Faculty Bibliography

Paired vagus nerve stimulation (VNS) has emerged as a promising strategy to potentiate recovery after neurological injury. This approach, which combines short bursts of electrical stimulation of the vagus nerve with rehabilitation exercises, received approval from the US Food and Drug Aministration in 2021 as the first neuromodulation-based therapy for chronic stroke. Because this treatment is increasingly implemented in clinical practice, there is a need to take stock of what we know about this approach and what we have yet to learn. Here, we provide a survey on the foundational basis of VNS therapy for stroke and offer insight into the mechanisms that underlie potentiated recovery, focusing on the principles of neuromodulatory reinforcement. We discuss the current state of observations regarding synaptic reorganization in motor networks that are enhanced by VNS, and we propose other prospective loci of neuromodulation that should be evaluated in the future. Finally, we highlight the future opportunities and challenges to be faced as this approach is increasingly translated to clinical use. Collectively, a clearer understanding of the mechanistic basis of VNS therapy may reveal ways to maximize its benefits.

Automatic assessment of impairment and disease severity is a key challenge in data-driven medicine. We propose a framework to address this challenge, which leverages AI models trained exclusively on healthy individuals. The COnfidence-Based chaRacterization of Anomalies (COBRA) score exploits the decrease in confidence of these models when presented with impaired or diseased patients to quantify their deviation from the healthy population. We applied the COBRA score to address a key limitation of current clinical evaluation of upper-body impairment in stroke patients. The gold-standard Fugl-Meyer Assessment (FMA) requires in-person administration by a trained assessor for 30-45 minutes, which restricts monitoring frequency and precludes physicians from adapting rehabilitation protocols to the progress of each patient. The COBRA score, computed automatically in under one minute, is shown to be strongly correlated with the FMA on an independent test cohort for two different data modalities: wearable sensors (ρ = 0.814, 95% CI [0.700,0.888]) and video (ρ = 0.736, 95% C.I [0.584, 0.838]). To demonstrate the generalizability of the approach to other conditions, the COBRA score was also applied to quantify severity of knee osteoarthritis from magnetic-resonance imaging scans, again achieving significant correlation with an independent clinical assessment (ρ = 0.644, 95% C.I [0.585,0.696]).

Music provides a reward that can enhance learning and motivation in humans. While music is often combined with exercise to improve performance and upregulate mood, the relationship between music-induced reward and motor output is poorly understood. Here, we study music reward and motor output at the same time by capitalizing on music playing. Specifically, we investigate the effects of music improvisation and live accompaniment on motor, autonomic, and affective responses. Thirty adults performed a drumming task while (i) improvising or maintaining the beat and (ii) with live or recorded accompaniment. Motor response was characterized by acceleration of hand movements (accelerometry), wrist flexor and extensor muscle activation (electromyography), and the drum strike count (i.e., the number of drum strikes played). Autonomic arousal was measured by tonic response of electrodermal activity (EDA) and heart rate (HR). Affective responses were measured by a 12-item Likert scale. The combination of improvisation and live accompaniment, as compared to all other conditions, significantly increased acceleration of hand movements and muscle activation, as well as participant reports of reward during music playing. Improvisation, regardless of type of accompaniment, increased the drum strike count and autonomic arousal (including tonic EDA responses and several measures of HR), as well as participant reports of challenge. Importantly, increased motor response was associated with increased reward ratings during music improvisation, but not while participants were maintaining the beat. The increased motor responses achieved with improvisation and live accompaniment have important implications for enhancing dose of movement during exercise and physical rehabilitation.

Transcranial direct current stimulation (tDCS) can be used to non-invasively augment cognitive training. However, the benefits of tDCS may be due in part to placebo effects, which have not been well-characterized. The purpose of this study was to determine whether tDCS can have a measurable placebo effect on cognitive training and to identify potential sources of this effect. Eighty-three right-handed adults were randomly assigned to one of three groups: control (no exposure to tDCS), sham tDCS, or active tDCS. The sham and active tDCS groups were double-blinded. Each group performed 20 min of an adapted Corsi Block Tapping Task (CBTT), a visuospatial working memory task. Anodal or sham tDCS was applied during CBTT training in a right parietal-left supraorbital montage. After training, active and sham tDCS groups were surveyed on expectations about tDCS efficacy. Linear mixed effects models showed that the tDCS groups (active and sham combined) improved more on the CBTT with training than the control group, suggesting a placebo effect of tDCS. Participants' tDCS expectations were significantly related to the placebo effect, as was the belief of receiving active stimulation. This placebo effect shows that the benefits of tDCS on cognitive training can occur even in absence of active stimulation. Future tDCS studies should consider how treatment expectations may be a source of the placebo effect in tDCS research, and identify ways to potentially leverage them to maximize treatment benefit.

