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Melancholia has been proposed as a qualitatively distinct depressive subtype associated with a characteristic symptom profile (psychomotor retardation, profound anhedonia) and a better response to biological therapies. Existing work has suggested that individuals with melancholia are blunted in their display of positive emotions and differ in their neural response to emotionally evocative stimuli. Here, we unify these brain and behavioural findings amongst a carefully phenotyped group of seventy depressed participants, drawn from an established Australian database (the Australian Genetics of Depression Study) and further enriched for melancholia (high ratings of psychomotor retardation and anhedonia). Melancholic (n = 30) or non-melancholic status (n = 40) was defined using a semi-structured interview (the Sydney Melancholia Prototype Index). Complex facial expressions were captured whilst participants watched a movie clip of a comedian and classified using a machine learning algorithm. Subsequently, the dynamics of sequential changes in brain activity were modelled during the viewing of an emotionally evocative movie in the MRI scanner. We found a quantitative reduction in positive facial expressivity amongst participants with melancholia, combined with differences in the synchronous expression of brain states during positive epochs of the movie. In non-melancholic depression, the display of positive affect was inversely related to the activity of cerebellar regions implicated in the processing of affect. However, this relationship was reduced in those with a melancholic phenotype. Our multimodal findings show differences in evaluative and motoric domains between melancholic and non-melancholic depression through engagement in ecologically valid tasks that evoke positive emotion. These findings provide new markers to stratify depression and an opportunity to support the development of targeted interventions., (© 2024. The Author(s).)

Caregiver burden is a term that refers to the adverse effect of caregiving on the physical, emotional, social, spiritual, and financial well-being of the caregiver. Caregiver burden is associated with providing care to an individual with a chronic illness or disability, and the unique symptoms of Parkinson disease (PD) can amplify a patient's needs and reliance on others, leading to adverse outcomes for patients and their caregivers. In this scoping review of the literature from January 2017 through April 2022 that included 114 studies, we provide an updated, evidence-based summary of patient and caregiver-related factors that contribute to caregiver burden in PD. We also describe the impact of caregiver stress and burden on caregivers based on qualitative research studies and review recent interventions to mitigate burden. By providing clinical updates for practitioners, this review is designed to improve recognition of caregiver burden in the post-pandemic era and foster the development of targeted interventions to reduce caregiver burden in PD., Competing Interests: Author’s ContributionAamodt: Conception, organization, design, and execution of the review, writing the first draft.Kluger: Conception and organizaion of the review, and critical revision of drafts.Mirham: Organization, literature search, and execution of the reviewJob: Organization, literature search, and execution of the reviewLettenberger: Organization, literature search, and execution of the review.Mosley: Organization and critical revision of drafts.Seshadri: Conception, organization, design, and execution of the review, writing the first draft. Declaration of Conflicting InterestsThe authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Increasing evidence points to a pathophysiological role for the cerebellum in Parkinson's disease (PD). However, regional cerebellar changes associated with motor and non-motor functioning remain to be elucidated., Objective: To quantify cross-sectional regional cerebellar lobule volumes using three dimensional T1-weighted anatomical brain magnetic resonance imaging from the global ENIGMA-PD working group., Methods: Cerebellar parcellation was performed using a deep learning-based approach from 2487 people with PD and 1212 age and sex-matched controls across 22 sites. Linear mixed effects models compared total and regional cerebellar volume in people with PD at each Hoehn and Yahr (HY) disease stage, to an age- and sex- matched control group. Associations with motor symptom severity and Montreal Cognitive Assessment scores were investigated., Results: Overall, people with PD had a regionally smaller posterior lobe (d max  = -0.15). HY stage-specific analyses revealed a larger anterior lobule V bilaterally (d max  = 0.28) in people with PD in HY stage 1 compared to controls. In contrast, smaller bilateral lobule VII volume in the posterior lobe was observed in HY stages 3, 4, and 5 (d max  = -0.76), which was incrementally lower with higher disease stage. Within PD, cognitively impaired individuals had lower total cerebellar volume compared to cognitively normal individuals (d = -0.17)., Conclusions: We provide evidence of a dissociation between anterior "motor" lobe and posterior "non-motor" lobe cerebellar regions in PD. Whereas less severe stages of the disease are associated with larger motor lobe regions, more severe stages of the disease are marked by smaller non-motor regions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

