Decision cost hypersensitivity underlies Huntington's disease apathy.

The neuropsychiatric syndrome of apathy is now recognized to be a common and disabling condition in Huntington's disease (HD). However, the mechanisms underlying it are poorly understood. One way to investigate apathy is to utilise a theoretical framework of normal motivated behaviour, to determine where breakdown has occurred in people with this behavioural disruption. A fundamental computation underlying motivated, goal-directed behaviour across species is weighing up the costs and rewards associated with actions. Here, we asked whether people with apathy are more sensitive to costs of actions (physical effort and time delay), less sensitive to rewarding outcomes, or both. Based on the unique anatomical substrates associated with HD pathology, we hypothesised that a general hypersensitivity to costs would underpin HD apathy. Genetically confirmed carriers of the expanded Huntingtin gene (premanifest to mild motor manifest disease (n=53) were compared to healthy controls (n = 38). Participants performed a physical effort-based decision-making task (Apple Gathering Task) and a delay discounting task (Money Choice Questionnaire). Choice data was analysed using linear regression and drift diffusion models that also accounted for the time taken to make decisions. Apathetic people with HD accepted fewer offers overall on the Apple Gathering Task, specifically driven by increased sensitivity to physical effort costs, and not explained by motor severity, mood, cognition, or medication. Drift diffusion modelling provided further evidence of effort hypersensitivity, with apathy associated with a faster drift rate towards rejecting offers as a function of varying effort. Increased delay sensitivity was also associated with apathy, both when analysing raw choice and also drift rate, where there was moderate evidence of HD apathy drifting faster towards the immediately available (low cost) option. Furthermore, the effort and delay sensitivity parameters from these tasks were positively correlated. The results demonstrate a clear mechanism for apathy in HD, cost hypersensitivity, which manifests in both the effort and time costs associated with actions towards rewarding goals. This suggests that HD pathology may cause a domain-general disruption of cost processing, which is distinct to apathy occurrence in other brain disorders, and may require different therapeutic approaches.

Altered nucleus accumbens functional connectivity precedes apathy in Parkinson's disease.

Work in animal and human neuroscience has identified neural regions forming a network involved in the production of motivated, goal-directed behaviour. In particular, the nucleus accumbens and anterior cingulate cortex are recognized as key network nodes underlying decisions of whether to exert effort for reward, to drive behaviour. Previous work has convincingly shown that this cognitive mechanism, known as effort-based decision making, is altered in people with Parkinson's disease with a syndrome of reduced goal-directed behaviour-apathy. Building on this work, we investigated whether the neural regions implementing effort-based decision-making were associated with apathy in Parkinson's disease, and more importantly, whether changes to these regions were evident prior to apathy development. We performed a large, multimodal neuroimaging analysis in a cohort of people with Parkinson's disease (n = 199) with and without apathy at baseline. All participants had ∼2-year follow-up apathy scores, enabling examination of brain structure and function specifically in those with normal motivation who converted to apathy by ∼2-year follow-up. In addition, of the people with normal motivation, a subset (n = 56) had follow-up neuroimaging data, allowing for examination of the 'rate of change' in key nodes over time in those who did, and did not, convert to apathy. Healthy control (n = 54) data were also included to aid interpretation of findings. Functional connectivity between the nucleus accumbens and dorsal anterior cingulate cortex was higher in people with normal motivation who later converted to apathy compared to those who did not, whereas no structural differences were evident between these groups. In contrast, grey matter volume in these regions was reduced in the group with existing apathy. Furthermore, of those with normal motivation who had undergone longitudinal neuroimaging, converters to apathy showed a higher rate of change in grey matter volume within the nucleus accumbens. Overall, we show that changes in functional connectivity between nucleus accumbens and anterior cingulate cortex precedes apathy in people with Parkinson's disease, with conversion to apathy associated with higher rate of grey matter volume loss in nucleus accumbens, despite no baseline differences. These findings significantly add to an accumulating body of transdiagnostic evidence that apathy arises from disruption to key nodes within a network in which normal goal-directed behaviour is instantiated, and raise the possibility of identifying those at risk for developing apathy before overt motivational deficits have arisen.

Multiple sclerosis mortality in New Zealand: a nationwide prospective study.

