their scalar product.
• Pairwise joint angle-to-angle correlation value [Baseline, six- week, 10-week, and 18-week follow-ups.]: Pairwise joint angle-to-angle correlation is a way to see the joint coupling using kinematic data. It will be calculated using Pearson's correlation coefficient between joint angles during the point-to-point reaching task.
• Active range of motion [Baseline, six-week, 10-week, and 18-week follow-ups.]: The active range of motion will be calculated from full active range tasks for shoulder flexion/extension, internal/external rotation, abduction/adduction, elbow flexion/extension, and wrist pronation/supination. Kinematic joint positions and angles will be used to calculate the same.
• EEG Spectral power ratios [Baseline and six-week follow-up.]: EEG-derived spectral power ratios will be calculated, in resting and task conditions, across different frequency bands (delta, theta, alpha, beta, gamma) and different events (onset, successful match, etc.) across four different directions of target match.
• EEG-derived Brain Symmetry Index [Baseline and six-week follow-up.]: The revised brain symmetry index with EEG signals will be computed in the resting state during eyes open and closed conditions.
• Cortico-muscular connectivity [Baseline and six-week follow-up.]: Functional connectivity using a directed transfer function will be computed to identify the information flow and coherence among EEG and EMG signals in the desired brain region and muscle activation associated with directional 4-target isometric force generation.
• Cortico-cortical connectivity [Baseline and six-week follow-up.]: Functional connectivity using a directed transfer function will be computed to identify the information flow and coherence among EEG signals from different regions of interest (sources, e.g., ipsi and contralesional fronto-parietal regions, primary motor cortex and somatosensory cortices).

Other outcomes

• Participant recruitment rate [From participant recruitment beginning to enrollment completion]: Recruitment rate will be calculated as the number of participants enrolled per month during the recruitment period. This is a feasibility outcome.
• Participant intervention adherence [Throughout the 6-week intervention period.]: Intervention adherence will be calculated as the percentage of scheduled intervention sessions completed by each participant. This is a feasibility outcome.
• Participant Tolerance of the Intervention [Throughout the 6-week intervention period.]: Participant tolerance will be measured as the number and percentage of participants who complete intervention sessions without stopping due to discomfort, fatigue, pain, or other intolerance-related reasons. This is a feasibility outcome.
• Intervention fidelity [Throughout the 6-week intervention period.]: Intervention fidelity will be calculated as the percentage of intervention sessions delivered according to the study protocol. This is a feasibility outcome.
• Dose equivalence between the intervention groups [Throughout the 6-week intervention period.]: Dose equivalence will be assessed by comparing total intervention dose between groups, measured as total minutes of training and/or number of completed sessions per participant. This is a feasibility outcome.
• NICE-specific training feasibility [Throughout the 6-week intervention period.]: NICE-specific feasibility will be assessed as the percentage of NICE intervention sessions in which the NICE training system/protocol is successfully implemented as intended. This is a feasibility outcome.
• Participant retention rate [Baseline, six-week, 10-week, and 18- week follow-ups and throughout the 6-week intervention period.]: Retention rate will be calculated as the percentage of enrolled participants who complete each scheduled follow-up assessment. This is a feasibility outcome.
• Successful acquisition of study data [Baseline, six-week, 10-week, and 18- week follow-ups and throughout the 6-week intervention period.]: Successful data acquisition will be calculated as the percentage of expected EMG, EEG, kinematic, and clinical outcome datasets successfully collected and usable for analysis. This is a feasibility outcome.
• Box and Block Test (BBT) score [Baseline, six-week follow-up, and 10-week follow-up. Keeping a 18-week follow-up as an exploratory time point.]: The gross manual dexterity and upper extremity coordination will be assessed through BBT, which involves transfer of blocks from one compartment of a box to the other within 60 seconds. The score is the number of blocks successfully transferred to the other side within 60 seconds.
• Modified Ashworth Scale (MAS) score [Baseline, six-week follow-up, and 10-week follow-up. Keeping a 18-week follow-up as an exploratory time point.]: The increase in muscle tone will be assessed through MAS around the elbow and shoulder. MAS score ranges from 0 to 5. The MAS score reflects the severity of muscle spasticity.
• Wolf Motor Function Test (WMFT) score [Baseline, six-week follow-up, and 10-week follow-up. Keeping a 18-week follow-up as an exploratory time point.]: Motor function will be assessed through WMFT, which evaluates both the time and quality of performance across 17 tasks that range from simple joint movements to complex functional activities (like lifting a can or folding a towel). Performance Time (sec) is measured, with a maximum time limit (usually 120 seconds). Functional Ability Scale rates the quality of movement, using a 6-point ordinal scale (0 = Does not attempt with the involved arm, 1 = Attempted but cannot complete task, 2 = Completes task with great difficulty or poor movement quality, 3 = Completes task with moderate difficulty or noticeable impairment, 4 = Completes task with minor difficulty or near-normal movement, 5 = Normal movement quality and speed). The WMFT score assesses upper extremity motor function.