BACKGROUND: Tourette syndrome is characterized by chronic motor and vocal tics. There is preliminary evidence of benefit from cannabis products containing Δ9-tetrahydrocannabinol (THC) and that coadministration of cannabidiol (CBD) improves the side-effect profile and safety. METHODS: In this double-blind, crossover trial, participants with severe Tourette syndrome were randomly assigned to a 6-week treatment period with escalating doses of an oral oil containing 5 mg/ml of THC and 5 mg/ml of CBD, followed by a 6-week course of placebo, or vice versa, separated by a 4-week washout period. The primary outcome was the total tic score on the Yale Global Tic Severity Scale (YGTSS; range, 0 to 50 [higher scores indicate greater severity of symptoms]). Secondary outcomes included video-based assessment of tics, global impairment, anxiety, depression, and obsessive-compulsive symptoms. Outcomes were correlated with plasma levels of cannabinoid metabolites. A computerized cognitive battery was administered at the beginning and the end of each treatment period. RESULTS: Overall, 22 participants (eight female participants) were enrolled. Reduction in total tic score (at week 6 relative to baseline) as measured by the YGTSS was 8.9 (±7.6) in the active group and 2.5 (±8.5) in the placebo group. In a linear mixed-effects model, there was a significant interaction of treatment (active/placebo) and visit number on tic score (coefficient = −2.28; 95% confidence interval, −3.96 to −0.60; P=0.008), indicating a greater decrease (improvement) in tics under active treatment. There was a correlation between plasma 11-carboxy-tetrahydrocannabinol levels and the primary outcome, which was attenuated after exclusion of an outlier. The most common adverse effect in the placebo period was headache (n=7); in the active treatment period, it was cognitive difficulties, including slowed mentation, memory lapses, and poor concentration (n=8). CONCLUSIONS: In severe Tourette syndrome, treatment with THC and CBD reduced tics and may reduce impairment due to tics, anxiety, and obsessive-compulsive disorder; although in some participants this was associated with slowed mentation, memory lapses, and poor concentration. (Funded by the Wesley Medical Research Institute, Brisbane, and the Lambert Initiative for Cannabinoid Therapeutics, a philanthropically-funded research organization at the University of Sydney, Australia; Australian and New Zealand Clinical Trials Registry number, ACTRN12618000545268.)

Importance: Physical health and chronic medical comorbidities are underestimated, inadequately treated, and often overlooked in psychiatry. A multiorgan, systemwide characterization of brain and body health in neuropsychiatric disorders may enable systematic evaluation of brain-body health status in patients and potentially identify new therapeutic targets., Objective: To evaluate the health status of the brain and 7 body systems across common neuropsychiatric disorders., Design, Setting, and Participants: Brain imaging phenotypes, physiological measures, and blood- and urine-based markers were harmonized across multiple population-based neuroimaging biobanks in the US, UK, and Australia, including UK Biobank; Australian Schizophrenia Research Bank; Australian Imaging, Biomarkers, and Lifestyle Flagship Study of Ageing; Alzheimer's Disease Neuroimaging Initiative; Prospective Imaging Study of Ageing; Human Connectome Project-Young Adult; and Human Connectome Project-Aging. Cross-sectional data acquired between March 2006 and December 2020 were used to study organ health. Data were analyzed from October 18, 2021, to July 21, 2022. Adults aged 18 to 95 years with a lifetime diagnosis of 1 or more common neuropsychiatric disorders, including schizophrenia, bipolar disorder, depression, generalized anxiety disorder, and a healthy comparison group were included., Main Outcomes and Measures: Deviations from normative reference ranges for composite health scores indexing the health and function of the brain and 7 body systems. Secondary outcomes included accuracy of classifying diagnoses (disease vs control) and differentiating between diagnoses (disease vs disease), measured using the area under the receiver operating characteristic curve (AUC)., Results: There were 85 748 participants with preselected neuropsychiatric disorders (36 324 male) and 87 420 healthy control individuals (40 560 male) included in this study. Body health, especially scores indexing metabolic, hepatic, and immune health, deviated from normative reference ranges for all 4 neuropsychiatric disorders studied. Poor body health was a more pronounced illness manifestation compared to brain changes in schizophrenia (AUC for body = 0.81 [95% CI, 0.79-0.82]; AUC for brain = 0.79 [95% CI, 0.79-0.79]), bipolar disorder (AUC for body = 0.67 [95% CI, 0.67-0.68]; AUC for brain = 0.58 [95% CI, 0.57-0.58]), depression (AUC for body = 0.67 [95% CI, 0.67-0.68]; AUC for brain = 0.58 [95% CI, 0.58-0.58]), and anxiety (AUC for body = 0.63 [95% CI, 0.63-0.63]; AUC for brain = 0.57 [95% CI, 0.57-0.58]). However, brain health enabled more accurate differentiation between distinct neuropsychiatric diagnoses than body health (schizophrenia-other: mean AUC for body = 0.70 [95% CI, 0.70-0.71] and mean AUC for brain = 0.79 [95% CI, 0.79-0.80]; bipolar disorder-other: mean AUC for body = 0.60 [95% CI, 0.59-0.60] and mean AUC for brain = 0.65 [95% CI, 0.65-0.65]; depression-other: mean AUC for body = 0.61 [95% CI, 0.60-0.63] and mean AUC for brain = 0.65 [95% CI, 0.65-0.66]; anxiety-other: mean AUC for body = 0.63 [95% CI, 0.62-0.63] and mean AUC for brain = 0.66 [95% CI, 0.65-0.66)., Conclusions and Relevance: In this cross-sectional study, neuropsychiatric disorders shared a substantial and largely overlapping imprint of poor body health. Routinely monitoring body health and integrated physical and mental health care may help reduce the adverse effect of physical comorbidity in people with mental illness.

