Developing and evaluating behavioural tasks to assess basal ganglia function

Huntington’s disease (HD) is a primary example of a basal ganglia disorder, from which, medium spiny neurons in the striatum degenerate. As this causes a breakdown in basal ganglia cortico-thalamic circuitry, this leads to a range of symptoms including motor, cognitive and behavioural deficits. One therapeutic option is to replace medium spiny neurons with precursor striatal cells and reconnect the lost circuitry. However, the lack of performance based functional outcome measures for people with HD have made it difficult to assess how the graft affects standards of daily living. Although neuroimaging techniques can be used to quantify the morphological and molecular effects that the intervention has on that brain region, and associated circuitry, an important question still remains, namely whether there has been any effect on functional ability. Using assessments that have high ecological validity, such as dual tasks could be a valuable measure, especially as previous studies suggest that the striatum is required for optimal performance in such tasks. Therefore the focus of this thesis was to design, develop and assess performance based functional tasks that involve the neurocircuity affected in HD; namely the basal ganglia. The aim of the study in Chapter 2 was to select, develop and evaluate motor-cognitive dual task paradigms for use in people with HD. The findings revealed that the Step and Stroop which targeted lower limb function, best distinguished disease stage in HD compared to the other lower limb assessments tested. During this experiment, it became apparent that upper limb assessments for people with HD were particularly limited. Therefore, in Part 2, a new upper limb dual task assessment was developed and called the Clinch token transfer test (C3t). The findings revealed that this was sensitive to disease stage and could provide a useful outcome measure for people with HD in the future. To take the findings from Chapter 2 further, a new, standardised C3t was developed. This version was evaluated, optimised, and then validated in a large group of people gene positive for HD, and in heathy controls. The findings revealed that the C3t significantly correlated with all the Unified Huntington Disease Rating Scale measures, successfully distinguished between all disease stages, and revealed that the performance in this task was also sensitive to the subtle disease symptoms in the early stages of HD. As the Stroop task is commonly used in people with HD, the aim of Chapter 3 was to use immediate early gene expression to identify if the striatum was activated during a rodent analogue of the Stroop task. The findings revealed what could be the first in a series of experiments in that, striatal activation significantly correlated with performance in the congruent and the incongruent versions of this test when compared to cage controls. The findings presented in this thesis support that dual task assessments could have an important role in assessing function in HD, which could translate to performance in tasks that affect the standards of daily living. Importantly, as different dual tasks can result in different levels of dual task interference, this suggests that practice effects could affect how sensitive some dual task paradigms are over others. In addition, selecting outcome measures that are specific to the regions affected in HD, in both clinic and in pre-clinical models, will permit sensitive tracking of neurodegeneration, and could also be used to assess the outcomes of therapies that target this specific neural region

Rethinking functional outcome measures: the development of an upper limb test to assess basal ganglia dysfunction

The basal ganglia is implicated in a wide range of motor, cognitive and behavioural activities required for normal function. This region is predominantly affected in Huntington’s disease (HD), meaning that functional ability progressively worsens. However, functional outcome measures for HD, particularly those for the upper limb, are limited meaning there is an imperative for well-defined, quantitative measures. Here we describe the development and evaluation of the Moneybox test (MBT). This novel, functional upper limb assessment was developed in accordance with translational neuroscience and physiological principles for people with a broad disease manifestation, such as HD. Participants with HD (n=64) and healthy controls (n=21) performed the MBT, which required subjects to transfer tokens into a container in order of size (Baseline Transfer), value (Complex Transfer) with and without reciting the alphabet (Dual Transfer). Disease specific measures of motor, cognition, behaviour and function were collected. HD patients were grouped into disease stage, from which, discriminative and convergent validity was assessed using Analysis of Variance and Pearson’s correlation respectively. Manifest HD participants were slower than pre-manifest and control participants, and achieved significantly lower MBT total scores. Performance in the Complex Transfer and Dual Transfer tasks were significantly different between pre-manifest and stage 1 HD. All MBT performance variables significantly correlated with routinely used measures of motor, cognition, behaviour and function. The MBT provides a valid, sensitive and affordable functional outcome measure. Unlike current assessments, MBT performance significantly distinguished the subtle differences between the earliest disease stages of HD, which are the populations typically targeted in clinical trials

