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Background: Stroke leads to complex chronic structural and functional brain changes that specifically affect motor outcomes. The brain-predicted age difference (brain-PAD) has emerged as a sensitive biomarker. Our previous study showed higher global brain-PAD associated with poorer motor function post-stroke. However, the relationship between local stroke lesion load, regional brain age, and motor impairment remains unclear., Methods: We studied 501 individuals with chronic unilateral stroke (>180 days post-stroke) from the ENIGMA Stroke Recovery Working Group dataset (34 cohorts). Structural T1-weighted MRI scans were used to estimate regional brain-PAD in 18 predefined functional subregions via a graph convolutional network algorithm. Lesion load for each region was calculated based on lesion overlap. Linear mixed-effects models assessed associations between lesion size, local lesion load, and regional brain-PAD. Machine learning classifiers predicted motor outcomes using lesion loads and regional brain-PADs. Structural equation modeling examined directional relationships among corticospinal tract lesion load (CST-LL), ipsilesional brain-PAD, motor outcomes, and contralesional brain-PAD., Findings: Larger total lesion size was positively associated with higher ipsilesional regional brain-PADs (older brain age) across most regions (p□<□0.05), and with lower contralesional brain-PAD, notably in the ventral attention-language network (p□<□0.05). Higher local lesion loads showed similar patterns. Specifically, lesion load in the salience network significantly influenced regional brain-PADs across both hemispheres. Machine learning models identified CST-LL, salience network lesion load, and regional brain-PAD in the contralesional frontoparietal network as the top three predictors of motor outcomes. Structural equation modeling revealed that larger stroke damage was associated with poorer motor outcomes (β□=□-0.355, p□<□0.001), which were further linked to younger contralesional brain age (β□=□0.204, p□<□0.001), suggesting that severe motor impairment is linked to compensatory decreases in contralesional brain age., Interpretation: Our findings reveal that larger stroke lesions are associated with accelerated aging in the ipsilesional hemisphere and paradoxically decelerated brain aging in the contralesional hemisphere, suggesting compensatory neural mechanisms. Assessing regional brain age may serve as a biomarker for neuroplasticity and inform targeted interventions to enhance motor recovery after stroke., Fundings: Micheal J Fox Foundation, National Institutes of Health, Canadian Institutes of Health Research, National Health and Medical Research Council, Australian Brain Foundation, Wicking Trust, Collie Trust, and Sidney and Fiona Myer Family Foundation, National Heart Foundation, Hospital Israelita Albert Einstein, Australian Research Council Future Fellowship, Wellcome Trust, National Institute for Health Research Imperial Biomedical Research Centre, European Research Council, Deutsche Forschungsgemeinschaft, REACT Pilot, National Resource Center, Research Council of Norway, South-Eastern Norway Regional Health Authority, Norwegian Extra Foundation for Health and Rehabilitation, Sunnaas Rehabilitation Hospital HT, University of Oslo, and VA Rehabilitation Research and Development.

Background: Children with developmental coordination disorder (DCD) have difficulty learning and performing movements, often requiring increased feedback. Technology may be useful for delivering augmented feedback. Co-design methodology for developing therapeutic interventions has become popular in healthcare, including for technology in rehabilitation. However, there are limited guidelines on how to use co-design methodology in healthcare. Methods: We applied three key principles, (1) Understanding, (2) Exploring, and (3) Materialising, to inform a co-design process. End-user participants included paediatric clinicians, young learners, their caregivers, and the research team, who shared their expertise and lived experience to inform the creation of a novel system. Results: A team of end-users designed and developed an augmented reality intervention prototype for practicing motor skills aimed at children with DCD using a generative co-design process. From understanding the unmet needs, we explored and then materialised a series of games using bespoke technology solutions. Conclusion: The use of a co-design process was beneficial in engaging end-users as the experts of their experience in the creation of a novel augmented reality intervention prototype aimed for children with DCD. The co-design process was successful in facilitating a prototype that meets consumer needs, and ensured all end-user voices were heard., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Purpose: Aphasia is an acquired language impairment that commonly results from stroke. Non-invasive brain stimulation (NIBS) might accelerate aphasia recovery trajectories and has seen mounting popularity in recent aphasia rehabilitation research. The present review aimed to: (1) summarise all existing literature on NIBS as a post-stroke aphasia treatment; and (2) provide recommendations for future NIBS-aphasia research., Materials and Methods: Databases for published and grey literature were searched using scoping review methodology. 278 journal articles, conference abstracts/posters, and books, and 38 items of grey literature, were included for analysis., Results: Quantitative analysis revealed that ipsilesional anodal transcranial direct current stimulation and contralesional 1-Hz repetitive transcranial magnetic stimulation were the most widely used forms of NIBS, while qualitative analysis identified four key themes including: the roles of the hemispheres in aphasia recovery and their relationship with NIBS; heterogeneity of individuals but homogeneity of subpopulations; individualisation of stimulation parameters; and much remains under-explored in the NIBS-aphasia literature., Conclusions: Taken together, these results highlighted systemic challenges across the field such as small sample sizes, inter-individual variability, lack of protocol optimisation/standardisation, and inadequate focus on aphasiology. Four key recommendations are outlined herein to guide future research and refine NIBS methods for post-stroke aphasia treatment.

