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Background In this study, we asked whether differences in striatal activity during a reinforcement learning (RL) task with gain and loss domains could be one of the earliest functional imaging features associated with carrying the Huntington's disease (HD) gene. Based on previous work, we hypothesized that HD gene carriers would show either neural or behavioral asymmetry between gain and loss learning. Methods We recruited 35 HD gene carriers, expected to demonstrate onset of motor symptoms in an average of 26 years, and 35 well-matched gene-negative control subjects. Participants were placed in a functional magnetic resonance imaging scanner, where they completed an RL task in which they were required to learn to choose between abstract stimuli with the aim of gaining rewards and avoiding losses. Task behavior was modeled using an RL model, and variables from this model were used to probe functional magnetic resonance imaging data. Results In comparison with well-matched control subjects, gene carriers more than 25 years from motor onset showed exaggerated striatal responses to gain-predicting stimuli compared with loss-predicting stimuli (p = .002) in our RL task. Using computational analysis, we also found group differences in striatal representation of stimulus value (p = .0004). We found no group differences in behavior, cognitive scores, or caudate volumes. Conclusions Behaviorally, gene carriers 9 years from predicted onset have been shown to learn better from gains than from losses. Our data suggest that a window exists in which HD-related functional neural changes are detectable long before associated behavioral change and 25 years before predicted motor onset. These represent the earliest functional imaging differences between HD gene carriers and control subjects.

Background Pathological processes in Huntington's disease (HD) begin many years prior to symptom onset. Recently we demonstrated that in a premanifest cohort approximately 24 years from predicted disease onset, despite intact function, there was evidence of subtle neurodegeneration. Here, we use novel imaging techniques to determine whether macro- and micro-structural changes can be detected across the whole-brain in the same cohort. Methods 62 premanifest HD (PreHD) and 61 controls from the HD Young Adult Study (HD-YAS) were included. Grey and white matter volume, diffusion weighted imaging (DWI) measures of white matter microstructure, multiparametric maps (MPM) estimating myelin and iron content from magnetization transfer (MT), proton density (PD), longitudinal relaxation (R1) and effective transverse relaxation (R2*), and myelin g-ratio were examined. Group differences between PreHD and controls were assessed; associations between all imaging metrics and disease burden and CSF neurofilament light (NfL) were also performed. Volumetric and MPM results were corrected at a cluster-wise value of familywise error (FWE) 0.05. Diffusion and g-ratio results were corrected via threshold-free cluster enhancement at FWE 0.05. Findings We showed significantly increased R1 and R2*, suggestive of increased iron, in the putamen, globus pallidum and external capsule of PreHD participants. There was also a significant association between lower cortical R2*, suggestive of reduced myelin or iron, and higher CSF NfL in the frontal lobe and the parieto-occipital cortices. No other results were significant at corrected levels. Interpretation Increased iron in subcortical structures and the surrounding white matter is a feature of very early PreHD. Furthermore, increases in CSF NfL were linked to microstructural changes in the posterior parietal-occipital cortex, a region previously shown to undergo some of the earliest cortical changes in HD. These findings suggest that disease related process are occurring in both subcortical and cortical regions more than 20 years from predicted disease onset.

BACKGROUND: Disease-modifying treatments are in development for Huntington's disease; crucial to their success is to identify a timepoint in a patient's life when there is a measurable biomarker of early neurodegeneration while clinical function is still intact. We aimed to identify this timepoint in a novel cohort of young adult premanifest Huntington's disease gene carriers (preHD) far from predicted clinical symptom onset. METHODS: We did the Huntington's disease Young Adult Study (HD-YAS) in the UK. We recruited young adults with preHD and controls matched for age, education, and sex to ensure each group had at least 60 participants with imaging data, accounting for scan fails. Controls either had a family history of Huntington's disease but a negative genetic test, or no known family history of Huntington's disease. All participants underwent detailed neuropsychiatric and cognitive assessments, including tests from the Cambridge Neuropsychological Test Automated Battery and a battery assessing emotion, motivation, impulsivity and social cognition (EMOTICOM). Imaging (done for all participants without contraindications) included volumetric MRI, diffusion imaging, and multiparametric mapping. Biofluid markers of neuronal health were examined using blood and CSF collection. We did a cross-sectional analysis using general least-squares linear models to assess group differences and associations with age and CAG length, relating to predicted years to clinical onset. Results were corrected for multiple comparisons using the false discovery rate (FDR), with FDR 0·16). CSF neurofilament light protein (NfL), plasma NfL, and CSF YKL-40 were elevated in this far-from-onset preHD cohort compared with controls (FDR

