Distinct Cortical Correlates of Perception and Motor Function in Balance Control.

Fluctuations in brain activity alter how we perceive our body and generate movements but have not been investigated in functional whole-body behaviors. During reactive balance, we recently showed that evoked brain activity is associated with the balance ability in young individuals. Furthermore, in PD, impaired whole-body motion perception in reactive balance is associated with impaired balance. Here, we investigated the brain activity during the whole-body motion perception in reactive balance in young adults (9 female, 10 male). We hypothesized that both ongoing and evoked cortical activity influences the efficiency of information processing for successful perception and movement during whole-body behaviors. We characterized two cortical signals using electroencephalography localized to the SMA: (1) the "N1," a perturbation-evoked potential that decreases in amplitude with expectancy and is larger in individuals with lower balance function, and (2) preperturbation ß power, a transient rhythm that favors maintenance of the current sensorimotor state and is inversely associated with tactile perception. In a two-alternative forced choice task, participants judged whether pairs of backward support surface perturbations during standing were in the "same" or "different" direction. As expected, lower whole-body perception was associated with lower balance ability. Within a perturbation pair, N1 attenuation was larger on correctly perceived trials and associated with better balance, but not perception. In contrast, preperturbation ß power was higher on incorrectly perceived trials and associated with poorer perception, but not balance. Together, ongoing and evoked cortical activity have unique roles in information processing that give rise to distinct associations with perceptual and balance ability.

Limitations in utilization and prioritization of standardized somatosensory assessments after stroke: A cross-sectional survey of neurorehabilitation clinicians.

BACKGROUND AND PURPOSE: Somatosensory impairments are common after stroke, but receive limited evaluation and intervention during neurorehabilitation, despite negatively impacting functional movement and recovery. OBJECTIVES: Our objective was to understand the scope of somatosensory assessments used by clinicians in stroke rehabilitation, and barriers to increasing use in clinical practice. METHODS: An electronic survey was distributed to clinicians (physical therapists, occupational therapists, physicians, and nurses) who assessed at least one individual with stroke in the past 6 months. The survey included questions on evaluation procedures, type, and use of somatosensory assessments, as well as barriers and facilitators in clinical practice. RESULTS: Clinicians (N = 431) indicated greater familiarity with non-standardized assessments, and greater utilization compared to standardized assessments (p < 0.0001). Components of tactile sensation were the most commonly assessed modality of somatosensation (25%), while proprioception was rarely assessed (1%). Overall, assessments of motor function were prioritized over assessments of somatosensory function (p < 0.0001). DISCUSSION: Respondents reported assessing somatosensation less frequently than motor function and demonstrated a reliance on rapid and coarse non-standardized assessments that ineffectively capture multi-modal somatosensory impairments, particularly for proprioceptive deficits common post-stroke. In general, clinicians were not familiar with standardized somatosensory assessments, and this knowledge gap likely contributes to lack of translation of these assessments into practice. CONCLUSIONS: Clinicians utilize somatosensory assessments that inadequately capture the multi-modal nature of somatosensory impairments in stroke survivors. Addressing barriers to clinical translation has the potential to increase utilization of standardized assessments to improve the characterization of somatosensory deficits that inform clinical decision-making toward enhancing stroke rehabilitation outcomes.

Delayed cortical engagement associated with balance dysfunction after stroke.