Chronic motor impairments are a leading cause of disability after stroke. Previous studies have associated motor outcomes with 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 model chronic motor outcomes after stroke and compares the accuracy of these associations 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 from the Enhancing NeuroImaging Genetics through Meta Analysis (ENIGMA) Stroke Recovery Working Group. Using the explained variance metric to measure the strength of the association between chronic motor outcomes and imaging biomarkers, we compared theory-based biomarkers, like lesion load to known motor tracts, to 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 stronger associations with chronic motor outcomes accuracy than theory-based biomarkers. Data-driven models of regional structural disconnection performed the best of all models tested ( R 2 = 0.210, P < 0.001), performing significantly better than the theory-based biomarkers of lesion load of the corticospinal tract ( R 2 = 0.132, P < 0.001) and of multiple descending motor tracts ( R 2 = 0.180, P < 0.001). They also performed slightly, but significantly, better than other data-driven biomarkers including lesion load of lesion-behaviour maps ( R 2 = 0.200, P < 0.001) and lesion load of structural networks associated with lesion-behaviour maps ( R 2 = 0.167, P < 0.001). Ensemble models - combining basic demographic variables like age, sex, and time since stroke - improved the strength of associations for theory-based and data-driven biomarkers. Combining both theory-based and data-driven biomarkers with demographic variables improved predictions, and the best ensemble model achieved R 2 = 0.241, P < 0.001. Overall, these results demonstrate that out-of-sample associations between chronic motor outcomes and data-driven imaging features, particularly when lesion data is represented in terms of structural disconnection, are stronger than associations between chronic motor outcomes and theory-based biomarkers. However, combining both theory-based and data-driven models provides the most robust associations., Competing Interests: S.C.C. serves as a consultant for Abbvie, Constant Therapeutics, BrainQ, Myomo, MicroTransponder, Neurolutions, Panaxium, NeuExcell, Elevian, Helius, Omniscient, Brainsgate, Nervgen, Battelle, and TRCare. B.H. has a clinical partnership with Fourier Intelligence. N.J.S. is an inventor for a patent US 10,071,015 B2. C.J. W. is a consultant for Microtransponder, BrainQ, and MedRhythm. G.F.W. sits on Advisory Boards for Myomo and Neuro-innovators., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Neuroplasticity is important for learning, development and recovery from injury. Therapies that can upregulate neuroplasticity are therefore of interest across a range of fields. We developed a novel virtual reality action observation and motor imagery (VR-AOMI) intervention and evaluated whether it could enhance the efficacy of mechanisms of neuroplasticity in the human motor cortex of healthy adults. A secondary question was to explore predictors of the change in neuroplasticity following VR-AOMI. A pre-registered, pilot randomized controlled cross-over trial was performed. Twenty right-handed adults (13 females; mean age: 23.0 ± 4.53 years) completed two experimental conditions in separate sessions; VR-AOMI and control. We used intermittent theta burst stimulation (iTBS) to induce long term potentiation-like plasticity in the motor cortex and recorded motor evoked potentials at multiple timepoints as a measure of corticospinal excitability. The VR-AOMI task did not significantly increase the change in MEP amplitude following iTBS when compared to the control task (Group × Timepoint interaction p = 0.17). However, regression analysis identified the change in iTBS response following VR-AOMI was significantly predicted by the baseline iTBS response in the control task. Specifically, participants that did not exhibit the expected increase in MEP amplitude following iTBS in the control condition appear to have greater excitability following iTBS in the VR-AOMI condition (r = -0.72, p < 0.001). Engaging in VR-AOMI might enhance capacity for neuroplasticity in some people who typically do not respond to iTBS. VR-AOMI may prime the brain for enhanced neuroplasticity in this sub-group., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Neurorehabilitation technologies are a novel approach to providing rehabilitation for patients with neurological conditions. There is a need to explore patient experiences. This study aimed; 1) To identify available questionnaires that assess patients' experiences with neurorehabilitation technologies, and 2) where reported, to document the psychometric properties of the identified questionnaires., Materials and Methods: Four databases were searched (Medline, Embase, Emcare and PsycInfo). The inclusion criteria were all types of primary data collection that included neurological patients of all ages who had experienced therapy with neurorehabilitation technologies and completed questionnaires to assess these experiences., Results: Eighty-eight publications were included. Fifteen different questionnaires along with many self-developed scales were identified. These were categorised as; 1) self-developed tools, 2) specific questionnaire for a particular technology, and 3) generic questionnaires originally developed for a different purpose. The questionnaires were used to assess various technologies, including virtual reality, robotics, and gaming systems. Most studies did not report any psychometric properties., Conclusion: Many tools have been used to evaluate patient experiences, but few were specifically developed for neurorehabilitation technologies and psychometric data was limited. A preliminary recommendation would be use of the User Satisfaction Evaluation Questionnaire to evaluate patient experience with virtual reality systems.

