Florey Department of Neuroscience and Mental Health - Research Publications

Permanent URI for this collection

Search Results

Now showing 1 - 10 of 33
  • Item
    No Preview Available
    Mice with an autism-associated R451C mutation in neuroligin-3 show intact attention orienting but atypical responses to methylphenidate and atomoxetine in the mouse-Posner task
    Li, S ; May, C ; Pang, TY ; Churilov, L ; Hannan, AJ ; Johnson, KA ; Burrows, EL (SPRINGER, 2024-03)
    RATIONALE: Atypical attention orienting has been associated with some autistic symptoms, but the neural mechanisms remain unclear. The human Posner task, a classic attention orienting paradigm, was recently adapted for use with mice, supporting the investigation of the neurobiological underpinnings of atypical attention orienting in preclinical mouse models. OBJECTIVE: The current study tested mice expressing the autism-associated R451C gene mutation in neuroligin-3 (NL3) on the mouse-Posner (mPosner) task. METHODS: NL3R451C and wild-type (WT) mice were trained to respond to a validly or invalidly cued target on a touchscreen. The cue was a peripheral non-predictive flash in the exogenous task and a central spatially predictive image in the endogenous task. The effects of dopaminergic- and noradrenergic-modulating drugs, methylphenidate and atomoxetine, on task performance were assessed. RESULTS: In both tasks, mice were quicker and more accurate in the validly versus invalidly cued trials, consistent with results in the human Posner task. NL3R451C and WT mice showed similar response times and accuracy but responded differently when treated with methylphenidate and atomoxetine. Methylphenidate impaired exogenous attention disengagement in NL3R451C mice but did not significantly affect WT mice. Atomoxetine impaired endogenous orienting in WT mice but did not significantly affect NL3R451C mice. CONCLUSIONS: NL3R451C mice demonstrated intact attention orienting but altered responses to the pharmacological manipulation of the dopaminergic and noradrenergic networks. These findings expand our understanding of the NL3R451C mutation by suggesting that this mutation may lead to selective alterations in attentional processes.
  • Item
    Thumbnail Image
    A mixed-methods feasibility study of a new digital health support package for people after stroke: the Recovery-focused Community support to Avoid readmissions and improve Participation after Stroke (ReCAPS) intervention
    Cameron, J ; Lannin, NA ; Harris, D ; Andrew, NE ; Kilkenny, MF ; Purvis, T ; Thrift, AG ; Thayabaranathan, T ; Ellery, F ; Sookram, G ; Hackett, M ; Kneebone, I ; Drummond, A ; Cadilhac, DA (BMC, 2022-11-19)
    BACKGROUND: Evidence for digital health programmes to support people living with stroke is growing. We assessed the feasibility of a protocol and procedures for the Recovery-focused Community support to Avoid readmissions and improve Participation after Stroke (ReCAPS) trial. METHODS: We conducted a mixed-method feasibility study. Participants with acute stroke were recruited from three hospitals (Melbourne, Australia). Eligibility: Adults with stroke discharged from hospital to home within 10 days, modified Rankin Score 0-4 and prior use of Short Message System (SMS)/email. While in hospital, recruited participants contributed to structured person-centred goal setting and completed baseline surveys including self-management skills and health-related quality of life. Participants were randomised 7-14 days after discharge via REDCap® (1:1 allocation). Following randomisation, the intervention group received a 12-week programme of personalised electronic support messages (average 66 messages sent by SMS or email) aligned with their goals. The control group received six electronic administrative messages. Feasibility outcomes included the following: number of patients screened and recruited, study retainment, completion of outcome measures and acceptability of the ReCAPS intervention and trial procedures (e.g. participant satisfaction survey, clinician interviews). Protocol fidelity outcomes included number of goals developed (and quality), electronic messages delivered, stop messages received and engagement with messages. We undertook inductive thematic analysis of interview/open-text survey data and descriptive analysis of closed survey questions. RESULTS: Between November 2018 and October 2019, 312 patients were screened; 37/105 (35%) eligible patients provided consent (mean age 61 years; 32% female); 33 were randomised (17 to intervention). Overall, 29 (88%) participants completed the12-week outcome assessments with 12 (41%) completed assessments in the allocated timeframe and 16 also completing the satisfaction survey (intervention=10). Overall, trial participants felt that the study was worthwhile and most would recommend it to others. Six clinicians participated in one of three focus group interviews; while they reported that the trial and the process of goal setting were acceptable, they raised concerns regarding the additional time required to personalise goals. CONCLUSION: The study protocol and procedures were feasible with acceptable retention of participants. Consent and goal personalisation procedures should be centralised for the phase III trial to reduce the burden on hospital clinicians. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12618001468213 (date 31/08/2018); Universal Trial Number: U1111-1206-7237.
