COPYRIGHT © 2023 Platz, Paik, Good and Sandrini. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Editorial: COVID-19: the neurorehabilitation perspective

The global burden of neurological disorders is substantial and increasing, especially in low-resource settings. The current increased global interest in brain health and its impact on population wellbeing and economic growth, highlighted in the World Health Organization’s new Intersectoral Global Action Plan on Epilepsy and other Neurological Disorders 2022–2031, presents an opportunity to rethink the delivery of neurological services. In this Perspective, we highlight the global burden of neurological disorders and propose pragmatic solutions to enhance neurological health, with an emphasis on building global synergies and fostering a ‘neurological revolution’ across four key pillars — surveillance, prevention, acute care and rehabilitation — termed the neurological quadrangle. Innovative strategies for achieving this transformation include the recognition and promotion of holistic, spiritual and planetary health. These strategies can be deployed through co-design and co-implementation to create equitable and inclusive access to services for the promotion, protection and recovery of neurological health in all human populations across the life course. In this Perspective, Owolabi et al. propose strategies to improve brain health and address the growing global burden of neurological disorders. They present a new framework — the neurological quadrangle — which aims to provide equitable and effective surveillance, prevention, acute care and rehabilitation of neurological disorders globally.

Typical upper limb-mediated activities of daily living involve coordination of both arms, often requiring distributed contributions to mechanically coupled tasks, such as stabilizing a loaf of bread with one hand while slicing with the other. We sought to examine whether mild paresis in one arm results in deficits in performance on a bilateral mechanically coupled task. We designed a virtual reality-based task requiring one hand to stabilize against a spring load that varies with displacement of the other arm. We recruited 15 chronic stroke survivors with mild hemiparesis and 7 age-matched neurologically intact adults. We found that stroke survivors produced less linear reaching movements and larger initial direction errors compared to controls (p < 0.05), and that contralesional hand performance was less linear than that of ipsilesional hand. We found a hand × group interaction (p < 0.05) for peak acceleration of the stabilizing hand, such that the dominant right hand of controls stabilized less effectively than the nondominant left hand while stroke survivors showed no differences between the hands. Our results indicate that chronic stroke survivors with mild hemiparesis show significant deficits in reaching aspects of bilateral coordination, but no deficits in stabilizing against a movement-dependent spring load in this task.

The ipsilesional arm of stroke patients often has functionally limiting deficits in motor control and dexterity that depend on the side of the brain that is lesioned and that increase with the severity of paretic arm impairment. However, remediation of the ipsilesional arm has yet to be integrated into the usual standard of care for upper limb rehabilitation in stroke, largely due to a lack of translational research examining the effects of ipsilesional-arm intervention. We now ask whether ipsilesional-arm training, tailored to the hemisphere-specific nature of ipsilesional-arm motor deficits in participants with moderate to severe contralesional paresis, improves ipsilesional arm performance and generalizes to improve functional independence. We assessed the effects of this intervention on ipsilesional arm unilateral performance [Jebsen–Taylor Hand Function Test (JHFT)], ipsilesional grip strength, contralesional arm impairment level [Fugl–Meyer Assessment (FM)], and functional independence [Functional independence measure (FIM)] ( N = 13). Intervention occurred over a 3 week period for 1.5 h/session, three times each week. All sessions included virtual reality tasks that targeted the specific motor control deficits associated with either left or right hemisphere damage, followed by graded dexterity training in real-world tasks. We also exposed participants to 3 weeks of sham training to control for the non-specific effects of therapy visits and interactions. We conducted five test-sessions: two pre-tests and three post-tests. Our results indicate substantial improvements in the less-impaired arm performance, without detriment to the paretic arm that transferred to improved functional independence in all three posttests, indicating durability of training effects for at least 3 weeks. We provide evidence for establishing the basis of a rehabilitation approach that includes evaluation and remediation of the ipsilesional arm in moderately to severely impaired stroke survivors. This study was originally a crossover design; however, we were unable to complete the second arm of the study due to the COVID-19 pandemic. We report the results from the first arm of the planned design as a longitudinal study.