Deep brain stimulation is an emerging therapy for treatment-refractory obsessive-compulsive disorder patients. Yet, accessibility is limited, treatment protocols are heterogeneous and there is no guideline or consensus on the best practices. Here, we combine evidence from scientific investigations, expert opinions and our clinical expertise to propose several clinical recommendations from the pre-operative, surgical and post-operative phases of deep brain stimulation care for treatment-refractory obsessive-compulsive disorder patients. A person-centered and biopsychosocial approach is adopted. Briefly, we discuss clinical characteristics associated with response, the use of improved educational materials, an evaluative consent process, comprehensive programming by an expert clinician, a more global assessment of treatment efficacy, multi-disciplinary adjunct psychotherapy and the importance of peer support programs. Furthermore, where gaps are identified, future research suggestions are made, including connectome surgical targeting, scientific evaluation of hardware models and health economic data. In addition, we encourage collaborative groups of data and knowledge sharing by way of a clinical registry and a peer group of programming clinicians. We aim to commence a discussion on the determinants of deep brain stimulation efficacy for treatment-refractory obsessive-compulsive disorder patients, a rare and severe patient group, and contribute to more standardized and evidence-based practices.

Deep brain stimulation has shown promise for the treatment of severe, treatment-refractory obsessive-compulsive disorder. With the recent publication of the first Australian, randomised, sham-controlled trial of deep brain stimulation for obsessive-compulsive disorder, there are now four placebo-controlled trials demonstrating the efficacy of this therapy. Together with recent data identifying a biological substrate of effective stimulation that can predict response and that has been successfully reproduced, studies comparing and finding equivalent efficacy among different targets, as well as recent, large, open trials supporting the long-term effectiveness of deep brain stimulation, we argue that this should now be considered an accepted therapy for a select group of patients in the Australasian setting. We call on the Royal Australian and New Zealand College of Psychiatrists to revise their memorandum describing deep brain stimulation for obsessive-compulsive disorder as an ' experimental ' treatment and recognise that it has proven efficacy. We stress that this should remain a therapy offered only to those with high treatment-refractory illnesses and only at specialised centres where there is an experienced multidisciplinary team involved in work-up, implantation and follow-up and also where frameworks are in place to provide careful clinical governance and ensure appropriate fully informed consent.