Cortical resources are typically engaged for balance and mobility in older adults, but these resources are impaired post-stroke. Although slowed balance and mobility after stroke have been well-characterized, the effects of unilateral cortical lesions due to stroke on neuromechanical control of balance is poorly understood. Our central hypothesis is that stroke impairs the ability to rapidly and effectively engage the cerebral cortex during balance and mobility behaviors, resulting in asymmetrical contributions of each limb to balance control. Using electroencephalography (EEG), we assessed cortical N1 responses evoked over fronto-midline regions (Cz) during balance recovery in response to backward support-surface perturbations loading both legs, as well as posterior-lateral directions that preferentially load the paretic or nonparetic leg. Cortical N1 responses were smaller and delayed in the stroke group. While older adults exhibited weak or absent relationships between cortical responses and clinical function, stroke survivors exhibited strong associations between slower N1 latencies and slower walking, lower clinical mobility, and lower balance function. We further assessed kinetics of balance recovery during perturbations using center of pressure rate of rise. During backward support-surface perturbations that loaded the legs bilaterally, balance recovery kinetics were not different between stroke and control groups and were not associated with cortical response latency. However, lateralized perturbations revealed slower kinetic reactions during paretic loading compared to controls, and to non-paretic loading within stroke participants. Individuals post stroke had similar nonparetic-loaded kinetic reactions to controls implicating that they effectively compensate for impaired paretic leg kinetics when relying on the non-paretic leg. In contrast, paretic-loaded balance recovery revealed time-synchronized associations between slower cortical responses and slower kinetic reactions only in the stroke group, potentially reflecting the limits of cortical engagement for balance recovery revealed within the behavioral context of paretic motor capacity. Overall, our results implicate individuals after stroke may be uniquely limited in their balance ability by the slowed speed of their cortical engagement, particularly under challenging balance conditions that rely on the paretic leg. We expect this neuromechanical insight will enable progress toward an individualized framework for the assessment and treatment of balance impairments based on the interaction between neuropathology and behavioral context.

Distinct cortical correlates of perception and motor function in balance control.

Fluctuations in brain state alter how we perceive our body and generate movements but have not been investigated in functional whole-body behaviors. During reactive balance control, we recently showed that evoked brain activity is associated with balance ability in healthy young individuals. Further, in individuals with Parkinson's disease, impairments in whole-body motion perception in reactive balance are associated with clinical balance impairment. Here we investigated brain activity during whole-body motion perception in reactive balance in healthy young adults. We hypothesized that flexibility in brain states underlies successful perception and movement during whole-body movement. We characterized two cortical sensorimotor signals using electroencephalography localized to the supplementary motor area: 1) the "N1 response", a perturbation-evoked potential that decreases in amplitude with expectancy and is larger in individuals with lower balance function; and 2) pre-perturbation beta oscillatory activity, a rhythm that favors maintenance of the current sensorimotor state and is inversely associated with perception in seated somatosensory perceptual tasks. In a two-alternative forced choice task, participants judged whether pairs of backward support-surface perturbations during standing were in the "same" or "different" direction. As expected, lower whole-body perception was associated with lower balance ability. Within a perturbation pair, N1 attenuation was larger on correctly perceived trials and associated with better balance, but not perception. In contrast, pre-perturbation beta power was higher on incorrectly perceived trials and associated with poorer perception, but not balance. Taken together, flexibility in different cortical processes influences perceptual accuracy but have distinct associations with balance and perceptual ability.

Data-driven biomarkers outperform theory-based biomarkers in predicting stroke motor outcomes.

Chronic motor impairments are a leading cause of disability after stroke. Previous studies have predicted motor outcomes based on the degree of damage to predefined structures in the motor system, such as the corticospinal tract. However, such theory-based approaches may not take full advantage of the information contained in clinical imaging data. The present study uses data-driven approaches to predict chronic motor outcomes after stroke and compares the accuracy of these predictions to previously-identified theory-based biomarkers. Using a cross-validation framework, regression models were trained using lesion masks and motor outcomes data from 789 stroke patients (293 female/496 male) from the ENIGMA Stroke Recovery Working Group (age 64.9±18.0 years; time since stroke 12.2±0.2 months; normalised motor score 0.7±0.5 (range [0,1]). The out-of-sample prediction accuracy of two theory-based biomarkers was assessed: lesion load of the corticospinal tract, and lesion load of multiple descending motor tracts. These theory-based prediction accuracies were compared to the prediction accuracy from three data-driven biomarkers: lesion load of lesion-behaviour maps, lesion load of structural networks associated with lesion-behaviour maps, and measures of regional structural disconnection. In general, data-driven biomarkers had better prediction accuracy - as measured by higher explained variance in chronic motor outcomes - than theory-based biomarkers. Data-driven models of regional structural disconnection performed the best of all models tested (R2 = 0.210, p < 0.001), performing significantly better than predictions using the theory-based biomarkers of lesion load of the corticospinal tract (R2 = 0.132, p< 0.001) and of multiple descending motor tracts (R2 = 0.180, p < 0.001). They also performed slightly, but significantly, better than other data-driven biomarkers including lesion load of lesion-behaviour maps (R2 =0.200, p < 0.001) and lesion load of structural networks associated with lesion-behaviour maps (R2 =0.167, p < 0.001). Ensemble models - combining basic demographic variables like age, sex, and time since stroke - improved prediction accuracy for theory-based and data-driven biomarkers. Finally, combining both theory-based and data-driven biomarkers with demographic variables improved predictions, and the best ensemble model achieved R2 = 0.241, p < 0.001. Overall, these results demonstrate that models that predict chronic motor outcomes using data-driven features, particularly when lesion data is represented in terms of structural disconnection, perform better than models that predict chronic motor outcomes using theory-based features from the motor system. However, combining both theory-based and data-driven models provides the best predictions.

