Global synergistic actions to improve brain health for human development.

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.

Remedial Training of the Less-Impaired Arm in Chronic Stroke Survivors With Moderate to Severe Upper-Extremity Paresis Improves Functional Independence: A Pilot Study.

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.

Deficits in Performance on a Mechanically Coupled Asymmetrical Bilateral Task in Chronic Stroke Survivors with Mild Unilateral Paresis.

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.

Left hemisphere damage produces deficits in predictive control of bilateral coordination.

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.

Functional Deficits in the Less-Impaired Arm of Stroke Survivors Depend on Hemisphere of Damage and Extent of Paretic Arm Impairment.

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.

Correction: The evolution of cost-efficiency in neural networks during recovery from traumatic brain injury.

[This corrects the article DOI: 10.1371/journal.pone.0170541.].

Effect of Dextroamphetamine on Poststroke Motor Recovery: A Randomized Clinical Trial.

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.

The evolution of cost-efficiency in neural networks during recovery from traumatic brain injury.

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.

Differential patterns of cortical reorganization following constraint-induced movement therapy during early and late period after stroke: A preliminary study.

OBJECTIVE: Constraint-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). METHODS: 17 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. RESULTS: The 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. CONCLUSION: CIMT 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. SIGNIFICANCE: The 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.

The rich get richer: brain injury elicits hyperconnectivity in core subnetworks.

There remains much unknown about how large-scale neural networks accommodate neurological disruption, such as moderate and severe traumatic brain injury (TBI). A primary goal in this study was to examine the alterations in network topology occurring during the first year of recovery following TBI. To do so we examined 21 individuals with moderate and severe TBI at 3 and 6 months after resolution of posttraumatic amnesia and 15 age- and education-matched healthy adults using functional MRI and graph theoretical analyses. There were two central hypotheses in this study: 1) physical disruption results in increased functional connectivity, or hyperconnectivity, and 2) hyperconnectivity occurs in regions typically observed to be the most highly connected cortical hubs, or the "rich club". The current findings generally support the hyperconnectivity hypothesis showing that during the first year of recovery after TBI, neural networks show increased connectivity, and this change is disproportionately represented in brain regions belonging to the brain's core subnetworks. The selective increases in connectivity observed here are consistent with the preferential attachment model underlying scale-free network development. This study is the largest of its kind and provides the unique opportunity to examine how neural systems adapt to significant neurological disruption during the first year after injury.

Contralesional Arm Preference Depends on Hemisphere of Damage and Target Location in Unilateral 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.

Contralesional motor deficits after unilateral stroke reflect hemisphere-specific control mechanisms.

We have proposed a model of motor lateralization, in which the left and right hemispheres are specialized for different aspects of motor control: the left hemisphere for predicting and accounting for limb dynamics and the right hemisphere for stabilizing limb position through impedance control mechanisms. Our previous studies, demonstrating different motor deficits in the ipsilesional arm of stroke patients with left or right hemisphere damage, provided a critical test of our model. However, motor deficits after stroke are most prominent on the contralesional side. Post-stroke rehabilitation has also, naturally, focused on improving contralesional arm impairment and function. Understanding whether contralesional motor deficits differ depending on the hemisphere of damage is, therefore, of vital importance for assessing the impact of brain damage on function and also for designing rehabilitation interventions specific to laterality of damage. We, therefore, asked whether motor deficits in the contralesional arm of unilateral stroke patients reflect hemisphere-dependent control mechanisms. Because our model of lateralization predicts that contralesional deficits will differ depending on the hemisphere of damage, this study also served as an essential assessment of our model. Stroke patients with mild to moderate hemiparesis in either the left or right arm because of contralateral stroke and healthy control subjects performed targeted multi-joint reaching movements in different directions. As predicted, our results indicated a double dissociation; although left hemisphere damage was associated with greater errors in trajectory curvature and movement direction, errors in movement extent were greatest after right hemisphere damage. Thus, our results provide the first demonstration of hemisphere specific motor control deficits in the contralesional arm of stroke patients. Our results also suggest that it is critical to consider the differential deficits induced by right or left hemisphere lesions to enhance post-stroke rehabilitation interventions.

The less BOLD, the wiser: support for the latent resource hypothesis after traumatic brain injury.

