Cranial Nerve Neuromodulation to Improve Arm Function and Brain Plasticity in Stroke

Stroke Clinical Trial

— CN-NINM  

Official title:

Can Stimulating the Tongue Help Improve Upper Limb Motor Function and Brain Plasticity in Individuals at the Chronic Stage of a Stroke: a Randomized Controlled Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06386510
• Other study ID #: 2025-5517
• Status: Not yet recruiting
• Phase: N/A
• Start date: November 1, 2024
• Est. completion date: July 1, 2027

Study information

• Verified date: April 2024
• Source: Université de Sherbrooke
• Contact: Marie-Helene Milot, PhD
• Phone: 819-780-2220
• Email: marie-helene.milot[@]usherbrooke.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Following a stroke, persistent residual muscle weakness in the upper limb (UL) drastically impacts the individuals' quality of life and level of independence. Training interventions are recommended to promote UL motor recovery, and recent studies have shown that training must be tailored to each individual's recovery potential to maximise training gains. Complementary to training interventions, non-invasive brain stimulation devices (NIBS) can help support the provision of post-stroke care by modulating brain excitability and enhancing recovery. Among NIBS, cranial nerve non-invasive neuromodulation (CN-NINM) is gaining increasing attention in rehabilitation since it can directly and non-invasively stimulate the tongue's cranial nerves. The impulses generated can then reach the motor cortex, induce neuroplastic changes and support recovery. Promising results in various neurological populations have been observed, but in stroke, the efficacy of CN-NINM at improving arm motor recovery and brain plasticity is yet to be determined. This is what the present project intends to address, using a stratified randomized controlled trial, where participants in the chronic phase of a stroke will take part in a 4-week individualized training program of their affected UL in combination with real or sham CN-NINM. Before and after the intervention, participants will undergo clinical and neurophysiological evaluations to thoroughly evaluate CN-NINM-induced changes in UL motor function and associated neuroplastic changes. The proposed study will allow an in-depth evaluation of the effects of CN-NINM for an eventual implementation in clinics and at home to support optimal post-stroke recovery.

Description:

Residual muscle weakness in the affected upper limb (UL) has a significant negative impact on the performance of activities of daily living (ADL) of individuals with a stroke. Studies report that the degree of UL weakness is strongly correlated to the level of functioning in ADL, thus affecting the overall level of independence post-stroke.

Motor recovery post-stroke is mainly associated with the central nervous system's ability to reorganize, or neuroplasticity. Neuroplasticity can be assessed with non-invasive transcranial magnetic stimulation (TMS). TMS allows for assessing the excitability of the descending corticospinal pathway, the main motor pathway controlling movements of the limbs and trunk. The amplitude of TMS-elicited motor evoked potentials (MEP) gives a direct measure of the excitability of corticospinal neurons and studies have shown that MEP amplitudes can be used to probe neuroplastic changes associated with motor recovery and are good predictors of an individual response to exercise post-stroke. In a recent study on UL exercises in chronic stroke survivors, baseline MEP amplitudes were used to estimate participants' potential for recovery and to tailor the intensity of the UL training program accordingly. By stratifying them based on their MEP amplitudes, all participants, regardless of their level of post-stroke recovery, showed significant improvements in UL function following their tailored training program. Collectively, these results suggest that assessing MEP amplitude can provide an efficient way to evaluate neuroplasticity as well as to assist in staging and tailoring individuals' training intervention to optimize post-stroke recovery.

