Kathleen Pirog Revill

BACKGROUND: Persistent compromised hand function is one of the most common long-term deficits after stroke. It is related to dysfunction of the primary motor cortex (M1) and corticospinal tract (CST) as assessed by magnetic resonance imaging-derived estimates of CST lesion load or by transcranial magnetic stimulation-derived measures, such as motor evoked potential (MEP) status. However, substantial interindividual variability remains with these measures. We tested whether a novel measure, mean motor disconnectivity (MMD), explains additional variation in the hand function of subacute stroke patients. METHODS: Thirty-two participants (15 M/17 F; age, 58.6±9.65 years) after unilateral ischemic stroke involving the CST and related upper extremity weakness were studied within 4 weeks of stroke in a cross-sectional study design at Emory University between 2015 and 2021. The primary outcome measure was skilled hand function assessed using the Jebsen-Taylor test. Gross hand function and proximal UE function were secondary outcome measures. Transcranial magnetic stimulation was used to measure MEP status. Lesion masks were hand-drawn on each participant’s structural magnetic resonance imaging image and were used to calculate lesion volume, CST lesion load, and MMD across a 20-region bilateral motor network consisting of the precentral gyrus, postcentral gyrus, thalamus, caudate, putamen, and brainstem regions. MMD is the mean of the disconnection values across the 20×20 nodes of this network of the adult human connectome; disconnection values quantify how severely a participant’s lesion disrupts structural connectivity between region pairs. RESULTS: Univariable analysis indicated MEP status (MEP+/−), CST lesion load, and MMD were significantly correlated with preserved hand function; lesion volume was not. Adding MMD to a model containing MEP status significantly improved the fit of a multivariable model. CONCLUSIONS: MMD explains additional variability in skilled hand function after accounting for MEP status, suggesting that disconnectivity measures capture stroke impact on motor areas beyond M1. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02544503.

BACKGROUND: Perivascular Spaces (PVS) are a marker of cerebral small vessel disease (CSVD) that are visible on brain imaging. Larger PVS has been associated with poor quality of life and cognitive impairment post-stroke. However, the association between PVS and post-stroke sensorimotor outcomes has not been investigated. METHODS: 602 individuals with a history of stroke across 24 research cohorts from the ENIGMA Stroke Recovery Working Group were included. PVS volume fractions were obtained using a validated, automated segmentation pipeline from the basal ganglia (BG) and white matter centrum semiovale (CSO), separately. Robust mixed effects regressions were used to a) examine the cross-sectional association between PVS volume fraction and post-stroke sensorimotor outcomes and b) to examine whether PVS volume fraction was associated with other measures of CSVD and overall brain health (e.g., white matter hyperintensities [WMHs], brain age [measured by predicted age difference, brain-PAD]). RESULTS: Larger PVS volume fraction in the CSO, but not BG, was associated with worse post-stroke sensorimotor outcomes (b = -0.06, p = 0.047). Higher burden of deep WMH (b = 0.25, p <0.001), periventricular WMH (b = 0.16, p <0.001) and higher brain-PAD (b = 0.09, p <0.001) were associated with larger PVS volume fraction in the CSO. CONCLUSIONS: Our data show that PVS volume fraction in the CSO is cross-sectionally associated with sensorimotor outcomes after stroke, above and beyond standard lesion metrics. PVS may provide insight into how the overall vascular health of the brain impacts inter-individual differences in post-stroke sensorimotor outcomes.

Variability in brain structure is associated with the capacity for behavioral change. However, a causal link between specific brain areas and behavioral change (such as motor learning) has not been demonstrated. We hypothesized that greater gray matter volume of a primary motor cortex (M1) area active during a hand motor learning task is positively correlated with subsequent learning of the task, and that the disruption of this area blocks learning of the task. Healthy participants underwent structural MRI before learning a skilled hand motor task. Next, participants performed this learning task during fMRI to determine M1 areas functionally active during this task. This functional ROI was anatomically constrained with M1 boundaries to create a group-level “Active-M1” ROI used to measure gray matter volume in each participant. Greater gray matter volume in the left hemisphere Active-M1 ROI was related to greater motor learning in the corresponding right hand. When M1 hand area was disrupted with repetitive transcranial stimulation (rTMS), learning of the motor task was blocked, confirming its causal link to motor learning. Our combined imaging and rTMS approach revealed greater cortical volume in a task-relevant M1 area is causally related to learning of a hand motor task in healthy humans.

Motor outcomes after stroke relate to corticospinal tract (CST) damage. Concurrent damage from white matter hyperintensities (WMHs) might impact neurological capacity for recovery after CST injury. Here, we evaluated if WMHs modulate the relationship between CST damage and post-stroke motor impairment outcome. We included 223 individuals from the ENIGMA Stroke Recovery Working Group. CST damage was indexed with weighted CST lesion load (CST-LL). Mixed effects beta-regression models were fit to test the impact of CST-LL, WMH volume, and their interaction on motor impairment. WMH volume related to motor impairment above and beyond CST-LL (β = 0.178, p = 0.022). We tested if relationships varied by WMH severity (mild vs. moderate-severe). In individuals with mild WMHs, motor impairment related to CST-LL (β = 0.888, p < 0.001) with a CST-LL x WMH interaction (β = -0.211, 0.026). In individuals with moderate-severe WMHs, motor impairment related to WMH volume (β = 0.299, p = 0.044), but did not significantly relate to CST-LL or a CST-LL x WMH interaction. WMH-related damage may be under-recognised in stroke research as a factor contributing to variability in motor outcomes. Our findings emphasize the importance of brain structural reserve in motor outcomes after brain injury.