Psychological therapies, such as CBT, are an important part of the treatment of a range of psychiatric disorders such as depression and anxiety. There is a growing desire to understand the mechanisms by which such therapies effect change so as to improve treatment outcomes. Here we argue that adopting a computational framework may be one such approach. Computational psychiatry aims to provide a theoretical framework for moving between higher-level psychological states (like emotions, decisions and beliefs) to neural circuits, by modeling these constructs mathematically. These models are explicit hypotheses that contain quantifiable variables and parameters derived from each individual's behavior. This approach has two advantages. Firstly, some of the variables described by these models appears to reflect the neural activity of specific brain regions. Secondly, the parameters estimated by these models may offer a unique description of a patient's symptoms which can be used to both tailor therapy and track its effect. In doing so this approach may offer some additional granularity in understanding how psychological therapies, such as CBT, are working. Although this field shows significant promise, we also highlight several of the key hurdles that must first be overcome before clinical translation of computational insights can be realized.

Importance Dysfunctional reward processing is a leading candidate mechanism for the development of certain depressive symptoms, such as anhedonia. However, to our knowledge, there has not yet been a systematic assessment of whether and to what extent depression is associated with impairments on behavioral reward-processing tasks. Objective To determine whether depression is associated with impairments in reward-processing behavior. Data Sources The MEDLINE/PubMed, Embase, and PsycInfo databases were searched for studies that investigated reward processing using performance on behavioral tasks by individuals with depression and nondepressed control groups, published between January 1, 1946, and August 16, 2019. Study Selection Studies that contained data regarding performance by depressed and healthy control groups on reward-processing tasks were included in the systematic review and meta-analysis. Data Extraction and Synthesis Summary statistics comparing performance between depressed and healthy groups on reward-processing tasks were converted to standardized mean difference (SMD) scores, from which summary effect sizes for overall impairment in reward processing and 4 subcomponent categories were calculated. Study quality, heterogeneity, replicability-index, and publication bias were also assessed. Main Outcome and Measures Performance on reward-processing tasks. Results The final data set comprised 48 case-control studies (1387 healthy control individuals and 1767 individuals with major depressive disorder). The mean age was 37.85 years and 58% of the participants were women. These studies used tasks assessing option valuation (n = 9), reward bias (n = 6), reward response vigor (n = 12), reinforcement learning (n = 20), and grip force (n = 1). Across all tasks, depression was associated with small to medium impairments in reward-processing behavior (SMD = 0.345; 95% CI, 0.209-0.480). When examining reward-processing subcomponent categories, impairment was associated with tasks assessing option valuation (SMD = 0.309; 95% CI, 0.147-0.471), reward bias (SMD = 0.644; 95% CI, 0.270-1.017), and reinforcement learning (SMD = 0.352; 95% CI, 0.115-0.588) but not reward response vigor (SMD = 0.083; 95% CI, −0.144 to 0.309). The medication status of the major depressive disorder sample did not explain any of the variance in the overall effect size. There was significant between-study heterogeneity overall and in all subcomponent categories other than option valuation. Significant publication bias was identified overall and in the reinforcement learning category. Conclusions and Relevance Relative to healthy control individuals, individuals with depression exhibit reward-processing impairments, particularly for tests of reward bias, option valuation, and reinforcement learning. Understanding the neural mechanisms driving these associations may assist in designing novel interventions.

Objective Antipsychotic drug sensitivity in very late-onset schizophrenia-like psychosis (VLOSLP) is well documented, but poorly understood. This study aimed to investigate blood drug concentration, D2/3 receptor occupancy and outcome in VLOSLP during open amisulpride prescribing, and compare this with Alzheimer's disease (AD). Methods Blood drug concentration, prolactin, symptoms and extrapyramidal side-effects (EPS) were serially assessed during dose titration. [18F]fallypride imaging was used to quantify D2/3 receptor occupancy. Average steady-state amisulpride concentration (Caverage, ng/ml) was estimated by incorporating pharmacokinetic (PK) data into an existing population PK model (25 AD participants, 20 healthy older people). Results Eight patients (target 20) were recruited (six women; 76 + − 6 years; six treatment compliant; five serially sampled; three with paired imaging data). Mean + − SD symptom reduction was 74 ± 12% (50–100 mg/day; 92.5 + −39.4 ng/ml). Mild EPS emerged at 96 ng/ml (in AD, severe EPS, 50 mg/day, 60 ng/ml). In three participants, imaged during optimal treatment (50 mg/day; 41–70 ng/ml), caudate occupancy was 44–59% (58–74% in AD across a comparable Caverage). Conclusions Despite the small sample size, our findings are highly relevant as they suggest that, as in AD, 50 mg/day amisulpride is associated with >40% occupancy and clinically relevant responses in VLOSLP. It was not possible to fully characterise concentration–occupancy relationships in VLOSLP, and it is thus unclear whether the greater susceptibility of those with AD to emergent EPS was accounted for by increased central drug access. Further investigation of age- and diagnosis-specific threshold sensitivities is warranted, to guide amisulpride prescribing in older people, and therapeutic drug monitoring studies offer a potentially informative future approach. Copyright © 2017 John Wiley & Sons, Ltd.