Purpose: Parkinson's disease (PD) is a neurodegenerative disorder associated with progressive disability. While the precise aetiology is unknown, there is evidence of significant genetic and environmental influences on individual risk. The Australian Parkinson's Genetics Study seeks to study genetic and patient-reported data from a large cohort of individuals with PD in Australia to understand the sociodemographic, genetic and environmental basis of PD susceptibility, symptoms and progression., Participants: In the pilot phase reported here, 1819 participants were recruited through assisted mailouts facilitated by Services Australia based on having three or more prescriptions for anti-PD medications in their Pharmaceutical Benefits Scheme records. The average age at the time of the questionnaire was 64±6 years. We collected patient-reported information and sociodemographic variables via an online (93% of the cohort) or paper-based (7%) questionnaire. One thousand five hundred and thirty-two participants (84.2%) met all inclusion criteria, and 1499 provided a DNA sample via traditional post., Findings to Date: 65% of participants were men, and 92% identified as being of European descent. A previous traumatic brain injury was reported by 16% of participants and was correlated with a younger age of symptom onset. At the time of the questionnaire, constipation (36% of participants), depression (34%), anxiety (17%), melanoma (16%) and diabetes (10%) were the most reported comorbid conditions., Future Plans: We plan to recruit sex-matched and age-matched unaffected controls, genotype all participants and collect non-motor symptoms and cognitive function data. Future work will explore the role of genetic and environmental factors in the aetiology of PD susceptibility, onset, symptoms, and progression, including as part of international PD research consortia., Competing Interests: Competing interests: CRS has collaborated with Pfizer, Opko, Proteome Sciences, Genzyme; has consulted for Genzyme; has served as Advisor to the Michael J. Fox Foundation, NIH, Department of Defense; is on the Scientific Advisory Board of the American Parkinson Disease Association; has received funding from the NIH, the U.S. Department of Defense, the Harvard NeuroDiscovery Center, the Michael J. Fox Foundation and American Parkinson Disease Association., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Obsessive-compulsive disorder is among the most disabling psychiatric disorders. Although deep brain stimulation is considered an effective treatment, its use in clinical practice is not fully established. This is, at least in part, due to ambiguity about the best suited target and insufficient knowledge about underlying mechanisms. Recent advances suggest that changes in broader brain networks are responsible for improvement of obsessions and compulsions, rather than local impact at the stimulation site. These findings were fueled by innovative methodological approaches using brain connectivity analyses in combination with neuromodulatory interventions. Such a connectomic approach for neuromodulation constitutes an integrative account that aims to characterize optimal target networks. In this critical review, we integrate findings from connectomic studies and deep brain stimulation interventions to characterize a neural network presumably effective in reducing obsessions and compulsions. To this end, we scrutinize methodologies and seemingly conflicting findings with the aim to merge observations to identify common and diverse pathways for treating obsessive-compulsive disorder. Ultimately, we propose a unified network that-when modulated by means of cortical or subcortical interventions-alleviates obsessive-compulsive symptoms., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Subthalamic deep brain stimulation for Parkinson's disease may not ameliorate burden among caregivers. An 8-session, manualized program of cognitive-behavioral therapy (CBT) was delivered to a pilot sample of 10 caregivers (6 females, mean age: 60, age range: 34-79). Primary outcome measures were caregiver burden (Zarit Burden Interview) and caregiver quality of life (Parkinson's Disease Questionnaire-Carer). Secondary outcome measures comprised ratings of depression and anxiety in the caregiver, in addition to relationship quality. Caregiver burden ( t = 2.91 P = .017) and caregiver anxiety ( t = 2.82 P = .020) symptoms were significantly reduced at completion of the program, and these benefits were maintained 3 months later. Caregiver quality of life had significantly improved by the end of the intervention ( t = 3.02 P = .015), but this effect was not sustained after 3 months. The longitudinal influence of participation in the program on caregiver burden was confirmed in a linear, mixed-effects model, χ 2 (3) = 15.1, P = .0017). The intervention was well received by participants, and qualitative feedback was obtained. These results indicate that caregiver burden is modifiable in this cohort with a short course of CBT, that benefits are maintained after termination of the program, and that psychological treatment is acceptable to participants. Larger, controlled trials are justified.

Deep brain stimulation (DBS) is a promising treatment for severe, treatment-resistant obsessive-compulsive disorder (OCD). Here, nine participants (four females, mean age 47.9 ± 10.7 years) were implanted with DBS electrodes bilaterally in the bed nucleus of the stria terminalis (BNST). Following a one-month postoperative recovery phase, participants entered a three-month randomised, double-blind, sham-controlled phase before a twelve-month period of open-label stimulation incorporating a course of cognitive behavioural therapy (CBT). The primary outcome measure was OCD symptoms as rated with the Yale-Brown Obsessive-Compulsive Scale (YBOCS). In the blinded phase, there was a significant benefit of active stimulation over sham (p = 0.025, mean difference 4.9 points). After the open phase, the mean reduction in YBOCS was 16.6 ± 1.9 points (χ 2 (11) = 39.8, p = 3.8 × 10 -5 ), with seven participants classified as responders. CBT resulted in an additive YBOCS reduction of 4.8 ± 3.9 points (p = 0.011). There were two serious adverse events related to the DBS device, the most severe of which was an infection during the open phase necessitating device explantation. There were no serious psychiatric adverse events related to stimulation. An analysis of the structural connectivity of each participant's individualised stimulation field isolated right-hemispheric fibres associated with YBOCS reduction. These included subcortical tracts incorporating the amygdala, hippocampus and stria terminalis, in addition to cortical regions in the ventrolateral and ventromedial prefrontal cortex, parahippocampal, parietal and extrastriate visual cortex. In conclusion, this study provides further evidence supporting the efficacy and tolerability of DBS in the region of the BNST for individuals with otherwise treatment-refractory OCD and identifies a connectivity fingerprint associated with clinical benefit.

