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    Upper-Limb Motor Intervention Elements That Drive Improvement in Biomarkers and Clinical Measures Post-Stroke: A Systematic Review in a Systems Paradigm
    Wingfield, M ; Fini, NA ; Brodtmann, A ; Williams, G ; Churilov, L ; Hayward, KS (SAGE PUBLICATIONS INC, 2022-11)
    OBJECTIVE: To use a systems paradigm to examine upper limb (UL) motor intervention elements driving biomarker and clinical measure improvement after stroke. METHODS: Databases were searched up to March 2022. Eligibility screening was completed by 2 authors. Studies using biomarkers and clinical measures pre- and post-upper limb intervention were included. Studies of adjunct interventions (eg, brain stimulation) were excluded. Cochrane Risk-of-Bias tools and Template for Intervention Description and Replication were used to rate studies. Studies were synthesized using a systems paradigm: intervention outcome was considered an emergent property of the systemic interactions of 4 intervention elements (demographics, type, quality, and dose) characterized by individual dimensions. RESULTS: Sixty-four studies (n = 1814 participants) containing 106 intervention groups (66 experimental; 40 control) were included. Combined biomarker and clinical outcomes defined 3 scenarios: restitution, mixed, and unchanged. The restitution scenario included more moderate-to-severely impaired participants in earlier recovery phases (<6 months). Interventions with graded difficulty were more frequently used in the restitution scenario compared with the unchanged scenario. No difference in quality or amount of therapy was identified when examining scenarios that demonstrated restitution compared to those that did not (mixed and unchanged). CONCLUSIONS: A systems paradigm may be one of many approaches to understand UL motor restitution. This review found no single element consistently delivered improvements in biomarkers and clinical measures in the examined intervention groups. Complex patterns formed by multiple interacting intervention elements were observed in participants with and without restitution.
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    Mood and Cognitive Trajectories Over the First Year after Mild Ischemic Stroke
    Ebaid, D ; Bird, LJ ; McCambridge, LJE ; Werden, E ; Bradshaw, J ; Cumming, T ; Tang, E ; Brodtmann, A (ELSEVIER, 2022-04)
    OBJECTIVES: Cognitive and mood dysfunction are major contributors to post-stroke disability. The longer-term trajectories of mood and cognition post-stroke remain unclear, as do which cognitive domains decline, improve, or remain stable after stroke, and in which patients. We aimed to characterize the cognitive trajectories of mild ischemic stroke survivors over one year compared to stroke-free controls, and to investigate whether symptoms of anxiety and depression were associated with cognitive function. MATERIALS AND METHODS: All participants were tested with a neuropsychological test battery at 3-months and 12-months post-stroke, assessing attention/processing speed, memory, visuospatial function, executive function, and language. Anxiety and depression symptomatology were also assessed at both timepoints. RESULTS: Stroke participants (N=126, mean age 68.44 years ±11.83, 87 males, median [Q1, Q3] admission NIHSS=2 [1, 4]) performed worse on cognitive tests and endorsed significantly higher depression and anxiety symptomatology than controls (N=40, mean age=68.82 years ±6.33, 25 males) at both timepoints. Mood scores were not correlated with cognitive performance. Stroke participants' scores trended higher across cognitive domains from 3- to 12-months but statistically significant improvement was only observed on executive function tasks. CONCLUSION: Stroke participants performed significantly worse than controls on all cognitive domains following mild ischemic stroke. Stroke participants only exhibited statistically significant improvement on executive function tasks between 3- and 12- months. Whilst anxiety and depression symptoms were higher in stroke participants, this was not correlated with cognitive performance. Further studies are needed to understand factors underlying cognitive recovery and decline after stroke.