Direct comparison of rat- and human-derived ganglionic eminence tissue grafts on motor function

Huntington’s disease (HD) is a debilitating, genetically-inherited neurodegenerative disorder that results in early loss of medium spiny neurons from the striatum and subsequent degeneration of cortical and other subcortical brain regions. Behavioural changes manifest as a range of motor, cognitive and neuropsychiatric impairments. It has been established that replacement of the degenerated medium spiny neurons with rat-derived fetal whole ganglionic eminence (rWGE) tissue can alleviate motor and cognitive deficits in preclinical rodent models of HD. However, clinical application of this cell replacement therapy requires the use of human-derived (hWGE), not rWGE, tissue. Despite this, little is currently known about the functional efficacy of hWGE. The aim of this study was to directly compare the ability of the gold-standard rWGE grafts, against the clinically-relevant hWGE grafts, on a range of behavioural tests of motor function. Lister-hooded rats either remained as unoperated controls or received unilateral excitotoxic lesions of the lateral neostriatum. Subsets of lesioned rats then received transplants of either rWGE or hWGE primary fetal tissue into the lateral striatum. All rats were tested post-lesion and post-graft on the following tests of motor function: staircase test, apomorphine-induced rotation, cylinder test, adjusting steps test and vibrissae-evoked touch test. At 21 weeks post-graft, brain tissue was taken for histological analysis. The results revealed comparable improvements in apomorphine-induced rotational bias and the vibrissae test, despite larger graft volumes in the hWGE cohort. hWGE grafts, but not rWGE grafts, stabilised behavioural performance on the adjusting steps test. These results have implications for clinical application of cell replacement therapies, as well as providing a foundation for the development of stem cell-derived cell therapy products

Novel application of behavioral assays allows dissociation of joint pathology from systemic extra-articular alterations induced by inflammatory arthritis

Introduction: Although rheumatoid arthritis (RA) is a disease of articular joints, patients often suffer from co-morbid neuropsychiatric changes, such as anxiety, that may reflect links between heightened systemic inflammation and abnormal regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Here, we apply behavioral neuroscience methods to assess the impact of antigen-induced arthritis (AIA) on behavioral performance in wild type (WT) and interleukin-10 deficient (Il10-/-) mice. Our aim was to identify limb-specific motor impairments, as well as neuropsychological responses to inflammatory arthritis. Methods: Behavioral testing was performed longitudinally in WT and Il10-/- mice before and after the induction of arthritic joint pathology. Footprint analysis, beam walking and open field assessment determined a range of motor, exploratory and anxiety-related parameters. Specific gene changes in HPA axis tissues were analyzed using qPCR. Results: Behavioral assessment revealed transient motor and exploratory impairments in mice receiving AIA, coinciding with joint swelling. Hind limb coordination deficits were independent of joint pathology. Behavioral impairments returned to baseline by 10 days post-AIA in WT mice. Il10-/- mice demonstrated comparable levels of swelling and joint pathology as WT mice up to 15 days post-AIA, but systemic differences were evident in mRNA expression in HPA axis tissues from Il10-/- mice post-AIA. Interestingly, the behavioral profile of Il10-/- mice revealed a significantly longer time post-AIA for activity and anxiety-related behaviors to recover. Conclusions: The novel application of sensitive behavioral tasks has enabled dissociation between behaviors that occur due to transient joint-specific pathology and those generated by more subtle systemic alterations that manifest post-AIA