  • Item
    Thumbnail Image
    Self-evaluation of personal needs by community-living young stroke survivors using an online English language questionnaire
    Sapuppo, D ; Bernhardt, J ; Carvalho, LB ; Churilov, L ; Thijs, V (TAYLOR & FRANCIS LTD, 2023-05-22)
    BACKGROUND: Identifying personal needs of young stroke survivors is crucial for their recovery. PURPOSE: Identify factors, burden, and significance of unmet needs of young community-living stroke survivors. MATERIALS AND METHODS: We used online advertising and word-of-mouth snowballing to recruit participants for an English language online questionnaire constructed for this purpose. Eligible participants aged 18-55 at time of stroke. Needs were classified into seven domains: Healthcare Experience, Impairments from Stroke, Everyday Activities, Work/Study, Finances, Relationships, and Social Participation. Random-effects logistic regression was used to determine the probability of unmet needs and X2 test to determine significance of distribution across domains. RESULTS: Out of 137 responses recorded: 32 did not meet inclusion criteria, 29 duplicates identified were discarded, and 76 eligible participants were analysed. Respondents were median 37 (IQR 32-47) years at time of stroke, and median 3 (1-5) years since stroke. Fifty-eight (76%) females. Modified Rankin Scale median score of 1 (1-3). Of 48 identified potential needs, 25 (IQR 19-30) were rated unmet. Twenty (IQR 15-25) considered of high significance. Unmet needs most frequently occurred in the domains: Impairments from Stroke, Finances, and Social Participation. CONCLUSIONS: There is high burden of unmet needs in community-living young stroke survivors which are spread disproportionately across the identified domains.IMPLICATIONS FOR REHABILITATIONIdentifying personal needs of young stroke survivors is crucial for their recovery.Impairments after Stroke, Finances, and Social Participation were often selected as being high burden unmet needs for community-living young people after stroke.Employing a post-stroke checklist to guide exploration of needs in young stroke may better capture which needs are unmet.
