Using mechanistic knowledge to appraise contemporary approaches to the rehabilitation of upper limb function following stroke.

It is a paradox of neurological rehabilitation that, in an era in which preclinical models have produced significant advances in our mechanistic understanding of neural plasticity, there is inadequate support for many therapies recommended for use in clinical practice. When the goal is to estimate the probability that a specific form of therapy will have a positive clinical effect, the integration of mechanistic knowledge (concerning 'the structure or way of working of the parts in a natural system') may improve the quality of inference. This is illustrated by analysis of three contemporary approaches to the rehabilitation of lateralized dysfunction affecting people living with stroke: constraint-induced movement therapy; mental practice; and mirror therapy. Damage to 'cross-road' regions of the structural (white matter) brain connectome generates deficits that span multiple domains (motor, language, attention and verbal/spatial memory). The structural integrity of these regions determines not only the initial functional status, but also the response to therapy. As structural disconnection constrains the recovery of functional capability, 'disconnectome' modelling provides a basis for personalized prognosis and precision rehabilitation. It is now feasible to refer a lesion delineated using a standard clinical scan to a (dis)connectivity atlas derived from the brains of other stroke survivors. As the individual disconnection pattern thus obtained suggests the functional domains most likely be compromised, a therapeutic regimen can be tailored accordingly. Stroke is a complex disorder that burdens individuals with distinct constellations of brain damage. Mechanistic knowledge is indispensable when seeking to ameliorate the behavioural impairments to which such damage gives rise.

Considerations for developing complex post-stroke upper limb behavioural interventions: An international qualitative study.

OBJECTIVE: To simultaneously explore the perspectives and opinions of different invested participant groups on the important considerations for development of upper limb behavioural interventions that drive optimal post-stroke upper limb motor recovery. DESIGN: A qualitative descriptive study in a constructivist epistemology. PARTICIPANTS: Purposively selected participant groups (preclinical research n = 9, clinical research n = 9, clinical experience n = 9 and lived experience n = 10). SETTING: Research participants were selected from top internationally published authors. Experiential participants were recruited internationally, through networks. RESULTS: Four themes were identified with embedded subthemes. Theme 1: 'Clinical relevance should be the core of a "good" research question' with two subthemes: 'Breaking down silos: forging interdisciplinary research teams', and 'Beyond the pipeline: bench to bedside and back'; theme 2: 'Balance restitution and compensation to maximise outcomes' with three subthemes: 'Good outcome: going beyond an outcome measure', 'Recovery is a puzzle: measure all the pieces', and 'Optimising capacity: knowing when and how'; theme 3: 'Stroke demands personalised solutions' with two subthemes: 'Condition-specific considerations', and 'Person-specific considerations'; theme 4: 'Upper limb recovery requires complex interventions' with four subthemes: 'Fuelling engagement', 'Content is crucial', 'Multidimensional dose', and 'Therapist sway'. CONCLUSIONS: This study suggests that post-stroke upper limb motor interventions are the interactions of multiple intervention elements (e.g. dose and content) shaped by different contextual considerations (e.g. stroke and personal factors). Development of such interventions may need to consider both content and context of the intervention to drive optimal recovery.

Neurophysiological effects of acute aerobic exercise in young adults: a systematic review and meta-analysis.

Evidence continues to accumulate that acute aerobic exercise (AAE) impacts neurophysiological excitability as measured by transcranial magnetic stimulation (TMS). Yet, uncertainty exists about which TMS measures are modulated after AAE in young adults. The influence of AAE intensity and duration of effects are also uncertain. This pre-registered meta-analysis (CRD42017065673) addressed these uncertainties by synthesizing data from 23 studies (including 474 participants) published until February 2024. Meta-analysis was run using a random-effects model and Hedge's g used as effect size. Our results demonstrated a decrease in short-interval intracortical inhibition (SICI) following AAE (g = 0.27; 95 % CI [0.16-0.38]; p <.0001), particularly for moderate (g = 0.18; 95 % CI [0.05-0.31]; p <.01) and high (g = 0.49; 95 % CI [0.27-0.71]; p <.0001) AAE intensities. These effects remained for 30 minutes after AAE. Additionally, increased corticospinal excitability was only observed for high intensity AAE (g = 0.28; 95 % CI, [0.07-0.48]; p <.01). Our results suggest potential mechanisms for inducing a more susceptible neuroplastic environment following AAE.

