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.

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.

Effort-based decision making and motivational deficits in stroke patients.

Motivational deficits in patients recovering from stroke are common and can reduce active participation in rehabilitation and thereby impede functional recovery. We investigated whether stroke patients with clinically reduced drive, initiation, and endurance during functional rehabilitative training (n = 30) display systematic alterations in effort-based decision making compared to age, sex, and severity-matched stroke patients (n = 30) whose drive appeared unaffected. Notably, the two groups did not differ in self-reported ratings of apathy and depression. However, on an effort-based decision-making task, stroke patients with clinically apparent drive impairment showed intact willingness to accept effort for reward, but were more likely to fail to execute the required effort compared to patients without apparent drive impairments. In other words, the decision behavioural assessment revealed that stroke patients that displayed reduced drive, initiation, and endurance during inpatient neurorehabilitation failed to persist in goal-directed effort production, even over very short periods. These findings indicate that reduced drive during rehabilitative therapy in post-stroke patients is not due to a diminished motivation to invest physical effort, but instead is related to a reduced persistence with effortful behaviour.

Reduced Sensitivity to Background Reward Underlies Apathy After Traumatic Brain Injury: Insights From an Ecological Foraging Framework.

BACKGROUND: Altered reward processing is increasingly recognised as a crucial mechanism underpinning apathy in many brain disorders. However despite its clinical relevance, little is known about the mechanisms of apathy following moderate-to-severe traumatic brain injury (TBI). In real-life situations, reward representations encompass both foreground (gains from current activity) and background (potential gains from the broader environment) elements. This latter variable provides a crucial set-point for switching behaviour in many naturalistic settings. We hypothesised apathy post-TBI would be associated with disrupted background reward sensitivity. METHODS: We administered a computer-based foraging task to 45 people with moderate-to-severe TBI (20 with apathy, 39 males) and 37 matched controls. Participants decided when to leave locations (patches) where foreground reward rates depleted at differing rates, to pursue greater rewards from other patches in the environment, which had either a high or low background reward rate. Primary analysis was performed using linear mixed effects models, with patch leaving time the dependent variable. RESULTS: Findings showed a significant interaction between apathy and background reward sensitivity, driven by apathetic TBI participants not altering patch-leaving decisions as environmental reward rate changed. In contrast, although TBI was associated with reduced sensitivity to changing foreground rewards, this did not vary as a function of apathy. CONCLUSIONS: These results provide the first evidence directly linking disrupted background reward processing to apathy in any brain disorder. They identify a novel mechanism for apathy following moderate-to-severe TBI, and point towards novel interventions to improve this debilitating complication of head injury.

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.

Clinical outcomes of delayed mechanical thrombectomy: Descriptive analysis and development of a screening tool.

BACKGROUND AND PURPOSE: Limited data guide the selection of patients with large vessel occlusion ischaemic stroke who may benefit from referral to a distant tertiary centre for mechanical thrombectomy (MT). We aimed to characterize this population, describe clinical outcomes and develop a screening system to identify patients most likely to benfit from delayed mechanical thrombectomy (MT). METHODS: We undertook a retrospective cohort analysis enrolling patients transferred from regional sites to one of two MT comprehensive stroke units with a time from non-contrast computed tomography (NCCT) of the brain to reperfusion of 4 h or more. We describe Alberta Stroke Programme Early Computed Tomography Score (ASPECTS), National Institute of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) in our patients and compare these patients to those in extended-time-window trials. Lastly, we developed and validated a scoring model to help clinicians identify appropriate patients based on variables associated with poor outcomes. RESULTS: We included 563 patients, 46% of whom received thrombolysis; the median (interquartile range [IQR]) ASPECTS was 8 (7-10) and the median (IQR) NIHSS score was 16 (11-20). The median (IQR) symptom to mechanical reperfusion time was 390 (300-580) min. Eight patients (1%) had a symptomatic haemorrhage. We achieved good clinical outcome (defined as mRS score ≤2) in 299 patients (54%). Age, diabetes, NIHSS score and ASPECTS were used to create a weighted scoring system with a validated area under the curve of 0.83 (95% confidence interval 0.74-0.92). CONCLUSION: Our study shows, in highly selected patients, that delayed MT many hours after baseline NCCT is associated with good clinical outcomes. However, older patients with diabetes, high NIHSS score and low ASPECTS may not benefit from transfer to a hub centre many hours away for MT in this model of care.

