Abstract
Apathy is pervasive across many neuropsychiatric disorders but is poorly characterized mechanistically, so targeted therapeutic interventions remain elusive. A key impediment has been the lack of validated assessment tools to facilitate translation of promising findings between preclinical disease models and patients. Apathy is a common symptom in Huntington's disease. Due to its established genetic basis and the availability of defined animal models, this disease offers a robust translational framework for linking motivated behavior with underlying neurobiology and an ideal context in which to evaluate a quantitative, translational apathy assessment method. In this study we therefore aimed to demonstrate the validity of using touchscreen-delivered progressive ratio tasks to mirror apathy assessment in Huntington's disease patients and a representative mouse model. To do this we evaluated Huntington's disease patients (n = 23) and age-matched healthy controls (n = 20), and male R6/1 mice (n = 23) and wildtype controls (n = 29) for apathy-like behavior using touchscreen-delivered progressive ratio tasks. The primary outcome measure of the assessment was breakpoint, defined as the highest number of touchscreen responses emitted before task engagement ceased. Patients and R6/1 mice were both found to exhibit significantly reduced breakpoints relative to their respective control groups, consistent with apathy-like behavior. This performance was also not associated with motoric differences in either species. These data demonstrate the utility of touchscreen-delivered progressive ratio tasks in detecting clinically relevant motivational deficits in Huntington's disease. This approach may offer a platform from which clinically relevant mechanistic insights concerning motivation symptoms can be derived and provide an effective route for translation of promising preclinical findings into viable therapeutic interventions.
Highlights
Apathy is a multidimensional construct that encompasses a wide range of clinical features, including reductions in goaldirected behavior, cognitive activity, and emotional expression [1,2,3,4]
We have demonstrated the potential of a fully quantitative, touchscreen-delivered motivational assessment to detect apathy-like behavior in Huntington’s disease (HD) patients and a wellcharacterized rodent disease model
We have shown that manifest HD patients exhibit lower breakpoints relative to healthy controls in a touchscreen progressive ratio (PR) assessment
Summary
Apathy is a multidimensional construct that encompasses a wide range of clinical features, including reductions in goaldirected behavior, cognitive activity, and emotional expression [1,2,3,4]. Despite its prevalence and impact on quality of life for both patients and caregivers, apathy remains a difficult symptom to treat effectively in HD, with no successful HD apathy treatment trial reported to date [17]. This is partly due to the often mixed neuropsychiatric presentation of these patients and concerns around polypharmacy related to medication interactions and side-effects leading to exacerbation of other neuropsychiatric symptoms [14, 18]. Identification of viable neuropharmacological targets and screening of prospective treatments for efficacy is challenging
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