Sex: All, ages: 21 Years to 80 Years, accepts healthy volunteers

Inclusion criteria for individuals after stroke are:

* Hemiparetic chronic stroke survivors more than 6 months after stroke onset
* Adults aged 21-80 years, including both female and male participants
* Individuals with a single unilateral ischemic or hemorrhagic stroke
* Individuals with Upper Extremity Fugl-Meyer Assessment score between 10 and 59 out of 66
* Individuals who have not received botulinum toxin injections in the upper extremity within the past 3 months
* Individuals without severe spasticity, defined as Modified Ashworth Scale score ≤3 at the elbow and shoulder

Exclusion criteria for individuals after stroke are:

* Individuals younger than 21 years of age or older than 80 years of age
* Individuals with an orthopedic disorder involving the upper limbs
* Individuals unable to produce voluntary upper-extremity muscle EMG activity;
* Individuals with cognitive impairment sufficient to interfere with informed consent or successful completion of the protocol, assessed using the Montreal Cognitive Assessment or other IRB-approved screening procedures.
* Individuals whose stroke-affected arm has an intermuscular coordination pattern similarity score >0.80 relative to the non-affected arm

Inclusion criteria for healthy individuals are:

* Healthy adults aged 21-80 years, including both female and male participants
* Individuals with no known neurological or orthopedic injuries

Exclusion criteria for healthy individuals are:

* Individuals younger than 21 years of age or older than 80 years of age
* Individuals with known neurological disorders
* Individuals with orthopedic injuries or conditions affecting upper-extremity movement
* Individuals unable to provide informed consent

• Seo G, Kishta A, Mugler E, Slutzky MW, Roh J. Myoelectric interface training enables targeted reduction in abnormal muscle co-activation. J Neuroeng Rehabil. 2022 Jul 1;19(1):67. doi: 10.1186/s12984-022-01045-z. PMID 35778757
• Li S. Stroke Recovery Is a Journey: Prediction and Potentials of Motor Recovery after a Stroke from a Practical Perspective. Life (Basel). 2023 Oct 15;13(10):2061. doi: 10.3390/life13102061. PMID 37895442
• Roh J, Cheung VC, Bizzi E. Modules in the brain stem and spinal cord underlying motor behaviors. J Neurophysiol. 2011 Sep;106(3):1363-78. doi: 10.1152/jn.00842.2010. Epub 2011 Jun 8. PMID 21653716
• Dewald JP, Sheshadri V, Dawson ML, Beer RF. Upper-limb discoordination in hemiparetic stroke: implications for neurorehabilitation. Top Stroke Rehabil. 2001 Spring;8(1):1-12. doi: 10.1310/WA7K-NGDF-NHKK-JAGD. PMID 14523747
• Nordin AD, Hairston WD, Ferris DP. Faster Gait Speeds Reduce Alpha and Beta EEG Spectral Power From Human Sensorimotor Cortex. IEEE Trans Biomed Eng. 2020 Mar;67(3):842-853. doi: 10.1109/TBME.2019.2921766. Epub 2019 Jun 13. PMID 31199248
• Roh J, Beer RF, Lai A, Rho M, Karvelas KR, Nader AM, Kendall MC, Rymer WZ. The Effects of Selective Muscle Weakness on Muscle Coordination in the Human Arm. Appl Bionics Biomech. 2018 Sep 19;2018:5637568. doi: 10.1155/2018/5637568. eCollection 2018. PMID 30402139
• Park JH, Lee H, Kwon HJ, Shin JH, Roh J, Park HS. Feasibility of Isokinetic Training to Modify Coupling of Upper Limb Muscle Synergy Activation in Stroke-affected Upper Limb. Annu Int Conf IEEE Eng Med Biol Soc. 2023 Jul;2023:1-4. doi: 10.1109/EMBC40787.2023.10339985. PMID 38082751
• Portilla-Jimenez M, Seo G, Houston M, Hong YNG, Li S, Park HS, Zhang Y, Roh J. Improving impaired intermuscular coordination after stroke through synergy-guided human-machine interaction: a pilot study. Annu Int Conf IEEE Eng Med Biol Soc. 2024 Jul;2024:1-4. doi: 10.1109/EMBC53108.2024.10782001. PMID 40031505
• Seo G, Park JH, Park HS, Roh J. Developing new intermuscular coordination patterns through an electromyographic signal-guided training in the upper extremity. J Neuroeng Rehabil. 2023 Sep 1;20(1):112. doi: 10.1186/s12984-023-01236-2. PMID 37658406

• Jinsook Roh, PhD, Principal investigator, University of Houston