Disordered Decision Making: A Cognitive Framework for Apathy and Impulsivity in Huntington's Disease.

A caregiver's all-too-familiar narrative - "He doesn't think through what he does, but mostly he does nothing." Apathy and impulsivity, debilitating and poorly understood, commonly co-occur in Huntington's disease (HD). HD is a neurodegenerative disease with manifestations bridging clinical neurology and psychiatry. In addition to movement and cognitive symptoms, neurobehavioral disturbances, particularly apathy and impulsivity, are prevalent features of HD, occurring early in the disease course, often worsening with disease progression, and substantially reducing quality of life. Treatments remain limited, in part because of limited mechanistic understanding of these behavioral disturbances. However, emerging work within the field of decision-making neuroscience and beyond points to common neurobiological mechanisms underpinning these seemingly disparate problems. These insights bridge the gap between underlying disease pathology and clinical phenotype, offering new treatment strategies, novel behavioral and physiological biomarkers of HD, and deeper understanding of human behavior. In this review, we apply the neurobiological framework of cost-benefit decision making to the problems of apathy and impulsivity in HD. Through this decision-making lens, we develop a mechanistic model that elucidates the occurrence of these behavioral disturbances and points to potential treatment strategies and crucial research priorities. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

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.

Higher perceived stress and exacerbated motor symptoms in Parkinson's disease during the COVID-19 lockdown in New Zealand.

AIMS: Stress plays a key role in Parkinson's disease (PD) by acting on the dopaminergic system and worsening patients' motor function. The impact of New Zealand's strict lockdown measures to contain COVID-19 on perceived stress and PD motor symptoms remains unknown. Here we examined the relationship between perceived levels of stress, changes in physical activity levels and PD motor symptoms during lockdown. METHODS: During lockdown, 134 participants with PD and 49 controls completed a survey assessing perceived stress, self-reported changes in PD motor symptoms and physical activity duration and intensity prior to and during lockdown. RESULTS: Perceived stress was higher in PD than controls, and in those reporting a worsening of tremor, balance/gait, dyskinesia and bradykinesia compared to those indicating no change during the COVID-19 lockdown. These effects were not modulated by physical activity. CONCLUSIONS: Reducing stressors may be an important adjunct treatment strategy to improve motor function in PD.

Apathy in small vessel cerebrovascular disease is associated with deficits in effort-based decision making.

Patients with small vessel cerebrovascular disease frequently suffer from apathy, a debilitating neuropsychiatric syndrome, the underlying mechanisms of which remain to be established. Here we investigated the hypothesis that apathy is associated with disrupted decision making in effort-based decision making, and that these alterations are associated with abnormalities in the white matter network connecting brain regions that underpin such decisions. Eighty-two patients with MRI evidence of small vessel disease were assessed using a behavioural paradigm as well as diffusion weighted MRI. The decision-making task involved accepting or rejecting monetary rewards in return for performing different levels of physical effort (hand grip force). Choice data and reaction times were integrated into a drift diffusion model that framed decisions to accept or reject offers as stochastic processes approaching a decision boundary with a particular drift rate. Tract-based spatial statistics were used to assess the relationship between white matter tract integrity and apathy, while accounting for depression. Overall, patients with apathy accepted significantly fewer offers on this decision-making task. Notably, while apathetic patients were less responsive to low rewards, they were also significantly averse to investing in high effort. Significant reductions in white matter integrity were observed to be specifically related to apathy, but not to depression. These included pathways connecting brain regions previously implicated in effort-based decision making in healthy people. The drift rate to decision parameter was significantly associated with both apathy and altered white matter tracts, suggesting that both brain and behavioural changes in apathy are associated with this single parameter. On the other hand, depression was associated with an increase in the decision boundary, consistent with an increase in the amount of evidence required prior to making a decision. These findings demonstrate altered effort-based decision making for reward in apathy, and also highlight dissociable mechanisms underlying apathy and depression in small vessel disease. They provide clear potential brain and behavioural targets for future therapeutic interventions, as well as modelling parameters that can be used to measure the effects of treatment at the behavioural level.