There is a growing interest in the clinical application of transcutaneous auricular vagus nerve stimulation (taVNS). However, its effect on cortical excitability, and whether this is modulated by stimulation duration, remains unclear. We evaluated whether taVNS can modify excitability in the primary motor cortex (M1) in middle-aged and older adults and whether the stimulation duration moderates this effect. In addition, we evaluated the blinding efficacy of a commonly reported sham method. In a double-blinded randomized cross-over sham-controlled study, 23 healthy adults (mean age 59.91 ± 6.87 years) received three conditions: active taVNS for 30 and 60 min and sham for 30 min. Single and paired-pulse transcranial magnetic stimulation was delivered over the right M1 to evaluate motor-evoked potentials. Adverse events, heart rate and blood pressure measures were evaluated. Participant blinding effectiveness was assessed via guesses about group allocation. There was an increase in short-interval intracortical inhibition (F = 7.006, p = .002) and a decrease in short-interval intracortical facilitation (F = 4.602, p = .014) after 60 min of taVNS, but not 30 min, compared to sham. taVNS was tolerable and safe. Heart rate and blood pressure were not modified by taVNS (p > .05). Overall, 96% of participants detected active stimulation and 22% detected sham stimulation. taVNS modifies cortical excitability in M1 and its effect depends on stimulation duration in middle-aged and older adults. taVNS increased GABA A ergic inhibition and decreased glutamatergic activity. Sham taVNS protocol is credible but there is an imbalance in beliefs about group allocation., (© 2024 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.)

Purpose: Transcutaneous auricular vagus nerve stimulation (taVNS) is an emerging non-invasive neuromodulation therapy. This study aimed to explore the therapeutic use of taVNS, optimal stimulation parameters, effective sham protocols, and safety., Methods: A scoping review was conducted. Five databases and grey literature were searched. The data extracted included stimulation parameters, adverse events (AEs), and therapeutic effects on clinical outcomes., Results: 109 studies were included. taVNS was used across 21 different clinical populations, most commonly in psychiatric, cardiac, and neurological disorders. Overall, 2,214 adults received active taVNS and 1,017 received sham taVNS. Reporting of stimulation parameters was limited and inconsistent. taVNS appeared to have a favourable therapeutic effect across a wide range of clinical populations with varied parameters. Three sham protocols were reported but their effectiveness was documented in only two of the 54 sham-controlled studies. Most reported adverse events were localised to stimulation site., Conclusion: There is growing evidence for taVNS therapeutic effect. taVNS appears safe and tolerable. Sham protocols need evaluation. Standardised and comprehensive reporting of both stimulation parameters and adverse events is required. Two different questionnaires have been proposed to evaluate adverse events and the effectiveness of sham methods in blinding participants.

Upregulation of neuroplasticity might help maximize stroke recovery. One intervention that appears worthy of investigation is aerobic exercise. This study aimed to determine whether a single bout of moderate intensity aerobic exercise can enhance neuroplasticity in people with stroke. Participants were randomly assigned (1:1) to a 20-min moderate intensity exercise intervention or remained sedentary (control). Transcranial magnetic stimulation measured corticospinal excitability of the contralesional hemisphere by recording motor evoked potentials (MEPs). Intermittent Theta Burst Stimulation (iTBS) was used to repetitively activate synapses in the contralesional primary motor cortex, initiating the early stages of neuroplasticity and increasing excitability. It was surmised that if exercise increased neuroplasticity, there would be a greater facilitation of MEPs following iTBS. Thirty-three people with stroke participated in this study (aged 63.87 ± 10.30 years, 20 male, 6.13 ± 4.33 years since stroke). There was an interaction between Time*Group on MEP amplitudes (P = 0.009). Participants allocated to aerobic exercise had a stronger increase in MEP amplitude following iTBS. A non-significant trend indicated time since stroke might moderate this interaction (P = 0.055). Exploratory analysis suggested participants who were 2-7.5 years post stroke had a strong MEP facilitation following iTBS (P < 0.001). There was no effect of age, sex, resting motor threshold, self-reported physical activity levels, lesion volume or weighted lesion load (all P > 0.208). Moderate intensity cycling may enhance neuroplasticity in people with stroke. This therapy adjuvant could provide opportunities to maximize stroke recovery., (© 2023. Springer Nature Limited.)