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    Smaller spared subcortical nuclei are associated with worse post-stroke sensorimotor outcomes in 28 cohorts worldwide
    Liew, S-L ; Zavaliangos-Petropulu, A ; Schweighofer, N ; Jahanshad, N ; Lang, CE ; Lohse, KR ; Banaj, N ; Barisano, G ; Baugh, LA ; Bhattacharya, AK ; Bigjahan, B ; Borich, MR ; Boyd, LA ; Brodtmann, A ; Buetefisch, CM ; Byblow, WD ; Cassidy, JM ; Charalambous, CC ; Ciullo, V ; Conforto, AB ; Craddock, RC ; Dula, AN ; Egorova, N ; Feng, W ; Fercho, KA ; Gregory, CM ; Hanlon, CA ; Hayward, KS ; Holguin, JA ; Hordacre, B ; Hwang, DH ; Kautz, SA ; Khlif, MS ; Kim, B ; Kim, H ; Kuceyeski, A ; Lo, B ; Liu, J ; Lin, D ; Lotze, M ; MacIntosh, BJ ; Margetis, JL ; Mohamed, FB ; Nordvik, JE ; Petoe, MA ; Piras, F ; Raju, S ; Ramos-Murguialday, A ; Revill, KP ; Roberts, P ; Robertson, AD ; Schambra, HM ; Seo, NJ ; Shiroishi, MS ; Soekadar, SR ; Spalletta, G ; Stinear, CM ; Suri, A ; Tang, WK ; Thielman, GT ; Thijs, VN ; Vecchio, D ; Ward, NS ; Westlye, LT ; Winstein, CJ ; Wittenberg, GF ; Wong, KA ; Yu, C ; Wolf, SL ; Cramer, SC ; Thompson, PM (OXFORD UNIV PRESS, 2021-10-01)
    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 T1-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.
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    Cortical thickness estimation in longitudinal stroke studies: A comparison of 3 measurement methods
    Li, Q ; Pardoe, H ; Lichter, R ; Werden, E ; Raffelt, A ; Cumming, T ; Brodtmann, A (ELSEVIER SCI LTD, 2015)
    There is considerable controversy about the causes of cognitive decline after stroke, with evidence for both the absence and coexistence of Alzheimer pathology. A reduction in cortical thickness has been shown to be an important biomarker for the progression of many neurodegenerative diseases, including Alzheimer's disease (AD). However, brain volume changes following stroke are not well described. Cortical thickness estimation presents an ideal way to detect regional and global post-stroke brain atrophy. In this study, we imaged a group of patients in the first month after stroke and at 3 months. We compared three methods of estimating cortical thickness on unmasked images: one surface-based (FreeSurfer) and two voxel-based methods (a Laplacian method and a registration method, DiRecT). We used three benchmarks for our analyses: accuracy of segmentation (especially peri-lesional performance), reproducibility, and biological validity. We found important differences between these methods in cortical thickness values and performance in high curvature areas and peri-lesional regions, but similar reproducibility metrics. FreeSurfer had less reliance on manual boundary correction than the other two methods, while reproducibility was highest in the Laplacian method. A discussion of the caveats for each method and recommendations for use in a stroke population is included. We conclude that both surface- and voxel-based methods are valid for estimating cortical thickness in stroke populations.