Chronic stroke survivors with severe contralesional arm paresis face numerous challenges to performing activities of daily living, which largely rely on the use of the less-affected ipsilesional arm. While use of the ipsilesional arm is often encouraged as a compensatory strategy in rehabilitation, substantial evidence indicates that motor control deficits in this arm can be functionally limiting, suggesting a role for remediation of this arm. Previous research has indicated that the nature of ipsilesional motor control deficits vary with hemisphere of damage and with the severity of contralesional paresis. Thus, in order to design rehabilitation that accounts for these deficits in promoting function, it is critical to understand the relative contributions of both ipsilesional and contralesional arm motor deficits to functional independence in stroke survivors with severe contralesional paresis. We now examine motor deficits in each arm of severely paretic chronic stroke survivors with unilateral damage (10 left-, 10 right-hemisphere damaged individuals) to determine whether hemisphere-dependent deficits are correlated with functional independence. Clinical evaluation of contralesional, paretic arm impairment was conducted with the upper extremity portion of the Fugl-Meyer assessment (UEFM). Ipsilesional arm motor performance was evaluated using the Jebsen-Taylor Hand Function Test (JTHFT), grip strength, and ipsilesional high-resolution kinematic analysis during a visually targeted reaching task. Functional independence was measured with the Barthel Index. Functional independence was better correlated with ipsilesional than contralesional arm motor performance in the left hemisphere damage group [JTHFT: [r(10) = −0.73, p = 0.017]; grip strength: [r(10) = 0.64, p = 0.047]], and by contralesional arm impairment in the right hemisphere damage group [UEFM: [r(10) = 0.66, p = 0.040]]. Ipsilesional arm kinematics were correlated with functional independence in the left hemisphere damage group only. Examination of hemisphere-dependent motor correlates of functional independence showed that ipsilesional arm deficits were important in determining functional outcomes in individuals with left hemisphere damage only, suggesting that functional independence in right hemisphere damaged participants was affected by other factors.

Previous research has demonstrated hemisphere-specific motor deficits in ipsilesional and contralesional unimanual movements in patients with hemiparetic stroke due to MCA infarct. Due to the importance of bilateral motor actions on activities of daily living, we now examine how bilateral coordination may be differentially affected by right or left hemisphere stroke. To avoid the caveat of simply adding unimanual deficits in assessing bimanual coordination, we designed a unique task that requires spatiotemporal coordination features that do not exist in unimanual movements. Participants with unilateral left (LHD) or right hemisphere damage (RHD) and age-matched controls moved a virtual rectangle (bar) from a midline start position to a midline target. Movement along the long axis of the bar was redundant to the task, such that the bar remained in the center of and parallel to an imaginary line connecting each hand. Thus, to maintain midline position of the bar, movements of one hand closer to or further away from the bar midline required simultaneous, but oppositely directed displacements with the other hand. Our findings indicate that left (LHD), but not right (RHD) hemisphere-damaged patients showed poor interlimb coordination, reflected by significantly lower correlations between displacements of each hand along the bar axis. These left hemisphere-specific deficits were only apparent prior to peak velocity, likely reflecting predictive control of interlimb coordination. In contrast, the RHD group bilateral coordination was not significantly different than that of the control group. We conclude that predictive mechanisms that govern bilateral coordination are dependent on left hemisphere mechanisms. These findings indicate that assessment and training in cooperative bimanual tasks should be considered as part of an intervention framework for post-stroke physical rehabilitation.

EDITORIAL article Front. Neurol., 14 December 2020 | https://doi.org/10.3389/fneur.2020.630830