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., Competing Interests: Disclosures Dr Hordacre has a clinical partnership with Fourier Intelligence. Dr Conforto is a consultant for Boehringer Ingelheim. Dr Kautz reports grants from US Department of Veterans Affairs and grants from National Institute of General Medical Sciences. Dr Thompson has received research grant support from Biogen, Inc, for research unrelated to this article. Dr Warach is a consultant for Genentech and BrainsGate. The other authors report no conflicts.

Purpose: To summarise body awareness assessment tools and interventions relevant for stroke rehabilitation using a framework that categorises key body awareness constructs, disorders and impairments., Materials and Methods: Online electronic databases and trial registries were searched from inception until July 2021, in addition to hand searching reference lists of included studies and reviews. Study selection included any study design where the investigation involved assessing and/or intervening in body awareness following stroke. Data were extracted based on predefined criteria by two independent reviewers and mapped to the emergent framework., Results: The final analysis included 144 papers that reported 43 assessment tools and 8 types of interventions for body awareness. Consensus was reached on a synthesised body awareness framework. This comprised specific impairments and disorders, constructs, sub-categories and main categories leading to the overarching term of body awareness. Clinical and psychometric properties of the assessment tools were not reported or poorly evaluated, and the interventions lacked robust study designs and rigorous methods., Conclusions: The framework produced will enable future research and clinical practice to be based on consistent concepts and definitions. Clinicians can also use this information to cautiously select assessment tools and/or interventions but are reminded of the limitations identified in this review.Implications for rehabilitationThere is limited understanding, compounded by inconsistent terminology and definitions regarding body awareness after stroke.A synthesized framework to define key constructs and definitions of body awareness is proposed.Assessment tools and interventions reported in the literature are mapped to the proposed framework.Psychometric properties of available tools are reported.Significant work remains to refine concepts of body awareness, develop and evaluate assessment tools and interventions.

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., (Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Background: Noninvasive electrical stimulation (ES) could have therapeutic potential in stroke recovery. However, there is no comprehensive evaluation of adverse events. This study systematically searched the literature to document frequency and prevalence of adverse events. A secondary aim was to explore associations between adverse events and ES parameters or participant characteristics. Methods: Databases were searched for studies evaluating ES in adults with stroke. All included studies were required to report on adverse events. Extracted data were: (1) study design; (2) adverse events; (3) participant characteristics; (4) ES parameters., Results: Seventy-five studies were included. Adverse events were minor in nature. The most frequently reported adverse events were tingling (37.3% of papers), burning (18.7%), headaches (14.7%) and fatigue (14.7%). Cathodal stimulation was associated with greater frequency of itching (p = .02), intensities of 1-2 mA with increased tingling (p = .04) and discomfort (p = .03), and current density <0.4mA/cm2 with greater discomfort (p = .03). Tingling was the most prevalent adverse event (18.1% of participants), with prevalence data not differing between active and control conditions (all p ≥ 0.37). Individual participants were more likely to report adverse events with increasing current density (r = 0.99, p = .001). Two severe adverse events were noted (a seizure and percutaneous endoscopic gastrostomy placement)., Conclusion: ES appears safe in people with stroke as reported adverse events were predominantly minor in nature. An adverse events questionnaire is proposed to enable a more comprehensive and nuanced analysis of the frequency and prevalence of adverse events.

