Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease with the age at which characteristic symptoms manifest strongly influenced by inherited HTT CAG length. Somatic CAG expansion occurs throughout life and understanding the impact of somatic expansion on neurodegeneration is key to developing therapeutic targets. In 57 HD gene expanded (HDGE) individuals, ~23 years before their predicted clinical motor diagnosis, no significant decline in clinical, cognitive or neuropsychiatric function was observed over 4.5 years compared with 46 controls (false discovery rate (FDR) > 0.3). However, cerebrospinal fluid (CSF) markers showed very early signs of neurodegeneration in HDGE with elevated neurofilament light (NfL) protein, an indicator of neuroaxonal damage (FDR = 3.2 × 10−12), and reduced proenkephalin (PENK), a surrogate marker for the state of striatal medium spiny neurons (FDR = 2.6 × 10−3), accompanied by brain atrophy, predominantly in the caudate (FDR = 5.5 × 10−10) and putamen (FDR = 1.2 × 10−9). Longitudinal increase in somatic CAG repeat expansion ratio (SER) in blood was a significant predictor of subsequent caudate (FDR = 0.072) and putamen (FDR = 0.148) atrophy. Atypical loss of interruption HTT repeat structures, known to predict earlier age at clinical motor diagnosis, was associated with substantially faster caudate and putamen atrophy. We provide evidence in living humans that the influence of CAG length on HD neuropathology is mediated by somatic CAG repeat expansion. These critical mechanistic insights into the earliest neurodegenerative changes will inform the design of preventative clinical trials aimed at modulating somatic expansion. ClinicalTrials.gov registration: NCT06391619 . A comprehensive longitudinal analysis of individuals with preclinical Huntington’s disease identifies biomarkers of neurodegeneration and somatic expansion in blood DNA, detectable years before symptom onset.

MS is a disease characterised by demyelination of the central nervous system resulting in decreased quality of life, increased anxiety, depression, fatigue, and cognitive dysfunction. Attention is frequently impaired in MS. A previous study demonstrated impairment specifically in the attentional alerting domain. However, this study did not establish whether the impairment was in intrinsic or extrinsic alertness, and did not examine the neural substrates associated with the impairment. To examine the alerting deficit in MS and establish the associated neural substrates, 40 female patients with MS and 40 age and gender match controls completed an alertness-motor paradigm designed to test both intrinsic and extrinsic alertness during functional magnetic resonance imaging. We found the MS group had a significant deficit in extrinsic alertness, which was associated with a lack of dorsal prefrontal cortex (DPFC) activation. In addition, reduced gray matter volume in the dorsal prefrontal cortex, thalamus, and basal ganglia were observed. Both fMRI and VBM correlations were observed between fatigue severity scale (FSS) scores and the DPFC. The combined results of our functional and structural MRI data analysis demonstrate that attention deficits in females with MS are a result of the complex relationship between brain tissue loss having a significant impact on functional brain regions subserving executive control of cognitive functions. Understanding the underlying mechanisms of cognitive performance and how they relate to fatigue are crucial to developing novel treatments for the symptoms of MS.

Laboratory studies show brain maturation involves synaptic pruning and cognitive development. Human studies suggest links between early cognitive performance and later mental health, but inconsistencies remain. It is unclear if specific brain regions mediate this relationship, and the molecular underpinnings are not well understood. Here, our longitudinal analyses in both the Adolescent Brain Cognitive Development and IMAGEN cohorts establish inverted U-shaped relationships between baseline executive function and subsequent symptom trajectories in the high-symptom individuals, whose externalizing (n = 963) or internalizing (n = 1762) symptoms exceed a clinical threshold at any point during the follow-up period, but not in the control group (n = 4291). Volumetric changes in the left lateral occipital cortex (LOC) mediated the relationship with externalizing symptoms (outwardly directed behaviors such as aggression), while changes in the right LOC and pars triangularis mediated the relationship with internalizing symptoms (inwardly directed emotional problems such as anxiety). Transcriptomic and genomic findings highlighted synaptic biology and particularly the gene ADCY1, which is implicated in synaptic pruning, as underlying both moderate executive function and its associated brain mediators. Notably, preadolescent cognitive performance predicts late-onset externalizing symptoms and remitting internalizing symptoms with high accuracies (area under the curve: 0.87 and 0.79). Our findings highlight the predictive value of cognitive performance for adolescent mental health trajectories, and indicate how this is mediated by specific brain regions, and underpinned by particular molecular pathways.