HD-YAS will study a cohort of young adult HD Gene Expansion Carriers (HDGEC) decades before expected symptom onset to characterize the very earliest signs of disease-related brain changes and identify whether there is any identifiable early functional impairment. Currently there is no detailed characterization of such a young adult HDGEC cohort and this represents the earliest time point after predictive genetic testing in which to gain disease insights. HD-YAS will be important in determining the earliest potential time window for therapeutic intervention. HD-YAS will recruit 120 participants-60 premanifest HDGECs and 60 gene negative or family controls-and will use a cross-sectional comparison with one visit per participant to assess the earliest time-point at which neurodegeneration can be detected. Participants will undergo 3T Volumetric MRI, rsfMRI and task fMRI, NODDI, and cognitive assessments including the CANTAB and EMOTICOM batteries, and biosamples such as CSF, blood and DNA will be collected to investigate biomarkers. Participants will be 18–40 years old and at-risk individuals must have a predictive genetic test; either carry the HD gene (gene-carrier) or not carry the HD gene (control). Individuals must not show any clinical symptoms of HD, have a disease burden score of ≤240, and must be willing and able to comply with the study visit and study procedures. HD-YAS began in August 2017 and is expected to complete by February 2019. HD-YAS collaborates with Enroll-HD, UK clinical genetics services and HD charity groups to identify potentially eligible participants throughout the UK. HD-YAS is funded by Wellcome, with CSF collection funded by CHDI. HD-YAS investigators – Participant Identification Site Investigators; Dr Oliver Quarrell, Dr Nayana Lahiri, Dr Andrea Nemeth, Dr Mary Porteous, Dr Elisabeth Rosser, Dr David Craufurd, Dr Rhona MacLeod, Dr Deborah Ruddy, Dr Roger Barker, Dr Simon Holden, Dr Hugh Rickards, Dr Anne Rosser, Dr Emma Hobson, Prof Angus Clarke, Dr Katherine Lachlan, Dr Reza Kiani, Dr Timothy Harrower. Thank you to the HDA, HDYO, SHA.

We have previously reported high dopamine D2/3 receptor occupancies at low amisulpride concentrations in older people with Alzheimer's disease (AD), during off-label treatment of AD-related psychosis. This post hoc analysis explored pharmacokinetic (concentration) and pharmacodynamic (prolactin, D2/3 occupancy) contributions to symptom reduction and extrapyramidal side effects (EPS) to inform AD-specific dose adjustments.Population pharmacokinetic-pharmacodynamic models were developed by combining pharmacokinetic data from a phase 1 study in 20 healthy older people with pharmacokinetic prolactin, [¹⁸F]fallypride D2/3 receptor imaging, and clinical outcome data from 28 older patients prescribed open amisulpride (25-75 mg/d) to treat AD-related psychosis. Model predictions were used to simulate dose-response and dose-EPS.Symptom reduction (delusions) was associated with amisulpride concentration (P = 1.3e-05) and D2/3 occupancy (P.01, caudate, putamen, thalamus). Model predictions suggested that across concentrations of 40-100 ng/mL, and occupancies of 40% to 70% in the caudate and thalamus and 30% to 60% in the putamen, there was a 50% to 90% probability of response and30% probability of EPS. Simulations, based on concentration-delusions and concentration-EPS model outputs, showed that 50 mg/d of amisulpride was the appropriate dose to achieve this target range in those aged75 years; increasing the dose to 75 mg/d increased the risk of EPS, particularly in those aged85 years of low body weight.These findings argue strongly for the consideration of age- and weight-based dose adjustments in older patients with AD-related psychosis and indicate that 50 mg/d of amisulpride may be both the minimal clinically effective dose and, in those aged75 years, the maximally tolerated dose.