Alpha-band oscillatory activity in human electroencephalography (EEG) becomes slower and lower in amplitude with advanced age. However, the influence of aperiodic activity on these measures has received little consideration. We investigated whether age-related differences in aperiodic activity explains differences in resting EEG peak alpha frequency and power. We assessed aperiodic activity in 85 younger and 92 older adults by fitting the 1/f-like background activity evident in EEG power spectra using the spectral parameterization ("specparam") algorithm. Across the scalp, the aperiodic exponent and offset were smaller in older compared to younger participants, reflecting a flatter 1/f-like slope and a downward broadband shift in power spectra with age. After correcting for aperiodic activity, peak alpha frequency remained slower in older adults; however, peak alpha power no longer differed statistically between age groups. The large sample size utilized in this study, as well as the depth of analysis, provides further evidence that the aperiodic component of the resting EEG signal is altered with aging and should be considered when investigating neural oscillatory activity., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Chronic subjective tinnitus is the constant perception of a sound that has no physical source. Brain imaging studies show alterations in tinnitus patients' resting-state networks (RSNs). This scoping review aims to provide an overview of resting-state fMRI studies in tinnitus, and to evaluate the evidence for changes in different RSNs. A total of 29 studies were included, 26 of which found alterations in networks such as the auditory network, default mode network, attention networks, and visual network; however, there is a lack of reproducibility in the field which can be attributed to the use of different regions of interest and analytical methods per study, and tinnitus heterogeneity. Future studies should focus on replication by using the same regions of interest in their analysis of resting-state data, and by controlling adequately for potential confounds. These efforts could potentially lead to the identification of a biomarker for tinnitus in the future., (© 2022. The Author(s).)

Purpose: Stroke is a global leading cause of adult disability with survivors often enduring persistent impairments and loss of function. Both intensity and dosage of training appear to be important factors to help restore behavior. However, current practice fails to achieve sufficient intensity and dose of training to promote meaningful recovery. The purpose of this review is to propose therapeutic solutions that can help achieve a higher dose and/or intensity of therapy. Raising awareness of these intensive, high-dose, treatment strategies might encourage clinicians to re-evaluate current practice and optimize delivery of stroke rehabilitation for maximal recovery., Methods: Literature that tested and evaluated solutions to increase dose or intensity of training was reviewed. For each therapeutic strategy, we outline evidence of clinical benefit, supporting neurophysiological data (where available) and discuss feasibility of clinical implementation., Results: Possible therapeutic solutions included constraint induced movement therapy, robotics, circuit therapy, bursts of training, gaming technologies, goal-oriented instructions, and cardiovascular exercise., Conclusion: Our view is that clinicians should evaluate current practice to determine how intensive high-dose training can be implemented to promote greater recovery after stroke., Competing Interests: Declaration of Competing Interest BH has a clinical partnership with Fourier Intelligence and a paid consultancy role with RecoveryVR. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To investigate whether cognitive reserve modifies the relationship between functional connectivity, lesion volume, stroke severity and upper-limb motor impairment and recovery in stroke survivors., Methods: Ten patients with first-ever ischemic middle cerebral artery stroke completed the Cognitive Reserve Index Questionnaire at baseline. Upper-limb motor impairment and functional connectivity were assessed using the Fugl-Meyer Assessment and electroencephalography respectively at baseline and 3-months post-stroke. A debiased weighted phase lag index was computed to estimate functional connectivity between electrodes. Partial least squares (PLS) regression identified a connectivity model that maximally predicted variance in the degree of upper-limb impairment. Regression models were generated to determine whether cognitive reserve modified the relationship between neural function (functional connectivity), neural injury (lesion volume), stroke severity (National Institutes of Health Stroke Scale) and upper-limb motor impairment at baseline and recovery at 3-months (Fugl-Meyer Assessment)., Results: The addition of cognitive reserve to a regression model with a dependent variable of upper-limb motor recovery and independent variables of functional connectivity between the ipsilesional motor cortex and parietal cortex, stroke severity and lesion volume improved model efficiency (∆BIC=-7.07) despite not reaching statistical significance (R 2 =0.90, p=0.07). Cognitive reserve did not appear to improve regression models examining motor impairment at baseline., Conclusions: Preliminary observations suggest cognitive reserve might modify the relationship between neural function, neural injury, stroke severity and upper-limb motor recovery. Further investigation of cognitive reserve in motor recovery post-stroke appears warranted., Competing Interests: Declaration of Competing Interest BH and SH have a clinical partnership with Fourier Intelligence. BH holds a paid consultancy role with RecoveryVR., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Interhemispheric inhibition is an important cortical mechanism to support motor control. Altered interhemispheric inhibition has been the target of neuromodulation interventions. This systematic review investigated the evidence for altered interhemispheric inhibition in adults with unilateral neurological conditions: stroke, amyotrophic lateral sclerosis, cerebral palsy, complex regional pain syndrome, traumatic brain injury, and cerebral palsy METHODS: We pre-registered the protocol and followed PRISMA guidelines. Five databases were systematically searched to identify studies reporting interhemispheric inhibition measures in unilateral neurological conditions and healthy controls. Data were grouped according to the measure (ipsilateral silent period and dual-coil), stimulated hemisphere, and stage of the condition (subacute and chronic)., Results: 1372 studies were identified, of which 14 were included (n = 226 adults with stroke and 161 age-matched controls). Ipsilateral silent period-duration was longer in people with stroke than in controls (stimulation of dominant hemisphere) regardless of stroke stage. Motor evoked potential was less suppressed in people with sub-acute stroke (stimulation of the unaffected hemisphere) than controls (stimulation of dominant hemisphere) and this reversed in chronic stroke., Conclusion: Detection of altered interhemispheric inhibition appears to be dependent on the measure of interhemispheric inhibition and the stage of recovery., Significance: Rebalancing interhemispheric inhibition using neuromodulation is considered a promising line of treatment for stroke rehabilitation. Our results did not find compelling evidence to support consistent alterations in interhemispheric inhibition in adults with stroke., Competing Interests: Declaration of Competing Interest GLM has received support from: Reality Health, ConnectHealth UK, Seqirus, Kaiser Permanente, Workers’ Compensation Boards in Australia, Europe and North America, AIA Australia, the International Olympic Committee, Port Adelaide Football Club, Arsenal Football Club. Professional and scientific bodies have reimbursed him for travel costs related to presentation of research on pain at scientific conferences/symposia. He has received speaker fees for lectures on pain and rehabilitation. He receives book royalties for books on pain and rehabilitation. CB has received support from Kaiser Permanente and speaker fees for lectures on pain and rehabilitation., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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.