BACKGROUND: Adolescents may respond differently to cannabis than adults, yet no previous functional magnetic resonance imaging study has examined acute cannabis effects in this age group. In this study, we investigated the neural correlates of reward anticipation after acute exposure to cannabis in adolescents and adults. METHODS: This was a double-blind, placebo-controlled, randomized, crossover experiment. Forty-seven adolescents (n = 24, 12 females, ages 16-17 years) and adults (n = 23, 11 females, ages 26-29 years) matched on cannabis use frequency (0.5-3 days/week) completed the Monetary Incentive Delay task during functional magnetic resonance imaging after inhaling cannabis with 0.107 mg/kg D9-tetrahydrocannabinol ("THC") (8 mg THC for a 75-kg person) or with THC plus 0.320 mg/kg cannabidiol ("THC+CBD") (24 mg CBD for a 75-kg person), or placebo cannabis. We investigated reward anticipation activity with whole-brain analyses and region of interest analyses in the right and left ventral striatum, right and left anterior cingulate cortex, and right insula.RESULTS: THC reduced anticipation activity compared with placebo in the right (p = .005, d = 0.49) and left (p = .003, d = 0.50) ventral striatum and the right insula (p = .01, d = 0.42). THC+CBD reduced activity compared with placebo in the right ventral striatum (p = .01, d = 0.41) and right insula (p = .002, d = 0.49). There were no differences between "THC" and "THC+CBD" conditions and no significant drug by age group interaction effect, supported by Bayesian analyses. There were no significant effects in the whole-brain analyses.CONCLUSIONS: In weekly cannabis users, cannabis suppresses the brain's anticipatory reward response to money, and CBD does not modulate this effect. Furthermore, the adolescent reward circuitry is not differentially sensitive to acute effects of cannabis on reward anticipation.

Abstract Background Individual lifestyle choices undeniably influence the risk of developing both somatic and brain diseases. Exploring the impact of multidimensional lifestyle factors on various diseases has the potential to provide evidence-based recommendations for treatments and prevention conditions by targeting modifiable health behaviours. This study aims to investigate the impact of both combined and individual lifestyle factors on an extensive range of diseases, and to further explore the effects across populations with different genetic profiles and socio-demographic statuses. Methods This prospective analysis used data from the UK biobank. Exposures include seven lifestyle behaviours (such as smoking, physical activity, alcohol consumption, diet, sleep duration, sedentary behaviour, and social connection) and their combined score. This combined lifestyle score was subsequently categorized as favourable (5 to 7 healthy lifestyle factors), intermediate (2 to 4 healthy lifestyle factors), and unfavourable (0 to 1 healthy lifestyle factor) lifestyle classes. Outcomes include diagnoses of 45 diseases across eight categories (including cardiovascular disease, brain disorders, endocrine disease, respiratory disease, immune disease, digestive disease, genitourinary system disease, and cancer). Multivariate Cox models were used to estimate hazard ratios for all incident diseases adjusting for age, sex, BMI, deprivation, and education. Results Over a median follow-up period spanning from 13.60 to 13.84 years, there were a range of 285,681 to 394,038 participants with diagnostic records for 45 diseases, of whom 108 to 47,695 individuals experienced the onset of a specific disease. The findings demonstrated the protective roles of seven lifestyle factors and combined lifestyle on the comprehensive disease profiles, with respiratory diseases (representative of lung diseases) (HR range: 0.10–0.59), brain disorders (representative of schizophrenia, multiple sclerosis, bipolar disorder, and depression) (0.23–0.69), cancer (representative of lung and liver cancers) (0.18–0.84) and digestive diseases (representative of liver diseases) (0.17–0.83) standing out as the top four categories exhibiting the most prominent protective effects. For representative diseases in the four categories, a favourable lifestyle was associated with adjusted hazard ratio (aHR) of 0.10 (95% CI: 0.09–0.12) for emphysema, aHR of 0.17 (0.14–0.20) for chronic liver disease, aHR of 0.18 (0.14–0.21) for lung cancer, and aHR of 0.24 (0.14–0.40) for schizophrenia. Integrating genetic risk and lifestyle classifications across 17 diseases, the study highlighted the consistent lifestyle-disease prospective associations across populations with diverse genetic risk profiles. Stratified analyses revealed the prospective associations of lifestyle with the risk of developing the majority of the diseases were significant, however the risk varied by sociodemographic status. Conclusions These results from a longitudinal study of very large cohort discovered that despite genetic vulnerability, having a healthy lifestyle can greatly reduce the risk of developing a wide range of diseases, including somatic and brain diseases.