Stroke commonly affects the ability of the upper extremities (UEs) to move normally. In clinical settings, identifying and measuring movement abnormality is challenging due to the imprecision and impracticality of available assessments. These challenges interfere with therapeutic tracking, communication, and treatment. We thus sought to develop an approach that blends precision and pragmatism, combining high-dimensional motion capture with out-of-distribution (OOD) detection. We used an array of wearable inertial measurement units to capture upper body motion in healthy and chronic stroke subjects performing a semi-structured, unconstrained 3D tabletop task. After data were labeled by human coders, we trained two deep learning models exclusively on healthy subject data to classify elemental movements (functional primitives). We tested these healthy subject-trained models on previously unseen healthy and stroke motion data. We found that model confidence, indexed by prediction probabilities, was generally high for healthy test data but significantly dropped when encountering OOD stroke data. Prediction probabilities worsened with more severe motor impairment categories and were directly correlated with individual impairment scores. Data inputs from the paretic UE, rather than trunk, most strongly influenced model confidence. We demonstrate for the first time that using OOD detection with high-dimensional motion data can reveal clinically meaningful movement abnormality in subjects with chronic 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:= 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.

OBJECTIVE:To determine if the distribution of transcallosal inhibition (TI) acting on proximal and distal upper extremity muscles is altered in chronic stroke. METHODS:We examined thirteen healthy controls and sixteen mildly to moderately impaired chronic stroke patients. We used transcranial magnetic stimulation (TMS) to probe TI from the contralesional onto ipsilesional hemisphere (assigned in controls). We recorded the ipsilateral silent period in the paretic biceps (BIC) and first dorsal interosseous (FDI). We measured TI strength, distribution gradient (TI difference between muscles), and motor impairment (Fugl-Meyer Assessment). RESULTS:Both groups had stronger TI acting on their FDIs than BICs (p < 0.001). However, stroke patients also had stronger TI acting on their BICs than controls (p = 0.034), resulting in a flatter distribution of inhibition (p = 0.028). In patients, stronger FDI inhibition correlated with less hand impairment (p = 0.031); BIC inhibition was not correlated to impairment. CONCLUSION/CONCLUSIONS:TI is more evenly distributed to the paretic FDI and BIC in chronic stroke. The relative increase in proximal inhibition does not relate to better function, as it does distally. SIGNIFICANCE/CONCLUSIONS:The results expand our knowledge about segment-specific neurophysiology and its relevance to impairment after stroke.

IMPORTANCE/OBJECTIVE:In laboratory settings, dual-tasking is a performance strategy affected by dominance and stroke. However, the volitional use of dual-tasking has not been examined during naturalistic performance of activities of daily living (ADLs). OBJECTIVE:To examine dual-tasking in the context of ADLs and identify whether dominance and stroke influence its use. DESIGN/METHODS:Cross-sectional, observational. SETTING/METHODS:Academic medical center. PARTICIPANTS/METHODS:Forty-three participants with chronic stroke and upper extremity (UE) motor impairment and 19 control participants without stroke. OUTCOMES AND MEASURES/METHODS:We identified dual-tasking as the performance of dual-object primitives (DOPs), a functional strategy to manage two objects simultaneously. We videotaped participants performing feeding and toothbrushing tasks and identified the initiation and frequency of DOPs. We assessed whether these outcomes were influenced by UE dominance or paresis and whether among participants with stroke these outcomes were influenced by motor impairment (using the Fugl-Meyer Assessment) or cognitive impairment (using the Montreal Cognitive Assessment). RESULTS:DOP initiation was reduced on the nondominant side of control UEs and in the paretic UE of participants with stroke. After DOPs were initiated, however, their frequency was not significantly related to dominance or paresis. Among participants with stroke, DOP initiation but not DOP frequency was influenced by motor impairment, and neither were influenced by cognitive impairment. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:The initiation of dual-tasking is curtailed in the nondominant and paretic UEs, extending previous laboratory-based findings to a more naturalistic setting. These results may reflect a demand on neural resources that is exceeded when these limbs are used. What This Article Adds: DOPs, a functional strategy to simultaneously engage two objects during ADLs, could serve as a behavioral marker of dual-tasking in real-world activities, supporting their investigation more broadly. Practicing DOPs in rehabilitation could also train the integration of dual-tasking strategies in activity execution.

Automatic action identification from video and kinematic data is an important machine learning problem with applications ranging from robotics to smart health. Most existing works focus on identifying coarse actions such as running, climbing, or cutting vegetables, which have relatively long durations and a complex series of motions. This is an important limitation for applications that require identification of more elemental motions at high temporal resolution. For example, in the rehabilitation of arm impairment after stroke, quantifying the training dose (number of repetitions) requires differentiating motions with sub-second durations. Our goal is to bridge this gap. To this end, we introduce a large-scale, multimodal dataset, StrokeRehab, as a new action-recognition benchmark that includes elemental short-duration actions labeled at a high temporal resolution. StrokeRehab consists of high-quality inertial measurement unit sensor and video data of 51 stroke-impaired patients and 20 healthy subjects performing activities of daily living like feeding, brushing teeth, etc. Because it contains data from both healthy and impaired individuals, StrokeRehab can be used to study the influence of distribution shift in action-recognition tasks. When evaluated on StrokeRehab, current state-of-the-art models for action segmentation produce noisy predictions, which reduces their accuracy in identifying the corresponding sequence of actions. To address this, we propose a novel approach for high-resolution action identification, inspired by speech-recognition techniques, which is based on a sequence-to-sequence model that directly predicts the sequence of actions. This approach outperforms current state-of-the-art methods on StrokeRehab, as well as on the standard benchmark datasets 50Salads, Breakfast, and Jigsaws.

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; 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<0.001; β=-0.21) and extent of sensorimotor damage (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.