Modulating brain plasticity in rehabilitation of stroke and other brain lesions

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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: We collaborated with research groups at the University of Texas Southwestern, MedStar National Rehabilitation Hospital and the Georgetown University Medical Center on a research project aimed at understanding the primary factors limiting patient enrollment in a clinical trial testing the efficacy of transcranial direct current stimulation (tDCS) on improving rehabilitation of motor function following stroke 1. Several non-invasive brain stimulation techniques are currently being investigated as adjuvant therapies to promote improved rehabilitation outcomes following brain injury or disease 2. Thus, the present research study provides important information on which specific factors need to be addressed to expand availability of these therapeutic interventions to more patients. This in turn will increase overall impact of these interventions on reducing disability in the US adult population. The study evaluated how specific items in the clinical trial inclusion/exclusion criteria influenced enrollment in the clinical trial (ClinicalTrials.gov ID: NCT01007136) within the context of an acute stroke clinic at the University of Texas Southwestern (UTSW) serving a racially and ethnically diverse local population. A total of 3124 (59.7 14.5 years; 38.4% non-Hispanic white, (W), Hispanic (H) 22%, African American (AA) 33.5%, Asian (A) 2.3%) patients were screened for enrollment in the trial through the acute stroke service at UTSW. Prospective information on patient demographics, overall medical history, stroke characteristics, and reasons for exclusion were recorded. 2327 of the 3124 screened patients (74.5%) had a medically documented and verified stroke. Out of the patients with verified stroke, only 44 (1.9%) were determined to be eligible for the study. The primary causes of study exclusion ranked in order of importance included: (A) the severity of upper extremity (UE) motor impairment, (B) a history of prior strokes, (C) a hemorrhagic stroke diagnosis, (D) psychiatric or cognitive impairments and complications and (E) exceeding the upper age limit. The African American patient cohort was more likely than other groups to be excluded due to history of prior strokes (28.1% vs. 19.9%, p< 0.001). Understanding the underlying health issues driving these differences requires further study. A total of 31 of the 44 eligible stroke patients were enrolled in the trial (non-Hispanic white 1.68%; Hispanic 1.37%; African American .77%; Asian 3.774%). Importantly, a large majority of all 2327 verified stroke patients (90.5%) met all safety criteria necessary for receiving brain stimulation. The main conclusions of the study were: (A) most stroke patients could safely receive tDCS-based therapies with minimal risk concerns and (B) more nuanced study inclusion criteria that takes into account risk factors more prevalent and specific demographic cohorts could expand access to to trial enrollment. We also made advances over the past year in our research work related to understanding lasting chronic symptoms related to acute COVID-19 infection (i.e. Long-Covid). Despite the high prevalence of neurological symptoms like brain fog and memory dysfunction in Long Covid, most research has relied on surveys or clinical tools typically used to assess declarative memory. In collaboration with other NINDS Intramural Research Program investigators, we examined the ability of Long-Covid patients to learn and consolidate a new procedural motor skill compared with a control cohort made up of healthy age- and gender-matched adult participants. Long-Covid patients (reporting persistent Covid-19 related symptoms for more than 4 weeks, n=105) and matched controls (denied Long-Covid symptoms, n=105) learned a motor sequence typing task over two consecutive days. This task is designed to assess learning of a procedural motor skill that is analogous to learning a short piece of piano music. The mean age for both groups was 46 years. All participants were between 18-90 years old, English speaking, right-handed, and able to type with the left hand. Participants also denied active fever or respiratory infection, and indicated they had no prior experience on the motor skill task. As a secondary control, data in these two groups were also compared to an age- and sex-matched control group that performed the same task prior to the Covid-19 pandemic (pre-pandemic controls, n=105). Results of the study indicated that performance improvements on Day 1 were comparable across all three groups (Long-Covid = 0.360.24 correct sequences/second; Pandemic Controls = 0.360.53; Pre-pandemic controls 0.380.57, p=.82). Despite similar improvements, both initial and final skill task performance on Days 1 and 2 was lower in patients compared with the two control groups. Furthermore, Long-Covid patients showed a significantly reduced overnight consolidation (i.e. reduced overnight offline performance gains that occur in the absence of additional practice). Thus, while early skill learning (i.e. change in performance associated with practice) was comparable between Long-Covid patients and controls, patients consistently lagged behind controls in the overall level of skill task performance. These performance deficits are consistent with executive disfunction previously reported in Long-Covid patients. Finally, the observed reduction in overnight consolidation may relate to deficits in procedural memory formation in patients with Long Covid. Additional research will be needed to understand the mechanisms of these deficits. This work is presently under review in the journal, Neurology.