BACKGROUND: Irritable bowel syndrome (IBS) interacts with psychopathology in a complex way; however, little is known about the underlying brain, biochemical, and genetic mechanisms. METHODS: To clarify the phenotypic and genetic associations between IBS and brain health, we performed a comprehensive retrospective cohort study on a large population. Our study included 171,104 participants from the UK Biobank who underwent a thorough assessment of IBS, with the majority also providing neuroimaging, behavioral, biochemical, and genetic information. Multistage linked analyses were conducted, including phenome-wide association analysis, polygenic risk score calculation, and 2 -sample Mendelian randomization analysis. RESULTS: The phenome-wide association analysis showed that IBS was linked to brain health problems, including anxiety and depression, and poor cognitive performance. Significantly lower brain volumes associated with more severe IBS were found in key areas related to emotional regulation and higher-order cognition, including the medial orbitofrontal cortex/ventromedial prefrontal cortex, anterior insula, anterior and mid-cingulate cortices, dorsolateral prefrontal cortex, and hippocampus. Higher triglycerides, lower high-intensity lipoprotein, and lower platelets were also related ( p , 1 3 10 210 ) to more severe IBS. Finally, Mendelian randomization analyses demonstrated potential causal relationships between IBS and brain health and indicated possible mediating effects of dyslipidemia and inflammation. CONCLUSIONS: For the first time, this study provides a comprehensive understanding of the relationship between IBS and brain health phenotypes, integrating perspectives from neuroimaging, behavioral performance, biochemical factors, and genetics, which is of great significance for clinical applications to potentially address brain health impairments in patients with IBS.

Short-term intake of selective serotonin reuptake inhibitors (SSRIs) modulates threat-related amygdala responses in healthy individuals. However, how SSRI intake over a clinically relevant time period modulates threat-related amygdala responses is less clear. In a semi-randomised, double-blind, placebo-controlled study of 64 healthy individuals (SSRI n = 32, placebo n = 32), we examined the effect of 3–5 weeks of SSRI escitalopram (20 mg daily) on brain response to angry, fearful and neutral faces using BOLD fMRI. Data was analysed using a whole-brain region-wise approach extracting standardised effects (i.e., Cohen’s D). The study was conducted at the Copenhagen University Hospital. A priori, we hypothesised that SSRI would attenuate amygdala responses to angry and fearful faces but not to neutral ones. Whether SSRI modulates correlations between amygdala responses to emotional faces and negative mood states was also explored. Compared to placebo, 3–5 weeks of SSRI intake did not significantly affect the amygdala response to angry, fearful, or neutral faces (|Cohen’s D|< 0.2, PFWER = 1). Whole-brain, region-wise analyses revealed significant differences in frontal (|Cohen’s D|< 0.6, PFWER < .01) and occipital regions (|Cohen’s D|< 0.5, PFWER < .01). SSRI did not modulate correlations between amygdala responses to emotional faces and negative mood states. Our findings indicate that a 3–5 week SSRI intake impacts cortical responses to emotional stimuli, an effect possibly involved in SSRI’s therapeutic efficacy. Trial registration Clinical Trials NCT04239339.

Emotion dysregulation is common in attention deficit hyperactivity disorder (ADHD), which is known to be clinically heterogeneous. However, it remains unclear whether emotion dysregulation represents a neuropsychological pathway to ADHD. Here, using a large population-based cohort (n = 6,053), we show that emotion dysregulation was associated with ADHD symptoms (partial eta2 = 0.21) and this persisted after controlling for the cognitive and motivational deficits. Emotion dysregulation mediated the association between smaller surface area of the right pars orbitalis and greater ADHD symptoms at 1-year follow-up, indicating an emotion pathway for ADHD. This pathway was associated with immune responses by both transcriptomic analyses and white blood cell markers. In an independent clinical sample for ADHD (n = 672), the emotion pathway improved the case/control classification accuracy. These findings suggest that emotion dysregulation is a core symptom and route to ADHD, which may not respond to the current pharmacological treatments for ADHD.