White Matter Integrity and Chronic Poststroke Upper Limb Function: An ENIGMA Stroke Recovery Analysis.

BACKGROUND: Integrity of the corticospinal tract (CST) is an important biomarker for upper limb motor function following stroke. However, when structurally compromised, other tracts may become relevant for compensation or recovery of function. METHODS: We used the ENIGMA Stroke Recovery data set, a multicenter, retrospective, and cross-sectional collection of patients with upper limb impairment during the chronic phase of stroke to test the relevance of tracts in individuals with less and more severe (laterality index of CST fractional anisotropy ≥0.25) CST damage in an observational study design. White matter integrity was quantified using fractional anisotropy for the CST, the superior longitudinal fascicle, and the callosal fibers interconnecting the primary motor cortices between hemispheres. Optic radiations served as a control tract as they have no a priori relevance for the motor system. Pearson correlation was used for testing correlation with upper limb motor function (Fugl-Meyer upper extremity). RESULTS: From 1235 available data sets, 166 were selected (by imaging, Fugl-Meyer upper extremity, covariates, stroke location, and stage) for analyses. Only individuals with severe CST damage showed a positive association of fractional anisotropy in both callosal fibers interconnecting the primary motor cortices (r[21]=0.49; P=0.025) and superior longitudinal fascicle (r[21]=0.51; P=0.018) with Fugl-Meyer upper extremity. CONCLUSIONS: Our data support the notion that individuals with more severe damage of the CST depend on residual pathways for achieving better upper limb outcome than those with less affected CST.

Association of Brain Age, Lesion Volume, and Functional Outcome in Patients With Stroke.

BACKGROUND AND OBJECTIVES: Functional outcomes after stroke are strongly related to focal injury measures. However, the role of global brain health is less clear. In this study, we examined the impact of brain age, a measure of neurobiological aging derived from whole-brain structural neuroimaging, on poststroke outcomes, with a focus on sensorimotor performance. We hypothesized that more lesion damage would result in older brain age, which would in turn be associated with poorer outcomes. Related, we expected that brain age would mediate the relationship between lesion damage and outcomes. Finally, we hypothesized that structural brain resilience, which we define in the context of stroke as younger brain age given matched lesion damage, would differentiate people with good vs poor outcomes. METHODS: We conducted a cross-sectional observational study using a multisite dataset of 3-dimensional brain structural MRIs and clinical measures from the ENIGMA Stroke Recovery. Brain age was calculated from 77 neuroanatomical features using a ridge regression model trained and validated on 4,314 healthy controls. We performed a 3-step mediation analysis with robust mixed-effects linear regression models to examine relationships between brain age, lesion damage, and stroke outcomes. We used propensity score matching and logistic regression to examine whether brain resilience predicts good vs poor outcomes in patients with matched lesion damage. RESULTS: We examined 963 patients across 38 cohorts. Greater lesion damage was associated with older brain age (ß = 0.21; 95% CI 0.04-0.38, p = 0.015), which in turn was associated with poorer outcomes, both in the sensorimotor domain (ß = -0.28; 95% CI -0.41 to -0.15, p < 0.001) and across multiple domains of function (ß = -0.14; 95% CI -0.22 to -0.06, p < 0.001). Brain age mediated 15% of the impact of lesion damage on sensorimotor performance (95% CI 3%-58%, p = 0.01). Greater brain resilience explained why people have better outcomes, given matched lesion damage (odds ratio 1.04, 95% CI 1.01-1.08, p = 0.004). DISCUSSION: We provide evidence that younger brain age is associated with superior poststroke outcomes and modifies the impact of focal damage. The inclusion of imaging-based assessments of brain age and brain resilience may improve the prediction of poststroke outcomes compared with focal injury measures alone, opening new possibilities for potential therapeutic targets.