BACKGROUND: Mortality data from Europe and North America show a shorter life expectancy for people with multiple sclerosis (MS). It is not known if a similar mortality risk exists in the southern hemisphere. We analysed the mortality outcomes of a comprehensive New Zealand (NZ) MS cohort, 15 years postrecruitment. METHODS: All participants of the nationwide 2006 NZ MS prevalence study were included and mortality outcomes were compared with life table data from the NZ population using classic survival analyses, standardised mortality ratios (SMRs) and excess death rates (EDRs). RESULTS: Of 2909 MS participants, 844 (29%) were deceased at the end of the 15-year study period. Median survival age for the MS cohort was 79.4 years (78.5, 80.3), compared with 86.6 years (85.5, 87.7) for the age-matched and sex-matched NZ population. The overall SMR was 1.9 (1.8, 2.1)). Symptom onset between 21 and 30 years corresponded to an SMR of 2.8 and a median survival age 9.8 years lower than the NZ population. Progressive-onset disease was associated with a survival gap of 9 years compared with 5.7 years for relapsing onset. The EDR for those diagnosed in 1997-2006 was 3.2 (2.6, 3.9) compared with 7.8 (5.8, 10.3) for those diagnosed between 1967 and 1976. CONCLUSIONS: New Zealanders with MS have a median survival age 7.2 years lower than the general population and twice the mortality risk. The survival gap was greater for progressive-onset disease and for those with an early age of onset.

Non-Contact Hand Movement Analysis for Optimal Configuration of Smart Sensors to Capture Parkinson's Disease Hand Tremor.

Parkinson's disease affects millions worldwide with a large rise in expected burden over the coming decades. More easily accessible tools and techniques to diagnose and monitor Parkinson's disease can improve the quality of life of patients. With the advent of new wearable technologies such as smart rings and watches, this is within reach. However, it is unclear what method for these new technologies may provide the best opportunity to capture the patient-specific severity. This study investigates which locations on the hand can be used to capture and monitor maximal movement/tremor severity. Using a Leap Motion device and custom-made software the volume, velocity, acceleration, and frequency of Parkinson's (n = 55, all right-handed, majority right-sided onset) patients' hand locations (25 joints inclusive of all fingers/thumb and the wrist) were captured simultaneously. Distal locations of the right hand, i.e., the ends of fingers and the wrist showed significant trends (p < 0.05) towards having the largest movement velocities and accelerations. The right hand, compared with the left hand, showed significantly greater volumes, velocities, and accelerations (p < 0.01). Supplementary analysis showed that the volumes, acceleration, and velocities had significant correlations (p < 0.001) with clinical MDS-UPDRS scores, indicating the potential suitability of using these metrics for monitoring disease progression. Maximal movements at the distal hand and wrist area indicate that these locations are best suited to capture hand tremor movements and monitor Parkinson's disease.

A Multi-Step Model of Parkinson's Disease Pathogenesis.

BACKGROUND: Parkinson's disease (PD) may result from the combined effect of multiple etiological factors. The relationship between disease incidence and age, as demonstrated in the cancer literature, can be used to model a multistep pathogenic process, potentially affording unique insights into disease development. OBJECTIVES: We tested whether the observed incidence of PD is consistent with a multistep process, estimated the number of steps required and whether this varies with age, and examined drivers of sex differences in PD incidence. METHODS: Our validated probabilistic modeling process, based on medication prescribing, generated nationwide age- and sex-adjusted PD incidence data spanning 2006-2017. Models of log(incidence) versus log(age) were compared using Bayes factors, to estimate (1) if a linear relationship was present (indicative of a multistep process); (2) the relationship's slope (one less than number of steps); (3) whether slope was lower at younger ages; and (4) whether slope or y-intercept varied with sex. RESULTS: Across >15,000 incident cases of PD, there was a clear linear relationship between log(age) and log(incidence). Evidence was strongest for a model with an initial slope of 5.2 [3.8, 6.4], an inflexion point at age 45, and beyond this a slope of 6.8 [6.4, 7.2]. There was evidence for the intercept varying by sex, but no evidence for slope being sex-dependent. CONCLUSIONS: The age-specific incidence of PD is consistent with a process that develops in multiple, discrete steps - on average six before age 45 and eight after. The model supports theories emphasizing the primacy of environmental factors in driving sex differences in PD incidence. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Childbirth and Delayed Parkinson's Onset: A Reproducible Nonbiological Artifact of Societal Change.