To enhance neuroplasticity, training exercises are critical to rehabilitation post-stroke since they allow for improvement in UL motor function and strength as well as promote brain plasticity, leading to increased use of the UL in ADLs. To capitalize on the benefit of strength training at promoting motor recovery and neuroplasticity, non-invasive brain neurostimulation (NIBS) modalities are increasingly studied as an adjunct therapy in stroke rehabilitation. To date, transcranial direct current stimulation (tDCS) is the most studied NIBS, but a great variability in response to tDCS is noted, with more than 50% of individuals not responding as expected. This heterogeneity across studies in tDCS response could be explained by the absence of a consensus on optimal stimulation parameters, the influence of individual brain anatomical characteristics on the response to tDCS and the presence of an electric current shunting through the skull. Thus, to counteract the impact of inter-individual anatomical variability and electrical current shunting by the skull, recent studies are now investigating cranial nerve stimulation as an adjunct therapy in stroke when paired with rehabilitation. An emerging NIBS therapeutic device, stimulating two major cranial nerves, the trigeminal and glossopharyngeal nerves, by tongue stimulation, is making its way into neurological rehabilitation, that is cranial nerve non-invasive neuromodulation (CN-NINM). By applying electrodes directly to the tongue, CN-NINM allows the generation of a direct flow of neural impulses that travel to the cranial nerve nuclei of the brainstem and then to the motor cortex to induce targeted neuroplastic changes when combined with rehabilitation treatments. Following various neurological injuries and combined with many interventions, CN-NINM results in improved functional performance such as walking and balance. Neuroplasticity changes have also been observed such as an increase in the brain beta activation measured with electroencephalography and increased activation in the primary motor cortex area. Post-stroke, only one study has compared the impact of CN-NINM combined with a 2-week balance and gait training program (experimental group) to a 2-week balance and gait training program alone (control group) on functional performance, as assessed with the Mini-Best test, in individuals in the subacute stage of a stroke. Based on Mini-Best test score, an improvement in balance in the experimental group compared with the control group was noted (p=0.032). Although promising, CN-NINM has not been studied to improve UL function, despite the negative impact of UL impairment on post-stroke functional performance. Also, to lay the foundation for the applicability of this NIBS in stroke, understanding the neurophysiological effects of CN-NINM by evaluating neuroplasticity changes is crucial.

Objective: The main objective is to assess the impact of CN-NINM combined with a tailored UL strength training program on improvement in UL function and brain excitability in individuals at the chronic stage of a stroke. The secondary objective is to assess the presence of a relationship between UL functional gain and change in brain excitability for the study sample.

Methods: In this multicentered stratified randomized controlled trial, 74 participants will be recruited and stratified according to the baseline amplitude of their TMS-induced MEP responses into three strata of training intensity: 1) low-intensity (MEP 20-49μV); 2) moderate-intensity (MEP 50-120uV) and 3) high-intensity (MEP>120uV). . Within each stratum, participants will be randomized into the experimental group (real CN-NINM + UL strength training) or the control group (sham CN-NINM + UL strength training). Sociodemographic and stroke-related variables (e.g., age, time since stroke) will be collected to confirm participant eligibility. Prior to and at the end of the intervention, participants will undergo a clinical evaluation of their affected UL as well as a neurophysiological brain evaluation with TMS. The intervention will consist of a 4-week UL strength training program (3X/week, 60-minute duration) combined to a 20-minute CN-NINM application. For the experimental group, the intensity of the stimulus will be set by each participant to a comfortable level of sensation, similar to the sensation in the mouth of a soft drink. For the control group, participants will wear the device such as the experimental group, but the intensity will be controlled by the trainer and set to a non-perceivable stimulus.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 74
• Est. completion date: July 1, 2027
• Est. primary completion date: May 1, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

Inclusion Criteria:

• be =18 years of age;

• have had a unilateral supratentorial stroke;

• be in a chronic stage of recovery (>6 months);

• present some UL motor recovery (Fugl-Meyer Stroke Assessment [FMA-UE] score =25/66);

• are not involved in rehabilitation treatments.