Huntington's Disease assessment using tri axis accelerometers

Huntington’s disease (HD) is a progressive inherited neurodegenerative disorder, causing involuntary movement and cognitive problems, severely affecting the quality of life. Controlling upper limb function is a core feature of daily activity and can prove problematic for people with HD. The Money Box Test (MBT) has been developed with a purpose of quantifying the involuntary movement frequently seen in people with HD. In this research, wearable and highly sensitive accelerometers are used to collect the acceleration of the hands and chest during the performance of the MBT. Using this data, a new approach is proposed to automatically classify the participants into two classes, healthy and HD, on the basis of the time series accelerometer data. A set of 90 time domain features is extracted from the accelerometer data, a feature selection technique is used to analyse the feature significance and to reduce the dimensionality of the dataset, and finally an SVM classifier is used to classify subjects into healthy and HD classes. The data of seven healthy controls and 15 HD patients are used in this study. The highest accuracy with the most significant eight features is 86.36% with the sensitivity and the specificity values being 87.50%, and 83.33% respectively

Objectively characterizing Huntington's disease using a novel upper limb dexterity test.

Background:The Clinch Token Transfer Test (C3t) is a bi-manual coin transfer task that incorporates cognitive tasks to add complexity. This study explored the concurrent and convergent validity of the C3t as a simple, objective assessment of impairment that is reflective of disease severity in Huntington's, that is not reliant on clinical expertise for administration. Methods:One-hundred-and-five participants presenting with pre-manifest (n = 16) or manifest (TFC-Stage-1 n = 39; TFC-Stage-2 n = 43; TFC-Stage-3 n = 7) Huntington's disease completed the Unified Huntington's Disease Rating Scale and the C3t at baseline. Of these, thirty-three were followed up after 12 months. Regression was used to estimate baseline individual and composite clinical scores (including cognitive, motor, and functional ability) using baseline C3t scores. Correlations between C3t and clinical scores were assessed using Spearman's R and visually inspected in relation to disease severity using scatterplots. Effect size over 12 months provided an indication of longitudinal behaviour of the C3t in relation to clinical measures.Results: Baseline C3t scores predicted baseline clinical scores to within 9-13% accuracy, being associated with individual and composite clinical scores. Changes in C3t scores over 12 months were small ([Formula: see text] ≤ 0.15) and mirrored the change in clinical scores. Conclusion: The C3t demonstrates promise as a simple, easy to administer, objective outcome measure capable of predicting impairment that is reflective of Huntington's disease severity and offers a viable solution to support remote clinical monitoring. It may also offer utility as a screening tool for recruitment to clinical trials given preliminary indications of association with the prognostic index normed for Huntington's disease

Rehabilitation training in neural restitution

Over the last decade, neural transplantation has emerged as one of the more promising, albeit highly experimental, potential therapeutics in neurodegenerative disease. Preclinical studies in rat lesion models of Huntington's disease (HD) and Parkinson's disease (PD) have shown that transplanted precursor neuronal tissue from a fetus into the lesioned striatum can survive, integrate, and reconnect circuitry. Importantly, specific training on behavioral tasks that target striatal function is required to encourage functional integration of the graft to the host tissue. Indeed, “learning to use the graft” is a concept recently adopted in preclinical studies to account for unpredicted profiles of recovery posttransplantation and is an emerging strategy for improving graft functionality. Clinical transplant studies in HD and PD have resulted in mixed outcomes. Small sample sizes and nonstandardized experimental procedures from trial to trial may explain some of this variability. However, it is becoming increasingly apparent that simply replacing the lost neurons may not be sufficient to ensure the optimal graft effects. The knowledge gained from preclinical grafting and training studies suggests that lifestyle factors, including physical activity and specific cognitive and/or motor training, may be required to drive the functional integration of grafted cells and to facilitate the development of compensatory neural networks. The clear implications of preclinical studies are that physical activity and cognitive training strategies are likely to be crucial components of clinical cell replacement therapies in the future. In this chapter, we evaluate the role of general activity in mediating the physical ability of cells to survive, sprout, and extend processes following transplantation in the adult mammalian brain, and we consider the impact of general and specific activity at the behavioral level on functional integration at the cellular and physiological level. We then highlight specific research questions related to timing, intensity, and specificity of training in preclinical models and synthesize the current state of knowledge in clinical populations to inform the development of a strategy for neural transplantation rehabilitation training

