Modulating brain plasticity in rehabilitation of stroke and other brain lesions

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

Background: Stroke and traumatic brain injury represent the two main causes of long-term disability 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 plasticity processes in patients with brain lesions via pharmacological, or non-invasive brain stimulation (NIBS) techniques. Some potential advantages of NIBS-based therapies for treating these conditions are: (1) greater specificity for facilitating central nervous system reorganization linked to positive neurorehabilitation outcomes; (2) elimination of potential surgery-related risks – a particular concern for this patient population; and (3) avoidance of side-effects associated with long-term use of prescription drugs targeting the central nervous system. Progress this year: To achieve the above goals, it is necessary to gain insight into three fundamental issues in stroke patients and healthy volunteers of comparable age: (1) the contribution of wakeful and sleep-dependent memory consolidation to skill learning; (2) the capability of closed-loop transcranial magnetic stimulation (TMS) to modulate motor function in these two populations; and (3) the ability to differentiate between responder and non-responder groups to brain stimulation-based neuromodulation (investigated in collaboration with the EPFL in Switzerland). In FY2025 we made considerable advances in data collection in two intramural research protocols addressing the first two issues, which were carried out under this project at the NIH Clinical Center. The first project is investigating how skill learning plasticity mechanisms active during wakeful rest (i.e. – short practice breaks) and short periods of sleep (i.e. – naps) differ between healthy adult humans and patients with brain lesions. During both wake and sleep, powerful intermittent synchronizing events occur in the brain that have been linked to memory consolidation in humans. During wakeful rest, sharp-wave ripples originating in the hippocampus are time-locked to the time-compressed (up to 20x) recapitulation of neural activity patterns observed during behavioral action sequences (i.e. – neural replay). A complimentary memory consolidation mechanism operating during sleep is tied to synchronizing events (called spindles) originating from the thalamus. Our lab previously reported that variation in the prevalence of wakeful neural replay across individuals is predictive of early skill learning. The overall aim of the present study is to characterize how fast skill memory consolidation mechanisms operating over several seconds differ from sleep-dependent mechanisms operating over 1-2 hours, and how these mechanisms are disrupted following stroke. Over the past year we have prioritized study enrollment and data collection at the NIH Clinical Center. Presently, data has been acquired from 119 enrolled participants. Our target sample size for this study is 174 participants. Data collection in stroke patients and healthy volunteers of comparable age is proceeding. Data analysis will commence once the target sample size has been achieved. During FY2025 we also made significant advances in data collection for a second project, which is investigating the efficacy of a closed-loop brain stimulation intervention on corticospinal plasticity. As stated above, non-invasive brain stimulation has emerged as a leading technology for therapeutic neurorehabilitation applications. One of the principle aims of our current research program is to improve the clinical efficacy of these applications, through the development of personalized stimulation protocols that are designed and dosed with respect to an individual patient’s existing brain anatomy and functional activity patterns. The rationale is that variations in brain anatomy need to be considered in order to target specific brain structures across individuals. This is accomplished by acquiring anatomical MRI scans used to develop detailed models of brain anatomy in all patients prior to the brain stimulation sessions. During sessions, these models are used with a camera-based neuronavigation system to guide stimulation delivery. Furthermore, timing of the stimulation delivery is also an important factor for dosing. Work in our lab and others has shown that that the overall effect of the stimulation is determined by its interaction with ongoing brain activity patterns. While some of these patterns can maximize the desired stimulation effects, others can minimize them. We address this problem by tracking brain activity patterns in real-time using high-definition non-invasive electroencephalography (EEG) recordings. Specifically, we the target a narrow phase ranges (e.g. - +/- 10 degrees) of brain oscillations in the sensorimotor cortex which cycle at 8-12Hz (i.e. – the sensorimotor rhythm). This approach is termed “closed-loop” non-invasive brain stimulation, and requires the use of fast, accurate predictive EEG processing algorithms capable of triggering the stimulation with millisecond or faster temporal resolution. The specific aim of the present study is to determine the specific sensorimotor rhythm phase range in which corticospinal effects of transcranial magnetic stimulation are maximized in healthy older adults (age 50 and over) and chronic stroke patients with uni- or bilateral upper limb hemiparesis. We have currently enrolled and acquired data from 75 participants (our target sample size is 114 participants) at the NIH Clinical Center. Data collection in stroke patients and healthy volunteers of comparable age is proceeding. Data analysis will commence once the target sample size has been achieved. Finally, a successful collaboration with the EPFL in Switzerland investigating characteristics separating responders and non-responders to brain stimulation protocols culminated with one FY2025 publication published in Nature Science of Learning (https://doi.org/10.1038/s41539-024-00278-y). Healthy aging often entails a decline in cognitive and motor functions, affecting independence and quality of life in older adults. Brain stimulation has shown potential to enhance these functions, but studies show variable effects. Previous work has tried to identify responders and non-responders to this intervention through correlations between behavioral change and baseline parameters, but results lack generalization to independent cohorts. In this work, we proposed a method to predict an individual's likelihood of benefiting from stimulation, based on baseline performance of a sequential motor task. Our results showed that individuals with less efficient learning mechanisms benefit from stimulation, while those with optimal learning strategies experience none or even detrimental effects. This differential effect, first identified in a public dataset and replicated here in an independent cohort, was linked to one's ability to integrate task-relevant information and not age. This study constitutes a further step towards personalized clinical-translational interventions based on brain stimulation.