Previous studies of the BOLD response in the injured brain have revealed neural recruitment relative to controls during working memory tasks in several brain regions, most consistently the right prefrontal cortex and anterior cingulate cortices. We previously proposed that the recruitment observed in this literature represents auxiliary support resources, and that recruitment of PFC is not abnormal or injury specific and should reduce as novelty and challenge decrease. The current study directly tests this hypothesis in the context of practice of a working memory task. It was hypothesized that individuals with brain injury would demonstrate recruitment of previously indicated regions, behavioral improvement following task practice, and a reduction in the BOLD signal in recruited regions after practice. Individuals with traumatic brain injury and healthy controls performed the n-back during fMRI acquisition, practiced each task out of the scanner, and returned to the scanner for additional fMRI n-back acquisition. Statistical parametric maps demonstrated a number of regions of recruitment in the 1-back in individuals with brain injury and a number of corresponding regions of reduced activation in individuals with brain injury following practice in both the 1-back and 2-back. Regions of interest demonstrated reduced activation following practice, including the anterior cingulate and right prefrontal cortices. Individuals with brain injury demonstrated modest behavioral improvements following practice. These findings suggest that neural recruitment in brain injury does not represent reorganization but a natural extension of latent mechanisms that engage transiently and are contingent upon cerebral challenge.

Dynamic dominance varies with handedness: reduced interlimb asymmetries in left-handers.

Our previous studies of interlimb asymmetries during reaching movements have given rise to the dynamic-dominance hypothesis of motor lateralization. This hypothesis proposes that dominant arm control has become optimized for efficient intersegmental coordination, which is often associated with straight and smooth hand-paths, while non-dominant arm control has become optimized for controlling steady-state posture, which has been associated with greater final position accuracy when movements are mechanically perturbed, and often during movements made in the absence of visual feedback. The basis for this model of motor lateralization was derived from studies conducted in right-handed subjects. We now ask whether left-handers show similar proficiencies in coordinating reaching movements. We recruited right- and left-handers (20 per group) to perform reaching movements to three targets, in which intersegmental coordination requirements varied systematically. Our results showed that the dominant arm of both left- and right-handers were well coordinated, as reflected by fairly straight hand-paths and low errors in initial direction. Consistent with our previous studies, the non-dominant arm of right-handers showed substantially greater curvature and large errors in initial direction, most notably to targets that elicited higher intersegmental interactions. While the right, non-dominant, hand-paths of left-handers were slightly more curved than those of the dominant arm, they were also substantially more accurate and better coordinated than the non-dominant arm of right-handers. Our results indicate a similar pattern, but reduced lateralization for intersegmental coordination in left-handers. These findings suggest that left-handers develop more coordinated control of their non-dominant arms than right-handers, possibly due to environmental pressure for right-handed manipulations.

Examining working memory task acquisition in a disrupted neural network.

There is mounting literature that examines brain activation during tasks of working memory in individuals with neurological disorders such as traumatic brain injury. These studies represent a foundation for understanding the functional brain changes that occur after moderate and severe traumatic brain injury, but the focus on topographical brain-'activation' differences ignores potential alterations in how nodes communicate within a distributed neural network. The present study makes use of the most recently developed connectivity modelling (extended-unified structural equation model) to examine performance during a well-established working-memory task (the n-back) in individuals sustaining moderate and severe traumatic brain injury. The goal is to use the findings observed in topographical activation analysis as the basis for second-level effective connectivity modelling. Findings reveal important between-group differences in within-hemisphere connectivity during task acquisition, with the control sample demonstrating rapid within-left hemisphere connectivity increases and the traumatic brain injury sample demonstrating consistently elevated within-right hemisphere connectivity. These findings also point to important maturational effects from 'early' to 'late' during task performance, including diminished right prefrontal cortex involvement and an anterior to posterior shift in connectivity with increased task exposure. We anticipate that this approach to functional imaging data analysis represents an important future direction for understanding how neural plasticity is expressed in brain disorders.

Stroke rehabilitation.

Despite improvements in prevention and acute management, stroke remains a common condition and a major cause of permanent disability. For patients who have had a stroke, an effective rehabilitation program is critical to maximize functional recovery and quality of life. Rehabilitation can occur in a number of different physical settings and is often coordinated by a comprehensive interdisciplinary team of professionals. Rehabilitation includes retraining to regain loss of function and teaching compensatory strategies when that is not possible. A number of interesting training approaches have been developed in recent years to supplement more traditional rehabilitation programs. A variety of adaptive devices is available to improve mobility and performance of self-cares, and these devices should be prescribed for appropriate patients. Physicians caring for patients during stroke rehabilitation must be aware of potential medical complications, as well as a number of special problems that may complicate recovery, including dysphagia, urinary incontinence, shoulder pain, spasticity, falls, and poststroke depression. Involvement of the patient and caregivers in the rehabilitation process is essential. It is important to train and educate these individuals in the physical aspects of poststroke care, the expectations for recovery, and secondary stroke prevention. Issues related to community reintegration, including driving and vocational aspects, should be addressed in appropriate patients. Stroke rehabilitation is an important part of the "stroke continuum of care," which includes prevention, acute management, rehabilitation, and secondary prevention.