  • Item
    No Preview Available
    Factors associated with paid employment 12 months after stroke in A Very Early Rehabilitation Trial (AVERT)
    Cain, S ; Churilov, L ; Collier, JM ; Carvalho, LB ; Borschmann, K ; Moodie, M ; Thijs, V ; Bernhardt, J (ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2022-05)
    BACKGROUND: Returning to work is an important outcome for stroke survivors. OBJECTIVES: This sub-study of a randomised controlled trial aimed to provide characteristics of working-age stroke participants and identify factors associated with return to work at 12 months. METHODS: We used paid employment data collected as part of A Very Early Rehabilitation Trial (AVERT, n=2104), an international randomised controlled trial studying the effects of very early mobilisation after stroke at 56 acute stroke units across Australia, New Zealand, the United Kingdom, Malaysia and Singapore. For the present analysis, data for trial participants < 65 years old were included if they were working at the time of stroke and had complete 12-month return-to-work data. The primary outcome was 12-month return to paid work. Univariable and multivariable logistic regression analyses were conducted to determine the association of multiple factors with return to work. RESULTS: In total, 376 AVERT participants met the inclusion criteria for this sub-study. By 12 months, 221 (59%) participants had returned to work at a median of 38 hr per week. Similar rates were found across geographic regions. On univariable analysis, the odds of returning to paid employment were increased with younger age (OR per year 0.95, 95%CI 0.92-0.97), no previous diabetes (0.4, 0.24-0.67), lower stroke severity (OR per National Institutes of Health Stroke Scale point 0.82, 0.78-0.86), less 3-month depressive traits (Irritability Depression Anxiety [IDA] scale) (OR per IDA point 0.87, 0.80-0.93), less 3-month disability (modified Rankin Scale), and prior full-time work (2.04, 1.23-3.38). On multivariable analysis, return to work remained associated with younger age (OR 0.94, 95%CI 0.91-0.98), lower stroke severity (0.92, 0.86-0.99), prior full-time work (2.33, 1.24-4.40), and less 3-month disability. CONCLUSIONS: Return to work at 12 months after stroke was associated with young age, acute stroke severity, 3-month disability and full-time employment before stroke. Greater understanding of this topic could help in developing programs to support successful resumption of work post-stroke.
  • Item
    No Preview Available
    Examining Dose Frameworks to Improve Aphasia Rehabilitation Research
    Harvey, S ; Rose, ML ; Brogan, E ; Pierce, JE ; Godecke, E ; Brownsett, SLE ; Churilov, L ; Copland, D ; Dickey, MW ; Dignam, J ; Lannin, NA ; Nickels, L ; Bernhardt, J ; Hayward, KS (W B SAUNDERS CO-ELSEVIER INC, 2023-05)
    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.
  • Item
    No Preview Available
    Healthy Life-Year Costs of Treatment Speed From Arrival to Endovascular Thrombectomy in Patients With Ischemic Stroke A Meta-analysis of Individual Patient Data From 7 Randomized Clinical Trials
    Almekhlafi, MA ; Goyal, M ; Dippel, DWJ ; Majoie, CBLM ; Campbell, BCV ; Muir, KW ; Demchuk, AM ; Bracard, S ; Guillemin, F ; Jovin, TG ; Mitchell, P ; White, P ; Hill, MD ; Brown, S ; Saver, JL (AMER MEDICAL ASSOC, 2021-06)
    IMPORTANCE: The benefits of endovascular thrombectomy (EVT) are time dependent. Prior studies may have underestimated the time-benefit association because time of onset is imprecisely known. OBJECTIVE: To assess the lifetime outcomes associated with speed of endovascular thrombectomy in patients with acute ischemic stroke due to large-vessel occlusion (LVO). DATA SOURCES: PubMed was searched for randomized clinical trials of stent retriever thrombectomy devices vs medical therapy in patients with anterior circulation LVO within 12 hours of last known well time, and for which a peer-reviewed, complete primary results article was published by August 1, 2020. STUDY SELECTION: All randomized clinical trials of stent retriever thrombectomy devices vs medical therapy in patients with anterior circulation LVO within 12 hours of last known well time were included. DATA EXTRACTION/SYNTHESIS: Patient-level data regarding presenting clinical and imaging features and functional outcomes were pooled from the 7 retrieved randomized clinical trials of stent retriever thrombectomy devices (entirely or predominantly) vs medical therapy. All 