State-dependent interhemispheric inhibition reveals individual differences in motor behavior in chronic stroke.

OBJECTIVE: To investigate state-dependent interhemispheric inhibition (IHI) in chronic stroke survivors compared to neurotypical older adult controls, and test whether abnormal IHI modulation was associated with upper extremity motor behavior. METHODS: Dual-coil transcranial magnetic stimulation (TMS) measured IHI bi-directionally, between non-lesioned and lesioned motor cortex (M1) in two activity states: (1) at rest and (2) during contralateral isometric hand muscle contraction. IHI was tested by delivering a conditioning stimulus 8-msec or 50-msec prior to a test stimulus over contralateral M1. Paretic motor behavior was assessed by clinical measures of impairment, strength, and dexterity, and mirroring activity in the non-paretic hand. RESULTS: Stroke survivors demonstrated reduced IHI at rest, and less IHI modulation (active - rest) compared to controls. Individual differences in IHI modulation were related to motor behavior differences where greater IHI modulation was associated with greater motor impairment and more mirroring. In contrast, there were no relationships between IHI at rest and motor behavior. CONCLUSIONS: Abnormal state-dependent interhemispheric circuit activity may be more sensitive to post-stroke motor deficits than when assessed in a single motor state. SIGNIFICANCE: Characterizing state-dependent changes in neural circuitry may enhance models of stroke recovery and inform rehabilitation interventions.

Associations between myelin water imaging and measures of fall risk and functional mobility in multiple sclerosis.

BACKGROUND AND PURPOSE: Myelin water fraction (MWF) deficits as measured by myelin water imaging (MWI) have been related to worse motor function in persons with multiple sclerosis (PwMS). However, it is unknown if measures from MWI metrics in motor areas relate to fall risk measures in PwMS. The objective of this study was to examine the relationship between MWI measures in motor areas to performance on clinical measures of fall risk and disability in PwMS. METHODS: Sixteen individuals with relapsing-remitting MS participated (1 male, 15 female; age 47.1 years [12.3]; Expanded Disability Status Scale 4.0 [range 0-6.5]) and completed measures of walking and fall risk (Timed 25 Foot Walk [T25FW] and Timed Up and Go). MWF and the geometric mean of the intra-/extracellular water T2 (geomT2IEW ) values reflecting myelin content and contribution of large-diameter axons/density, respectively, were assessed in three motor-related regions. RESULTS: The geomT2IEW of the corticospinal tract (r = -.599; p = .018) and superior cerebellar peduncles (r = -.613; p = .015) demonstrated significant inverse relationships with T25FW, suggesting that decreased geomT2IEW was related to slower walking. Though not significant, MWF in the corticospinal tract and superior cerebellar peduncles also demonstrated fair relationships with the T25FW, suggesting that worse performance on the T25FW was associated with lower MWF values. CONCLUSIONS: MWI of key motor regions was associated with walking performance in PwMS. Further MWI studies are needed to identify relationships between pathology and clinical function in PwMS to guide targeted rehabilitation therapies aimed at preventing falls.

Effects of short-term arm immobilization on motor skill acquisition.

Learning to sequence movements is necessary for skillful interaction with the environment. Neuroplasticity, particularly long-term potentiation (LTP), within sensorimotor networks underlies the acquisition of motor skill. Short-term immobilization of the arm, even less than 12 hours, can reduce corticospinal excitability and increase the capacity for LTP-like plasticity within the contralateral primary motor cortex. However, it is still unclear whether short-term immobilization influences motor skill acquisition. The current study aimed to evaluate the effect of short-term arm immobilization on implicit, sequence-specific motor skill acquisition using a modified Serial Reaction Time Task (SRTT). Twenty young, neurotypical adults underwent a single SRTT training session after six hours of immobilization of the non-dominant arm or an equivalent period of no immobilization. Our results demonstrated that participants improved SRTT performance overall after training, but there was no evidence of an effect of immobilization prior to task training on performance improvement. Further, improvements on the SRTT were not sequence-specific. Taken together, motor skill acquisition for sequential, individuated finger movements improved following training but the effect of six hours of immobilization was difficult to discern.