See Caravaggio and Graff-Guerrero (doi:10.1093/awx023) for a scientific commentary on this article.Antipsychotic drugs, originally developed to treat schizophrenia, are used to treat psychosis, agitation and aggression in Alzheimer's disease. In the absence of dopamine D2/3 receptor occupancy data to inform antipsychotic prescribing for psychosis in Alzheimer's disease, the mechanisms underpinning antipsychotic efficacy and side effects are poorly understood. This study used a population approach to investigate the relationship between amisulpride blood concentration and central D2/3 occupancy in older people with Alzheimer's disease by combining: (i) pharmacokinetic data (280 venous samples) from a phase I single (50 mg) dose study in healthy older people (n = 20, 65-79 years); (ii) pharmacokinetic, 18F-fallypride D2/3 receptor imaging and clinical outcome data on patients with Alzheimer's disease who were prescribed amisulpride (25-75 mg daily) to treat psychosis as part of an open study (n = 28; 69-92 years; 41 blood samples, five pretreatment scans, 19 post-treatment scans); and (iii) 18F-fallypride imaging of an antipsychotic free Alzheimer's disease control group (n = 10, 78-92 years), to provide additional pretreatment data. Non-linear mixed effects modelling was used to describe pharmacokinetic-occupancy curves in caudate, putamen and thalamus. Model outputs were used to estimate threshold steady state blood concentration and occupancy required to elicit a clinically relevant response (>25% reduction in scores on delusions, hallucinations and agitation domains of the Neuropsychiatric Inventory) and extrapyramidal side effects (Simpson Angus Scale scores > 3). Average steady state blood levels were low (71 ± 30 ng/ml), and associated with high D2/3 occupancies (65 ± 8%, caudate; 67 ± 11%, thalamus; 52 ± 11%, putamen). Antipsychotic clinical response occurred at a threshold concentration of 20 ng/ml and D2/3 occupancies of 43% (caudate), 25% (putamen), 43% (thalamus). Extrapyramidal side effects (n = 7) emerged at a threshold concentration of 60 ng/ml, and D2/3 occupancies of 61% (caudate), 49% (putamen) and 69% (thalamus). This study has established that, as in schizophrenia, there is a therapeutic window of D2/3 receptor occupancy for optimal treatment of psychosis in Alzheimer's disease. We have also shown that occupancies within and beyond this window are achieved at very low amisulpride doses in Alzheimer's disease due to higher than anticipated occupancies for a given blood drug concentration. Our findings support a central pharmacokinetic contribution to antipsychotic sensitivity in Alzheimer's disease and implicate the blood-brain barrier, which controls central drug access. Whether high D2/3 receptor occupancies are primarily accounted for by age- or disease-specific blood-brain barrier disruption is unclear, and this is an important future area of future investigation, as it has implications beyond antipsychotic prescribing.

Introduction Current prescribing guidelines for the antipsychotic amisulpride are based largely on pharmacokinetic (PK) studies in young adults, and there is a relative absence of data on older patients, who are at greatest risk of developing adverse events. Methods This study aimed to develop a population PK model for amisulpride specifically in older people, by combining data from a richly sampled phase 1, single (50 mg) dose study in healthy older people (n = 20, 65–79 years), with a clinical dataset obtained during off label, low-dose (25–75 mg daily) amisulpride prescribing in older people with Alzheimer’s disease (AD) (n = 25, 69–92 years), as part of an observational study. Results After introducing a scaling factor based on body weight, age accounted for 20 % of the inter-individual variability in drug clearance (CL), resulting in a 54 % difference in CL between those aged 65 and those aged 85 years, and higher blood concentrations in older patients. Discussion These findings argue for the consideration of age and weight-based dose stratification to optimise amisulpride prescribing in older people, particularly in those aged 85 years and above. Electronic supplementary material The online version of this article (doi:10.1007/s00213-016-4379-6) contains supplementary material, which is available to authorized users.

SummaryDespite rigorous research into the genetics of neuropsychiatric disorders, the mechanism by which polygenic risk leads to complex clinical phenotypes remains unclear. The Encyclopedia of DNA Elements (ENCODE) project gives us new insight into gene regulation, and gene–gene and gene–environment interaction.Better understanding of these key genomic mechanisms may provide the answers we have been searching for.

I read with great interest the article by Crossley et al [1][1] and, although commending their work, I was surprised to arrive at the opposite conclusion to that of the authors. In their meta-analysis of structural magnetic resonance imaging correlates of ‘psychiatric’ and ‘neurological’