BACKGROUND:Irritable bowel syndrome (IBS) interacts with psychopathology in a complex way; however, little is known about the underlying brain, biochemical, and genetic mechanisms. METHODS:To clarify the phenotypic and genetic associations between IBS and brain health, we performed a comprehensive retrospective cohort study on a large population. Our study included 171,104 participants from the UK Biobank who underwent a thorough assessment of IBS, with the majority also providing neuroimaging, behavioral, biochemical, and genetic information. Multistage linked analyses were conducted, including phenome-wide association analysis, polygenic risk score calculation, and 2-sample Mendelian randomization analysis. RESULTS:The phenome-wide association analysis showed that IBS was linked to brain health problems, including anxiety and depression, and poor cognitive performance. Significantly lower brain volumes associated with more severe IBS were found in key areas related to emotional regulation and higher-order cognition, including the medial orbitofrontal cortex/ventromedial prefrontal cortex, anterior insula, anterior and mid-cingulate cortices, dorsolateral prefrontal cortex, and hippocampus. Higher triglycerides, lower high-intensity lipoprotein, and lower platelets were also related (p < 1 × 10-10) to more severe IBS. Finally, Mendelian randomization analyses demonstrated potential causal relationships between IBS and brain health and indicated possible mediating effects of dyslipidemia and inflammation. CONCLUSIONS:For the first time, this study provides a comprehensive understanding of the relationship between IBS and brain health phenotypes, integrating perspectives from neuroimaging, behavioral performance, biochemical factors, and genetics, which is of great significance for clinical applications to potentially address brain health impairments in patients with IBS.

Serotonin is critical for adapting behavior flexibly to meet changing environmental demands. Cognitive flexibility is important for successful attainment of goals, as well as for social interactions, and is frequently impaired in neuropsychiatric disorders, including obsessive–compulsive disorder. However, a unifying mechanistic framework accounting for the role of serotonin in behavioral flexibility has remained elusive. Here, we demonstrate common effects of manipulating serotonin function across two species (rats and humans) on latent processes supporting choice behavior during probabilistic reversal learning, using computational modelling. The findings support a role of serotonin in behavioral flexibility and plasticity, indicated, respectively, by increases or decreases in choice repetition (‘stickiness’) or reinforcement learning rates following manipulations intended to increase or decrease serotonin function. More specifically, the rate at which expected value increased following reward and decreased following punishment (reward and punishment ‘learning rates’) was greatest after sub-chronic administration of the selective serotonin reuptake inhibitor (SSRI) citalopram (5 mg/kg for 7 days followed by 10 mg/kg twice a day for 5 days) in rats. Conversely, humans given a single dose of an SSRI (20 mg escitalopram), which can decrease post-synaptic serotonin signalling, and rats that received the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), which destroys forebrain serotonergic neurons, exhibited decreased reward learning rates. A basic perseverative tendency (‘stickiness’), or choice repetition irrespective of the outcome produced, was likewise increased in rats after the 12-day SSRI regimen and decreased after single dose SSRI in humans and 5,7-DHT in rats. These common effects of serotonergic manipulations on rats and humans—identified via computational modelling—suggest an evolutionarily conserved role for serotonin in plasticity and behavioral flexibility and have clinical relevance transdiagnostically for neuropsychiatric disorders.