Short-term arm immobilization modulates excitability of inhibitory circuits within, and between, primary motor cortices.

Previous research has suggested that short-term immobilization of the arm may be a low-cost, non-invasive strategy to enhance the capacity for long-term potentiation (LTP)-like plasticity in primary motor cortex (M1). Short-term immobilization reduces corticospinal excitability (CSE) in the contralateral M1, and interhemispheric inhibition (IHI) from ipsi- onto contralateral M1 is increased. However, it is unclear whether reduced CSE and increased IHI are associated with changes in intracortical inhibition, which has been shown to be important for regulating neuroplasticity in M1. The current study used transcranial magnetic stimulation to evaluate the effects of short-term (6 h) arm immobilization on CSE, IHI, and intracortical inhibition measured bilaterally in 43 neurotypical young adults (23 immobilized). We replicated previous findings demonstrating that immobilization decreased CSE in, and increased IHI onto, the immobilized hemisphere, but a significant change in intracortical inhibition was not observed at the group level. Across individuals, decreased CSE was associated with a decreased short-interval intracortical inhibition, an index of GABAA -ergic inhibition, within the immobilized hemisphere only in the immobilization group. Previous research has demonstrated that decreases in GABAA -ergic inhibition are necessary for the induction of LTP-like plasticity in M1; therefore, decreased intracortical inhibition after short-term arm immobilization may provide a novel mechanism to enhance the capacity for LTP-like plasticity within M1 and may be a potential target for strategies to augment plasticity capacity to enhance motor learning in health and disease.

A large, curated, open-source stroke neuroimaging dataset to improve lesion segmentation algorithms.

Accurate lesion segmentation is critical in stroke rehabilitation research for the quantification of lesion burden and accurate image processing. Current automated lesion segmentation methods for T1-weighted (T1w) MRIs, commonly used in stroke research, lack accuracy and reliability. Manual segmentation remains the gold standard, but it is time-consuming, subjective, and requires neuroanatomical expertise. We previously released an open-source dataset of stroke T1w MRIs and manually-segmented lesion masks (ATLAS v1.2, N = 304) to encourage the development of better algorithms. However, many methods developed with ATLAS v1.2 report low accuracy, are not publicly accessible or are improperly validated, limiting their utility to the field. Here we present ATLAS v2.0 (N = 1271), a larger dataset of T1w MRIs and manually segmented lesion masks that includes training (n = 655), test (hidden masks, n = 300), and generalizability (hidden MRIs and masks, n = 316) datasets. Algorithm development using this larger sample should lead to more robust solutions; the hidden datasets allow for unbiased performance evaluation via segmentation challenges. We anticipate that ATLAS v2.0 will lead to improved algorithms, facilitating large-scale stroke research.

Chronic Stroke Sensorimotor Impairment Is Related to Smaller Hippocampal Volumes: An ENIGMA Analysis.

Background Persistent sensorimotor impairments after stroke can negatively impact quality of life. The hippocampus is vulnerable to poststroke secondary degeneration and is involved in sensorimotor behavior but has not been widely studied within the context of poststroke upper-limb sensorimotor impairment. We investigated associations between non-lesioned hippocampal volume and upper limb sensorimotor impairment in people with chronic stroke, hypothesizing that smaller ipsilesional hippocampal volumes would be associated with greater sensorimotor impairment. Methods and Results Cross-sectional T1-weighted magnetic resonance images of the brain were pooled from 357 participants with chronic stroke from 18 research cohorts of the ENIGMA (Enhancing NeuoImaging Genetics through Meta-Analysis) Stroke Recovery Working Group. Sensorimotor impairment was estimated from the FMA-UE (Fugl-Meyer Assessment of Upper Extremity). Robust mixed-effects linear models were used to test associations between poststroke sensorimotor impairment and hippocampal volumes (ipsilesional and contralesional separately; Bonferroni-corrected, P<0.025), controlling for age, sex, lesion volume, and lesioned hemisphere. In exploratory analyses, we tested for a sensorimotor impairment and sex interaction and relationships between lesion volume, sensorimotor damage, and hippocampal volume. Greater sensorimotor impairment was significantly associated with ipsilesional (P=0.005; ß=0.16) but not contralesional (P=0.96; ß=0.003) hippocampal volume, independent of lesion volume and other covariates (P=0.001; ß=0.26). Women showed progressively worsening sensorimotor impairment with smaller ipsilesional (P=0.008; ß=-0.26) and contralesional (P=0.006; ß=-0.27) hippocampal volumes compared with men. Hippocampal volume was associated with lesion size (P<0.001; ß=-0.21) and extent of sensorimotor damage (P=0.003; ß=-0.15). Conclusions The present study identifies novel associations between chronic poststroke sensorimotor impairment and ipsilesional hippocampal volume that are not caused by lesion size and may be stronger in women.

