CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury.

We tested a newly described molecular memory system, CCR5 signaling, for its role in recovery after stroke and traumatic brain injury (TBI). CCR5 is uniquely expressed in cortical neurons after stroke. Post-stroke neuronal knockdown of CCR5 in pre-motor cortex leads to early recovery of motor control. Recovery is associated with preservation of dendritic spines, new patterns of cortical projections to contralateral pre-motor cortex, and upregulation of CREB and DLK signaling. Administration of a clinically utilized FDA-approved CCR5 antagonist, devised for HIV treatment, produces similar effects on motor recovery post stroke and cognitive decline post TBI. Finally, in a large clinical cohort of stroke patients, carriers for a naturally occurring loss-of-function mutation in CCR5 (CCR5-Δ32) exhibited greater recovery of neurological impairments and cognitive function. In summary, CCR5 is a translational target for neural repair in stroke and TBI and the first reported gene associated with enhanced recovery in human stroke.

Structural Plasticity in Adulthood with Motor Learning and Stroke Rehabilitation.

The development of advanced noninvasive techniques to image the human brain has enabled the demonstration of structural plasticity during adulthood in response to motor learning. Understanding the basic mechanisms of structural plasticity in the context of motor learning is essential to improve motor rehabilitation in stroke patients. Here, we review and discuss the emerging evidence for motor-learning-related structural plasticity and the implications for stroke rehabilitation. In the clinical context, a few studies have started to assess the effects of rehabilitation on structural measures to understand recovery poststroke and additionally to predict intervention outcomes. Structural imaging will likely have a role in the future in providing measures that inform patient stratification for optimal outcomes.

Encouraging an excitable brain state: mechanisms of brain repair in stroke.

Stroke induces a plastic state in the brain. This period of enhanced plasticity leads to the sprouting of new axons, the formation of new synapses and the remapping of sensory-motor functions, and is associated with motor recovery. This is a remarkable process in the adult brain, which is normally constrained in its levels of neuronal plasticity and connectional change. Recent evidence indicates that these changes are driven by molecular systems that underlie learning and memory, such as changes in cellular excitability during memory formation. This Review examines circuit changes after stroke, the shared mechanisms between memory formation and brain repair, the changes in neuronal excitability that underlie stroke recovery, and the molecular and pharmacological interventions that follow from these findings to promote motor recovery in animal models. From these findings, a framework emerges for understanding recovery after stroke, central to which is the concept of neuronal allocation to damaged circuits. The translation of the concepts discussed here to recovery in humans is underway in clinical trials for stroke recovery drugs.

Electrophysiological Correlates of Dentate Nucleus Deep Brain Stimulation for Poststroke Motor Recovery.

While ipsilesional cortical electroencephalography has been associated with poststroke recovery mechanisms and outcomes, the role of the cerebellum and its interaction with the ipsilesional cortex is still largely unknown. We have previously shown that poststroke motor control relies on increased corticocerebellar coherence (CCC) in the low beta band to maintain motor task accuracy and to compensate for decreased excitability of the ipsilesional cortex. We now extend our work to investigate corticocerebellar network changes associated with chronic stimulation of the dentato-thalamo-cortical pathway aimed at promoting poststroke motor rehabilitation. We investigated the excitability of the ipsilesional cortex, the dentate (DN), and their interaction as a function of treatment outcome measures. Relative to baseline, 10 human participants (two women) at the end of 4-8 months of DN deep brain stimulation (DBS) showed (1) significantly improved motor control indexed by computerized motor tasks; (2) significant increase in ipsilesional premotor cortex event-related desynchronization that correlated with improvements in motor function; and (3) significant decrease in CCC, including causal interactions between the DN and ipsilesional cortex, which also correlated with motor function improvements. Furthermore, we show that the functional state of the DN in the poststroke state and its connectivity with the ipsilesional cortex were predictive of motor outcomes associated with DN-DBS. The findings suggest that as participants recovered, the ipsilesional cortex became more involved in motor control, with less demand on the cerebellum to support task planning and execution. Our data provide unique mechanistic insights into the functional state of corticocerebellar-cortical network after stroke and its modulation by DN-DBS.