7 identified trials published in a peer-reviewed journal (by August 1, 2020) contributed data. Detailed time metrics were collected including last known well-to-door (LKWTD) time; last known well/onset-to-puncture (LKWTP) time; last known well-to-reperfusion (LKWR) time; door-to-puncture (DTP) time; and door-to-reperfusion (DTR) time. MAIN OUTCOMES AND MEASURES: Change in healthy life-years measured as disability-adjusted life-years (DALYs). DALYs were calculated as the sum of years of life lost (YLL) owing to premature mortality and years of healthy life lost because of disability (YLD). Disability weights were assigned using the utility-weighted modified Rankin Scale. Age-specific life expectancies without stroke were calculated from 2017 US National Vital Statistics. RESULTS: Among the 781 EVT-treated patients, 406 (52.0%) were early-treated (LKWTP ≤4 hours) and 375 (48.0%) were late-treated (LKWTP >4-12 hours). In early-treated patients, LKWTD was 188 minutes (interquartile range, 151.3-214.8 minutes) and DTP 105 minutes (interquartile range, 76-135 minutes). Among the 298 of 380 (78.4%) patients with substantial reperfusion, median DTR time was 145.0 minutes (interquartile range, 111.5-185.5 minutes). Care process delays were associated with worse clinical outcomes in LKW-to-intervention intervals in early-treated patients and in door-to-intervention intervals in early-treated and late-treated patients, and not associated with LKWTD intervals, eg, in early-treated patients, for each 10-minute delay, healthy life-years lost were DTP 1.8 months vs LKWTD 0.0 months; P < .001. Considering granular time increments, the amount of healthy life-time lost associated with each 1 second of delay was DTP 2.2 hours and DTR 2.4 hours. CONCLUSIONS AND RELEVANCE: In this study, care delays were associated with loss of healthy life-years in patients with acute ischemic stroke treated with EVT, particularly in the postarrival time period. The finding that every 1 second of delay was associated with loss of 2.2 hours of healthy life may encourage continuous quality improvement in door-to-treatment times.
  • Item
    Thumbnail Image
    Tenecteplase versus Alteplase for Stroke Thrombolysis Evaluation Trial in the Ambulance (Mobile Stroke Unit-TASTE-A): protocol for a prospective randomised, open-label, blinded endpoint, phase II superiority trial of tenecteplase versus alteplase for ischaemic stroke patients presenting within 4.5 hours of symptom onset to the mobile stroke unit
    Bivard, A ; Zhao, H ; Coote, S ; Campbell, B ; Churilov, L ; Yassi, N ; Yan, B ; Valente, M ; Sharobeam, A ; Balabanski, A ; Dos Santos, A ; Ng, F ; Langenberg, F ; Stephenson, M ; Smith, K ; Bernard, S ; Thijs, V ; Cloud, G ; Choi, P ; Ma, H ; Wijeratne, T ; Chen, C ; Olenko, L ; Davis, SM ; Donnan, GA ; Parsons, M (BMJ PUBLISHING GROUP, 2022-04)
    INTRODUCTION: Mobile stroke units (MSUs) equipped with a CT scanner are increasingly being used to assess and treat stroke patients' prehospital with thrombolysis and transfer them to the most appropriate hospital for ongoing stroke care and thrombectomy when indicated. The effect of MSUs in both reducing the time to reperfusion treatment and improving patient outcomes is now established. There is now an opportunity to improve the efficacy of treatment provided by the MSU. Tenecteplase is a potent plasminogen activator, which may have benefits over the standard of care stroke lytic alteplase. Specifically, in the MSU environment tenecteplase presents practical benefits since it is given as a single bolus and does not require an infusion over an hour like alteplase. OBJECTIVE: In this trial, we seek to investigate if tenecteplase, given to patients with acute ischaemic stroke as diagnosed on the MSU, improves the rate of early reperfusion. METHODS AND ANALYSIS: TASTE-A is a prospective, randomised, open-label, blinded endpoint (PROBE) phase II trial of patients who had an ischaemic stroke assessed in an MSU within 4.5 hours of symptom onset. The primary endpoint is early reperfusion measured by the post-lysis volume of the CT perfusion lesion performed immediately after hospital arrival. ETHICS AND DISSEMINATION: The study was approved by the Royal Melbourne Hospital Human Ethics committee. The findings will be published in peer-reviewed journals, presented at academic conferences and disseminated among consumer and healthcare professional audiences. TRIAL REGISTRATION NUMBER: NCT04071613.