BACKGROUND: Uncontrolled studies have reported associations between later Parkinson's disease onset in women and a history of giving birth, with age at onset delayed by nearly 3 years per child. We tested this association in two independent data sets, but, as a control to test for nonbiological explanations, also included men with PD. METHODS: We analyzed valid cases from the Parkinson's Progressive Markers Initiative incident sample (145 women, 276 men) and a prevalent sample surveyed by the New Zealand Brain Research Institute (210 women, 394 men). RESULTS: The association was present in both women and men in the Parkinson's Progressive Markers Initiative study, and absent in both in the New Zealand Brain Research Institute study. This is consistent with generational differences common to men and women, which confound with age at onset in incident-dominant samples. CONCLUSIONS: Despite being replicable in certain circumstances, associations between childbirth and later PD onset are an artifact of generational cohort differences. © 2020 International Parkinson and Movement Disorder Society.

Ocular drift reflects volitional action preparation.

Human cognitive behavior is predictive rather than reflexive because of volitional action preparation. Recent studies have shown that the covert process of volitional action preparation can be decoded from overt fixational eye movements of fixational/microsaccades and pupil dilation. Ocular drift, the slowest fixational eye movements, is also under the active neural control, but its relationship with cognitive behavior is unknown. Here, we examined whether ocular drift also reflects volitional action preparation. We analyzed ocular drift while adult humans maintained fixation on a central visual stimulus as they prepared to generate a volitional saccade. We adopted the antisaccade paradigm in which subjects generate a targeting saccade toward the opposite direction of a peripheral visual stimulus. Our findings are the following five points. First, ocular drift was slower when subjects prepared for targeting saccade initiation than when such preparation was unnecessary. Second, ocular drift was slowed down with elapsed time from fixation initiation, which was associated with the facilitation of targeting saccade initiation. Third, ocular drift was further slowed on correct antisaccade trials than when subjects failed to suppress targeting saccades toward peripheral stimuli. Fourth, such correlation with antisaccade performance was observed immediately after fixation initiation in ocular drift, but it emerged more slowly in the other fixational eye movements. Fifth, subjects with unstable fixation because of faster ocular drift had poorer antisaccade performance. We suggest that fixation stability measured by ocular drift can be used to decode the covert process of volitional action preparation along with the other fixational eye movements.

PsychoPy2: Experiments in behavior made easy.

PsychoPy is an application for the creation of experiments in behavioral science (psychology, neuroscience, linguistics, etc.) with precise spatial control and timing of stimuli. It now provides a choice of interface; users can write scripts in Python if they choose, while those who prefer to construct experiments graphically can use the new Builder interface. Here we describe the features that have been added over the last 10 years of its development. The most notable addition has been that Builder interface, allowing users to create studies with minimal or no programming, while also allowing the insertion of Python code for maximal flexibility. We also present some of the other new features, including further stimulus options, asynchronous time-stamped hardware polling, and better support for open science and reproducibility. Tens of thousands of users now launch PsychoPy every month, and more than 90 people have contributed to the code. We discuss the current state of the project, as well as plans for the future.

Parkinson's disease across ethnicities: A nationwide study in New Zealand.

BACKGROUND: New Zealand is an ethnically diverse country with a unified national prescribing system. This provides a good framework to use drug-tracing methodology to establish the prevalence and incidence of Parkinson's disease across different ethnic groups. The objective of this study was to determine the prevalence and incidence of Parkinson's disease in the major ethnic groups in New Zealand. METHODS: Information on Parkinson's disease-related medications was extracted from the national Pharmaceutical Collection of community-dispensed medications for the period January 1, 2005, to December 31, 2014. Diagnoses for a large subset of individuals were independently determined through national mortality and hospital admissions data sets. We used a Bayesian model, accommodating uncertainty and bias, to estimate the number of people with Parkinson's disease. RESULTS: We found the highest rate of Parkinson's disease in the European ethnic group and the lowest rate in the indigenous Maori. The 2006-2013 age-standardized incidence (per 100,000 population per year) was European, 33; Asian, 28; Pasifika, 27; Maori, 20. The 2013 age-standardized prevalence (per 100,000 population) was European, 223; Asian, 174; Pasifika, 160; Maori, 114. CONCLUSIONS: There is a differential occurrence of Parkinson's disease across the major ethnic groups within the New Zealand population, with indigenous Maori showing the lowest incidence. Varying susceptibility profiles, gene-environment interactions, and inequalities in accessing health care may play a role in the variation in rates of Parkinson's disease in New Zealand. © 2018 International Parkinson and Movement Disorder Society.