Ultra-early navigated transcranial magnetic stimulation for perioperative stroke: anatomo-functional report.

Navigated repetitive transmagnetic stimulation is a non-invasive and safe brain activity modulation technique. When combined with the classical rehabilitation process in stroke patients it has the potential to enhance the overall neurologic recovery. We present a case of a peri-operative stroke, treated with ultra-early low frequency navigated repetitive transmagnetic stimulation over the contralesional hemisphere. The patient received low frequency navigated repetitive transmagnetic stimulation within 12 hours of stroke onset for seven consecutive days and a significant improvement in his right sided weakness was noticed and he was discharge with normal power. This was accompanied by an increase in the number of positive responses evoked by navigated repetitive transmagnetic stimulation and a decrease of the resting motor thresholds at a cortical level. Subcortically, a decrease in the radial, axial, and mean diffusivity were recorded in the ipsilateral corticospinal tract and an increase in fractional anisotropy, axial diffusivity, and mean diffusivity was observed in the interhemispheric fibers of the corpus callosum responsible for the interhemispheric connectivity between motor areas. Our case demonstrates clearly that ultra-early low frequency navigated repetitive transmagnetic stimulation applied to the contralateral motor cortex can lead to significant clinical motor improvement in patients with subcortical stroke.

Making Sense of Vagus Nerve Stimulation for Stroke.

Implantable vagus nerve stimulation, paired with high-dose occupational therapy, has been shown to be effective in improving upper limb function among patients with stroke and received regulatory approval from the US Food and Drug Administration and the Centers for Medicare & Medicaid Services. Combining nonsurgical and surgical approaches of vagus nerve stimulation in recent meta-analyses has resulted in misleading reports on the efficacy of each type of stimulation among patients with stroke. This article aims to clarify the confusion surrounding implantable vagus nerve stimulation as a poststroke treatment option, highlighting the importance of distinguishing between transcutaneous auricular vagus nerve stimulation and implantable vagus nerve stimulation. Recent meta-analyses on vagus nerve stimulation have inappropriately combined studies of fundamentally different interventions, outcome measures, and participant selection, which do not conform to methodological best practices and, hence, cannot be used to deduce the relative efficacy of the different types of vagus nerve stimulation for stroke rehabilitation. Health care providers, patients, and insurers should rely on appropriately designed research to guide well-informed decisions.

Outside the Laboratory Assessment of Upper Limb Laterality in Patients With Stroke: A Cross-Sectional Study.

BACKGROUND: The rehabilitation of upper limb sensorimotor performance after stroke requires the assessment of daily use, the identification of key levels of impairment, and monitoring the course of recovery. It needs to be answered, how laboratory-based assessments and everyday behavior are connected, which dimension of metrics, that is, volume, intensity, or quality, is most sensitive to reduced function, and what sensor, that is, gyroscope or accelerometer, is best suited to gather such data. METHODS: Performance in laboratory-based sensorimotor tests, as well as smartwatch-derived kinematic data of everyday life relative upper limb activity, during 1 day of inpatient neurorehabilitation (Germany, 2022) of 50 patients with stroke, was cross-sectionally assessed and resulting laterality indices (performance ratios) between the limbs were analyzed using ANCOVAs and principal component analysis. RESULTS: Laboratory-based tests revealed the strongest laterality indices, followed by smartwatch-based (intensity>quality>volume) metrics. Angular velocity-based metrics revealed higher laterality indices than acceleration-based ones. Laterality indices were overall well associated; however, a principal component analysis suggested upper limb impairments to be unidimensional. CONCLUSIONS: Our findings suggest that the use of sensors can deliver valid information of stroke-related laterality. It appeared that commonly used metrics that estimate the volume of use (ie, energy expenditure) are not the most sensitive. Especially reached intensities could be well used for monitoring, because they are more dependent on the performance of the sensorimotor system and less on confounders like age. The unidimensionality of the upper limb laterality suggests that an impaired limb with reduced movement quality and the inability to reach higher intensities will be used less in everyday life, especially when it is the nondominant side.