  • Item
    Thumbnail Image
    Why hospital design matters: A narrative review of built environments research relevant to stroke care
    Bernhardt, J ; Lipson-Smith, R ; Davis, A ; White, M ; Zeeman, H ; Pitt, N ; Shannon, M ; Crotty, M ; Churilov, L ; Elf, M (SAGE PUBLICATIONS LTD, 2022-04)
    Healthcare facilities are among the most expensive buildings to construct, maintain, and operate. How building design can best support healthcare services, staff, and patients is important to consider. In this narrative review, we outline why the healthcare environment matters and describe areas of research focus and current built environment evidence that supports healthcare in general and stroke care in particular. Ward configuration, corridor design, and staff station placements can all impact care provision, staff and patient behavior. Contrary to many new ward design approaches, single-bed rooms are neither uniformly favored, nor strongly evidence-based, for people with stroke. Green spaces are important both for staff (helping to reduce stress and errors), patients and relatives, although access to, and awareness of, these and other communal spaces is often poor. Built environment research specific to stroke is limited but increasing, and we highlight emerging collaborative multistakeholder partnerships (Living Labs) contributing to this evidence base. We believe that involving engaged and informed clinicians in design and research will help shape better hospitals of the future.
  • Item
    Thumbnail Image
    Progressive impairments in executive function in the APP/PS1 model of Alzheimer’s disease as measured by translatable touchscreen testing
    Shepherd, A ; Lim, JKH ; Wong, VHY ; Zeleznikow-Johnston, AM ; Churilov, L ; Nguyen, CTO ; Bui, BV ; Hannan, AJ ; Burrows, EL ( 2019-08-21)
    Executive function deficits in Alzheimer’s disease (AD) occur early in disease progression and may be predictive of cognitive decline. However, no preclinical studies have identified deficits in rewarded executive function in the commonly used APP/PS1 mouse model. To address this, we assessed 12-26 month old APP/PS1 mice on rewarded reversal and/or extinction tasks. 16-month-old, but not 13- or 26-month-old, APP/PS1 mice showed an attenuated rate of extinction. Reversal deficits were seen in 22-month-old, but not 13-month-old APP/PS1 animals. We then confirmed that impairments in reversal were unrelated to previously reported visual impairments in both AD mouse models and humans. Age, but not genotype, had a significant effect on markers of retinal health, indicating the deficits seen in APP/PS1 mice were directly related to cognition. This is the first characterisation of rewarded executive function in APP/PS1 mice, and has great potential to facilitate translation from preclinical models to the clinic.
  • Item
    Thumbnail Image
    Progressive impairments in executive function in the APP/PS1 model of Alzheimer's disease as measured by translatable touchscreen testing
    Shepherd, A ; Lim, JKH ; Wong, VHY ; Zeleznikow-Johnston, AM ; Churilov, L ; Nguyen, CTO ; V. Bui, B ; Hannan, AJ ; Burrows, EL (ELSEVIER SCIENCE INC, 2021-12)
    Executive function deficits in Alzheimer's disease (AD) occur early in disease progression and may be predictive of cognitive decline. However, no preclinical studies have identified deficits in rewarded executive function in the commonly used APPSwe/PS1∆E9 (APP/PS1) mouse model. To address this, we assessed 12-26 month old APP/PS1 mice on rewarded reversal and/or extinction tasks. 16-month-old, but not 13- or 26-month-old, APP/PS1 mice showed an attenuated rate of extinction. Reversal deficits were seen in 22-month-old, but not 13-month-old APP/PS1 animals. We then confirmed that impairments in reversal were unrelated to previously reported visual impairments in both AD mouse models and humans. Age, but not genotype, had a significant effect on markers of retinal health, indicating the deficits seen in APP/PS1 mice were directly related to cognition. This is the first characterisation of rewarded executive function in APP/PS1 mice, and has great potential to facilitate translation from preclinical models to the clinic.