This prospective cohort study, "Prospective Imaging Study of Ageing: Genes, Brain and Behaviour" (PISA) seeks to characterise the phenotype and natural history of healthy adult Australians at high future risk of Alzheimer's disease (AD). In particular, we are recruiting midlife and older Australians with high and low genetic risk of dementia to discover biological markers of early neuropathology, identify modifiable risk factors, and establish the very earliest phenotypic and neuronal signs of disease onset. PISA utilises genetic prediction to recruit and enrich a prospective cohort and follow them longitudinally. Online surveys and cognitive testing are used to characterise an Australia-wide sample currently totalling over 3800 participants. Participants from a defined at-risk cohort and positive controls (clinical cohort of patients with mild cognitive impairment or early AD) are invited for onsite visits for detailed functional, structural and molecular neuroimaging, lifestyle monitoring, detailed neurocognitive testing, plus blood sample donation. This paper describes recruitment of the PISA cohort, study methodology and baseline demographics., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

The subthalamic nucleus (STN) is a subcortical, glutamatergic, excitatory, relay nucleus that increases the inhibitory drive of the basal ganglia and suppresses action. It is of central relevance to the neuropsychological construct of inhibition, as well as the pathophysiology of Parkinson's disease (PD). Deep brain stimulation (DBS) of the STN (STN-DBS) is an established surgical treatment for PD that can be complicated by adverse neuropsychiatric side effects, most commonly characterized by impulsivity and mood elevation, although depression, anxiety, apathy, and cognitive changes have also been reported. Notwithstanding these adverse neuropsychiatric effects in PD, STN-DBS may also have a role in the treatment of refractory psychiatric disorders, as more is understood about the physiology of this nucleus and techniques in neuromodulation are refined. In this chapter, we link neuropsychiatric symptoms after STN-DBS for PD to the biological effects of electrode implantation, neurostimulation, and adjustments to dopaminergic medication, in the setting of neurodegeneration affecting cortico-striatal connectivity. We then provide an overview of clinical trials that have employed STN-DBS to treat obsessive-compulsive disorder and discuss future directions for subthalamic neuromodulation in psychiatry., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Initiation and inhibition are executive functions whose disruption in Parkinson's disease impacts substantially on everyday activities. Management of Parkinson's disease with subthalamic deep brain stimulation (DBS) modifies initiation and inhibition, with prior work suggesting that these effects may be mediated via the connectivity of the subthalamic nucleus (STN) with the frontal cortex. Here, we employed high-resolution structural neuroimaging to investigate the variability in initiation, inhibition and strategy use in a cohort of twenty-five (ten females, mean age 62.5, mean Hoehn and Yahr stage 2.5) participants undertaking subthalamic DBS for Parkinson's disease. Neuropsychological assessment of initiation and inhibition was performed preoperatively and at six months postoperatively. We first reconstructed the preoperative connectivity of the STN with a frontal network of anterior and superior medial cortical regions. We then modelled the postoperative site of subthalamic stimulation and reconstructed the connectivity of the stimulation field within this same network. We found that, at both pre- and postoperative intervals, inter-individual variability in inhibition and initiation were strongly associated with structural network connectivity. Measures of subcortical atrophy and local stimulation effects did not play a significant role. Preoperatively, we replicated prior work, including a role for the right inferior frontal gyrus in inhibition and strategy use, as well as the left inferior frontal gyrus in tasks requiring selection under conditions of maintained inhibition. Postoperatively, greater connectivity of the stimulation field with right anterior cortical regions was associated with greater rule violations and suppression errors, supporting prior work implicating right-hemispheric STN stimulation in disinhibition. Our findings suggest that, in Parkinson's disease, connectivity of the frontal cortex with the STN is an important mediator of individual variability in initiation and inhibition,. Personalised information on brain network architecture could guide individualised brain circuit manipulation to minimise neuropsychological disruption after STN-DBS., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Subthalamic deep brain stimulation (STN-DBS) for Parkinson's disease treats motor symptoms and improves quality of life, but can be complicated by adverse neuropsychiatric side-effects, including impulsivity. Several clinically important questions remain unclear: can 'at-risk' patients be identified prior to DBS; do neuropsychiatric symptoms relate to the distribution of the stimulation field; and which brain networks are responsible for the evolution of these symptoms? Using a comprehensive neuropsychiatric battery and a virtual casino to assess impulsive behaviour in a naturalistic fashion, 55 patients with Parkinson's disease (19 females, mean age 62, mean Hoehn and Yahr stage 2.6) were assessed prior to STN-DBS and 3 months postoperatively. Reward evaluation and response inhibition networks were reconstructed with probabilistic tractography using the participant-specific subthalamic volume of activated tissue as a seed. We found that greater connectivity of the stimulation site with these frontostriatal networks was related to greater postoperative impulsiveness and disinhibition as assessed by the neuropsychiatric