Response to "Parkinson's disease mild cognitive impairment classifications and neurobehavioral symptoms".

A recent paper, "Parkinson's disease mild cognitive impairment classifications and neurobehavioral symptoms" (McDermott et al., 2017), provides an interesting comparison of the influence of different criteria for Parkinson's disease with mild cognitive impairment (PD-MCI) on progression to dementia (PDD). Unfortunately, McDermott et al. (2017) incorrectly stated that "only 21% of PD-MCI participants (identified with a 1.5 SD cut-off) converted to PDD within four years" (p.6) in our study (Wood et al., 2016). However, the important point made by Wood et al. (2016) was that the proportion of conversions to PDD was 51% when the PD-MCI diagnosis required a minimum of two 1.5 SD impairments within any single cognitive domain, whereas additional PD-MCI patients classified with one impairment at 1.5 SD in each of the two domains (but never two impairments in the same domain) had a non-significant risk of dementia relative to non-MCI patients (11% vs. 6% converted, respectively). Our PDD conversion rate was 38% when combining both 1.5 SD criteria (21/56 PD-MCI patients vs. 4/65 non-MCI patients converted); McDermott et al. (2017) found a 42% conversion rate over three years for similarly described PD-MCI patients (10/24 PD-MCI patients vs. 0/27 non-MCI patients converted). Our study was also part of a multinational study (n = 467) showing that PD-MCI has predictive validity beyond known demographic and PD-specific factors of influence (Hoogland et al., 2017). All three studies found that multiple cognitive domain impairments are common in PD-MCI. Nonetheless, the research community needs to clarify the association between PD-MCI subtypes and, especially, the optimal cognitive markers for dementia risk in PD patients.

The Symbol-Digit Modalities Test in Mild Cognitive Impairment: Evidence from Parkinson's Disease Patients.

BACKGROUND: The evaluation process of the performance of the symbol-digit modalities test (SDMT) has focused much on numerical scores paying only little attention to the qualitative aspects of performance. Incorporating the gaze analysis technique, we aimed to investigate the performance of Parkinson's disease (PD) patients on the written SDMT task. METHODS: Twelve patients with PD and normal cognition (PD-N), 11 with PD and mild cognitive impairment (PD-MCI), and 13 healthy participants (NC) controlled for age, sex and education were recruited. RESULTS: PD-MCI participants achieved significantly lower scores than NC and PD-N participants. Eye-movement parameters, however, did not differ among the study groups, and were not correlated with task performance. CONCLUSIONS: Impaired performance on the SDMT by PD-MCI participants despite relatively preserved oculomotor performance indicates that lower SDMT scores are not due - even in part - to visuomotor impairments otherwise seen in PD patients.

Errors on the MoCA's animal-naming: findings from Parkinson's disease patients.

We read the findings by Cecato et al. (2016) with great interest. In their study, naming the rhinoceros discriminated between patients with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) but not healthy controls (HC). Of note, HC participants were significantly younger than aMCI and AD patients. All participants were administered the original version of the Montreal Cognitive Assessment (MoCA) instrument.

Eye movements in neurodegenerative diseases.

PURPOSE OF REVIEW: Abnormalities of oculomotor control accompany the pathological changes underlying many neurodegenerative diseases. Clinical examination of eye movements can contribute to differential diagnosis, whereas quantitative laboratory measures can provide detailed insight into the disease process. In this review of eye movements in neurodegenerative disease, we summarise recent empirical findings and conceptual advances. RECENT FINDINGS: Oculomotor researchers continue to be particularly prolific in studying Parkinson's disease but there is also substantial activity in Alzheimer's disease and spinocerebellar ataxia. Interesting findings have been reported in Huntington's, motor neuron disease, and glaucoma. Most studies report laboratory-based investigations but useful progress in clinical description continues to be made. SUMMARY: Eye movements remain an active field of investigation across a variety of neurodegenerative conditions. Progress continues to be made at the clinical level as well by using laboratory techniques.