Dose Response to Upper Extremity Stroke Rehabilitation Varies by Individual: Early Indicators of Treatment Response.

BACKGROUND: Dose response has remained a priority area in motor rehabilitation research for decades, prompting several large randomized trials and meta-analyses. These between-subjects comparisons have revealed equivocal relationships between the duration of motor practice and rehabilitation response. Prior reliance on time-consuming clinical assessments made it infeasible to capture within-subjects dose response, as tracking the dose-response trajectory of an individual requires dozens of repeated administrations. METHODS: This secondary observational cohort analysis of existing data from the gaming arms of the VIGoROUS multisite trial (Video Game Rehabilitation for Outpatient Stroke) describes the rehabilitation dose response of 80 participants with mild-moderate chronic stroke. The 3-dimensional joint position data were captured via the Kinect v2 optical sensor as participants completed a prescribed 15 hours of in-home unsupervised game-based motor practice. Kinematic dose response trajectories were fitted from hundreds to thousands of in-game repetitions for 4 separate upper extremity movements for each participant. RESULTS: Of 75 participants with sufficient data for dose-response analysis, 85% showed improved motor capacity for at least 1 movement. Dose response was bimodal; 42% required <5 hours of motor practice before reaching a plateau in movement kinematics, whereas 55% required >10 and 34% required >30 hours. We could predict with 93% accuracy whether or not an individual would ultimately respond to game-based motor practice within 5 hours of gameplay. CONCLUSIONS: Dose response varies considerably between individuals. About half of chronic stroke patients benefit from higher doses of motor practice than the current standard of care. Individualized dose-response data from motion capture rehabilitation gaming can guide clinical decision-making early on in treatment. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02631850.

Re-Imagining Hospital Patient Room Design for People After stroke: A Randomized Controlled Study Using Virtual Reality.

BACKGROUND: The hospital's physical environment can impact health and well-being. Patients spend most of their time in their hospital rooms. However, little experimental evidence supports specific physical design variables in these rooms, particularly for people poststroke. The study aimed to explore the influence of patient room design variables modeled in virtual reality using a controlled experimental design. METHODS: Adults within 3 years of stroke who had spent >2 nights in hospital for stroke and were able to consent were included (Melbourne, Australia). Using a factorial design, we immersed participants in 16 different virtual hospital patient rooms in both daytime and nighttime conditions, systematically varying design attributes: patient room occupancy, social connectivity, room size (spaciousness), noise (nighttime), greenery outlook (daytime). While immersed, participants rated their affect (Pick-A-Mood Scale) and preference. Mixed-effect regression analyses were used to explore participant responses to design variables in both daytime and nighttime conditions. Feasibility and safety were monitored throughout. Australian New Zealand Clinical Trials Registry, Trial ID: ACTRN12620000375954. RESULTS: Forty-four adults (median age, 67 [interquartile range, 57.3-73.8] years, 61.4% male, and a third with stroke in the prior 3-6 months) completed the study in 2019-2020. We recorded and analyzed 701 observations of affective responses (Pick-A-Mood Scale) in the daytime (686 at night) and 698 observations of preference responses in the daytime (685 nighttime) while continuously immersed in the virtual reality scenarios. Although single rooms were most preferred overall (daytime and nighttime), the relationship between affective responses differed in response to different combinations of nighttime noise, social connectivity, and greenery outlook (daytime). The virtual reality scenario intervention was feasible and safe for stroke participants. CONCLUSIONS: Immediate affective responses can be influenced by exposure to physical design variables other than room occupancy alone. Virtual reality testing of how the physical environment influences patient responses and, ultimately, outcomes could inform how we design new interventions for people recovering after stroke. REGISTRATION: URL: https://anzctr.org.au; Unique identifier: ACTRN12620000375954.