Observational Study of Neuroimaging Biomarkers of Severe Upper Limb Impairment After Stroke.

BACKGROUND AND OBJECTIVES: It is difficult to predict post-stroke outcome for people with severe motor impairment, as both clinical tests and corticospinal tract (CST) microstructure may not reliably indicate severe motor impairment. Here, we test whether imaging biomarkers beyond the CST relate to severe upper limb impairment post-stroke by evaluating white matter microstructure in the corpus callosum (CC). In an international, multisite hypothesis-generating observational study we determined if: a) CST asymmetry index can differentiate between individuals with mild-moderate and severe upper limb impairment; and b) CC biomarkers relate to upper limb impairment within individuals with severe impairment post-stroke. We hypothesised that CST asymmetry index would differentiate between mild-moderate and severe impairment, but CC microstructure would relate to motor outcome for individuals with severe upper limb impairment. METHODS: Seven cohorts with individual diffusion imaging and motor impairment (Fugl Meyer-Upper Limb) data were pooled. Hand-drawn regions-of-interest were used to seed probabilistic tractography for CST (ipsilesional/contralesional) and CC (prefrontal/premotor/motor/sensory/posterior) tracts. Our main imaging measure was mean fractional anisotropy. Linear mixed-effect regression explored relationships between candidate biomarkers and motor impairment, controlling for observations nested within cohorts, as well as age, sex, time post-stroke and lesion volume. RESULTS: Data from 110 individuals (30 mild-moderate, 80 with severe motor impairment) were included. In the full sample, greater CST asymmetry index (i.e., lower fractional anisotropy in the ipsilesional hemisphere, p<.001) and larger lesion volume (p=.139) were negatively related to impairment. In the severe subgroup, CST asymmetry index was not reliably associated with impairment across models. Instead, lesion volume and CC microstructure explained impairment in the severe group beyond CST asymmetry index (p's<.010). CONCLUSIONS: Within a large cohort of individuals with severe upper limb impairment, CC microstructure related to motor outcome post-stroke. Our findings demonstrate that CST microstructure does relate to upper limb outcome across the full range of motor impairment but was not reliably associated within the severe subgroup. Therefore, CC microstructure may provide a promising biomarker for severe upper limb outcome post-stroke, which may advance our ability to predict recovery in people with severe motor impairment after stroke.

Clinical Imaging-Derived Metrics of Corticospinal Tract Structural Integrity Are Associated With Post-stroke Motor Outcomes: A Retrospective Study.

OBJECTIVE: The primary objective of this study was to retrospectively investigate associations between clinical magnetic resonance imaging-based (MRI) metrics of corticospinal tract (CST) status and paretic upper extremity (PUE) motor recovery in patients that completed acute inpatient rehabilitation (AR) post-stroke. METHODS: We conducted a longitudinal chart review of patients post-stroke who received care in the Emory University Hospital system during acute hospitalization, AR, and outpatient therapy. We extracted demographic information, stroke characteristics, and longitudinal documentation of post-stroke motor function from institutional electronic medical records. Serial assessments of paretic shoulder abduction and finger extension were estimated (E-SAFE) and an estimated Action Research Arm Test (E-ARAT) score was used to quantify 3-month PUE motor function outcome. Clinically-diagnostic MRI were used to create lesion masks that were spatially normalized and overlaid onto a white matter tract atlas delineating CST contributions emanating from six cortical seed regions to obtain the percentage of CST lesion overlap. Metric associations were investigated with correlation and cluster analyses, Kruskal-Wallis tests, classification and regression tree analysis. RESULTS: Thirty-four patients met study eligibility criteria. All CST overlap percentages were correlated with E-ARAT however, ventral premotor tract (PMv) overlap was the only tract that remained significantly correlated after multiple comparisons adjustment. Lesion overlap percentage in CST contributions from all seed regions was significantly different between outcome categories. Using MRI metrics alone, dorsal premotor (PMd) and PMv tracts classified recovery outcome category with 79.4% accuracy. When clinical and MRI metrics were combined, AR E-SAFE, patient age, and overall CST lesion overlap classified patients with 88.2% accuracy. CONCLUSIONS: Study findings revealed clinical MRI-derived CST lesion overlap was associated with PUE motor outcome post-stroke and that cortical projections within the CST, particularly those emanating from non-M1 cortical areas, prominently ventral premotor (PMv) and dorsal premotor (PMd) cortices, distinguished between PUE outcome groups. Exploratory predictive models using clinical MRI metrics, either alone or in combination with clinical measures, were able to accurately identify recovery outcome category for the study cohort during both the acute and early subacute phases of post-stroke recovery. Prospective studies are recommended to determine the predictive utility of including clinical imaging-based biomarkers of white matter tract structural integrity in predictive models of post-stroke recovery.