Background. Previous research has detailed the hemisphere dependence and specific kinematic deficits observed for the less-affected arm of patients with unilateral stroke. Objective. We now examine whether functional motor deficits in the less-affected arm, measured by standardized clinical measures of motor function, also depend on the hemisphere that was damaged and on the severity of contralesional impairment. Methods. We recruited 48 left-hemisphere-damaged (LHD) participants, 62 right-hemisphere-damaged participants, and 54 age-matched control participants. Measures of motor function included the following: (1) Jebsen-Taylor Hand Function Test (JHFT), (2) Grooved Pegboard Test (GPT), and (3) grip strength. We measured the extent of contralesional arm impairment with the upper-extremity component of the Fugl-Meyer (UEFM) assessment of motor impairment. Results. Ipsilesional limb functional performance deficits (JHFT) varied with both the damaged hemisphere and severity of contralesional arm impairment, with the most severe deficits expressed in LHD participants with severe contralesional impairment (UEFM). GPT and grip strength varied with severity of contralesional impairment but not with hemisphere. Conclusions. Stroke survivors with the most severe paretic arm impairment, who must rely on their ipsilesional arm for performing daily activities, have the greatest motor deficit in the less-affected arm. We recommend remediation of this arm to improve functional independence in this group of stroke patients.

Importance:Data from animal models show that the administration of dextroamphetamine combined with task-relevant training facilitates recovery after focal brain injury. Results of clinical trials in patients with stroke have been inconsistent. Objectives:To collect data important for future studies evaluating the effect of dextroamphetamine combined with physiotherapy for improving poststroke motor recovery and to test the efficacy of the approach. Design, Setting, Participants:This pilot, double-blind, block-randomized clinical trial included patients with cortical or subcortical ischemic stroke and moderate or severe motor deficits from 5 rehabilitation hospitals or units. Participants were screened and enrolled from March 2001 through March 2003. The primary outcome was assessed 3 months after stroke. Study analysis was completed December 31, 2015. A total of 1665 potential participants were screened and 64 were randomized. Participants had to begin treatment 10 to 30 days after ischemic stroke. Data analysis was based on intention to treat. Interventions:Participants were allocated to a regimen of 10 mg of dextroamphetamine (n = 32) or placebo (n = 32) combined with a 1-hour physical therapy session beginning 1 hour after drug or placebo administration every 4 days for 6 sessions in addition to standard rehabilitation. Main Outcomes and Measures:The primary outcome was the difference between groups in change in Fugl-Meyer motor scores from baseline to 3 months after stroke (intention to treat with dextroamphetamine). Secondary exploratory measures included the National Institutes of Health Stroke Scale, Canadian Neurological Scale, Action Research Arm Test, modified Rankin Scale score, Functional Independence Measure, Ambulation Speed and Distance, Mini-Mental State Examination, Beck Depression Inventory, and Stroke Impact Scale. Results:Among the 64 patients randomized to dextroamphetamine vs placebo (55% men; median age, 66 years; age range, 27-91 years), no overall treatment-associated difference in the mean (SEM) change in Fugl-Meyer motor scores from baseline to 3 months after stroke was noted (-18.65 [2.27] points with dextroamphetamine vs -20.83 [2.94] points with placebo; P = .58). No overall treatment-associated differences in any of the study's secondary measures and no differences in subgroups based on stroke location or baseline severity were found. No adverse events were attributed to study treatments. Conclusions and Relevance:Treatment with dextroamphetamine combined with physical therapy did not improve recovery of motor function compared with placebo combined with physical therapy as assessed 3 months after hemispheric ischemic stroke. The studied treatment regimen was safe. Trial Registration:ClinicalTrials.gov identifier: NCT01905371.

A somewhat perplexing finding in the systems neuroscience has been the observation that physical injury to neural systems may result in enhanced functional connectivity (i.e., hyperconnectivity) relative to the typical network response. The consequences of local or global enhancement of functional connectivity remain uncertain and this is particularly true for the overall metabolic cost of the network. We examine the hyperconnectivity hypothesis in a sample of 14 individuals with TBI with data collected at approximately 3, 6, and 12 months following moderate and severe TBI. As anticipated, individuals with TBI showed increased network strength and cost early after injury, but by one-year post injury hyperconnectivity was more circumscribed to frontal DMN and temporal-parietal attentional control regions. Cost in these subregions was a significant predictor of cognitive performance. Cost-efficiency analysis in the Power 264 data parcellation suggested that at 6 months post injury the network requires higher cost connections to achieve high efficiency as compared to the network 12 months post injury. These results demonstrate that networks self-organize to re-establish connectivity while balancing cost-efficiency trade-offs.