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    Structural MRI markers of brain aging early after ischemic stroke
    Werden, E ; Cumming, T ; Li, Q ; Bird, L ; Veldsman, M ; Pardoe, HR ; Jackson, G ; Donnan, GA ; Brodtmann, A (LIPPINCOTT WILLIAMS & WILKINS, 2017-07-11)
    OBJECTIVE: To examine associations between ischemic stroke, vascular risk factors, and MRI markers of brain aging. METHODS: Eighty-one patients (mean age 67.5 ± 13.1 years, 31 left-sided, 61 men) with confirmed first-ever (n = 66) or recurrent (n = 15) ischemic stroke underwent 3T MRI scanning within 6 weeks of symptom onset (mean 26 ± 9 days). Age-matched controls (n = 40) completed identical testing. Multivariate regression analyses examined associations between group membership and MRI markers of brain aging (cortical thickness, total brain volume, white matter hyperintensity [WMH] volume, hippocampal volume), normalized against intracranial volume, and the effects of vascular risk factors on these relationships. RESULTS: First-ever stroke was associated with smaller hippocampal volume (p = 0.025) and greater WMH volume (p = 0.004) relative to controls. Recurrent stroke was in turn associated with smaller hippocampal volume relative to both first-ever stroke (p = 0.017) and controls (p = 0.001). These associations remained significant after adjustment for age, sex, education, and, in stroke patients, infarct volume. Total brain volume was not significantly smaller in first-ever stroke patients than in controls (p = 0.056), but the association became significant after further adjustment for atrial fibrillation (p = 0.036). Cortical thickness and brain volumes did not differ as a function of stroke type, infarct volume, or etiology. CONCLUSIONS: Brain structure is likely to be compromised before ischemic stroke by vascular risk factors. Smaller hippocampal and total brain volumes and increased WMH load represent proxies for underlying vascular brain injury.
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    STROKOG (stroke and cognition consortium): An international consortium to examine the epidemiology, diagnosis, and treatment of neurocognitive disorders in relation to cerebrovascular disease.
    Sachdev, PS ; Lo, JW ; Crawford, JD ; Mellon, L ; Hickey, A ; Williams, D ; Bordet, R ; Mendyk, A-M ; Gelé, P ; Deplanque, D ; Bae, H-J ; Lim, J-S ; Brodtmann, A ; Werden, E ; Cumming, T ; Köhler, S ; Verhey, FRJ ; Dong, Y-H ; Tan, HH ; Chen, C ; Xin, X ; Kalaria, RN ; Allan, LM ; Akinyemi, RO ; Ogunniyi, A ; Klimkowicz-Mrowiec, A ; Dichgans, M ; Wollenweber, FA ; Zietemann, V ; Hoffmann, M ; Desmond, DW ; Linden, T ; Blomstrand, C ; Fagerberg, B ; Skoog, I ; Godefroy, O ; Barbay, M ; Roussel, M ; Lee, B-C ; Yu, K-H ; Wardlaw, J ; Makin, SJ ; Doubal, FN ; Chappell, FM ; Srikanth, VK ; Thrift, AG ; Donnan, GA ; Kandiah, N ; Chander, RJ ; Lin, X ; Cordonnier, C ; Moulin, S ; Rossi, C ; Sabayan, B ; Stott, DJ ; Jukema, JW ; Melkas, S ; Jokinen, H ; Erkinjuntti, T ; Mok, VCT ; Wong, A ; Lam, BYK ; Leys, D ; Hénon, H ; Bombois, S ; Lipnicki, DM ; Kochan, NA ; STROKOG, (Wiley, 2017)
    INTRODUCTION: The Stroke and Cognition consortium (STROKOG) aims to facilitate a better understanding of the determinants of vascular contributions to cognitive disorders and help improve the diagnosis and treatment of vascular cognitive disorders (VCD). METHODS: Longitudinal studies with ≥75 participants who had suffered or were at risk of stroke or TIA and which evaluated cognitive function were invited to join STROKOG. The consortium will facilitate projects investigating rates and patterns of cognitive decline, risk factors for VCD, and biomarkers of vascular dementia. RESULTS: Currently, STROKOG includes 25 (21 published) studies, with 12,092 participants from five continents. The duration of follow-up ranges from 3 months to 21 years. DISCUSSION: Although data harmonization will be a key challenge, STROKOG is in a unique position to reuse and combine international cohort data and fully explore patient level characteristics and outcomes. STROKOG could potentially transform our understanding of VCD and have a worldwide impact on promoting better vascular cognitive outcomes.