A Randomized Controlled Feasibility Trial of a Specific Cueing Program for Falls Management in Persons With Parkinson Disease and Freezing of Gait.

BACKGROUND AND PURPOSE: Freezing of gait (FOG) increases fall risk in persons with Parkinson disease (PD). Cueing improves gait parameters associated with freezing, but it is unclear whether a cueing program can address falling. METHODS: We used a parallel-groups delayed- (n = 12) or immediate-start (n = 9) randomized controlled trial design to evaluate a cueing exercise program for FOG and falls in participants with PD. Each group received preintervention falls monitoring, followed by a 6-month standardized, home-based, cueing exercise and education program. Participant questionnaires rated program value and compliance. Freezing was measured with the New Freezing of Gait Questionnaire (NFOGQ). Falls were recorded by weekly diaries. RESULTS: Self-reported adherence was high; 83% of participants reported exercising after 6 months. Participants reported that the program was beneficial (89%), walking improved (78%), falls were fewer (73%), and self-management of freezing improved (61%). Mean (standard deviation) NFOGQ scores were 14.8 (5.0), for the immediate (n = 10), and 16.0 (7.7) for the delayed group (n = 9), after 6 months (difference -1.0 [95% confidence interval, -7.9 to 6.0; P = 0.78]). With baseline NFOGQ scores as a covariate, the estimate of difference was -0.7 (95% confidence interval, -6.1 to 4.7; P = 0.79). The relative rate of falls for immediate compared with delayed groups was 1.22 (95% confidence interval, 0.45 to 3.26). CONCLUSIONS: The cueing program intervention is acceptable and participants feel they improve; however, this small feasibility study lacks statistical power to detect important changes in falls rates or FOG severity. A larger study is warranted to further investigate the potential to influence FOG and falls.Video Abstract available for more insights from the authors (Supplemental Digital Content 1, http://links.lww.com/JNPT/A105).

Parkinson's Disease in the Gulf Countries: An Updated Review.

BACKGROUND: The Arabian Gulf region is a rapidly developing part of the world. With the increase in average life-expectancy, idiopathic Parkinson's disease (PD), is also expected to increase in prevalence. Furthermore, the high rate of consanguinity among Arabs probably makes familial cases of PD more likely to be encountered than other areas in the world. This review provides an update on the published literature on sporadic and familial PD in Gulf Arabs. SUMMARY: Although the Arab population of this region shares religious beliefs and demographic characteristics with other Arabs, their environmental exposures and genetic makeup may be different. This could account for the relatively low prevalence of PD reported in the Al-Thugba study (27 per 100,000) compared with prevalence rates by most other studies on Arab (mainly North African) populations (31.4-557.4 per 100,000). KEY MESSAGES: Gulf countries are considered rich countries, which makes conducting nation-wide or even international studies logistically easier than it is in many other countries. Such multinational research can be organized by the existing Gulf Cooperation Council, or through a collaboration of the Ministries of Health. This would, hopefully, culminate in the introduction of more research centers, as well as the implementation of better health care policies and practices for the ageing community.

Fixational saccades alter the gap effect.

The reaction times of saccadic eye movements have been studied extensively as a probe for cognitive behavior controlled by large-scale cortical and subcortical neural networks. Recent studies have shown that the reaction times of targeting saccades toward peripheral visual stimuli are prolonged by fixational saccades, the largest miniature eye movements including microsaccades. We have shown previously that the frequency of fixational saccades is decreased by volitional action preparation controlled internally during the antisaccade paradigm (look away from a stimulus). Instead, here we examined whether fixational saccade modulation induced externally by sensory events could also account for targeting saccade facilitation by the same sensory events. When targeting saccades were facilitated by prior fixation stimulus disappearance (gap effect), fixational saccade occurrence was reduced, which could theoretically facilitate targeting saccades. However, such reduction was followed immediately by the rebound of fixational saccade occurrence in some subjects, which could eliminate potential benefits from the previous fixational saccade reduction. These results do not mean that fixational saccades were unrelated to the gap effect because they indeed altered that effect by delaying targeting saccade initiation on trials without the fixation gap more strongly than trials with it. Such changes might be attributed to the disruption of volitional saccade preparation because the frequency of fixational saccades observed in this study was associated with the ability of volitional control over antisaccade behavior. These results suggest that fixational saccades alter the gap effect on targeting saccade reaction times, presumably by disrupting volitional saccade commands.