Angioedema results from the release of one or more mediators, most often histamine and bradykinin, in the deeper layers of the skin and mucous membranes. There is an increase in vascular permeability of the affected tissue that leads to asymmetric, non-dependent and non-pitting swelling. There are several types of angioedema, including hereditary angioedema (HAE) types I and II, HAE with normal C1 inhibitor (C1-INH or type III), non-allergic ACE inhibitor (ACEI)-induced angioedema (ACEI-AAE) and acquired angioedema due to C1-INH deficiency (C1-INH-AAE).1 The most well-documented cause of drug-induced angioedema is secondary to ACEI use, and attacks commonly affect the head and neck, particularly the mouth, tongue and larynx.1 The reported incidence of ACEI-AAE is 0.1%–2%; however, other medications are capable of causing similar symptoms. Angioedema of the tongue subsequent to intravenous tissue plasminogen activator (tPA) is rare with prevalence of 0.2%–5.1%.2 A 70-year-old, right-handed, Caucasian male with a history of hypertension …

Brain lateralization is a ubiquitous feature of neural organization across the vertebrate spectrum. We have developed a model of motor lateralization that attributes different motor control processes to each cerebral hemisphere. This bilateral hemispheric model of motor control has successfully predicted hemisphere-specific motor control and motor learning deficits in the ipsilesional, or non-paretic, arm of patients with unilateral stroke. We now show across large number and range of stroke patients that these motor performance deficits in the non-paretic arm of stroke patients vary with both the side of the lesion, as well as with the severity of contralesional impairment. This last point can be functionally devastating for patients with severe contralesional paresis because for these individuals, performance of upper extremity activities of daily living depends primarily and often exclusively on ipsilesional arm function. We present a pilot study focused on improving the speed and coordination of ipsilesional arm function in a convenience sample of three stroke patients with severe contralesional impairment. Over a three-week period, patients received a total of nine 1.5 h sessions of training that included intense practice of virtual reality and real-life tasks. Our results indicated substantial improvements in ipsilesional arm movement kinematics, functional performance, and that these improvements carried over to improve functional independence. In addition, the contralesional arm improved in our measure of contralesional impairment, which was likely due to improved participation in activities of daily living. We discuss of our findings for physical rehabilitation.

Background: The Post Stroke Checklist (PSC) is an easily administered tool to identify unmet needs in stroke patients. The relative value of the PSC compared to other outcome measures has yet to be determined. We have evaluated the utility of the PSC at 30 days post-stroke, and now report the use of the PSC at 90 days post-stroke. Methods: We evaluated 213 ischemic stroke patients 90 days post discharge in our Stroke Clinic. The PSC was administered as well as the Barthel Index (BI) and modified Rankin Scale (mRS) - scored by a nurse and reviewed by a stroke physician. We stratified each scale according to severity and identified actionable PSC items. Using Fisher’s Exact Test we tested for differences in each of the 11 individual items across the two mRS and BI stratified severity groups. Wilcoxon Rank Sum test measured differences in total PSC score (range 0-9) across mRS and BI severity groups. Results: 103 patients responded positively to one or more PSC items. The cognition item had the highest frequency, 51 (23.9%) of positive responses followed by the mood item, 33 (15.49). The median (range) BI was 100 (10-100) and mRS was 1 (0-5). Patients were distributed across the two BI and mRS severity groups: BI-S (more severe) 0-89 (n=26) and BI-L (less severe) 90-100 (n=187); mRS-S (more severe) 3-5 (n=31) and mRS-L (less severe) 0-2 (n=159). There were significant differences in total PSC scores across both mRS (p=<0.0001) and BI (p=.002) severity groups. There were significant differences in the mood (p=<0.0001), cognition (p=0.004), and life after stroke (p=0.014) items across the mRS severity groups. Patients in the more severe mRS group had higher proportion of positive responses on the mood, cognition and life after stroke items. Conclusion: The PSC identified a substantial proportion of unmet needs in both low severity and high severity stroke patients. The highest frequency related to cognitive function and mood/mental health - often overlooked if not probed for. Our results suggest the importance of cognitive and mental health assessment/referral, especially for high severity stroke patients.