instruments. Larger bet sizes in the virtual casino postoperatively were associated with greater connectivity of the stimulation site with right and left orbitofrontal cortex, right ventromedial prefrontal cortex and left ventral striatum. For all assessments, the baseline connectivity of reward evaluation and response inhibition networks prior to STN-DBS was not associated with postoperative impulsivity; rather, these relationships were only observed when the stimulation field was incorporated. This suggests that the site and distribution of stimulation is a more important determinant of postoperative neuropsychiatric outcomes than preoperative brain structure and that stimulation acts to mediate impulsivity through differential recruitment of frontostriatal networks. Notably, a distinction could be made amongst participants with clinically-significant, harmful changes in mood and behaviour attributable to DBS, based upon an analysis of connectivity and its relationship with gambling behaviour. Additional analyses suggested that this distinction may be mediated by the differential involvement of fibres connecting ventromedial subthalamic nucleus and orbitofrontal cortex. These findings identify a mechanistic substrate of neuropsychiatric impairment after STN-DBS and suggest that tractography could be used to predict the incidence of adverse neuropsychiatric effects. Clinically, these results highlight the importance of accurate electrode placement and careful stimulation titration in the prevention of neuropsychiatric side-effects after STN-DBS., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Impulsivity in Parkinson's disease may be mediated by faulty evaluation of rewards or the failure to inhibit inappropriate choices. Despite prior work suggesting that distinct neural networks underlie these cognitive operations, there has been little study of these networks in Parkinson's disease, and their relationship to inter-individual differences in impulsivity. High-resolution diffusion MRI data were acquired from 57 individuals with Parkinson's disease (19 females, mean age 62, mean Hoehn and Yahr stage 2.6) prior to surgery for deep brain stimulation. Reward evaluation and response inhibition networks were reconstructed with seed-based probabilistic tractography. Impulsivity was evaluated using two approaches: (i) neuropsychiatric instruments were used to assess latent constructs of impulsivity, including trait impulsiveness and compulsivity, disinhibition, and also impatience; and (ii) participants gambled in an ecologically-valid virtual casino to obtain a behavioural read-out of explorative, risk-taking, impulsive behaviour. Multivariate analyses revealed that different components of impulsivity were associated with distinct variations in structural connectivity, implicating both reward evaluation and response inhibition networks. Larger bet sizes in the virtual casino were associated with greater connectivity of the reward evaluation network, particularly bilateral fibre tracts between the ventral striatum and ventromedial prefrontal cortex. In contrast, weaker connectivity of the response inhibition network was associated with increased exploration of alternative slot machines in the virtual casino, with right-hemispheric tracts between the subthalamic nucleus and the pre-supplementary motor area contributing most strongly. Further, reduced connectivity of the reward evaluation network was associated with more 'double or nothing' gambles, weighted by connections between the subthalamic nucleus and ventromedial prefrontal cortex. Notably, the variance explained by structural connectivity was higher for behavioural indices of impulsivity, derived from clinician-administered tasks and the gambling paradigm, as compared to questionnaire data. Lastly, a clinically-meaningful distinction could be made amongst participants with a history of impulse control behaviours based on the interaction of their network connectivity with medication dosage and gambling behaviour. In summary, we report structural brain-behaviour covariation in Parkinson's disease with distinct reward evaluation and response inhibition networks that underlie dissociable aspects of impulsivity (cf. choosing and stopping). More broadly, our findings demonstrate the potential of using naturalistic paradigms and neuroimaging techniques in clinical settings to assist in the identification of those susceptible to harmful behaviours., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Subthalamic deep brain stimulation (DBS) for Parkinson's disease (PD) may modulate chronometric and instrumental aspects of choice behaviour, including motor inhibition, decisional slowing, and value sensitivity. However, it is not well known whether subthalamic DBS affects more complex aspects of decision-making, such as the influence of subjective estimates of uncertainty on choices. In this study, 38 participants with PD played a virtual casino prior to subthalamic DBS (whilst 'on' medication) and again, 3-months postoperatively (whilst 'on' stimulation). At the group level, there was a small but statistically significant decrease in impulsivity postoperatively, as quantified by the Barratt Impulsiveness Scale (BIS). The gambling behaviour of participants (bet increases, slot machine switches and double or nothing gambles) was associated with this self-reported measure of impulsivity. However, there was a large variance in outcome amongst participants, and we were interested in whether individual differences in subjective estimates of uncertainty (specifically, volatility) were related to differences in pre- and postoperative impulsivity. To examine these individual differences, we fit a computational model (the Hierarchical Gaussian Filter, HGF), to choices made during slot machine game play as well as a simpler reinforcement learning model based on the Rescorla-Wagner formalism. The HGF was superior in accounting for the behaviour of our