Florey Department of Neuroscience and Mental Health - Research Publications
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ItemProgressive impairments in executive function in the APP/PS1 model of Alzheimer’s disease as measured by translatable touchscreen testing( 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.
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ItemParadoxical effects of exercise on hippocampal plasticity and cognition in mice with a heterozygous null mutation in the serotonin transporter gene(WILEY, 2019-09)BACKGROUND AND PURPOSE: Exercise is known to improve cognitive function, but the exact synaptic and cellular mechanisms remain unclear. We investigated the potential role of the serotonin (5-HT) transporter (SERT) in mediating these effects. EXPERIMENTAL APPROACH: Hippocampal long-term potentiation (LTP) and neurogenesis were measured in standard-housed and exercising (wheel running) wild-type (WT) and SERT heterozygous (HET) mice. We also assessed hippocampal-dependent cognition using the Morris water maze (MWM) and a spatial pattern separation touchscreen task. KEY RESULTS: SERT HET mice had impaired hippocampal LTP regardless of the housing conditions. Exercise increased hippocampal neurogenesis in WT mice. However, this was not observed in SERT HET animals, even though both genotypes used the running wheels to a similar extent. We also found that standard-housed SERT HET mice displayed altered cognitive flexibility than WT littermate controls in the MWM reversal learning task. However, SERT HET mice no longer exhibited this phenotype after exercise. Cognitive changes, specific to SERT HET mice in the exercise condition, were also revealed on the touchscreen spatial pattern separation task, especially when the cognitive pattern separation load was at its highest. CONCLUSIONS AND IMPLICATIONS: Our study is the first evidence of reduced hippocampal LTP in SERT HET mice. We also show that functional SERT is required for exercise-induced increase in adult neurogenesis. Paradoxically, exercise had a negative impact on hippocampal-dependent cognitive tasks, especially in SERT HET mice. Taken together, our results suggest unique complex interactions between exercise and altered 5-HT homeostasis.
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ItemProtocol for evaluation of enhanced models of primary care in the management of stroke and other chronic disease (PRECISE): A data linkage healthcare evaluation study.(Swansea University, 2019-08-05)INTRODUCTION: The growing burden of chronic diseases means some governments have been providing financial incentives for multidisciplinary care and self-management support delivered within primary care. Currently, population-based evaluations of the effectiveness of these policies are lacking. AIM: To outline the methodological approach for our study that is designed to evaluate the effectiveness (including cost) of primary care policies for chronic diseases in Australia using stroke as a case study. METHODS: Person-level linkages will be undertaken between registrants from the Australian Stroke Clinical Registry (AuSCR) and (i) Government-held Medicare Australia claims data, to identify receipt or not of chronic disease management and care coordination primary care items; (ii) state government-held hospital data, to define outcomes; and (iii) government-held pharmaceutical and aged care claims data, to define covariates. N=1500 randomly selected AuSCR registrants will be sent surveys to obtain patient experience information. In Australia, unique identifiers are unavailable. Therefore, personal-identifiers will be submitted to government data linkage units. Researchers will merge the de-identified datasets for analysis using a project identifier. An economic evaluation will also be undertaken. ANALYSIS: The index event will be the first stroke recorded in the AuSCR. Multivariable competing risks Poisson regression for multiple events, adjusted by a propensity score, will be used to test for differences in the rates of hospital presentations and medication adherence for different care (policy) types. Our estimated sample size of 25,000 patients will provide 80% estimated power (ɑ>0.05) to detect a 6-8% difference in rates. The incremental costs per Quality-adjusted life years gained of community-based care following the acute event will be estimated from a health sector perspective. CONCLUSION: Completion of this study will provide a novel and comprehensive evaluation of the effectiveness and cost-effectiveness of Australian primary care policies. Its success will enable us to highlight the value of data-linkage for this type of research.
