Adaptive Trials in Stroke: Current Use and Future Directions.

Inclusion of adaptive design features in a clinical trial provides preplanned flexibility to dynamically modify a trial during its conduct while preserving validity and integrity. Adaptive trials are needed to accelerate the conduct of more efficient, informative, and ethical clinical research in the field of neurology. Stroke is a natural candidate for adoption of these innovative approaches to trial design. This Research Methods in Neurology article is informed by a scoping review that identified 45 completed or ongoing adaptive clinical trials in stroke that were appraised: 15 trials had published results with or without a published protocol and 30 ongoing trials (14 trials had a published protocol, and 16 trials were registered only). Interventions spanned acute (n = 28), rehabilitation (n = 8), prevention (n = 8), and rehabilitation and prevention (n = 1). A subsample of these trials was selected to illustrate the utility of adaptive design features and discuss why each adaptive feature was incorporated in the design to best achieve the aim; whether each individual feature was used and whether it resulted in expected efficiencies; and any learnings during preparation, conduct, or reporting. We then discuss the operational, ethical, and regulatory considerations that warrant careful consideration during adaptive trial planning and reflect on the workforce readiness to deliver adaptive trials in practice. We conclude that adaptive trials can be designed, funded, conducted, and published for a wide range of research questions and offer future directions to support adoption of adaptive trial designs in stroke and neurologic research more broadly.

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.

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.

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.

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.

ZOom Delivered Intervention Against Cognitive decline (ZODIAC) COVID-19 pandemic adaptations to the Post-Ischaemic Stroke Cardiovascular Exercise Study (PISCES): protocol for a randomised controlled trial of remotely delivered fitness training for brain health.

BACKGROUND: Stroke increases subsequent dementia risk yet there are no specific post-stroke therapies to protect cognition. Cardiorespiratory exercise is recommended for secondary prevention of stroke and may be neuroprotective. The Post Ischaemic Stroke Cardiovascular Exercise Study (PISCES) aims to reduce post-stroke secondary neurodegeneration and cognitive decline. During the pandemic, we pivoted to a ZOom Delivered Intervention Against Cognitive decline (ZODIAC) protocol, reducing pandemic-amplified barriers to exercise. METHODS: We present pandemic adaptions for a multicentre phase IIb assessor-blinded randomised controlled trial of ischaemic stroke survivors testing the efficacy and feasibility of an 8-week home-based exercise intervention delivered at 2 months post-stroke. We compare cardiorespiratory exercise (intervention arm) versus balance and stretching (active control arm). Participants are assessed with magnetic resonance imaging (MRI), fitness, blood, microbiome, and neuropsychological tests at three study visits: before and after the exercise intervention and at 12 months. Modifications to the original protocol include pre-exercise safety home visits, commercial delivery of exercise equipment to facilitate assessor blinding, and reconsideration of statistical plan to allow pooling of the studies. We have reduced in-person study visits from 27 to 3. Primary outcome remains between-group (intervention versus control) difference in brain volume change; secondary outcome is between-group difference in global cognitive ability to allow remote administration of a validated cognitive scale. DISCUSSION: Remotely delivered exercise interventions reduce participant burden and may reduce barriers to recruitment. A decrease in the number of in-person study visits can be supported by greater information capture via self-reported questionnaires and phone surveys. TRIAL REGISTRATION: Prospectively ACTRN12616000942459. Registered on July 2016.

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.

Identifying and Mapping Canadian Dietetic Students' Interaction(s) with Simulation-Based Education: A Scoping Review.

This scoping review mapped literature available on Canadian dietetics, nutrition, and foods students' and graduates' interaction(s) with simulation-based education (SBE) during undergraduate and/or practicum. One certified Librarian led the preliminary search (Summer, 2021), while three Joanna Briggs Institute-trained reviewers conducted the comprehensive search via MEDLINE (OVID), CINAHL (EBSCO), Academic Search Premier (EBSCO), Embase (Elsevier), Scopus (Elsevier), and Google (February 2022). A data extraction tool designed specifically for the study objectives and research inclusion criteria was used. We recorded 354 results and included 7. Seven types of SBE were recorded: (i) comprehensive care plan (n = 2); (ii) nutritional diagnosis/assessment (n = 2); (iii) body composition assessment (n = 1); (iv) introducing patient to dysphagia care (n = 1); (v) nutrition counselling session (n = 1); (vi) nutrition-focused physical examination (n = 1); and (vii) professional communications via social media (n = 1). Results indicate that Canadian dietitian-led SBE includes the use of simulated patients, nutritional diagnosis/assessment, and the creation of comprehensive care plans, among others. Students have been assessed for performance of trained tasks through exams, self-awareness surveys, and interviews, and SBE activities have been evaluated for effectiveness through questionnaires and interviews with users/students. Canadian literature is limited, and more can be learned by exploring the global context within and outside the profession.

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.