The ENIGMA Stroke Recovery Working Group: Big data neuroimaging to study brain-behavior relationships after stroke.

The goal of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Stroke Recovery working group is to understand brain and behavior relationships using well-powered meta- and mega-analytic approaches. ENIGMA Stroke Recovery has data from over 2,100 stroke patients collected across 39 research studies and 10 countries around the world, comprising the largest multisite retrospective stroke data collaboration to date. This article outlines the efforts taken by the ENIGMA Stroke Recovery working group to develop neuroinformatics protocols and methods to manage multisite stroke brain magnetic resonance imaging, behavioral and demographics data. Specifically, the processes for scalable data intake and preprocessing, multisite data harmonization, and large-scale stroke lesion analysis are described, and challenges unique to this type of big data collaboration in stroke research are discussed. Finally, future directions and limitations, as well as recommendations for improved data harmonization through prospective data collection and data management, are provided.

Smaller spared subcortical nuclei are associated with worse post-stroke sensorimotor outcomes in 28 cohorts worldwide.

Up to two-thirds of stroke survivors experience persistent sensorimotor impairments. Recovery relies on the integrity of spared brain areas to compensate for damaged tissue. Deep grey matter structures play a critical role in the control and regulation of sensorimotor circuits. The goal of this work is to identify associations between volumes of spared subcortical nuclei and sensorimotor behaviour at different timepoints after stroke. We pooled high-resolution T1-weighted MRI brain scans and behavioural data in 828 individuals with unilateral stroke from 28 cohorts worldwide. Cross-sectional analyses using linear mixed-effects models related post-stroke sensorimotor behaviour to non-lesioned subcortical volumes (Bonferroni-corrected, P < 0.004). We tested subacute (≤90 days) and chronic (≥180 days) stroke subgroups separately, with exploratory analyses in early stroke (≤21 days) and across all time. Sub-analyses in chronic stroke were also performed based on class of sensorimotor deficits (impairment, activity limitations) and side of lesioned hemisphere. Worse sensorimotor behaviour was associated with a smaller ipsilesional thalamic volume in both early (n = 179; d = 0.68) and subacute (n = 274, d = 0.46) stroke. In chronic stroke (n = 404), worse sensorimotor behaviour was associated with smaller ipsilesional putamen (d = 0.52) and nucleus accumbens (d = 0.39) volumes, and a larger ipsilesional lateral ventricle (d = -0.42). Worse chronic sensorimotor impairment specifically (measured by the Fugl-Meyer Assessment; n = 256) was associated with smaller ipsilesional putamen (d = 0.72) and larger lateral ventricle (d = -0.41) volumes, while several measures of activity limitations (n = 116) showed no significant relationships. In the full cohort across all time (n = 828), sensorimotor behaviour was associated with the volumes of the ipsilesional nucleus accumbens (d = 0.23), putamen (d = 0.33), thalamus (d = 0.33) and lateral ventricle (d = -0.23). We demonstrate significant relationships between post-stroke sensorimotor behaviour and reduced volumes of deep grey matter structures that were spared by stroke, which differ by time and class of sensorimotor measure. These findings provide additional insight into how different cortico-thalamo-striatal circuits support post-stroke sensorimotor outcomes.