participants, suggesting that participants incorporated beliefs about environmental uncertainty when updating their beliefs about gambling outcome and translating these beliefs into action. A specific aspect of subjective uncertainty, the participant's estimate of the tendency of the slot machine's winning probability to change (volatility), increased subsequent to DBS. Additionally, the decision temperature of the response model decreased post-operatively, implying greater stochasticity in the belief-to-choice mapping of participants. Model parameter estimates were significantly associated with impulsivity; specifically, increased uncertainty was related to increased postoperative impulsivity. Moreover, changes in these parameter estimates were significantly associated with the maximum post-operative change in impulsivity over a six month follow up period. Our findings suggest that impulsivity in PD patients may be influenced by subjective estimates of uncertainty (environmental volatility) and implicate a role for the subthalamic nucleus in the modulation of outcome certainty. Furthermore, our work outlines a possible approach to characterising those persons who become more impulsive after subthalamic DBS, an intervention in which non-motor outcomes can be highly variable.

Subthalamic deep brain stimulation is an advanced therapy that typically improves quality of life for persons with Parkinson's disease (PD). However, the effect on caregiver burden is unclear. We recruited 64 persons with PD and their caregivers from a movement disorders clinic during the assessment of eligibility for subthalamic DBS. We used clinician-, patient- and caregiver-rated instruments to follow the patient-caregiver dyad from pre- to postoperative status, sampling repeatedly in the postoperative period to ascertain fluctuations in phenotypic variables. We employed multivariate models to identify key drivers of burden. We clustered caregiver-rated variables into 'high' and 'low' symptom groups and examined whether postoperative cluster assignment could be predicted from baseline values. Psychiatric symptoms in the postoperative period made a substantial contribution to longitudinal caregiver burden. The development of stimulation-dependent mood changes was also associated with increased burden. However, caregiver burden and caregiver-rated psychiatric symptom clusters were temporally stable and thus predicted only by their baseline values. We confirmed this finding using frequentist and Bayesian statistics, concluding that in our sample, subthalamic DBS for PD did not significantly influence caregiver burden or caregiver-rated psychiatric symptoms. Specifically, patient-caregiver dyads with high burden and high levels of psychiatric symptoms at baseline were likely to maintain this profile during follow-up. These findings support the importance of assessing caregiver burden prior to functional neurosurgery. Furthermore, they suggest that interventions addressing caregiver burden in this population should target those with greater symptomatology at baseline and may usefully prioritise psychiatric symptoms reported by the caregiver., Competing Interests: The authors declare no competing interests.

Deep brain stimulation of the subthalamic nucleus for Parkinson's disease is an established advanced therapy that addresses motor symptoms and improves quality of life. However, it has also been associated with neuropsychiatric symptoms such as impulsivity and hypomania. When significant, these symptoms can be distressing, necessitating psychiatric intervention. However, a comprehensive analysis of neurocognitive and neuropsychiatric outcomes with reference to the site of subthalamic stimulation has not been undertaken. We examined this matter in a consecutive sample of 64 persons with Parkinson's disease undertaking subthalamic deep brain stimulation. Participants were assessed with a battery of neuropsychiatric instruments at baseline and at repeated postoperative intervals. A psychiatrist identified patients with emergent, clinically-significant symptoms due to stimulation. The site of the active electrode contact and a simulated volume of activated tissue were evaluated with reference to putative limbic, associative and motor subregions of the subthalamic nucleus. We studied anatomical correlates of longitudinal neuropsychiatric change and delineated specific subthalamic regions associated with neuropsychiatric impairment. We tested the ability of these data to predict clinically-significant symptoms. Subthalamic stimulation within the right associative subregion was associated with inhibitory errors on the Excluded Letter Fluency task at 6-weeks ( p  = 0.023) and 13-weeks postoperatively ( p  = 0.0017). A cluster of subthalamic voxels associated with inhibitory errors was identified in the right associative and motor subregions. At 6-weeks, clinically-significant neuropsychiatric symptoms were associated with the distance of the active contact to the right associative subregion ( p  = 0.0026) and stimulation within the right associative subregion ( p  = 0.0009). At 13-weeks, clinically-significant symptoms were associated with the distance to the right ( p =  0.0027) and left ( p  = 0.0084) associative subregions and stimulation within the right associative subregion ( p  = 0.0026). Discrete clusters of subthalamic voxels associated with high and low likelihood of postoperative neuropsychiatric symptoms were identified in ventromedial and dorsolateral zones, respectively. When a classifier was trained on these data, clinically-significant symptoms were predicted with an accuracy of 79%. These data underscore the importance of accurate electrode targeting, contact selection and device programming to reduce postoperative neuropsychiatric impairment. The ability to predict neuropsychiatric symptoms based on subthalamic data may permit anticipation and prevention of these occurrences, improving safety and tolerability.