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ItemPatient and service factors associated with referral and admission to inpatient rehabilitation after the acute phase of stroke in Australia and Norway(BMC, 2019-11-21)BACKGROUND: Unequal access to inpatient rehabilitation after stroke has been reported. We sought to identify and compare patient and service factors associated with referral and admission to an inpatient rehabilitation facility (IRF) after acute hospital care for stroke in two countries with publicly-funded healthcare. METHODS: We compared two cohorts of stroke patients admitted consecutively to eight acute public hospitals in Australia in 2013-2014 (n = 553), and to one large university hospital in Norway in 2012-2013 (n = 723). Outcomes were: referral to an IRF; admission to an IRF if referred. Logistic regression models were used to identify and compare factors associated with each outcome. RESULTS: Participants were similar in both cohorts: mean age 73 years, 40-44% female, 12-13% intracerebral haemorrhage, ~ 77% mild stroke (National Institutes of Health Stroke Scale < 8). Services received during the acute admission differed (Australia vs. Norway): stroke unit treatment 82% vs. 97%, physiotherapy 93% vs. 79%, occupational therapy 83% vs. 77%, speech therapy 78% vs. 13%. Proportions referred to an IRF were: 48% (Australia) and 37% (Norway); proportions admitted: 35% (Australia) and 28% (Norway). Factors associated with referral in both countries were: moderately severe stroke, receiving stroke unit treatment or allied health assessments during the acute admission, living in the community, and independent pre-stroke mobility. Directions of associations were mostly congruent; however younger patients were more likely to be referred and admitted in Norway only. Models for admission among patients referred identified few associated factors suggesting that additional factors were important for this stage of the process. CONCLUSIONS: Similar factors were associated with referral to inpatient rehabilitation after acute stroke in both countries, despite differing service provision and access rates. Assuming it is not feasible to provide inpatient rehabilitation to all patients following stroke, the criteria for the selection of candidates need to be understood to address unwanted biases.
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ItemDose Articulation in Preclinical and Clinical Stroke Recovery: Refining a Discovery Research Pipeline and Presenting a Scoping Review Protocol(FRONTIERS MEDIA SA, 2019-11-06)Introduction: Despite an increase in the quality of clinical trials in stroke recovery, interventions have failed to markedly impact the trajectory of recovery after stroke. Failure may be due to the lack of consideration for the complexity of dose and its articulation within research trials. Prior to commencing the scoping review, we identified two research gaps to be addressed. Firstly, transparent application of a multidimensional definition of dose to clinical trial phases and secondly, the development of a quality tool to critique the articulation of dose across the pipeline. Building on this, we present the protocol for a scoping review that aims to synthesis what is known about dose articulation in stroke recovery in preclinical and clinical populations, and characterize research designs and statistical approaches used in dose articulation trials, and the associated advantages and disadvantages. Methods: The scoping review will apply Arksey and O'Malley's methodological framework. Two systematic searches that target preclinical and clinical literature will be run in Medline and Embase, which will be complimented by consultation with field experts and hand searching of included trials and relevant reviews. Search results will be imported into Covidence for transparent management. One reviewer will screen all abstracts and titles. Two reviewers will screen full text and a third reviewer included to resolve discrepancies. A standardized data charting form will be used to extract information and appraise the intervention description, risk of bias, and quality of both preclinical and clinical studies. Results will be summarized in tabular and narrative format to inform the development of recommendations for future research. Ethics approval is not required as data used will be secondary and de-identified. Conclusion: Development of a new quality tool to appraise the quality of both preclinical and clinical dose studies may serve to strengthen collaborative efforts between the fields. The findings from this review will advance the use of a discovery pipeline in stroke recovery research to ultimately inform clinical practice.
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ItemMutations in neuroligin-3 in male mice impact behavioral flexibility but not relational memory in a touchscreen test of visual transitive inference(BioMed Central, 2019)Cognitive dysfunction including disrupted behavioral flexibility is central to neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). A cognitive measure that assesses relational memory, and the ability to flexibly assimilate and transfer learned information is transitive inference. Transitive inference is highly conserved across vertebrates and disrupted in cognitive disorders. Here, we examined how mutations in the synaptic cell-adhesion molecule neuroligin-3 (Nlgn3) that have been documented in ASD impact relational memory and behavioral flexibility. We first refined a rodent touchscreen assay to measure visual transitive inference, then assessed two mouse models of Nlgn3 dysfunction (Nlgn3−/y and Nlgn3R451C). Deep analysis of touchscreen behavioral data at a trial level established we could measure trajectories in flexible responding and changes in processing speed as cognitive load increased. We show that gene mutations in Nlgn3 do not disrupt relational memory, but significantly impact flexible responding. Our study presents the first analysis of reaction times in a rodent transitive inference test, highlighting response latencies from the touchscreen system are useful indicators of processing demands or decision-making processes. These findings expand our understanding of how dysfunction of key components of synaptic signaling complexes impact distinct cognitive processes disrupted in neurodevelopmental disorders, and advance our approaches for dissecting rodent behavioral assays to provide greater insights into clinically relevant cognitive symptoms.