Apathy and Impulsivity Co-Occur in Huntington's Disease.

BACKGROUND: Apathy is a debilitating behavioral change in Huntington's disease (HD), but impulsivity in HD has not been well documented, and the co-occurrence of these behaviors in HD has not been investigated. OBJECTIVE: Our objective was to determine whether apathy and impulsivity co-occur in people with HD and their associations with quality of life. METHODS: Carriers of Huntington's gene expansion (premanifest to mild motor manifest disease; n = 42) along with healthy controls (n = 20) completed measures of apathy (Apathy Evaluation Scale and Apathy Motivation Index) and impulsivity (Barratt Impulsiveness Scale-11 and UPPS-P impulsivity scale), along with mood, cognition, clinical, and quality of life measures. Apathy and impulsivity measures were each reduced to a single metric per patient using principal component analysis. Correlations and multiple linear regression models determined associations between apathy and impulsivity and the potential influence of other covariates. RESULTS: Apathy and impulsivity were significantly correlated (r = 0.6, p < 0.001, 95% CI [0.36, 0.76]) in HD, with this association remaining after controlling for depressive symptoms, motor disease severity, and cognitive function. Furthermore, apathy and depressive symptoms were associated with poorer quality of life. CONCLUSIONS: Apathy and impulsivity co-occur in individuals with premanifest to mild manifest HD and have a significant impact on wellbeing. We add to a growing evidence body that apathy and impulsivity may be intrinsically linked.

Cross-Sectional and Longitudinal Association of Clinical and Neurocognitive Factors With Apathy in Patients With Parkinson Disease.

BACKGROUND AND OBJECTIVES: A robust understanding of the natural history of apathy in Parkinson disease (PD) is foundational for developing effective clinical management tools. However, large longitudinal studies are lacking while the literature is inconsistent about even cross-sectional associations. We aimed to determine the longitudinal predictors of apathy development in a large cohort of people with PD and its cross-sectional associations and trajectories over time, using sophisticated Bayesian modeling techniques. METHODS: People with PD followed up in the longitudinal New Zealand Parkinson's progression project were included. Apathy was defined using the neuropsychiatric inventory subscale ≥4, and analyses were also repeated using a less stringent cutoff of ≥1. Both MoCA and comprehensive neuropsychological testing were used as appropriate to the model. Depression was assessed using the hospital anxiety and depression scale. Cross-sectional Bayesian regressions were conducted, and a multistate predictive model was used to identify factors that predict the initial onset of apathy in nonapathetic PD, while also accounting for the competing risk of death. The relationship between apathy presence and mortality was also investigated. RESULTS: Three hundred forty-six people with PD followed up for up to 14 years across a total of 1,392 sessions were included. Apathy occurrence did not vary significantly across the disease course (disease duration odds ratio [OR] = 0.55, [95% CI 0.28-1.12], affecting approximately 11% or 22% of people at any time depending on the NPI cutoff used. Its presence was associated with a significantly higher risk of death after controlling for all other factors (hazard ratio [HR] = 2.92 [1.50-5.66]). Lower cognition, higher depression levels, and greater motor severity predicted apathy development in those without motivational deficits (HR [cognition] = 0.66 [0.48-0.90], HR [depression] = 1.45 [1.04-2.02], HR [motor severity] = 1.37 [1.01-1.86]). Cognition and depression were also associated with apathy cross-sectionally, along with male sex and possibly lower dopaminergic therapy level, but apathy still occurred across the full spectrum of each variable (OR [cognition] = 0.58 [0.44-0.76], OR [depression] = 1.43 [1.04-1.97], OR [female sex] = 0.45 [0.22-0.92], and OR [levodopa equivalent dose] = 0.78 [0.59-1.04]. DISCUSSION: Apathy occurs across the PD time course and is associated with higher mortality. Depressive symptoms and cognitive impairment in particular predict its future development in those with normal motivation.