Background Previous research has shown that during simulated activities of daily living, right-handed stroke patients use their contralesional arm more after left- than right-hemisphere stroke. These findings were attributed to a hand preference effect. However, these decisions about when to use the contralesional arm may be modulated by where in the work space the task is performed, a factor that could be used in physical rehabilitation to influence recovery by decreasing learned nonuse. Objective To examine how target location and side of stroke influences arm selection choices for simple reaching movements. Methods A total of 14 right-handed stroke patients (7 with left-hemisphere and 7 with right-hemisphere damage [RHD]), with similar degrees of hemiparesis (Fugl-Meyer motor score), and 16 right-handed controls participated in this experiment. In a pseudorandom fashion, 32 targets were presented throughout the reachable horizontal plane work space, and the participants were asked to select 1 hand to reach the target on each trial. Results The group with left-hemisphere damage chose their contralesional arm significantly more often than the group with RHD. Patients with RHD also chose their left (contralesional) arm significantly less often than the control group. However, these patterns of choice were most pronounced in the center of the workspace. Conclusion Both the side of hemisphere damage and work space location played a significant role in the choice of whether to use the contralesional arm for reaching. These findings have implications for structuring rehabilitation for unilateral stroke patients.

OBJECTIVE: The AESR trial was a multicenter, double-blind, pilot clinical trial designed to collect data to support the design of a Phase-3 clinical trial testing the efficacy of d-amphetamine combined with physical therapy to facilitate motor recovery following hemispheric ischemic stroke. BACKGROUND: Extensive data from a variety of animal models show that the administration of d-amphetamine combined with task relevant training facilitates recovery after focal sensorimotor cortex injury. The results of clinical trials have been inconsistent. The AESR trial was designed to evaluate two different treatment regimens, collect data to inform sample size calculations, determine safety, explore a variety of potential outcome measures, and identify logistic barriers important for future trials. DESIGN/METHODS: Using block randomization (cortical vs. subcortical; moderate vs. severe motor deficits based on the Fugl-Meyer scale) patients who could begin treatment 10-30 days after ischemic stroke were allocated to a regimen of 10mg of d-amphetamine or placebo combined with a 1-hour physical therapy session beginning 1-hour after drug/placebo administration every 4-days for 6-sessions in addition to standard rehabilitation (Regimen-1). Assessments were performed at baseline, end of treatment, and 3-months poststroke. A 12-point difference in Fugl-Meyer scores between groups was considered clinically significant. A sample size of 25 subjects per group was estimated to be necessary to detect this difference with 80% power. Assuming a 30% drop out rate, a total of 65-subjects were to be enrolled in each regimen. RESULTS: A total of 64-subjects were randomized (n=32 per group; d-amphetamine vs placebo mean age (±SD) 66±13 vs. 65±14 years; Caucasian 81% vs. 72%; men 50% vs. 59%). The mean (±SE) baseline Fugl-Meyer scores were similar (d-amphetamine 23.2±0.6 vs. placebo 24.5±0.6 points). The drop our rate was 9.5%; no subjects were withdrawn due to study-related adverse events. CONCLUSIONS: The studied treatment regimen was safe. Primary results will be presented. Study Supported by: NIH-NS39934

OBJECTIVEConstraint-induced movement therapy (CIMT) has been shown to improve upper extremity voluntary movement and change cortical movement representation after stroke. Direct comparison of the differential degree of cortical reorganization according to chronicity in stroke subjects receiving CIMT has not been performed and was the purpose of this study. We hypothesized that a higher degree of cortical reorganization would occur in the early (less than 9 months post-stroke) compared to the late group (more than 12 months post-stroke).METHODS17 early and 9 late subjects were enrolled. Each subject was evaluated using transcranial magnetic stimulation (TMS) and the Wolf Motor Function Test (WMFT) and received CIMT for 2 weeks.RESULTSThe early group showed greater improvement in WMFT compared with the late group. TMS motor maps showed persistent enlargement in both groups but the late group trended toward more enlargement. The map shifted posteriorly in the late stroke group. The main limitation was the small number of TMS measures that could be acquired due to high motor thresholds, particularly in the late group.CONCLUSIONCIMT appears to lead to greater improvement in motor function in the early phase after stroke. Greater cortical reorganization in map size and position occurred in the late group in comparison.SIGNIFICANCEThe contrast between larger functional gains in the early group vs larger map changes in the late group may indicate that mechanisms of recovery change over the several months following stroke or that map changes are a time-dependent epiphenomenon.