Motor Cortical Network Flexibility is Associated With Biomechanical Walking Impairment in Chronic Stroke.

Background: The inability to flexibly modulate motor behavior with changes in task demand or environmental context is a pervasive feature of motor impairment and dysfunctional mobility after stroke. Objective: The purpose of this study was to test the reactive and modulatory capacity of lower-limb primary motor cortical (M1) networks using electroencephalography (EEG) measures of cortical activity evoked by transcranial magnetic stimulation (TMS) and to evaluate their associations with clinical and biomechanical measures of walking function in chronic stroke. Methods: TMS assessments of motor cortex excitability were performed during rest and active ipsilateral plantarflexion in chronic stroke and age-matched controls. TMS-evoked motor cortical network interactions were quantified with simultaneous EEG as the post-TMS (0-300 ms) beta (15-30 Hz) coherence between electrodes overlying M1 bilaterally. We compared TMS-evoked coherence between groups during rest and active conditions and tested associations with poststroke motor impairment, paretic propulsive gait deficits, and the presence of paretic leg motor evoked potentials (MEPs). Results: Stroke (n = 14, 66 ± 9 years, F = 4) showed lower TMS-evoked cortical coherence and activity-dependent modulation compared to controls (n = 9, 68 ± 6 years, F = 3). Blunted reactivity and atypical modulation of TMS-evoked coherence were associated with lower paretic ankle moments for propulsive force generation during walking and absent paretic MEPs. Conclusions: Impaired flexibility of motor cortical networks to react to TMS and modulate during motor activity is distinctly associated with paretic limb biomechanical walking impairment, and may provide useful insight into the neuromechanistic underpinnings of chronic post-stroke mobility deficits.

Cortical Engagement Metrics During Reactive Balance Are Associated With Distinct Aspects of Balance Behavior in Older Adults.

Heightened reliance on the cerebral cortex for postural stability with aging is well-known, yet the cortical mechanisms for balance control, particularly in relation to balance function, remain unclear. Here we aimed to investigate motor cortical activity in relation to the level of balance challenge presented during reactive balance recovery and identify circuit-specific interactions between motor cortex and prefrontal or somatosensory regions in relation to metrics of balance function that predict fall risk. Using electroencephalography, we assessed motor cortical beta power, and beta coherence during balance reactions to perturbations in older adults. We found that individuals with greater motor cortical beta power evoked following standing balance perturbations demonstrated lower general clinical balance function. Individual older adults demonstrated a wide range of cortical responses during balance reactions at the same perturbation magnitude, showing no group-level change in prefrontal- or somatosensory-motor coherence in response to perturbations. However, older adults with the highest prefrontal-motor coherence during the post-perturbation, but not pre-perturbation, period showed greater cognitive dual-task interference (DTI) and elicited stepping reactions at lower perturbation magnitudes. Our results support motor cortical beta activity as a potential biomarker for individual level of balance challenge and implicate prefrontal-motor cortical networks in distinct aspects of balance control involving response inhibition of reactive stepping in older adults. Cortical network activity during balance may provide a neural target for precision-medicine efforts aimed at fall prevention with aging.

Resting State Connectivity Is Modulated by Motor Learning in Individuals After Stroke.

OBJECTIVE: Activity patterns across brain regions that can be characterized at rest (ie, resting-state functional connectivity [rsFC]) are disrupted after stroke and linked to impairments in motor function. While changes in rsFC are associated with motor recovery, it is not clear how rsFC is modulated by skilled motor practice used to promote recovery. The current study examined how rsFC is modulated by skilled motor practice after stroke and how changes in rsFC are linked to motor learning. METHODS: Two groups of participants (individuals with stroke and age-matched controls) engaged in 4 weeks of skilled motor practice of a complex, gamified reaching task. Clinical assessments of motor function and impairment, and brain activity (via functional magnetic resonance imaging) were obtained before and after training. RESULTS: While no differences in rsFC were observed in the control group, increased connectivity was observed in the sensorimotor network, linked to learning in the stroke group. Relative to healthy controls, a decrease in network efficiency was observed in the stroke group following training. CONCLUSIONS: Findings indicate that rsFC patterns related to learning observed after stroke reflect a shift toward a compensatory network configuration characterized by decreased network efficiency.