Burden is a negative psychological state induced in caregivers by the demands of providing care to a person with an illness or a disability. Managing caregiver burden in Parkinson disease (PD) is significant because informal caregivers make a substantial contribution to the well-being of persons with PD, incurring financial, social, and personal losses. Failure to recognize and manage caregiver burden may lead to burnout and premature institutionalization of the person with PD. We conducted a comprehensive literature review to identify and summarize factors that may amplify burden, including motor and nonmotor symptoms of PD, caregiver psychiatric symptoms, and caregiver coping style. We review instruments designed to sample the construct of burden among caregivers and evaluate interventions that may reduce burden, either by directly targeting caregivers or by treating PD symptoms associated with burden. We aim to provide a concise synopsis of these issues for the clinician or researcher working with this population in order to facilitate recognition of caregiver burden, provide accurate assessment, administer appropriate interventions, and stimulate further research in this area.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established treatment for the motor symptoms of Parkinson's disease (PD). Nonmotor features of PD, however, may not improve with STN DBS, and a specific constellation of neuropsychiatric symptoms may emerge in the postoperative period. Mania, impulsivity, depression, and apathy may curtail the potential gains from surgery. In this paper, the authors discuss surgical candidacy, postoperative management of neuropsychiatric issues, and clinical dilemmas for the psychiatrist at the DBS center. A paradigm that considers stimulation effects and dopamine replacement therapy to be key drivers of postoperative neuropsychiatric problems is presented.

Objective: Deep brain stimulation is an experimental intervention for treatment-resistant depression. Open trials have shown a sustained response to chronic stimulation in many subjects. However, two recent randomised, double-blind, placebo-controlled trials failed to replicate these results. This article is a conceptual paper examining potential explanations for these discrepant findings., Method: We conducted a systematic review of the published studies obtained from PubMed and PsycINFO. Studies were selected if they directly examined the impact of deep brain stimulation on depressive symptoms. We excluded case reports and papers re-describing the same cohort of patients. We compared them with data from the placebo-controlled trials, available from Clinicaltrials.gov and abstracts of the American Society for Stereotactic and Functional Neurosurgery. We supplemented our investigation by reviewing additional publications by the major groups undertaking deep brain stimulation for mood disorders., Results: We selected 10 open studies reporting on eight cohorts of patients using four different operative targets. All published studies reported positive results. This was not replicated in data available from the randomised, placebo-controlled trials. Many studies reported suicide or suicide attempts in the postoperative period., Conclusion: We consider the placebo effect, the pattern of network activation, surgical candidacy and design of a blinded trial including the length of a crossover period. We suggest a greater focus on selecting patients with melancholia. We anticipate that methodological refinements may facilitate further investigation of this technology for intractable depression. We conclude by noting the psychiatric adverse events that have been reported in the literature to date, as these will also influence the design of future trials of deep brain stimulation for depression., (© The Royal Australian and New Zealand College of Psychiatrists 2015.)

Muscle dysmorphia is an emerging condition that primarily affects male bodybuilders. Such individuals obsess about being inadequately muscular. Compulsions include spending hours in the gym, squandering excessive amounts of money on ineffectual sports supplements, abnormal eating patterns or even substance abuse. In this essay, I illustrate the features of muscle dysmorphia by employing the first-person account of a male bodybuilder afflicted by this condition. I briefly outline the history of bodybuilding and examine whether the growth of this sport is linked to a growing concern with body image amongst males. I suggest that muscle dysmorphia may be a new expression of a common pathology shared with the eating disorders.