Modulation of the Association Between Corticospinal Tract Damage and Outcome After Stroke by White Matter Hyperintensities.

BACKGROUND AND OBJECTIVES: Motor outcomes after stroke relate to corticospinal tract (CST) damage. The brain leverages surviving neural pathways to compensate for CST damage and mediate motor recovery. Thus, concurrent age-related damage from white matter hyperintensities (WMHs) might affect neurologic capacity for recovery after CST injury. The role of WMHs in post-stroke motor outcomes is unclear. In this study, we evaluated whether WMHs modulate the relationship between CST damage and post-stroke motor outcomes. METHODS: We used data from the multisite ENIGMA Stroke Recovery Working Group with T1 and T2/fluid-attenuated inversion recovery imaging. CST damage was indexed with weighted CST lesion load (CST-LL). WMH volumes were extracted with Freesurfer's SAMSEG. Mixed-effects beta-regression models were fit to test the impact of CST-LL, WMH volume, and their interaction on motor impairment, controlling for age, days after stroke, and stroke volume. RESULTS: A total of 223 individuals were included. WMH volume related to motor impairment above and beyond CST-LL (ß = 0.178, 95% CI 0.025-0.331, p = 0.022). Relationships varied by WMH severity (mild vs moderate-severe). In individuals with mild WMHs, motor impairment related to CST-LL (ß = 0.888, 95% CI 0.604-1.172, p < 0.001) with a CST-LL × WMH interaction (ß = -0.211, 95% CI -0.340 to -0.026, p = 0.026). In individuals with moderate-severe WMHs, motor impairment related to WMH volume (ß = 0.299, 95% CI 0.008-0.590, p = 0.044), but did not significantly relate to CST-LL or a CST-LL × WMH interaction. DISCUSSION: WMHs relate to motor outcomes after stroke and modify relationships between motor impairment and CST damage. WMH-related damage may be under-recognized 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.

Prevalence of Arm Weakness, Pre-Stroke Outcomes and Other Post-Stroke Impairments Using Routinely Collected Clinical Data on an Acute Stroke Unit.

INTRODUCTION: The prevalence of upper limb motor weakness early post-stroke may be changing, which can have clinical and research implications. Our primary aim was to describe the prevalence of upper limb motor weakness early post-stroke, with a secondary aim to contextualize this prevalence by describing pre-stroke outcomes, other post-stroke impairments, functional activities, and discharge destination. METHODS: This cross-sectional observational study extracted clinical data from confirmed stroke patients admitted to a metropolitan stroke unit over 15-months. The primary upper limb weakness measure was Shoulder Abduction and Finger Extension (SAFE) score. Demographics (eg, age), clinical characteristics (eg, stroke severity), pre-stroke outcomes (eg, clinical frailty), other post-stroke impairments (eg, command following), functional activities (eg, ambulation), and discharge destination were also extracted. RESULTS: A total of 463 participants had a confirmed stroke and SAFE score. One-third of patients received ≥1 acute medical intervention(s). Nearly one-quarter of patients were classified as frail pre-stroke. Upper limb weakness (SAFE≤8) was present in 35% [95% CI: 30%-39%] at a median of 1-day post-stroke, with 22% presenting with mild-moderate weakness (SAFE5-8). The most common other impairments were upper limb coordination (46%), delayed recall (41%), and upper limb sensation (26%). After a median 3-day acute stroke stay, 52% of the sample were discharged home. CONCLUSION: Upper limb weakness was present in just over a third (35%) of the sample early post-stroke. Data on pre-stroke outcomes and the prevalence of other post-stroke impairments highlights the complexity and heterogeneity of stroke recovery. Further research is required to tease out meaningful recovery phenotypes and their implications.

Control intervention design for preclinical and clinical trials: Consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable.

