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

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.

• Change in participants' subjective real life functional UL performance on the Motor Activity Log [Time frame: The assessments will be done at the baseline and in the week after completion of the training program and CN-NINM.]
• Change in active and passive range of motion at both UL in shoulder flexion, elbow flexion and wrist extension [Time frame: The assessments will be done at the baseline and in the week after completion of the training program and CN-NINM.]
• Change in resting motor threshold of the affected and unaffected FDI [Time frame: The assessments will be done at the baseline and in the week after completion of the training program and CN-NINM.]