Intermittent Theta-Burst Stimulation for Stroke: Primary Motor Cortex Versus Cerebellar Stimulation: A Randomized Sham-Controlled Trial.

BACKGROUND: Stroke survivors with impaired balance and motor function tend to have relatively poor functional outcomes. The cerebellum and primary motor cortex (M1) have been suggested as targets for neuromodulation of balance and motor recovery after stroke. This study aimed to compare the efficacy and safety of intermittent theta-burst stimulation (iTBS) to the cerebellum or M1 on balance and motor recovery in patients with stroke. METHODS: In this randomized, double-blind, sham-controlled clinical trial, patients with subacute stroke were randomly divided into 3 groups: M1-, cerebellar-, and sham-iTBS (n=12 per group; 15 sessions, 3 weeks). All outcomes were evaluated before intervention (T0), after 1 week of intervention (T1), after 3 weeks of intervention (T2), and at follow-up (T3). The primary outcome was the Berg balance scale score at T2. Secondary outcomes include the Fugl-Meyer assessment scale for lower extremities, the trunk impairment scale, the Barthel index, the modified Rankin Scale, the functional ambulation categories, and cortical excitability. RESULTS: A total of 167 inpatients were screened, 36 patients (age, 57.50±2.41 years; 10 women, 12 ischemic) were enrolled between December 2020 and January 2023. At T2, M1- or cerebellar-iTBS significantly improved Berg balance scale scores by 10.7 points ([95% CI, 2.7-18.6], P=0.009) and 14.2 points ([95% CI, 1.2-27.2], P=0.032) compared with the sham-iTBS group. Moreover, the cerebellar-iTBS group showed a significantly greater improvement in Fugl-Meyer assessment scale for lower extremities scores by 5.6 points than the M1-iTBS ([95% CI, 0.3-10.9], P=0.037) and by 7.8 points than the sham-iTBS ([95% CI, 1.1-14.5], P=0.021) groups at T2. The motor-evoked potential amplitudes of the M1- and cerebellar-iTBS groups were higher than those of the sham-iTBS group (P<0.001). CONCLUSIONS: Both M1- and cerebellar-iTBS could improve balance function. Moreover, cerebellar-iTBS, but not M1-iTBS, induced significant effects on motor recovery. Thus, cerebellar-iTBS may be a valuable new therapeutic option in stroke rehabilitation programs. REGISTRATION: URL: https://www.chictr.org.cn/; Unique identifier: ChiCTR2100047002.

Exploring the Inclusion of Person-Centered Care Domains in Stroke Transitions of Care Interventions: A Scientific Statement From the American Heart Association.

BACKGROUND: Health care teams along the stroke recovery continuum have a responsibility to support care transitions and return to the community. Ideally, individualized care will consider patient and family preferences, best available evidence, and health care professional input. Person-centered care can improve patient-practitioner interactions through shared decision-making in which health professionals and institutions are sensitive to those for whom they provide care. However, it is unclear how the concepts of person-centered care have been described in reports of stroke transitional care interventions. METHODS: A secondary analysis of a systematic review and meta-analysis was undertaken. We retrieved all included articles (n=17) and evaluated the extent to which each intervention explicitly addressed 7 domains of person-centered care: alignment of care with patients' values, preferences, and needs; coordination of care; information and education; physical comfort; emotional support; family and friend involvement; and smooth transition and continuity of care. RESULTS: Most of the articles included some aspects of person-centeredness; we found that certain domains were not addressed in the descriptions of transitional care interventions, and no articles mentioned all 7 domains of person-centered care. We identified 3 implications for practice and research: (1) delineating person-centered care components when reporting interventions, (2) elucidating social and cultural factors relevant to the study sample and intervention, and (3) clearly describing the role of family and nonmedical support in the intervention. CONCLUSIONS: There is still room for greater consistency in the reporting of person-centeredness in stroke transitions of care interventions, despite a long-standing definition and conceptualization of person-centered care in academic and clinically focused literature.