Control comparator selection is a critical trial design issue. Preclinical and clinical investigators who are doing trials of stroke recovery and rehabilitation interventions must carefully consider the appropriateness and relevance of their chosen control comparator as the benefit of an experimental intervention is established relative to a comparator. Establishing a strong rationale for a selected comparator improves the integrity of the trial and validity of its findings. This Stroke Recovery and Rehabilitation Roundtable (SRRR) taskforce used a graph theory voting system to rank the importance and ease of addressing challenges during control comparator design. "Identifying appropriate type of control" was ranked easy to address and very important, "variability in usual care" was ranked hard to address and of low importance, and "understanding the content of the control and how it differs from the experimental intervention" was ranked very important but not easy to address. The CONtrol DeSIGN (CONSIGN) decision support tool was developed to address the identified challenges and enhance comparator selection, description, and reporting. CONSIGN is a web-based tool inclusive of seven steps that guide the user through control comparator design. The tool was refined through multiple rounds of pilot testing that included more than 130 people working in neurorehabilitation research. Four hypothetical exemplar trials, which span preclinical, mood, aphasia, and motor recovery, demonstrate how the tool can be applied in practice. Six consensus recommendations are defined that span research domains, professional disciplines, and international borders.

Control intervention design for preclinical and clinical trials: Consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable.

Control comparator selection is a critical trial design issue. Preclinical and clinical investigators who are doing trials of stroke recovery and rehabilitation interventions must carefully consider the appropriateness and relevance of their chosen control comparator as the benefit of an experimental intervention is established relative to a comparator. Establishing a strong rationale for a selected comparator improves the integrity of the trial and validity of its findings. This Stroke Recovery and Rehabilitation Roundtable (SRRR) taskforce used a graph theory voting system to rank the importance and ease of addressing challenges during control comparator design. "Identifying appropriate type of control" was ranked easy to address and very important, "variability in usual care" was ranked hard to address and of low importance, and "understanding the content of the control and how it differs from the experimental intervention" was ranked very important but not easy to address. The CONtrol DeSIGN (CONSIGN) decision support tool was developed to address the identified challenges and enhance comparator selection, description, and reporting. CONSIGN is a web-based tool inclusive of seven steps that guide the user through control comparator design. The tool was refined through multiple rounds of pilot testing that included more than 130 people working in neurorehabilitation research. Four hypothetical exemplar trials, which span preclinical, mood, aphasia, and motor recovery, demonstrate how the tool can be applied in practice. Six consensus recommendations are defined that span research domains, professional disciplines, and international borders.

Perseverance with home-based upper limb practice after stroke: perspectives of stroke survivors and their significant others.

PURPOSE: The aim of this study was to explore factors that influence stroke survivors' ability to persevere with home-based upper limb practice. METHODS: A qualitative descriptive study embedded within a theoretical framework was conducted. Data were collected through semi-structured focus group, dyadic, and individual interviews. The Theoretical Domains Framework and Capability, Opportunity, Motivation - Behaviour (COM-B) model guided data collection and directed content analysis. FINDINGS: Participants were 31 adult stroke survivors with upper limb impairment, with 13 significant other/s, who were living at home in Queensland, Australia. Three central tenants aligned with the COM-B and six themes were identified. Stroke survivors' capability to persevere was influenced by being physically able to practice and being able to understand, monitor and modify practice, their opportunity to persevere was influenced by accessing therapy and equipment required for practice and fitting practice into everyday life, and their motivation to persevere was influenced by having goals and experiencing meaningful outcomes and having support and being accountable. CONCLUSION: Persevering with practice is multifaceted for stroke survivors. All facets need to be addressed in the design of strategies to enhance stroke survivors' ability to persevere and in turn, enhance their potential for continued upper limb recovery.IMPLICATIONS FOR REHABILITATIONMany stroke survivors do not persevere with long-term home-based upper limb practice despite the belief that high dose practice will promote continued recovery.Therapists need to support stroke survivors to setup individualised goal-based home programs that they can complete independently, or with support, within their everyday life.Stroke survivors need coaching to monitor and modify their practice and map their progress, so that they can recognise and experience meaningful recovery.To optimise upper limb recovery after stroke, strategies to enhance stroke survivors' capability, opportunity, and motivation to persevere across the continuum of recovery, need to be co-designed by stroke survivors, therapists and researchers.