Abstract Background Cannabis use may be linked with anhedonia and apathy. However, previous studies have shown mixed results, and few have examined the association between cannabis use and specific reward sub-processes. Adolescents may be more vulnerable than adults to harmful effects of cannabis. This study investigated (1) the association between non-acute cannabis use and apathy, anhedonia, pleasure, and effort-based decision-making for reward; and (2) whether these relationships were moderated by age group. Methods We used data from the “CannTeen” study. Participants were 274 adult (26–29 years) and adolescent (16–17 years) cannabis users (1–7 d/wk use in the past 3 months) and gender- and age-matched controls. Anhedonia was measured with the Snaith-Hamilton Pleasure Scale (n = 274), and apathy was measured with the Apathy Evaluation Scale (n = 215). Effort-based decision-making for reward was measured with the Physical Effort task (n = 139), and subjective wanting and liking of rewards was measured with the novel Real Reward Pleasure task (n = 137). Results Controls had higher levels of anhedonia than cannabis users (F1,258 = 5.35, P = .02, η p2 = .02). There were no other significant effects of user-group and no significant user-group*age-group interactions. Null findings were supported by post hoc Bayesian analyses. Conclusion Our results suggest that cannabis use at a frequency of 3 to 4 d/wk is not associated with apathy, effort-based decision-making for reward, reward wanting, or reward liking in adults or adolescents. Cannabis users had lower anhedonia than controls, albeit at a small effect size. These findings are not consistent with the hypothesis that non-acute cannabis use is associated with amotivation.

Abstract Selective serotonin reuptake inhibitors (SSRIs) are widely used for treating neuropsychiatric disorders. However, the exact mechanism of action and why effects can take several weeks to manifest is not clear. The neuroplasticity hypothesis is supported by preclinical studies, but the evidence in humans is limited. Here, we investigate the effects of the SSRI escitalopram on presynaptic density as a proxy for synaptic plasticity. In a double-blind placebo-controlled study (NCT04239339), 32 healthy participants were randomized to receive daily oral dosing of either 20 mg escitalopram (n = 17) or a placebo (n = 15). After an intervention period of 3-5 weeks, participants underwent a [11C]UCB-J PET scan to quantify synaptic vesicle glycoprotein 2A (SV2A) density in the hippocampus and the neocortex. Group means were compared using t-tests, and effect of intervention duration was assessed with linear models. Whereas there was only a small difference in [11C]UCB-J binding between the escitalopram and placebo groups after an average of 29 (range: 24-38) days of intervention (Cohen’s d of 0.31-0.42, p values > 0.26), we identified time-dependent group effects (neocortex: p = 0.020; hippocampus: p = 0.058). Linear models showed positive associations between [11C]UCB-J binding and duration of escitalopram intervention: pNeocortex = 0.016; pHippocampus = 0.11). Our findings suggest that brain synaptic plasticity evolves over 3-5 weeks in healthy humans following daily intake of escitalopram. This is the first in vivo evidence to support the hypothesis of neuroplasticity as a mechanism of action for SSRIs in humans, and it offers a plausible biological explanation for the delayed treatment response commonly observed in patients treated with SSRIs.

Selective serotonin reuptake inhibitors (SSRIs) are widely used for treating neuropsychiatric disorders. However, the exact mechanism of action and why effects can take several weeks to manifest is not clear. The hypothesis of neuroplasticity is supported by preclinical studies, but the evidence in humans is limited. Here, we investigate the effects of the SSRI escitalopram on presynaptic density as a proxy for synaptic plasticity. In a double-blind placebo-controlled study (NCT04239339), 32 healthy participants with no history of psychiatric or cognitive disorders were randomized to receive daily oral dosing of either 20 mg escitalopram ( n = 17) or a placebo ( n = 15). After an intervention period of 3–5 weeks, participants underwent a [ 11 C]UCB-J PET scan (29 with full arterial input function) to quantify synaptic vesicle glycoprotein 2A (SV2A) density in the hippocampus and the neocortex. Whereas we find no statistically significant group difference in SV2A binding after an average of 29 (range: 24–38) days of intervention, our secondary analyses show a time-dependent effect of escitalopram on cerebral SV2A binding with positive associations between [ 11 C]UCB-J binding and duration of escitalopram intervention. Our findings suggest that brain synaptic plasticity evolves over 3–5 weeks in healthy humans following daily intake of escitalopram. This is the first in vivo evidence to support the hypothesis of neuroplasticity as a mechanism of action for SSRIs in humans and it offers a plausible biological explanation for the delayed treatment response commonly observed in patients treated with SSRIs. While replication is warranted, these results have important implications for the design of future clinical studies investigating the neurobiological effects of SSRIs.