Endovascular Brain-Computer Interfaces in Poststroke Paralysis.

Stroke is a leading cause of paralysis, most frequently affecting the upper limbs and vocal folds. Despite recent advances in care, stroke recovery invariably reaches a plateau, after which there are permanent neurological impairments. Implantable brain-computer interface devices offer the potential to bypass permanent neurological lesions. They function by (1) recording neural activity, (2) decoding the neural signal occurring in response to volitional motor intentions, and (3) generating digital control signals that may be used to control external devices. While brain-computer interface technology has the potential to revolutionize neurological care, clinical translation has been limited. Endovascular arrays present a novel form of minimally invasive brain-computer interface devices that have been deployed in human subjects during early feasibility studies. This article provides an overview of endovascular brain-computer interface devices and critically evaluates the patient with stroke as an implant candidate. Future opportunities are mapped, along with the challenges arising when decoding neural activity following infarction. Limitations arise when considering intracerebral hemorrhage and motor cortex lesions; however, future directions are outlined that aim to address these challenges.

Increasing Activity After Stroke: A Randomized Controlled Trial of High-Intensity Walking and Step Activity Intervention.

BACKGROUND: Physical inactivity in people with chronic stroke profoundly affects daily function and increases recurrent stroke risk and mortality, making physical activity improvements an important target of intervention. We compared the effects of a high-intensity walking intervention (FAST), a step activity monitoring behavioral intervention (SAM), or a combined intervention (FAST+SAM) on physical activity (ie, steps/day). We hypothesized the combined intervention would yield the greatest increase in steps/day. METHODS: This assessor-blinded multisite randomized controlled trial was conducted at 4 university/hospital-based laboratories. Participants were 21 to 85 years old, walking without physical assistance following a single, unilateral noncerebellar stroke of ≥6 months duration, and randomly assigned to FAST, SAM, or FAST+SAM for 12 weeks (2-3 sessions/week). FAST training consisted of walking-related activities at 70% to 80% heart rate reserve, while SAM received daily feedback and goal setting of walking activity (steps/day). Assessors and study statistician were masked to group assignment. The a priori-determined primary outcome and end point was a comparison of the change in steps/day between the 3 intervention groups from pre- to post-intervention. Adverse events were tracked after randomization. All randomized participants were included in the intent-to-treat analysis. RESULTS: Participants were enrolled from July 18, 2016, to November 16, 2021. Of 2385 participants initially screened, 250 participants were randomized (mean [SE] age, 63 [0.80] years; 116 females/134 males), with 89 assigned to FAST, 81 to SAM, and 80 to FAST+SAM. Steps/day significantly increased in both the SAM (mean [SE], 1542 [267; 95% CI, 1014-2069] P<0.001) and FAST+SAM group (1307 [280; 95% CI, 752-1861] P<0.001) but not in the FAST group (406 [238; 95% CI, -63 to 876] P=0.09). There were no deaths or serious study-related adverse events. CONCLUSIONS: Only individuals with chronic stroke who completed a step activity monitoring behavioral intervention with skilled coaching and goal progression demonstrated improvements in physical activity (steps/day). REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02835313.

Acute Intermittent Hypoxia With High-Intensity Gait Training in Chronic Stroke: A Phase II Randomized Crossover Trial.