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    Fractional amplitude of low-frequency fluctuations (fALFF) in post-stroke depression
    Egorova, N ; Veldsman, M ; Cumming, T ; Brodtmann, A (ELSEVIER SCI LTD, 2017)
    Depression is a common outcome following stroke, associated with reduced quality of life and poorer recovery. Despite attempts to associate depression symptoms with specific lesion sites, the neural basis of post-stroke depression remains poorly understood. Resting state fMRI has provided new insights into the neural underpinnings of post-stroke depression, but has been limited to connectivity analyses exploring interregional correlations in the time-course of activity. Other aspects of resting state BOLD signal remain unexamined. Measuring the amplitude of low frequency fluctuations allows the detection of spontaneous neural activity across the whole brain. It provides complementary information about frequency-specific local neural activity. We calculated the fractional amplitude of low frequency fluctuations (fALFF) in a group of 64 participants scanned 3 months post-stroke. Twenty showed depression symptoms when assessed with the Patient Health Questionnaire (PHQ-9). We performed analyses in both the typical 0.01-0.08 Hz range, as well as separately in the slow-5 (0.01-0.027 Hz) and slow-4 (0.027-0.073 Hz) ranges. We found significantly higher fALFF in the depressed compared to non-depressed participants in the left dorsolateral prefrontal cortex (DLPFC) and the right precentral gyrus, and a significant association between higher depression scores and higher fALFF in the left insula. The group differences were detected in the slow-5 fluctuations, while the association with depression severity was observed in the slow-4 range. We conclude that post-stroke depression can be characterised by aberrant spontaneous local neural activity, which in small samples could be a more sensitive measure than lesion volume and location.
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    The ENIGMA Stroke Recovery Working Group: Big data neuroimaging to study brain-behavior relationships after stroke
    Liew, S-L ; Zavaliangos-Petropulu, A ; Jahanshad, N ; Lang, CE ; Hayward, KS ; Lohse, KR ; Juliano, JM ; Assogna, F ; Baugh, LA ; Bhattacharya, AK ; Bigjahan, B ; Borich, MR ; Boyd, LA ; Brodtmann, A ; Buetefisch, CM ; Byblow, WD ; Cassidy, JM ; Conforto, AB ; Craddock, RC ; Dimyan, MA ; Dula, AN ; Ermer, E ; Etherton, MR ; Fercho, KA ; Gregory, CM ; Hadidchi, S ; Holguin, JA ; Hwang, DH ; Jung, S ; Kautz, SA ; Khlif, MS ; Khoshab, N ; Kim, B ; Kim, H ; Kuceyeski, A ; Lotze, M ; MacIntosh, BJ ; Margetis, JL ; Mohamed, FB ; Piras, F ; Ramos-Murguialday, A ; Richard, G ; Roberts, P ; Robertson, AD ; Rondina, JM ; Rost, NS ; Sanossian, N ; Schweighofer, N ; Seo, NJ ; Shiroishi, MS ; Soekadar, SR ; Spalletta, G ; Stinear, CM ; Suri, A ; Tang, WKW ; Thielman, GT ; Vecchio, D ; Villringer, A ; Ward, NS ; Werden, E ; Westlye, LT ; Winstein, C ; Wittenberg, GF ; Wong, KA ; Yu, C ; Cramer, SC ; Thompson, PM (WILEY, 2022-01)
    The goal of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Stroke Recovery working group is to understand brain and behavior relationships using well-powered meta- and mega-analytic approaches. ENIGMA Stroke Recovery has data from over 2,100 stroke patients collected across 39 research studies and 10 countries around the world, comprising the largest multisite retrospective stroke data collaboration to date. This article outlines the efforts taken by the ENIGMA Stroke Recovery working group to develop neuroinformatics protocols and methods to manage multisite stroke brain magnetic resonance imaging, behavioral and demographics data. Specifically, the processes for scalable data intake and preprocessing, multisite data harmonization, and large-scale stroke lesion analysis are described, and challenges unique to this type of big data collaboration in stroke research are discussed. Finally, future directions and limitations, as well as recommendations for improved data harmonization through prospective data collection and data management, are provided.