Routine Use of Tenecteplase for Thrombolysis in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: In ischemic stroke, intravenous tenecteplase is noninferior to alteplase in selected patients and has some practical advantages. Several stroke centers in New Zealand changed to routine off-label intravenous tenecteplase due to improved early recanalization in large vessel occlusion, inconsistent access to thrombectomy within stroke networks, and for consistency in treatment protocols between patients with and without large vessel occlusion. We report the feasibility and safety outcomes in tenecteplase-treated patients. METHODS: We performed a retrospective analysis of consecutive patients thrombolyzed with intravenous tenecteplase at 1 comprehensive and 2 regional stroke centers from July 14, 2018, to February 29, 2020. We report the baseline clinical characteristics, rates of symptomatic intracranial hemorrhage, and angioedema. These were then compared with patient outcomes with those treated with intravenous alteplase at 2 other comprehensive stroke centers. Multivariable mixed-effects logistic regression models were performed assessing the association of tenecteplase with symptomatic intracranial hemorrhage and independent outcome (modified Rankin Scale score, 0-2) at day 90. RESULTS: There were 165 patients treated with tenecteplase and 254 with alteplase. Age (75 versus 74 years), sex (56% versus 60% male), National Institutes of Health Stroke Scale scores (8 versus 10), median door-to-needle times (47 versus 48 minutes), or onset-to-needle time (129 versus 130 minutes) were similar between the groups. Symptomatic intracranial hemorrhage occurred in 3 (1.8% [95% CI, 0.4-5.3]) tenecteplase patients compared with 7 (2.7% [95% CI, 1.1-5.7]) alteplase patients (P=0.75). There were no differences between tenecteplase and alteplase in the rates of angioedema (4 [2.4%; 95% CI, 0.7-6.2] versus 1 [0.4%; 95% CI, 0.01-2.2], P=0.08) or 90-day functional independence (100 [61%] versus 140 [57%], P=0.47), respectively. In mixed-effects logistic regression models, there was no significant association between thrombolytic choice and symptomatic intracranial hemorrhage (odds ratio tenecteplase, 0.62 [95% CI, 0.14-2.80], P=0.53) or functional independence (odds ratio tenecteplase, 1.20 [95% CI, 0.74-1.95], P=0.46). CONCLUSIONS: Routine use of tenecteplase for stroke thrombolysis was feasible and had comparable safety profile and outcome to alteplase.

Functional neurological disorders presenting as emergencies to secondary care.

BACKGROUND: Functional neurological disorders (FND) represent a significant proportion of presentations to outpatient adult neurology services. There is little information relating to patients presenting to acute inpatient care. METHODS: We identified patients presenting as acute admissions with FND to Christchurch Hospital, Christchurch, New Zealand, from 2016 to 2018. We analyzed relevant demographic and clinical data from electronic records and measured incidence of presentation to secondary care and healthcare utilization. RESULTS: One hundred sixty-two patients presented on 173 occasions with FND, representing 9% of all admissions to the neurology service during the 3-year study period. The mean age was 40 (SD 17) years, 111 (69%) patients were female and the median length of stay was 3 (IQR 2-4) days. A total of 92 computed tomography brain scans, 77 magnetic resonance imaging brain scans and 42 electroencephalograms were carried out. On 22 (13%) occasions, patients were referred for outpatient psychological therapy. In the 3 years prior to each patient's last presentation in the study period, these 162 patients had a total of 671 presentations to the emergency department. Healthcare demand did not decrease after the index admission. The rate of acute inpatient admission for FND was 10 per 100,000 per year for the total Christchurch Hospital catchment, 6/100,000/year in rural areas, and 11/100,000/year in urban areas. CONCLUSION: FND represented almost 1 in 10 acute neurology admissions with significant inpatient healthcare resource utilization.

