Modulating brain plasticity in rehabilitation of stroke and other brain lesions

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications, trials & patents

Abstract

Background: Disability resulting from stroke and traumatic brain injury represent the main causes of long-term complications in adults. There are no universally accepted treatments available to treat these conditions and the financial, personal, familial and social cost of these disabilities cannot be underestimated. Preliminary data from different laboratories have shown that it is possible to modulate plastic processes in the lesioned brain via pharmacological, or brain and somatosensory stimulation techniques. The purpose of this project is to identify mechanisms of stroke motor disability and characterize the most promising techniques to improve cortical plasticity in these patients to enhance functional recovery. Findings this year: Over the past year, we successfully published a proof-of-principle study aimed at translating recent closed-loop transcranial magnetic stimulation (TMS) work we have performed in healthy adults to therapeutic intervention in chronic stroke patients. In the published study, we validated the accuracy of a brain-phase-dependent TMS technique (developed through a successful international collaboration) in a total of three chronic stroke patients. Phase-dependent TMS aims to reduce inter-individual variability to therapeutic interventions by delivering TMS stimuli at pre-defined phases of endogenous oscillatory brain activity. While early results using phase-dependent TMS in healthy adults suggests that TMS targeting specific sensorimotor mu oscillatory phases could be more clinically effective, the ability to accurately target these phases in the stroke lesioned brain remains unknown and is likely complicated by factors such as inter-individual differences in brain lesion pathology, reorganization of mu rhythm generators, or unstable mu rhythm phase progression over time (i.e. dysrhythmia). Here, we examined the accuracy of delivering phase-dependent TMS to the lesioned hemisphere after stroke in a small cohort of chronic stroke patients. Importantly, we found that TMS application could be accurately targeted to pre-defined brain oscillatory phases in all patients despite substantial inter-individual variability in lesion location and motor impairment. We have followed up these findings by beginning data collection in a larger study aimed at determining if TMS delivered during mu-phase troughs can robustly enhance evoked corticospinal output in a much larger cohort of chronic stroke patients. In collaborative work, we developed a protocol to study repetitive peripheral nerve sensory stimulation (RPSS), which has emerged as a potential adjuvant strategy to motor training in stroke rehabilitation. The aim was to test the hypothesis that 3 h sessions of active RPSS associated with functional electrical stimulation (FES) and task-specific training (TST) distributed three times a week, over 6 weeks, is more beneficial to improve upper limb motor function than sham RPSS in addition to FES and TST, in subjects with moderate to severe hand motor impairments in the chronic phase (>6 months) after stroke. In this single-center, randomized, placebo controlled, parallel-group, double-blind study we compare the effects of 18 sessions of active and sham RPSS as add-on interventions to FES and task-specific training of the paretic upper limb, in 40 subjects in the chronic phase after ischemic or hemorrhagic stroke, with Fugl-Meyer upper limb scores ranging from 7 to 50 and able to voluntarily activate any active range of wrist extension. The primary outcome measure was the Wolf Motor Function Test (WMFT) after 6 weeks of treatment. The secondary outcomes were the WMFT at 3, 10, and 18 weeks after beginning of treatment, as well as the following outcomes measured at 3, 6, 10, and 18 weeks: Motor Activity Log; active range of motion of wrist extension and flexion; grasp and pinch strength in the paretic and non-paretic sides (the order of testing is randomized within and across subjects); Modified Ashworth Scale; Fugl-Meyer Assessment-Upper Limb in the paretic arm; Barthel Index; Stroke Impact Scale. This project represents a major step in developing a rehabilitation strategy with potential to have impact on the treatment of stroke patients with poor motor recovery in developing countries worldwide. The study preliminarily evaluates a straightforward, non-invasive, inexpensive intervention. If feasibility and preliminary efficacy are demonstrated, further investigations of the proposed intervention (underlying mechanisms/ effects in larger numbers of patients) should be performed (Trial Registration: NCT02658578).