Background: Impairments in body awareness are common after stroke and are associated with decreased participation and performance in everyday activities., Objectives: To explore the feasibility and safety of a body awareness program after stroke, and identify the preliminary efficacy of class-based lessons compared to home-based lessons on sensation, body awareness, motor impairment and quality of life., Methods: A two-armed pilot randomized controlled trial with a nested qualitative descriptive study was conducted. Individuals with a diagnosis of stroke (at least three months post injury) were randomized to either class-based face-to-face body awareness lessons or home-based individually performed body awareness lessons. Outcome measures were safety, feasibility, sensation, body awareness, motor impairment, self-efficacy and quality of life. Semi-structured interviews were used to allow greater exploration and understanding of participants' experience of the program., Results: Twenty participants were randomized, 16 participants completed the program. Feasibility was greater in the class-based group. No adverse events were detected. The class-based group led to improvement in body awareness (p = 0.002), quality of life (p = 0.002), and the arm (p = 0.025) and leg (p = 0.005) motor impairment scores. Qualitative data similarly indicated that the class-based group experienced a stronger sense of awareness, achievement and connection than the home-based group., Conclusions: Body awareness training was safe, feasible and acceptable in people with stroke. Individuals in the class-based group showed greater benefit compared to those receiving home-based therapy.

Resting-state functional magnetic resonance imaging (rs-fMRI) has been actively used in the last decade to investigate brain functional connectivity alterations in Type 2 Diabetes Mellitus (T2DM) to understand the neuropathophysiology of T2DM in cognitive degeneration. Given the emergence of new analysis techniques, this scoping review aims to map the rs-fMRI analysis techniques that have been applied in the literature and reports the latest rs-fMRI findings that have not been covered in previous reviews. Graph theory, the contemporary rs-fMRI analysis, has been used to demonstrate altered brain topological organisations in people with T2DM, which included altered degree centrality, functional connectivity strength, the small-world architecture and network-based statistics. These alterations were correlated with T2DM patients' cognitive performances. Graph theory also contributes to identify unbiased seeds for seed-based analysis. The expanding rs-fMRI analytical approaches continue to provide new evidence that helps to understand the mechanisms of T2DM-related cognitive degeneration., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Accumulating evidence suggests that low frequency repetitive transcranial magnetic stimulation (rTMS), which generally decreases cortical excitability and remodels plastic connectivity, improves sleep quality in patients with insomnia disorder. However, the effects of rTMS vary substantially across individuals and treatment is sometimes unsatisfactory, calling for biomarkers for predicting clinical outcomes., Objective: This study aimed to investigate whether functional connectivity of the target network in electroencephalography is associated with the clinical response to low frequency rTMS in patients with insomnia disorder., Methods: Twenty-five patients with insomnia disorder were subjected to 10 sessions of treatment with 1 Hz rTMS over the right dorsolateral prefrontal cortex. Resting-state electroencephalography was collected before rTMS. Pittsburgh Sleep Quality Index, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, and Mini-Mental State Exam were performed before and after rTMS treatment, with a follow-up after one month. Electroencephalographic connectivity was measured by the power envelope connectivity at the source level. Partial least squares regression identified models of connectivity that maximally accounted for the rTMS response., Results: Scores of Pittsburgh Sleep Quality Index, Hamilton Depression Rating Scale, and Hamilton Anxiety Rating Scale were decreased after rTMS and one-month later. Baseline weaker connectivity of a network in the beta and alpha bands between a brain region approximating the stimulated right dorsolateral prefrontal cortex and areas located in the frontal, insular, and limbic cortices was associated with a greater change in Pittsburgh Sleep Quality Index and Hamilton Depression Rating Scale following rTMS., Conclusions: Low frequency rTMS could improve sleep quality and depressive moods in patients with insomnia disorder. Moreover, electroencephalographic functional connectivity would potentially be a robust biomarker for predicting the therapeutic effects., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Body awareness (BA) is a process that involves sensory awareness originating from the body's physiological states, processes and actions, and is shaped by one's attitudes, perceptions, beliefs and experience of social and cultural context. Impairments in body awareness after stroke are believed to be common and may be an important influence on recovery outcomes. However, recovery of body awareness is poorly understood and receives little consideration in rehabilitation. Aims: To investigate if body awareness changes over time following stroke; and identify if body awareness after stroke is associated with sensation, motor impairment, self-efficacy and quality of life. Methods: An exploratory longitudinal observational study was performed. Participants with a stroke diagnosis and associated motor impairment were recruited from an acute stroke unit. An assessment battery consisting of sensory and motor impairment and function, body awareness, self-efficacy and quality of life measures were used at baseline, 1, 3 and 6 months. Results: A total of 105 people with stroke were recruited. Most recovery in sensation and body awareness occurred within the first month after stroke (all p < 0.01). Sensation and body awareness were correlated with other clinical outcomes (motor impairment, self-efficacy and quality of life), demographics, and stroke specific clinical characteristics (all p < 0.01). Conclusions: This is the first study to track recovery of body awareness after stroke and investigate the relationship it may have in recovery of sensation, motor impairment and function, self-efficacy and quality of life. Further research is now warranted to continue investigation of body awareness and to develop effective stroke-specific assessment and intervention strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Serrada, Hordacre and Hillier.)