White matter hyperintensities modify relationships between corticospinal tract damage and motor outcomes after stroke.

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 (ß = 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 (ß = 0.888, p < 0.001) with a CST-LL x WMH interaction (ß = -0.211, 0.026). In individuals with moderate-severe WMHs, motor impairment related to WMH volume (ß = 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.

Stroke survivors' perspectives on decision-making about rehabilitation and the prospect of taking recovery-promoting drugs: A qualitative study.

Objectives: To investigate factors which influence stroke survivors' decision-making about their rehabilitation and the prospect of taking recovery-promoting drugs, to enhance their recovery. Methods: Seventeen stroke survivors who had undertaken stroke rehabilitation, and three spouses, participated in focus groups and individual interviews in northern Queensland, Australia. Inductive thematic analysis of the interview data was conducted in accordance with Braun and Clarke's six-phase process. Results: Two specific, pivotal decision points during participants' stroke recovery process were identified: 1) overall, when deciding what rehabilitation they would undertake and hypothetically what recovery-promoting drugs they would take, and 2) on a daily basis, when deciding whether to participate in rehabilitation and take recovery-promoting drugs on any given day. Six themes which described factors influencing their decision-making were: 'My options for rehabilitation and recovery-promoting drugs'; 'The costs of rehabilitation and recovery-promoting drugs'; 'My recovery goals'; 'What I can deal with today'; 'The people my rehabilitation and recovery-promoting drugs affect'; and 'Fitting rehabilitation and recovery-promoting drugs into my life.' These themes were applicable at either one or both of the identified decision points. Conclusion: Factors that influence stroke survivors' decision-making, overall and on a day-to-day basis, need to be considered to ensure they can make the best decisions for themselves to achieve their full recovery potential. Understanding the conditions under which a stroke survivor would take a recovery-promoting drug will contribute to the development of dosing protocols to which stroke survivors could adhere.

Dose, Content, and Context of Usual Care in Stroke Upper Limb Motor Interventions: A Systematic Review.

OBJECTIVE: The objectives of this systematic review were to describe the current dose and content of usual care upper limb motor intervention for inpatients following stroke and examine if context factors alter dose and content. DATA SOURCES: A systematic search (EMBASE, MEDLINE) was completed from January 2015 to February 2023 (PROSPERO CRD42021281986). METHODS: Studies were eligible if they reported non-protocolised usual care upper limb motor intervention dose data for stroke inpatients. Studies were rated using the Johanna Briggs Institute critical appraisal tool. Data were descriptively reported for dose dimensions of time (on task or, in therapy) and intensity (repetitions, repetition/minute), content (intervention type/mode), and context (e.g., severity strata). RESULTS: Eight studies were included from four countries, largely reflecting inpatient rehabilitation. Time in therapy ranged from 23 to 121 min/day. Time on task ranged from 8 to 44 min/day. Repetitions ranged from 36 to 57/session, and 15 to 282/day. Time on task was lowest in the stratum of people with severe upper limb impairment (8 min/day), the upper limit for this stratum was 41.5 min/day. There was minimal reporting of usual care content across all studies. CONCLUSION: Upper limb motor intervention dose appears to be increasing in usual care compared to prior reports (e.g., average 21 min/day and 23 to 32 repetitions/session). Context variability suggests that doses are lowest in the stratum of patients with a severely impaired upper limb. Consistent reporting of the multiple dimensions of dose and content is necessary to better understand usual care offered during inpatient rehabilitation.

Self-reported sleep disturbances among people who have had a stroke: a cross-sectional analysis.