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ItemEconomic evaluation of a phase III international randomised controlled trial of very early mobilisation after stroke (AVERT)(BMJ PUBLISHING GROUP, 2019-05)OBJECTIVES: While very early mobilisation (VEM) intervention for stroke patients was shown not to be effective at 3 months, 12 month clinical and economical outcomes remain unknown. The aim was to assess cost-effectiveness of a VEM intervention within a phase III randomised controlled trial (RCT). DESIGN: An economic evaluation alongside a RCT, and detailed resource use and cost analysis over 12 months post-acute stroke. SETTING: Multi-country RCT involved 58 stroke centres. PARTICIPANTS: 2104 patients with acute stroke who were admitted to a stroke unit. INTERVENTION: A very early rehabilitation intervention within 24 hours of stroke onset METHODS: Cost-utility analyses were undertaken according to pre-specified protocol measuring VEM against usual care (UC) based on 12 month outcomes. The analysis was conducted using both health sector and societal perspectives. Unit costs were sourced from participating countries. Details on resource use (both health and non-health) were sourced from cost case report form. Dichotomised modified Rankin Scale (mRS) scores (0 to 2 vs 3 to 6) and quality adjusted-life years (QALYs) were used to compare the treatment effect of VEM and UC. The base case analysis was performed on an intention-to-treat basis and 95% CI for cost and QALYs were estimated by bootstrapping. Sensitivity analysis were conducted to examine the robustness of base case results. RESULTS: VEM and UC groups were comparable in the quantity of resource use and cost of each component. There were no differences in the probability of achieving a favourable mRS outcome (0.030, 95% CI -0.022 to 0.082), QALYs (0.013, 95% CI -0.041 to 0.016) and cost (AUD1082, 95% CI -$2520 to $4685 from a health sector perspective or AUD102, 95% CI -$6907 to $7111, from a societal perspective including productivity cost). Sensitivity analysis achieved results with mostly overlapped CIs. CONCLUSIONS: VEM and UC were associated with comparable costs, mRS outcome and QALY gains at 12 months. Compared with to UC, VEM is unlikely to be cost-effective. The long-term data collection during the trial also informed resource use and cost of care post-acute stroke across five participating countries. TRIAL REGISTRATION NUMBER: ACTRN12606000185561; Results.
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ItemA systematic review protocol of timing, efficacy and cost effectiveness of upper limb therapy for motor recovery post-stroke(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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ItemNo Preview AvailableA stroke recovery trial development framework: Consensus-based core recommendations from the Second Stroke Recovery and Rehabilitation Roundtable(SAGE PUBLICATIONS LTD, 2019-10)A major goal of the Stroke Recovery and Rehabilitation Roundtable (SRRR) is to accelerate development of effective treatments to enhance stroke recovery beyond that expected to occur spontaneously or with current approaches. In this paper, we describe key issues for the next generation of stroke recovery treatment trials and present the Stroke Recovery and Rehabilitation Roundtable Trials Development Framework (SRRR-TDF). An exemplar (an upper limb recovery trial) is presented to demonstrate the utility of this framework to guide the GO, NO-GO decision-making process in trial development.
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ItemA Framework for Designing Inpatient Stroke Rehabilitation Facilities: A New Approach Using Interdisciplinary Value-Focused Thinking(SAGE PUBLICATIONS INC, 2019-10)AIM: To use Value-Focused Thinking to investigate what is important in the design of inpatient stroke rehabilitation facility buildings. BACKGROUND: Many stroke patients require inpatient rehabilitation in a dedicated facility. Rehabilitation facilities are healthcare spaces, but they are also learning spaces where patients practice targeted tasks to acquire new skills and to reacquire skills and abilities that were compromised as a result of their stroke. There is currently no consensus regarding how the design of inpatient rehabilitation facilities could be optimized for patients' learning. METHOD: We used Value-Focused Thinking to develop a framework of what interdisciplinary experts consider important for inpatient stroke rehabilitation facility design. Two workshops were conducted. The following experts were invited to participate: past patients with experience of stroke rehabilitation; stroke rehabilitation clinicians; stroke rehabilitation academics; healthcare environments academics; learning environments academics; architects, designers, and wayfinders with experience designing healthcare or learning environments; and healthcare design policy makers. RESULTS: Thirty experts participated. The experts' final framework included 16 criteria that were considered fundamentally important for inpatient stroke rehabilitation facility design, and 14 criteria that were considered instrumentally important. Inpatient stroke rehabilitation facility design should maximize efficiency, maximize effectiveness (i.e., patients' clinical and functional outcomes), foster emotional well-being, and maximize safety. Opportunities to practice physical, cognitive, and social activity were considered important for patients' outcomes. CONCLUSIONS: Value-Focused Thinking was an effective and equitable means of engaging experts from multiple disciplines. Designers, planners, and developers of inpatient stroke rehabilitation facilities should consider the rehabilitation-specific framework developed in this study alongside evidence from other healthcare settings.