Exclusion Criteria:

• significant spasticity at UL (score >3 on the modified Ashworth scale);

• major sensory deficit at UL (a score <25/34 on the Nottingham sensory assessment and a score <6 on the vibration threshold assessment);

• hemineglect (> 70% of unshaded lines on the same side as the motor deficit on the Line Cancellation test);

• apraxia (score >2.5 on the Alexander test);

• a neurological disorder other than stroke-related;

• orthopedic problems at UL;

• cognitive impairment (score <2/5 on the Mini-Cog);

• significant pain intensity at UL (a score = 6/10 on the Visual Analog Pain Scale);

• absence of MEP (peak-to-peak MEP amplitude <20µV);

• contraindications to CN-NINM and TMS.

Related Conditions & MeSH terms

• Stroke

Intervention

Procedure:
• Strength training
The strength training program will last 4 weeks (3 X/week, 60 minutes). Using dead weights, the 1RM (i.e. the maximal load that an individual can lift once) will be estimated by the 10RM for the wrist extensors and the elbow and shoulder flexors. The grip muscles of the affected hand will also be trained with a JAMAR® dynamometer. Depending on each participant's intensity training group, training will start at 35%, 50% or 70% of 1RM and will be increased by 5% each week to reach, by week 4, 50%, 65% and 85%, for the low, moderate, and high-intensity group, respectively.
• Cranial nerve non-invasive neuromodulation
For the first 20 minutes of each training session, CN-NINM will be applied (50 µsec at 150 Hz), using a portable stimulator (Cthulhu Shield, USA) with a network of 18 electrodes, directly on the participants' tongue. The participants will hold the device in place by pressing their tongue upwards and the intensity of the stimulus will be set by each participant to a comfortable level of sensation (experimental group) or set by a trainer to a non-perceivable stimulus (control group).

Locations

Country	Name	City	State
Canada	CRIR/Feil/Oberfeld Research Center; Centre intégré de santé et de services sociaux de Laval; Jewish Rehabilitation Hospital	Laval	Quebec
Canada	CIRRIS	Québec
Canada	Centre de recherche sur le vieillissement	Sherbrooke	Quebec

Sponsors (1)

Lead Sponsor	Collaborator
Université de Sherbrooke

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in UL motor function on the Fugl-Meyer Stroke Assessment Scale	Change in motor function of the affected UL will be assessed using the Fugl-Meyer Stroke Assessment. The score of this scale range from 0 (no motor recovery) to 66 (full motor recovery).	The assessments will be done at the baseline and in the week after completion of the training program and CN-NINM
Primary	Change in UL functional performance on the Wolf Motor Function Test	Change in functional performance of the affected UL will be assessed with the timed score of the Wolf Motor Function Test; comprising 17 tasks. The maximal time allocated to each task is 120 seconds.	The assessments will be done at the baseline and in the week after completion of the training program and CN-NINM.
Primary	Change in motor cortex excitability by means of resting MEP amplitudes elicited by TMS over both hemispheres.	Change in motor cortex excitability will be assessed by resting peak-to-peak MEP amplitudes of the affected and unaffected first dorsal interosseous muscles (FDI) at 130% of the FDI resting motor threshold over 20 trials	The assessments will be done at the baseline and in the week after completion of the training program and CN-NINM.
Secondary	Change in participants' subjective real life functional UL performance on the Motor Activity Log	Change in participants' self-reported affected UL performance in everyday activities will be assessed with the Motor Activity Log (MAL). The MAL comprises 14 task scored on a 0 to 5 Likert scale, where a score of 5 represents normal quantity and quality of use of affected UL.	The assessments will be done at the baseline and in the week after completion of the training program and CN-NINM.
Secondary	Change in active and passive range of motion at both UL in shoulder flexion, elbow flexion and wrist extension	Change in active and passive range of motion at both UL will be assessed in degrees with a manual goniometer	The assessments will be done at the baseline and in the week after completion of the training program and CN-NINM.
Secondary	Change in resting motor threshold of the affected and unaffected FDI	Change in resting motor threshold of the affected and unaffected FDI will be assessed with TMS and described as % of output stimulator	The assessments will be done at the baseline and in the week after completion of the training program and CN-NINM.