Leonardo G. Cohen - US grants

Background: Cortical reorganization occurs in the adult central nervous system, especially during motor skill acquisition. This plasticity contributes to various forms of human behavior including skill learning and memory formation, consolidation, reconsolidation and short- and long-term retention. It is very important to understand the role of these different behavioral processes and of the mechanisms underlying these various forms of human plasticity during skill acquisition to improve skill learning and memory in healthy adults. Findings this year: Over the past year, we have advanced several research initiatives aimed at characterizing intra- and inter-individual variability in responses to non-invasive brain stimulation. The rationale for this work is that a more nuanced understanding of these sources of variability is crucial for the development of personalized neuromodulatory protocols using non-invasive brain stimulation into effective therapies for neurorehabilitation in individual patients. While the link between the local primary motor cortex structure motor function has been well documented, motor function is known to result from a network of interconnected brain regions over large areas of the brain. The relationship between the features characterizing these distributed structural brain networks and motor function remains poorly understood. Here, we examined whether distributed patterns of brain structure, extending beyond the primary motor cortex can predict inter-individual variance in corticospinal excitability and intracortical inhibition, two clinically well described features of motor function. We acquired high-resolution structural MRI scans, motor evoked potentials (MEPs, a measure of corticospinal excitability) elicited by single-pulse transcranial magnetic stimulation (TMS) and short-interval intracortical inhibition (SICI) in 25 healthy volunteers. We used support vector machine (SVM) pattern classification to identify distributed multi-voxel gray-matter areas, which distinguished subjects who had lower and higher MEPs and SICIs, respectively. The results of this machine learning-based approach revealed that low or high MEP and SICI classification could be predicted based on a widely distributed, largely non-overlapping pattern of voxels in frontal, parietal, temporal, occipital, and cerebellar regions. Thus, distributed structural brain network features play a significant role in inter-individual variability of TMS effects. A second project compared the effects of different types of non-invasive brain stimulation (NIBS) on motor skill learning in healthy adults. A anodal transcranial direct current stimulation (tDCS), paired associative stimulation (PAS25), and intermittent theta burst stimulation (iTBS), along with a sham tDCS control condition were applied in a between-subject design. A total of 28 participants were randomly assigned to different groups and trained on a motor skill learning task. Online, offline and retention components of motor learning were calculated. The effects of NIBS on corticospinal excitability was also evaluated. We did not find consistent effects across the non-invasive brain stimulation types on motor learning or cortical excitability. The preliminary results observed in this small sample size, which require replication with larger samples, are consistent with previous reports of small and variable effect sizes of these interventions on motor learning between individuals and techniques. A third project conducted in collaboration with Dr. Julien Doyon at the McGill University investigated reconsolidation of long-term motor memories in healthy humans. Previous animal work showed that consolidated memories return to labile states when reactivated and that restabilization through reconsolidation processes is necessary for these memories to persist over the long time periods (i.e. years). This is supported by the finding that application of pharmacological agents following memory reactivation that block protein synthesis within the hippocampus results in failure to sustain the same memories over time. In humans, the hypothesis that memory reactivation paired with a competitive task can interfere with memory restabilitation has been proposed. Here, new skill learning was performed to interfere with the restabilization of an existing motor memory acquired through training on a finger tapping sequence task. When the interfering task was introduced immediately following memory reactivation, offline learning (i.e. continued performance gains that normally occur following the end of the training period) is extinguished. In summary, these results support the idea that instead of reactivation-induced plasticity resulting in reconsolidation of existing memories, memories are maintained within a competitive structure in which new information acquired during interfering experiences is integrated into existing memories through biological consolidation processes.

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 by pharmacological, brain stimulation 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: We reviewed strategies using TMS and tDCS to influence regional neural activity underlying the stimulation location and also distant interconnected network activity throughout the brain. Most stroke rehabilitation studies have been performed in high-income countries. The aim of one study was to identify the main barriers for patient inclusion in a research protocol performed in Brazil. We evaluated reasons for exclusion of patients in a pilot, randomized, double-blinded clinical trial of stroke rehabilitation. Descriptive statistical analysis was performed and report that only 5.6% of 571 screened patients were included. Recurrent stroke was responsible for exclusion of 45.4% of potentially eligible patients We concluded that recurrent stroke represented a big barrier to enroll patients in the protocol. External validity of rehabilitation trials will benefit from definition of study criteria according to regional characteristics of patients, including rates of recurrent stroke. In one study we report changes in interhemispheric inhibition targeting the ipsilesional primary motor cortex (M1) during nonparetic arm force. Healthy age-matched controls had significantly greater increases in inhibition from their active to resting M1 than patients with stroke from their active contralesional to resting ipsilesional M1 in the same scenario. Patients with greater increases in contralesional to ipsilesional inhibition were better performers on the 9-hole peg test of paretic arm function. Our findings reveal that producing force with the nonparetic arm does not necessarily overinhibit the paretic arm. Though our study is limited in generalizability by the small sample size, we found that greater active contralesional to resting ipsilesional M1 inhibition was related with better recovery in this subset of patients with chronic post stroke. In one study on brain-computer interface, in collaboration with a group in Germany, we found a significant group time interaction in upper limb (combined hand and modified arm) Fugl-Meyer assessment (cFMA) motor scores. cFMA scores improved more in the experimental than in the control group, presenting a significant improvement of cFMA scores (3.41 0.563-point difference, p = 0.018) reflecting a clinically meaningful change from no activity to some in paretic muscles. cFMA improvements in the experimental group correlated with changes in fMRI laterality index and with paretic hand electromyography activity. Placebo-expectancy scores were comparable for both groups. We concluded that the addition of BMI training to behaviorally oriented physiotherapy can be used to induce functional improvements in motor function in chronic stroke patients without residual finger movements and may open a new door in stroke neurorehabilitation.