Background: The Post Stroke Checklist (PSC) is an easily administered, recently developed clinical tool to identify unmet needs in stroke patients. The relative value of the PSC compared to other outcome measures has yet to be determined. Method: We evaluated 126 ischemic stroke patients (median age 68, range 31-97) 30 days following discharge in the outpatient clinic of our Comprehensive Stroke Center. Items were originally scored by a nurse and reviewed with a stroke physician. The PSC was administered to all patients as well as the Barthel Index (BI) and modified Rankin Scale (mRS). We stratified each scale according to severity and identified actionable PSC items in each severity group. Using Fisher’s Exact Test we searched for correlation between the total number of PSC items scored positively and the total score of other outcome measures. We also looked for correlations between individual PSC items and other outcome scores. Results: The median (range) BI was 100 (10-100) and mRS was 1 (0-4). We stratified each outcome measure into 2 groups: BI-S (more severe) 0-89 (n=23) and BI-L (less severe) 90-100 (n=103); mRS-S (more severe) 3-5 (n=23) and mRS-L (less severe) 0-2 (n=103). 79 patients responded positively to one or more items in the PSC. There was no difference in total positive scores for any of the stratified groups, mRS (p=0.69) and BI (p=0.28). The frequency of positive responses for individual patients ranged from 1 to 6. The most common items identified are listed in the table below. No significant differences were noted. Conclusion: The PSC is simple to administer and was well accepted by clinicians and patients. Depression/Anxiety, Cognitive Dysfunction, Instrumental ADL’s, and New Onset Pain are not included in the BI and mRS but are easily identified using the PSC. Our results suggest that the PSC provides important information about these unmet needs in stroke patients independent of stroke severity.

Background: Stroke care often focuses on acute intervention and treatment, but important long-term sequelae are sometimes overlooked and may not be captured in standard outcome measures. The Post Stroke Checklist (PSC) is a simple tool recently developed by a global panel of stroke experts to identify the unmet needs of stroke survivors. It consists of 11 items addressing a variety of important medical, functional and social issues. The intent is to improve stroke survivor follow-up and ensure that treatable complications are identified and referred for treatment. Methods: The PSC was administered at 30 days post ischemic stroke in 126 recently hospitalized patients in the outpatient clinic of a Comprehensive Stroke Center. Items were originally scored by a nurse and reviewed with a stroke physician. Age range (median) was 31-97 (68) years. All patients were also scored with Barthel Index (BI), NIH Stroke Scale (NIHSS), and modified Rankin Scale (mRS) during the clinic visit. Actionable items were identified by positive responses to any question on the PSC. The number of patients with actionable items was tabulated. Results: The median (range) BI was 100 (10-100), NIHSS was 1 (0-28), and mRS was 1 (0-4). The PSC identified actionable items in 79/124 (64%) patients. In 39/79 (49%) patients, more than one actionable item was identified. The most common items were depression/anxiety 32 (26%), cognitive dysfunction 28 (23%), decreased ability to perform instrumental ADL’s 18 (15%), and any new pain 13 (10%). All other items were scored positively in less than 10% of patients. The PSC was judged acceptable by both stroke professionals and patients, who felt the items on the PSC identified important issues that otherwise, may have been overlooked in a clinic setting. Conclusions: The PSC proved to be a useful tool at 30 days to identify important unmet needs in stroke survivors with mild deficits. The next step in this research is to evaluate patients at 90 days post stroke, when a larger range of deficits is expected.