Dopamine Modulates Dynamic Decision-Making during Foraging.

The mesolimbic dopaminergic system exerts a crucial influence on incentive processing. However, the contribution of dopamine in dynamic, ecological situations where reward rates vary, and decisions evolve over time, remains unclear. In such circumstances, current (foreground) reward accrual needs to be compared continuously with potential rewards that could be obtained by traveling elsewhere (background reward rate), to determine the opportunity cost of staying versus leaving. We hypothesized that dopamine specifically modulates the influence of background, but not foreground, reward information when making a dynamic comparison of these variables for optimal behavior. On a novel foraging task based on an ecological account of animal behavior (marginal value theorem), human participants of either sex decided when to leave locations in situations where foreground rewards depleted at different rates, either in rich or poor environments with high or low background reward rates. In line with theoretical accounts, people's decisions to move from current locations were independently modulated by changes in both foreground and background reward rates. Pharmacological manipulation of dopamine D2 receptor activity using the agonist cabergoline significantly affected decisions to move on, specifically modulating the effect of background reward rates. In particular, when on cabergoline, people left patches in poor environments much earlier. These results demonstrate a role of dopamine in signaling the opportunity cost of rewards, not value per se. Using this ecologically derived framework, we uncover a specific mechanism by which D2 dopamine receptor activity modulates decision-making when foreground and background reward rates are dynamically compared.SIGNIFICANCE STATEMENT Many decisions, across economic, political, and social spheres, involve choices to "leave". Such decisions depend on a continuous comparison of a current location's value, with that of other locations you could move on to. However, how the brain makes such decisions is poorly understood. Here, we developed a computerized task, based around theories of how animals make decisions to move on when foraging for food. Healthy human participants had to decide when to leave collecting financial rewards in a location, and travel to collect rewards elsewhere. Using a pharmacological manipulation, we show that the activity of dopamine in the brain modulates decisions to move on, with people valuing other locations differently depending on their dopaminergic state.

Automated lesion segmentation with BIANCA: Impact of population-level features, classification algorithm and locally adaptive thresholding.

White matter hyperintensities (WMH) or white matter lesions exhibit high variability in their characteristics both at population- and subject-level, making their detection a challenging task. Population-level factors such as age, vascular risk factors and neurodegenerative diseases affect lesion load and spatial distribution. At the individual level, WMH vary in contrast, amount and distribution in different white matter regions. In this work, we aimed to improve BIANCA, the FSL tool for WMH segmentation, in order to better deal with these sources of variability. We worked on two stages of BIANCA by improving the lesion probability map estimation (classification stage) and making the lesion probability map thresholding stage automated and adaptive to local lesion probabilities. Firstly, in order to take into account the effect of population-level factors, we included population-level lesion probabilities, modelled with respect to a parametric factor (e.g. age), in the classification stage. Secondly, we tested BIANCA performance when using four alternative classifiers commonly used in the literature with respect to K-nearest neighbour algorithm (currently used for lesion probability map estimation in BIANCA). Finally, we propose LOCally Adaptive Threshold Estimation (LOCATE), a supervised method for determining optimal local thresholds to apply to the estimated lesion probability map, as an alternative option to global thresholding (i.e. applying the same threshold to the entire lesion probability map). For these experiments we used data from a neurodegenerative cohort, a vascular cohort and the cohorts available publicly as a part of a segmentation challenge. We observed that including population-level parametric lesion probabilities with respect to age and using alternative machine learning techniques provided negligible improvement. However, LOCATE provided a substantial improvement in the lesion segmentation performance, when compared to the global thresholding. It allowed to detect more deep lesions and provided better segmentation of periventricular lesion boundaries, despite the differences in the lesion spatial distribution and load across datasets. We further validated LOCATE on a cohort of CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) patients, a genetic form of cerebral small vessel disease, and healthy controls, showing that LOCATE adapts well to wide variations in lesion load and spatial distribution.