BACKGROUND: Studies in individuals with chronic stroke indicate high-intensity training (HIT) focused on walking improves locomotor function, which may be due to repeated activation of locomotor circuits and serotonin-dependent modulation of motor output. Separate studies in animals and individuals with spinal cord injury suggest acute intermittent hypoxia (AIH) can augment the effects of locomotor interventions through similar serotonin-dependent mechanisms, although no studies have coupled AIH with HIT in individuals poststroke. The goal of this study was to evaluate the safety and efficacy of AIH+HIT versus HIT alone in individuals with chronic stroke. METHODS: This phase II double-blind randomized, crossover trial recruited individuals between 18 and 85 years old, >6 months poststroke, and self-selected speeds <1.0 m/s. Participants received up to 15 sessions of AIH for 30 minutes using 15 cycles of hypoxia (60-90 seconds; 8%-9% O2) and normoxia (30-60 seconds; 21% O2), followed by 1 hour of HIT targeting >75% heart rate reserve. The control condition received normoxia for 30 minutes before HIT. Following the first training phase, participants performed the second phase >1 month later. The primary outcomes were self-selected speed and fastest speed, a 6-minute walk test, and peak treadmill speed. A 3-way mixed-model ANOVA assessed the effects of time, training, and order of interventions. RESULTS: Of 55 individuals screened, 35 were randomized to AIH+HIT or normoxia+HIT first, and 28 individuals completed both interventions, revealing greater gains in self-selected speeds (0.14 [0.08-0.18] versus 0.05 [0.01-0.10] m/s), fastest speed (0.16 [0.10-0.21] versus 0.06 [0.02-0.10] m/s), and peak treadmill speed (0.21 [0.14-0.29] versus 0.11 [0.06-0.16] m/s) following AIH+HIT versus normoxia+HIT (P<0.01) with no order effects. Greater gains in spatiotemporal symmetry were observed with AIH+HIT, with worse outcomes for those prescribed serotonin-mediated antidepressant medications. CONCLUSIONS: AIH+HIT resulted in greater gains in locomotor function than normoxia+HIT. Subsequent phase III trials should further evaluate the efficacy of this intervention. REGISTRATION: URL: https://clinicaltrials.gov/; Unique identifier: NCT04472442.

High-Intensity Aphasia Therapy Is Cost-Effective in People With Poststroke Aphasia: Evidence From the COMPARE Trial.

BACKGROUND: Evidence from systematic reviews confirms that speech and language interventions for people with aphasia during the chronic phase after stroke (>6 months) improve word retrieval, functional communication, and communication-related quality of life. However, there is limited evidence of their cost-effectiveness. We aimed to estimate the cost per quality-adjusted life year gained from 2 speech and language therapies compared with usual care in people with aphasia during the chronic phase (median, 2.9 years) after stroke. METHODS: A 3-arm, randomized controlled trial compared constraint-induced aphasia therapy plus (CIAT-Plus) and multimodality aphasia therapy (M-MAT) with usual care in 216 people with chronic aphasia. Participants were administered a standardized questionnaire before intervention and at 12 weeks after the 2-week intervention/control period to ascertain health service utilization, employment changes, and informal caregiver burden. Unit prices from Australian sources were used to estimate costs in 2020. Quality-adjusted life years were estimated using responses to the EuroQol-5 Dimension-3 Level questionnaire. To test uncertainty around the differences in costs and outcomes between groups, bootstrapping was used with the cohorts resampled 1000 times. RESULTS: Overall 201/216 participants were included (mean age, 63 years, 29% moderate or severe aphasia, 61 usual care, 70 CIAT-Plus, 70 M-MAT). There were no statistically significant differences in mean total costs ($13 797 usual care, $17 478 CIAT-Plus, $11 113 M-MAT) and quality-adjusted life years (0.19 usual care, 0.20 CIAT-Plus, 0.20 M-MAT) between groups. In bootstrapped analysis of CIAT-Plus, 21.5% of iterations were likely to result in better outcomes and be cost saving (dominant) compared with usual care. In contrast, 72.4% of iterations were more favorable for M-MAT than usual care. CONCLUSIONS: We observed that both treatments, but especially M-MAT, may result in better outcomes at an acceptable additional cost, or potentially with cost savings. These findings are relevant in advocating for the use of these therapies for chronic aphasia after stroke.

High-Intensity Aphasia Intervention Is Minimally Fatiguing in Chronic Aphasia: An Analysis of Participant Self-Ratings From a Large Randomized Controlled Trial.