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 T 1 -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., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Non-invasive brain stimulation is a useful tool to probe brain function and provide therapeutic treatments in disease. When applied to the right posterior parietal cortex (PPC) of healthy participants, it is possible to temporarily shift spatial attention and mimic symptoms of spatial neglect. However, the field of brain stimulation is plagued by issues of high response variability. The aim of this study was to investigate baseline functional connectivity as a predictor of response to an inhibitory brain stimulation paradigm applied to the right PPC. In fourteen healthy adults (9 female, aged 24.8 ± 4.0 years) we applied continuous theta burst stimulation (cTBS) to suppress activity in the right PPC. Resting state functional connectivity was quantified by recording electroencephalography and assessing phase consistency. Spatial attention was assessed before and after cTBS with the Landmark Task. Finally, known determinants of response to brain stimulation were controlled for to enable robust investigation of the influence of resting state connectivity on cTBS response. We observed significant inter-individual variability in the behavioral response to cTBS with 53.8% of participants demonstrating the expected rightward shift in spatial attention. Baseline high beta connectivity between the right PPC, dorsomedial pre-motor region and left temporal-parietal region was strongly associated with cTBS response ( R 2 = 0.51). Regression analysis combining known cTBS determinants (age, sex, motor threshold, physical activity, stress) found connectivity between the right PPC and left temporal-parietal region was the only significant variable ( p = 0.011). These results suggest baseline resting state functional connectivity is a strong predictor of a shift in spatial attention following cTBS. Findings from this study help further understand the mechanism by which cTBS modifies cortical function and could be used to improve the reliability of brain stimulation protocols., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mariner, Loetscher and Hordacre.)

New treatments that can facilitate neural repair and reduce persistent impairments have significant value in promoting recovery following stroke. One technique that has gained interest is transcranial direct current stimulation (tDCS) as early research suggested it could enhance plasticity and enable greater behavioral recovery. However, several studies have now identified substantial intersubject variability in response to tDCS and clinical trials revealed insufficient evidence of treatment effectiveness. A possible explanation for the varied and negative findings is that the physiologic model of stroke recovery that researchers have used to guide the application of tDCS-based treatments in stroke is overly simplistic and does not account for stroke heterogeneity or known determinants that affect the tDCS response. Here, we propose that tDCS could have a more clearly beneficial role in enhancing stroke recovery if greater consideration is given to individualizing treatment. By critically reviewing the proposed mechanisms of tDCS, stroke physiology across the recovery continuum, and known determinants of tDCS response, we propose a new, theoretical, patient-tailored approach to delivering tDCS after stroke. The proposed model includes a step-by-step principled selection strategy for identifying optimal neuromodulation targets and outlines key areas for further investigation. Tailoring tDCS treatment to individual neuroanatomy and physiology is likely our best chance at producing robust and meaningful clinical benefit for people with stroke and would therefore accelerate opportunities for clinical translation., (© 2021 American Academy of Neurology.)