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    A systematic review protocol of timing, efficacy and cost effectiveness of upper limb therapy for motor recovery post-stroke
    Hayward, KS ; Kramer, SF ; Thijs, V ; Ratcliffe, J ; Ward, NS ; Churilov, L ; Jolliffe, L ; Corbett, D ; Cloud, G ; Kaffenberger, T ; Brodtmann, A ; Bernhardt, J ; Lannin, NA (BMC, 2019-07-25)
    BACKGROUND: Improving upper limb (UL) motor recovery after stroke represents a major clinical and scientific goal. We aim to complete three systematic reviews to estimate the (1) association between time to start of UL therapy and motor recovery, (2) relative efficacy of different UL therapy approaches post-stroke and (3) cost-effectiveness of UL therapy interventions. METHODS: We have designed a systematic review protocol to address three systematic review questions that were each registered with PROSPERO. The search will be conducted in MEDLINE, EMBASE, and Cochrane Controlled Register of Trials. We will include randomised controlled trials, non-randomised clinical trials, before-after studies and observational studies of adult stroke survivors with an average stroke onset < 6 months, undergoing hospital-based therapy to improve UL function. Eligible interventions will aim to promote UL functional recovery. Two reviewers will independently screen, select and extract data. Study risk of bias will be appraised using appropriate tools. Clinical measures of motor recovery will be investigated (primary measure Fugl Meyer UL assessment), as well as measures of health-related quality of life (primary measure EQ-5D) and all cost-effectiveness analyses completed. Secondary outcomes include therapy dose (minutes, weeks, repetitions as available) and safety (i.e. adverse events, serious adverse events). A narrative synthesis will describe quality and content of the evidence. If feasible, we will conduct random effects meta-analyses where appropriate. DISCUSSION: We anticipate the findings of this review will increase our understanding of UL therapy and inform the generation of novel, data-driven hypotheses for future UL therapy research post-stroke. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018019367, http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018111629, http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018111628.
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    Does left ventricular hypertrophy affect cognition and brain structural integrity in type 2 diabetes? Study design and rationale of the Diabetes and Dementia (D2) study
    Patel, SK ; Restrepo, C ; Werden, E ; Churilov, L ; Ekinci, EI ; Srivastava, PM ; Ramchand, J ; Wai, B ; Chambers, B ; O'Callaghan, CJ ; Darby, D ; Hachinski, V ; Cumming, T ; Donnan, G ; Burrell, LM ; Brodtmann, A (BMC, 2017-04-07)
    BACKGROUND: Cognitive impairment is common in type 2 diabetes mellitus, and there is a strong association between type 2 diabetes and Alzheimer's disease. However, we do not know which type 2 diabetes patients will dement or which biomarkers predict cognitive decline. Left ventricular hypertrophy (LVH) is potentially such a marker. LVH is highly prevalent in type 2 diabetes and is a strong, independent predictor of cardiovascular events. To date, no studies have investigated the association between LVH and cognitive decline in type 2 diabetes. The Diabetes and Dementia (D2) study is designed to establish whether patients with type 2 diabetes and LVH have increased rates of brain atrophy and cognitive decline. METHODS: The D2 study is a single centre, observational, longitudinal case control study that will follow 168 adult patients aged >50 years with type 2 diabetes: 50% with LVH (case) and 50% without LVH (control). It will assess change in cardiovascular risk, brain imaging and neuropsychological testing between two time-points, baseline (0 months) and 24 months. The primary outcome is brain volume change at 24 months. The co-primary outcome is the presence of cognitive decline at 24 months. The secondary outcome is change in left ventricular mass associated with brain atrophy and cognitive decline at 24 months. DISCUSSION: The D2 study will test the hypothesis that patients with type 2 diabetes and LVH will exhibit greater brain atrophy than those without LVH. An understanding of whether LVH contributes to cognitive decline, and in which patients, will allow us to identify patients at particular risk. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ( ACTRN12616000546459 ), date registered, 28/04/2016.