Constraint-induced movement therapy results in increased motor map area in subjects 3 to 9 months after stroke.

BACKGROUND: Constraint-induced movement therapy (CIMT) has received considerable attention as an intervention to enhance motor recovery and cortical reorganization after stroke. OBJECTIVE: The present study represents the first multi-center effort to measure cortical reorganization induced by CIMT in subjects who are in the subacute stage of recovery. METHODS: A total of 30 stroke subjects in the subacute phase (>3 and <9 months poststroke) were recruited and randomized into experimental (receiving CIMT immediately after baseline evaluation) and control (receiving CIMT after 4 months) groups. Each subject was evaluated using transcranial magnetic stimulation (TMS) at baseline, 2 weeks after baseline, and at 4-month follow-up (ie, after CIMT in the experimental groups and before CIMT in the control groups). The primary clinical outcome measure was the Wolf Motor Function Test. RESULTS: Both experimental and control groups demonstrated improved hand motor function 2 weeks after baseline. The experimental group showed significantly greater improvement in grip force after the intervention and at follow-up (P = .049). After adjusting for the baseline measures, the experimental group had an increase in the TMS motor map area compared with the control group over a 4-month period; this increase was of borderline significance (P = .053). CONCLUSIONS: Among subjects who had a stroke within the previous 3 to 9 months, CIMT produced statistically significant and clinically relevant improvements in arm motor function that persisted for at least 4 months. The corresponding enlargement of TMS motor maps, similar to that found in earlier studies of chronic stroke subjects, appears to play an important role in CIMT-dependent plasticity.

Dynamic course of intracortical TMS paired-pulse responses during recovery of motor function after stroke.

BACKGROUND: Recovery of motor function after stroke may be associated with changes in inhibitory and facilitatory circuits within the motor cortex. OBJECTIVE: We explored such changes longitudinally after stroke, using transcranial magnetic stimulation (TMS). METHODS: Subjects (N = 27) with a single cerebral infarction affecting movement of either hand were studied at <10 days poststroke, 1 month, and 6 months. Age-matched control subjects (N = 9) were studied at 2 times. RESULTS: In contrast to previous studies, paired-pulse inhibition was increased in patients with a subcortical stroke compared to control subjects. After a cortical stroke, paired-pulse facilitation was also increased. Stroke location affected the time course of inhibition. Subcortical stroke resulted in increased inhibition initially that decreased over time, whereas cortical stroke had no significant effect on inhibition and a more immediate and lasting effect on facilitation. CONCLUSIONS: The time course of a decline in inhibition based on TMS after subcortical stroke followed the gain in motor recovery. Increased facilitation in cortical stroke patients is more likely to represent the effect of early cortical circuit disruption and may not play a role in subacute changes in motor function.

Atomoxetine enhances a short-term model of plasticity in humans.

OBJECTIVE: To evaluate the role of 2 noradrenergic drugs in modulating use-dependent plasticity in humans. DESIGN: Double-blind, randomized, and placebo-controlled crossover design. SETTING: A laboratory in a hospital. PARTICIPANTS: A convenience sample of 10 healthy subjects. INTERVENTION: An established paradigm that measures motor memory as a short-term model of use-dependent plasticity. Subjects attended 3 sessions, separated by at least 1 week to allow drug washout. Subjects received atomoxetine (Strattera), venlafaxine (Effexor), or placebo. MAIN OUTCOME MEASURE: Increase in the proportion of movements into the training target zone (TTZ), an indicator of enhanced plasticity. RESULTS: Atomoxetine, but not venlafaxine, significantly increased movements into the TTZ. CONCLUSIONS: These results support a role for norepinephrine in enhancing cortical plasticity and suggest potential benefits in using these drugs for improving motor recovery after stroke.

Timing, intensity, and duration of rehabilitation for hip fracture and stroke: report of a workshop at the National Center for Medical Rehabilitation Research.

This article summarizes the proceedings of an NIH workshop on timing, intensity, and duration of rehabilitation for acute stroke and hip fracture. Participants concentrated on methodological issues facing investigators and suggested priorities for future research in this area.