BACKGROUND: High-intensity therapy is recommended in current treatment guidelines for chronic poststroke aphasia. Yet, little is known about fatigue levels induced by treatment, which could interfere with rehabilitation outcomes. We analyzed fatigue experienced by people with chronic aphasia (>6 months) during high-dose interventions at 2 intensities. METHODS: A retrospective observational analysis was conducted on self-rated fatigue levels of people with chronic aphasia (N=173) collected during a previously published large randomized controlled trial of 2 treatments: constraint-induced aphasia therapy plus and multi-modality aphasia therapy. Interventions were administered at a higher intensity (30 hours over 2 weeks) or lower intensity (30 hours over 5 weeks). Participants rated their fatigue on an 11-point scale before and after each day of therapy. Data were analyzed using Bayesian ordinal multilevel models. Specifically, we considered changes in self-rated participant fatigue across a therapy day and over the intervention period. RESULTS: Data from 144 participants was analyzed. Participants were English speakers from Australia or New Zealand (mean age, 62 [range, 18-88] years) with 102 men and 42 women. Most had mild (n=115) or moderate (n=52) poststroke aphasia. Median ratings of the level of fatigue by people with aphasia were low (1 on a 0-10-point scale) at the beginning of the day. Ratings increased slightly (+1.0) each day after intervention, with marginally lower increases in the lower intensity schedule. There was no evidence of accumulating fatigue over the 2- or 5-week interventions. CONCLUSIONS: Findings suggest that intensive intervention was not associated with large increases in fatigue for people with chronic aphasia enrolled in the COMPARE trial (Constraint-Induced or Multimodality Personalised Aphasia Rehabilitation). Fatigue did not change across the course of the intervention. This study provides evidence that intensive treatment was minimally fatiguing for stroke survivors with chronic aphasia, suggesting that fatigue is not a barrier to high-intensity treatment.

Combining muscle-computer interface guided training with bihemispheric tDCS improves upper limb function in patients with chronic stroke.

Transcranial direct current stimulation (tDCS) may facilitate neuroplasticity but with a limited effect when administered while patients with stroke are at rest. Muscle-computer interface (MCI) training is a promising approach for training patients with stroke even if they cannot produce overt movements. However, using tDCS to enhance MCI training has not been investigated. We combined bihemispheric tDCS with MCI training of the paretic wrist and examined the effect of this intervention in patients with chronic stroke. A crossover, double-blind, randomized trial was conducted. Twenty-six patients with chronic stroke performed MCI wrist training for three consecutive days at home while receiving either real tDCS or sham tDCS in counterbalanced order and separated by at least 8 mo. The primary outcome measure was the Fugl-Meyer Assessment Upper Extremity Scale (FMA-UE) that was measured 1 wk before training, on the first training day, on the last training day, and 1 wk after training. There was neither a significant difference in the baseline FMA-UE score between groups nor between intervention periods. Patients improved 3.9 ± 0.6 points in FMA-UE score when receiving real tDCS, and 1.0 ± 0.7 points when receiving sham tDCS (P = 0.003). In addition, patients also showed continuous improvement in their motor control of the MCI tasks over the training days. Our study showed that the training paradigm could lead to functional improvement in patients with chronic stroke. We argue that appropriate MCI training in combination with bihemispheric tDCS could be a useful adjuvant for neurorehabilitation in patients with stroke.NEW & NOTEWORTHY Bihemispheric tDCS combined with a novel MCI training for motor control of wrist extensor can improve upper limb function especially a training-specific effect on the wrist movement in patients with chronic stroke. The training regimen can be personalized with adjustments made daily to accommodate the functional change throughout the intervention. This demonstrates that bihemispheric tDCS with MCI training could complement conventional poststroke neurorehabilitation.

Biochemical, biomechanical and imaging biomarkers of ischemic stroke: Time for integrative thinking.

