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

Abstract

Background: 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. Subcortical regions play critical roles in the control and regulation of sensorimotor circuits. Identifying relationships between sensorimotor behavior and non-lesioned subcortical volumes will reveal new neural targets for improving outcomes. Methods: We pooled high-resolution T1-weighted MRI brain scans and behavioral data in 828 individuals with unilateral stroke from 28 cohorts worldwide (age: median 63, interquartile range 19 years; 516 males, 312 females). Cross-sectional analyses using linear mixed-effects models related post-stroke sensorimotor behavior to non-lesioned subcortical volumes. We analyzed subacute (≤90 days) and chronic (≥180 days) stroke; sub-analyses in chronic stroke were performed on class of sensorimotor deficit (impairment, activity limitations) and side of lesioned hemisphere, with exploratory analyses in early stroke (≤21 days) and across time (Bonferroni-corrected, p<0.004). Results: Worse sensorimotor behavior was associated with a smaller ipsilesional thalamic volume in both subacute (n=274, d=0.46) and early stroke (n=179; d=0.68). In chronic stroke (n=404), worse sensorimotor behavior was associated with smaller ipsilesional putamen (d=0.52) and nucleus accumbens (d=0.39) volumes, and a larger ipsilesional lateral ventricle volume (d=-0.42), representing atrophy. In chronic stroke, worse sensorimotor impairment specifically (measured by the Fugl-Meyer Assessment; n=256) was associated with a smaller ipsilesional putamen (d=0.72), and larger lateral ventricle (d=-0.41), while several measures of activity limitations (n=116) showed no significant relationships. Side of lesion (left=214, right=190) had no impact. The full cohort (n=828) revealed associations of sensorimotor behavior with the ipsilesional nucleus accumbens (d=0.23), putamen (d=0.33), thalamus (d=0.33), and lateral ventricle (d=-0.23). Discussion: This analysis identified significant relationships between sensorimotor behavior and key subcortical regions at different times post-stroke. While further longitudinal studies are needed, these findings may represent brain imaging markers of resilience and reserve and provide putative neuroanatomical targets for improving sensorimotor outcomes post-stroke.

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

“…This is critical because recent work suggests that cross-sectional brain age may reflect either early-life differences or volume loss due to isolated incidents, such as stroke. 45 Furthermore, as previously noted, 24,25 although our large heterogeneous dataset provides statistical power and diverse data to test hypotheses, there are limited covariates that are present across the entire dataset. Additional factors known to influence brain age-such as genetics, neurodegenerative copathology such as microvascular damage, lifestyle factors, and comorbidities-should be examined in future studies.…”

“…We further hypothesized that if this brain-behavior relationship is reflective of post-stroke atrophy, it should be strongest in the ipsilesional hemisphere in chronic stroke. We therefore examined ipsilesional versus contralesional brain-PAD separately, and at two different times post-stroke as in our previous work 24 (early stroke (≤6 weeks post-stroke, thought to represent the premorbid brain prior to secondary degeneration) 20 and chronic stroke (≥180 days post-stroke)).…”

“…A full description of the data and procedures used by the ENIGMA Stroke Recovery Working Group has been reported elsewhere (see also eMethods, links.lww.com/WNL/C720 ). 24 , 27 In brief, stroke neuroimaging and behavioral data from retrospective studies are contained in a repository, which is queried to extract data meeting study-specific eligibility criteria. For this study, we extracted data that had the following: (1) FreeSurfer outputs from 3-dimensional T1-weighted structural brain MRI volumes (see MRI Data Analysis), (2) a sensorimotor behavioral outcome measure (see Behavioral Data), (3) covariates of age and sex, and (4) a primary stroke reported in either cerebral hemisphere.…”

“…We anticipated that this relationship would be strongest in the ipsilesional hemisphere, which should undergo more changes with functional relevance compared with the contralesional hemisphere, and in chronic stroke, allowing for time after stroke for secondary atrophy to occur. 24 - 26 Third, we hypothesized that brain-PAD would mediate the impact of known focal injury measures, such as corticospinal tract lesion load (CST-LL), 1 - 3 on sensorimotor outcomes and that this relationship would again be strongest in the ipsilesional hemisphere in chronic stroke. Finally, we hypothesized that greater brain resilience despite stroke-related injury would distinguish people with better vs worse sensorimotor outcomes.…”

Chronic stroke sensorimotor impairment is related to smaller hippocampal volumes: An ENIGMA analysis

“…To help clinicians, caregivers, and patients make informed and effective rehabilitation treatment decisions, there is a critical need to identify biomarkers that accurately predict a patient's potential for sensorimotor recovery 2,3 . MRI studies of regional brain volumes suggest secondary degeneration of adjacent or remote regions may contribute to sensorimotor impairment and could influence post-stroke sensorimotor outcomes 4,5 .…”