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 (β = 0.21; 95% CI 0.04–0.38, p = 0.015), which in turn was associated with poorer outcomes, both in the sensorimotor domain (β = −0.28; 95% CI −0.41 to −0.15, p < 0.001) and across multiple domains of function (β = −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.

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 P =0.005; β=0.16) but not contralesional ( P =0.96; β=0.003) hippocampal volume, independent of lesion volume and other covariates ( P =0.001; β=0.26). Women showed progressively worsening sensorimotor impairment with smaller ipsilesional ( P =0.008; β=−0.26) and contralesional ( P =0.006; β=−0.27) hippocampal volumes compared with men. Hippocampal volume was associated with lesion size ( P P =0.003; β=−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.

Background. Stroke often involves primary motor cortex (M1) and its corticospinal (CST) projections. As hand function is critically dependent on these structures, its recovery is often incomplete. Objective. To determine whether impaired hand function in patients with chronic ischemic stroke involving M1 or CST benefits from the enhancing effect of Hebbian-type stimulation (pairing M1 afferent stimulation and M1 activity in a specific temporal relationship) on M1 plasticity and hand function. Methods. In a double-blind, randomized, sham-controlled design, 20 patients with chronic ischemic stroke affecting M1 or CST were randomly assigned to 5 days of hand motor training that was combined with either Hebbian-type (training_Hebb) or sham stimulation (training_sham) of the lesioned M1. Measures of hand function and task-based M1 functional magnetic resonance imaging (fMRI) activity were collected prior to, immediately following, and 4 weeks after the intervention. Results. Both interventions were effective in improving affected hand function at the completion of training, but only participants in the training_Hebb group maintained functional gains. Changes in hand function and fMRI activity were positively correlated in both ipsilesional and contralesional M1. Compared with training_sham, participants in the training_Hebb group showed a stronger relationship between improved hand function and changes in M1 functional activity. Conclusions. Only when motor training was combined with Hebbian-type stimulation were functional gains maintained over time and correlated with measures of M1 functional plasticity. As hand dexterity is critically dependent on M1 function, these results suggest that functional reorganization in M1 is facilitated by Hebbian-type stimulation. ClinicalTrials.gov Identifier: NCT01569607.

Stroke often involves primary motor cortex (M1) and its corticospinal projections (CST). As hand function is critically dependent on these structures, its recovery is often incomplete. The neuronal substrate supporting affected hand function is not well understood but likely involves reorganized M1 and CST of the lesioned hemisphere (M1_IL and CST_IL). We hypothesized that affected hand function in chronic stroke is related to structural and functional reorganization of M1_IL and CST_IL. We tested 18 patients with chronic ischemic stroke involving M1 or CST. Their hand function was compared with 18 age-matched healthy subjects. M1_IL thickness and CST_IL fractional anisotropy (FA) were determined with MRI and compared with measures of the other hemisphere. Transcranial magnetic stimulation (TMS) was applied to M1_IL to determine its input-output function [stimulus response curve (SRC)]. The plateau of the SRC (MEPmax), inflection point, and slope parameters of the curve were extracted. Results were compared with measures in 12 age-matched healthy controls. MEPmax of M1_IL was significantly smaller ( P = 0.02) in the patients, indicating reduced CST_IL motor output, and was correlated with impaired hand function ( P = 0.02). M1_IL thickness ( P < 0.01) and CST_IL-FA ( P < 0.01) were reduced but did not correlate with hand function. The results indicate that employed M1_IL or CST_IL structural measures do not explain the extent of impairment in hand function once M1 and CST are sufficiently functional for TMS to evoke a motor potential. Instead, impairment of hand function is best explained by the abnormally low output from M1_IL. NEW & NOTEWORTHY Hand function often remains impaired after stroke. While the critical role of the primary motor cortex (M1) and its corticospinal output (CST) for hand function has been described in the nonhuman primate stroke model, their structure and function have not been systematically evaluated for patients after stroke. We report that in chronic stroke patients with injury to M1 and/or CST an abnormally reduced M1 output is related to impaired hand function.

Although the relationship between sound and meaning in language is assumed to be largely arbitrary, reliable correspondences between sound and meaning in natural language appear to facilitate word learning. Using a set of independently normed pseudoword and shape stimuli, we examined the real-time effects of sound-to-shape correspondences at initial presentation and throughout an extended learning process resulting in high accuracy. In addition to accuracy and response time (RT) measures, we monitored participants' eye movements to investigate the extent to which visual orienting to objects is influenced by the sound symbolic characteristics of novel labels at initial exposure and throughout learning. Over the course of word learning, congruency of sound and shape properties affected both accuracy and RT with higher accuracy and faster responses for congruent than incongruent items. Eye tracking data reveal that congruent targets were fixated faster than incongruent targets throughout learning and that nontargets consistent with the sound symbolic properties of the word remained attractive distracters, even after overt behavioral differences in accuracy disappeared. This demonstrates the sustained influence of sound symbolism and the importance of sensitive, continuous measures of assessing sound symbolic effects in word learning and lexical processing. Arbitrariness resulted in better final individuation performance only when the arbitrary items were more phonologically distinct than the sound symbolic stimuli. These findings suggest that the advantages of sound symbolism may persist beyond early word learning and serve to significantly influence online lexical processing. (PsycINFO Database Record