Image_1_Rethinking Functional Outcome Measures: The Development of a Novel Upper Limb Token Transfer Test to Assess Basal Ganglia Dysfunction.PDF

<p>The basal ganglia are implicated in a wide range of motor, cognitive and behavioral activities required for normal function. This region is predominantly affected in Huntington's disease (HD), meaning that functional ability progressively worsens. However, functional outcome measures for HD, particularly those for the upper limb, are limited meaning there is an imperative for well-defined, quantitative measures. Here we describe the development and evaluation of the Moneybox test (MBT). This novel, functional upper limb assessment was developed in accordance with translational neuroscience and physiological principles for people with a broad disease manifestation, such as HD. Participants with HD (n = 64) and healthy controls (n = 21) performed the MBT, which required subjects to transfer tokens into a container in order of size (Baseline Transfer), value (Complex Transfer) with and without reciting the alphabet (Dual Transfer). Disease specific measures of motor, cognition, behavior, and function were collected. HD patients were grouped into disease stage, from which, discriminative and convergent validity was assessed using Analysis of Variance and Pearson's correlation respectively. Manifest HD participants were slower than pre-manifest and control participants, and achieved significantly lower MBT total scores. Performance in the Complex Transfer and Dual Transfer tasks were significantly different between pre-manifest and stage 1 HD. All MBT performance variables significantly correlated with routinely used measures of motor, cognition, behavior, and function. The MBT provides a valid, sensitive, and affordable functional outcome measure. Unlike current assessments, MBT performance significantly distinguished the subtle differences between the earliest disease stages of HD, which are the populations typically targeted in clinical trials.</p

Developing Angelman syndrome-specific clinician-reported and caregiver-reported measures to support holistic, patient-centered drug development

Abstract Background Angelman syndrome (AS) is a rare, heterogenous neurogenetic condition, which significantly impacts the lives of people with AS and their families. Valid and reliable measures reporting key symptoms and functional impairments of AS are required to support development of patient-centered therapies. We describe the development of clinician- and caregiver-reported, AS-specific Global Impression scales for incorporation into clinical trials. Best practice US Food and Drug Administration guidance for measure development was followed with input from expert clinicians, patient advocates, and caregivers during content generation and refinement. Results Initial measurement domains for the Symptoms of AS—Clinician Global Impression (SAS-CGI) and the Caregiver-reported AS Scale (CASS) were identified from a conceptual disease model of AS symptoms and impacts, derived from interviews with caregivers and clinicians. Two rounds of cognitive debriefing (CD) interviews were performed; clinicians debriefed the SAS-CGI, with patient advocates and caregivers debriefing the CASS to ensure relevance and comprehension. Feedback was used to refine items and ensure wording was age-appropriate and captured AS-specific symptoms, as well as associated impacts and functional impairments. The SAS-CGI and CASS capture global assessments of seizures, sleep, maladaptive behaviors, expressive communication, fine and gross motor skills, cognition, and self-care, which were determined by clinicians, patient advocates, and caregivers to be the most challenging aspects of AS. Additionally, the measures include items for assessing overall AS symptoms and the meaningfulness of any change. In addition to ratings for severity, impact, and change, a notes field was included in the SAS-CGI to provide the rationale for the chosen rating. CD interviews confirmed the measures covered key concepts of AS from the perspective of clinicians and caregivers, and demonstrated that the measures’ instructions, items, and response options were clear and appropriate. Interview feedback informed adjustments to the wording of the instructions and the items. Conclusions The SAS-CGI and CASS were designed to capture multiple AS symptoms, reflecting the heterogeneity and complexity of AS in children 1 to 12 years old. These clinical outcome assessments have been incorporated into AS clinical studies, which will allow for the evaluation of their psychometric properties and inform further refinements if needed