Stroke is one of the leading causes of adult disability affecting millions of people worldwide. Post-stroke cognitive and motor impairments diminish quality of life and functional independence. There is an increased risk of having a second stroke and developing secondary conditions with long-term social and economic impacts. With increasing number of stroke incidents, shortage of medical professionals and limited budgets, health services are struggling to provide a care that can break the vicious cycle of stroke. Effective post-stroke recovery hinges on holistic, integrative and personalized care starting from improved diagnosis and treatment in clinics to continuous rehabilitation and support in the community. To improve stroke care pathways, there have been growing efforts in discovering biomarkers that can provide valuable insights into the neural, physiological and biomechanical consequences of stroke and how patients respond to new interventions. In this review paper, we aim to summarize recent biomarker discovery research focusing on three modalities (brain imaging, blood sampling and gait assessments), look at some established and forthcoming biomarkers, and discuss their usefulness and complementarity within the context of comprehensive stroke care. We also emphasize the importance of biomarker guided personalized interventions to enhance stroke treatment and post-stroke recovery.

Resting state functional connectivity associated with impaired proprioception post-stroke.

Deficits in proprioception, the knowledge of limb position and movement in the absence of vision, occur in ~50% of all strokes; however, our lack of knowledge of the neurological mechanisms of these deficits diminishes the effectiveness of rehabilitation and prolongs recovery. We performed resting-state functional magnetic resonance imaging (fMRI) on stroke patients to determine functional brain networks that exhibited changes in connectivity in association with proprioception deficits determined by a Kinarm robotic exoskeleton assessment. Thirty stroke participants were assessed for proprioceptive impairments using a Kinarm robot and underwent resting-state fMRI at 1 month post-stroke. Age-matched healthy control (n = 30) fMRI data were also examined and compared to stroke data in terms of the functional connectivity of brain regions associated with proprioception. Stroke patients exhibited reduced connectivity of the supplementary motor area and the supramarginal gyrus, relative to controls. Functional connectivity of these regions plus primary somatosensory cortex and parietal opercular area was significantly associated with proprioceptive function. The parietal lobe of the lesioned hemisphere is a significant node for proprioception after stroke. Assessment of functional connectivity of this region after stroke may assist with prognostication of recovery. This study also provides potential targets for therapeutic neurostimulation to aid in stroke recovery.

The Role of Ascending Ventral-Tegmental Fibers for Recovery after Stroke.

OBJECTIVES: The integrity of cortical motor networks and their descending effector pathway (the corticospinal tract [CST]) is a major determinant motor recovery after stroke. However, this view neglects the importance of ascending tracts and their modulatory effects on cortical physiology. Here, we explore the role of such a tract that connects dopaminergic ventral tegmental midbrain nuclei to the motor cortex (the VTMC tract) for post-stroke recovery. METHODS: Lesion data and diffusivity parameters (fractional anisotropy) of the ipsi- and contralesional VTMC tract and CST were obtained from 133 patients (63.9 ± 13.4 years, 45 women) during the acute and chronic stage after the first ever ischemic stroke in the middle cerebral artery territory. Degeneration of VTMC tract and CST was quantified and related to clinical outcome parameters (National Institute of Health Stroke Scale with motor and cortical symptom subscores; modified Fugl-Meyer upper extremity score; modified Ranking Scale [mRS]). RESULTS: A significant post-stroke degeneration occurred in both tracts, but only VTMC degeneration was associated with lesion size. Using multiple regression models, we dissected the impact of particular tracts on recovery: Changes in VTMC tract integrity were stronger associated with independence in daily activities (mRS), upper limb motor impairment (modified Fugl-Meyer upper extremity score) and cortical symptoms (aphasia, neglect) captured by National Institute of Health Stroke Scale compared to CST. Changes in CST integrity merely were associated with the degree of hemiparesis (National Institute of Health Stroke Scale motor subscale). INTERPRETATION: Post-stroke outcome is influenced by ascending (VTMC) and descending (CST) fiber tracts. Favorable outcome regarding independence (modified Ranking Scale), upper limb motor function (modified Fugl-Meyer upper extremity score), and cortical symptoms (aphasia, neglect) was more strongly related to the ascending than descending tract. ANN NEUROL 2023;93:922-933.