BACKGROUND: Sleep disturbances and their potential association with stroke remains understudied at a population level. We sought to determine the prevalence of sleep disturbances among people who have effects of stroke compared with the general population. METHODS: We used data from people aged 18 years or older who responded to the sleep and chronic disease modules of the 2017-2018 cycle of the Canadian Community Health Survey (CCHS). We measured sleep disturbances by self-reports of having trouble staying awake most or all of the time; either short (< 5 h) or long (> 9 h) nightly sleep duration; having trouble going to or staying asleep most or all of the time; and never, rarely or sometimes having refreshing sleep. We used log-binomial and multinomial regression to investigate prevalence of sleep disturbances among respondents who reported effects of stroke compared with others, adjusting for confounding factors. RESULTS: We included 46 404 CCHS respondents, 682 of whom reported effects of stroke. The prevalence of sleep disturbances for those with effects of stroke was higher than among others in the sample with regard to trouble staying awake (13.0% v. 6.1%; adjusted relative risk [RR] 2.16, 95% confidence interval [CI] 1.59-2.94), short or long duration sleep (28.9% v. 10.0%; adjusted RR 1.93, 95% CI 1.57-2.38), trouble going to or staying asleep, (28.1% v. 17.6%; adjusted RR 1.53, 95% CI 1.28-1.83) and lack of refreshing sleep (41.1% v. 37.1%; adjusted RR 1.30, 95% CI 1.14-1.49). The prevalence of at least 1 reported measure of sleep disturbance was 61.6% among those with effects of stroke, compared with 48.2% among others (adjusted RR 1.28, 95% CI 1.18-1.40). INTERPRETATION: Self-report of having effects of stroke was associated with increased prevalence of sleep disturbances compared with the general population. Sleep disturbances were reported by a high proportion of respondents with effects of stroke, indicating the importance of screening for related disorders.

Examining Dose Frameworks to Improve Aphasia Rehabilitation Research.

The effect of treatment dose on recovery of post-stroke aphasia is not well understood. Inconsistent conceptualization, measurement, and reporting of the multiple dimensions of dose hinders efforts to evaluate dose-response relations in aphasia rehabilitation research. We review the state of dose conceptualization in aphasia rehabilitation and compare the applicability of 3 existing dose frameworks to aphasia rehabilitation research-the Frequency, Intensity, Time, and Type (FITT) principle, the Cumulative Intervention Intensity (CII) framework, and the Multidimensional Dose Articulation Framework (MDAF). The MDAF specifies dose in greater detail than the CII framework and the FITT principle. On this basis, we selected the MDAF to be applied to 3 diverse examples of aphasia rehabilitation research. We next critically examined applicability of the MDAF to aphasia rehabilitation research and identified the next steps needed to systematically conceptualize, measure, and report the multiple dimensions of dose, which together can progress understanding of the effect of treatment dose on outcomes for people with aphasia after stroke. Further consideration is required to enable application of this framework to aphasia interventions that focus on participation, personal, and environmental interventions and to understand how the construct of episode difficulty applies across therapeutic activities used in aphasia interventions.

Enhancing generalizability of stroke clinical trial results: Illustrations from upper-limb motor recovery trials.

INTRODUCTION: Broadening eligibility criteria has been a focus to increase the generalizability of trial findings. Using upper-limb motor trials conducted early post-stroke as the illustrative domain, we sought to (1) investigate whether the published aim and conclusion statements adequately reflect the generalizability of findings and (2) explore internal validity and feasibility as constraints to achieving generalizability. METHODS: We systematically applied a conceptual model of a trial sampling process to published literature from systematic review and prospective cross-sectional data. The eligibility criteria reported and used to exclude patients were classified by consensus as related to safety, internal validity, feasibility, or a combination thereof. Categorical data were reported as counts/proportions, and continuous data were reported as median (interquartile range (IQR)). RESULTS: Thirty trials (n = 1638 participants) were included in the published literature and 1013 patients in the prospective data set. Thirty-seven percent of trials did not describe their target population in the aim and conclusion, and 80% did not report all trial screening data. Eligibility criteria related to internal validity were the most common type reported and applied to exclude patients across both data sets. In the prospective data set, 70% of patients were excluded for more than one reason. CONCLUSION: Key information to support the generalizability of trial findings was insufficiently reported in published upper-limb motor research conducted early post-stroke. Broadening eligibility criteria alone is unlikely to sufficiently improve trial inclusivity due to internal validity constraints. Trials could achieve inclusivity through targeting multiple sub-populations, that in combination, produce clinically relevant results that are applicable to a broader population.