Background: Increasing evidence demonstrates that repetitive transcranial magnetic stimulation (rTMS) treatment of the dorsolateral prefrontal cortex is beneficial for improving cognitive function in patients with Alzheimer's disease (AD); however, the underlying mechanism of its therapeutic effect remains unclear. Objectives/Hypothesis: The aim of this study was to investigate the impact of rTMS to the dorsolateral prefrontal cortex on functional connectivity along with treatment response in AD patients with different severity of cognitive impairment. Methods: We conducted a 2-week treatment course of 10-Hz rTMS over the left dorsolateral prefrontal cortex in 23 patients with AD who were split into the mild or moderate cognitive impairment subgroup. Resting state electroencephalography and general cognition was assessed before and after rTMS. Power envelope connectivity was used to calculate functional connectivity at the source level. The functional connectivity of AD patients and 11 cognitively normal individuals was compared. Results: Power envelope connectivity was higher in the delta and theta bands but lower in the beta band in the moderate cognitive impairment group, compared to the cognitively normal controls, at baseline ( p < 0.05). The mild cognitive impairment group had no significant abnormities. Montreal Cognitive Assessment scores improved after rTMS in the moderate and mild cognitive impairment groups. Power envelope connectivity in the beta band post-rTMS was increased in the moderate group ( p < 0.05) but not in the mild group. No significant changes in the delta and theta band were found after rTMS in both the moderate and mild group. Conclusion: High-frequency rTMS to the dorsolateral prefrontal cortex modulates electroencephalographic functional connectivity while improving cognitive function in patients with AD. Increased beta connectivity may have an important mechanistic role in rTMS therapeutic effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Guo, Dang, Hordacre, Su, Yan, Chen, Ren, Shi, Cai, Zhang and Lan.)

A patterned repetitive transcranial magnetic stimulation protocol, known as continuous theta burst stimulation (cTBS), can suppress corticospinal excitability via mechanisms that appear similar to long-term depression synaptic plasticity. Despite much potential, this technique is currently limited by substantial response variability. The purpose of this study was to investigate whether baseline resting state functional connectivity is a determinant of response to cTBS. Eighteen healthy young adults participated in up to three experimental sessions. Single-pulse transcranial magnetic stimulation was used to quantify change in corticospinal excitability following cTBS. Three minutes of resting electroencephalographic activity was recorded, and functional connectivity was estimated using the debiased weighted phase lag index across different frequency bands. Partial least squares regression identified models of connectivity between a seed region (C3) and the whole scalp that maximally accounted for variance in cTBS responses. There was no group-level effect of a single cTBS train or spaced cTBS trains on corticospinal excitability (p = 0.092). A low beta frequency band model of connectivity accounted for the largest proportion of variance in spaced cTBS response (R 2  = 0.50). Based on the low beta frequency model, a-priori regions of interest were identified and predicted 39% of variance in response to spaced cTBS at a subsequent session. Importantly, weaker connectivity between the seed electrode (C3) and a cluster approximating a frontocentral region was associated with greater spaced cTBS response (p = 0.02). It appears M1-frontocentral networks may have an important role in determining the effects of cTBS on corticospinal excitability.

The ability of repetitive transcranial magnetic stimulation (rTMS) to non-invasively induce neuroplasticity in the human cortex has opened exciting possibilities for its application in both basic and clinical research. Changes in the amplitude of motor evoked potentials (MEPs) elicited by single-pulse transcranial magnetic stimulation has so far provided a convenient model for exploring the neurophysiology of rTMS effects on the brain, influencing the ways in which these stimulation protocols have been applied therapeutically. However, a growing number of studies have reported large inter-individual variability in the mean MEP response to rTMS, raising legitimate questions about the usefulness of this model for guiding therapy. Although the increasing application of different neuroimaging approaches has made it possible to probe rTMS-induced neuroplasticity outside the motor cortex to measure changes in neural activity that impact other aspects of human behaviour, the high variability of rTMS effects on these measurements remains an important issue for the field to address. In this review, we seek to move away from the conventional facilitation/inhibition dichotomy that permeates much of the rTMS literature, presenting a non-standard approach for measuring rTMS-induced neuroplasticity. We consider the evidence that rTMS is able to modulate an individual's moment-to-moment variability of neural activity, and whether this could have implications for guiding the therapeutic application of rTMS., (Copyright © 2021 Elsevier Ltd. All rights reserved.)