Biological Psychiatry

Psychotic disorders are increasingly recognized as the extreme end of a progressive psychopathology continuum, with less advanced stages including the asymptomatic familial high-risk state (FHR), the help-seeking clinical high-risk state (CHR), and first episode psychosis (FEP). However, we lack a comprehensive study of clinical, cognitive, functional, and neuroanatomical markers across all three early stages of psychosis, limiting our understanding of how the multimodal phenotypes which define ...

Deficits in inhibitory control are common across a wide range of psychiatric disorders and are closely linked to symptom severity, including emotional dysregulation, anxiety, substance misuse, and self-harm, making them an appealing target for intervention. Cognitive training offers a low-cost, scalable, and non-invasive strategy to strengthen inhibitory control; however, most existing paradigms target only a single facet of inhibition and rarely account for environmental influences, such as aff...

In-scanner head motion is a recognized source of bias in structural magnetic resonance imaging (sMRI), yet it remains under-addressed in psychiatric neuroimaging where structural difference in patient populations are considered foundational. We examined motion-related bias in grey matter volume estimates across eight independent cohorts comprising 9,664 individuals, including 8,979 neurotypical controls (NC), 497 patients with schizophrenia (SCZ), and 188 patients with bipolar disorder (BD). Mot...

BackgroundWhile growing evidence implicates sleep-wake and circadian rhythm disturbances (SCRDs) in the onset and course of mood and psychotic disorders, longitudinal studies using objective measures are limited. This clinical cohort study examined whether actigraphy-derived SCRDs (sleep duration, timing, and efficiency) predicted transition to (i) any full-threshold mental disorders; and then specifically: (ii) full-threshold bipolar or psychotic disorders or (iii) other full-threshold (i.e. de...

BackgroundLight plays a critical role in mental health, as the primary input to the circadian system, which regulates mood, energy, and the sleep-wake cycle. Altered light sensitivity is a potential mechanism in circadian-associated mental disorders. MethodsActigraphy-derived sleep, physical activity, and circadian rhythm correlates of the pupillary light reflex were explored in young people with emerging mental disorders. Participants were 27 healthy controls (Mean age=25.67 {+/-} 2.83, 52% fe...

Background At present, there are no approved pharmacological treatments for people at clinical high risk for psychosis (CHR-P). We sought to assess the acceptability of cannabidiol (CBD): a promising candidate treatment for this population. Methods CHR-P individuals completed a survey which assessed their views on the acceptability of CBD, its expected effectiveness and side effects, and on formulation preferences. Results The sample comprised 55 CHR-P individuals (24.3 years and 69% female). Mo...

Actigraphy is a popular behavioral sleep assessment tool in research and clinical practice. Hierarchical hand-scoring approaches remain the standard for actigraphy rest interval estimation, but can be impractical for large cohort studies and suffer from reproducibility problems. We developed a semi-automated pipeline (actiSleep) to set rest intervals consistent with best-practice hand-scoring algorithms incorporating event marker, diary, light, and activity data. To evaluate actiSleep performanc...

Objective: Posttraumatic stress disorder (PTSD) after a traumatic birth is a serious but overlooked maternal morbidity, affecting ~20% of women following medically complicated deliveries. PTSD can undermine maternal caregiving. Rapid screening tools suited to busy obstetric settings are lacking. We developed and evaluated a brief screener, derived from the 20-item PTSD Checklist for DSM-5 (PCL-5), to identify PTSD related to childbirth. Study Design: We enrolled 107 women with traumatic childbir...

IntroductionMaternal mental health conditions, comprising maternal suicide and drug overdose, are currently the leading cause of maternal mortality in the United States. However, the relationship between suicidality and drug use behavior in the perinatal period is not well understood. We examined the association between suicidality and drug use behavior among perinatal individuals. Given the racial disparities in both drug use and suicide rates in the U.S., we also examined any differences in su...

Digital therapeutics for mental health often face low patient engagement, which limits their clinical impact. Interventions that deliver treatment using a video game medium may improve engagement and therapeutic efficacy, but the putative emergence of gaming-related problems remains a concern among clinical stakeholders. We examined whether long-term engagement with Meliora, a video game therapeutic for adult major depressive disorder, was associated with changes in gaming-related problems in a ...

BackgroundDespite widespread recognition of the value of lived experience (LE) involvement in healthcare research and increased LE involvement activity, we lack established implementation methods and instruments for reporting and evaluating impact. We present a protocol for an innovative LE-led Impact Log tool and co-production framework, which may help to address some fundamental barriers to co-production. The Impact Log will be implemented within a five-year multidisciplinary transdiagnostic r...

BackgroundThe relationship between hip osteoarthritis (hip OA) and Alzheimers disease (AD) presents a critical paradox within the emerging "bone-brain axis": widespread phenotypic comorbidity sharply contradicts evolutionary theories of biological antagonism. This study integrates longitudinal and multi-omic analyses to determine whether this clinical overlap masks an underlying genetic neuroprotection. MethodsWe analyzed longitudinal phenotypic data from 261,767 UK Biobank participants using C...

We report a previously undescribed genotypic configuration identified in twins with HNRNPU-related neurodevelopmental disorder. Both twins have two closely spaced mosaic variants on the same allele that never co-occur on any single DNA molecule, resulting in three distinct cell lineages within each individual. We define this genotypic configuration as clustered monoallelic mosaicism (cMoMa). Recognizing the extreme improbability of such a configuration, we systematically explore two potential me...

Oscillatory coupling between respiration, heart rate, and cortical function is fundamental to physiological regulation yet remains poorly characterized in humans. Diminished respiratory heart rate variability (RespHRV)--the rhythmic heart rate modulation accompanying respiration--has emerged as a transdiagnostic biomarker of mental and physical health, reduced in anxiety, depression, cardiovascular disease, and aging (Beauchaine & Thayer, 2015; Menuet & Gourine et al., 2025). However, the cortic...

Resting-state electroencephalography (EEG) has been proposed as a scalable source of biomarkers for chronic pain, but its clinical potential remains uncertain. To systematically evaluate this potential, we benchmarked nine modeling strategies, spanning conventional machine learning with handcrafted features to state-of-the-art deep learning. Across 72 configurations of signal representations and model architectures, we trained models to predict self-reported pain intensity, using chronological a...

In this randomized, double-blind, controlled trial of 8 weeks of repetitive transcranial magnetic stimulation (rTMS) for chronic pain, we compared the classic primary motor cortex (M1) rTMS with a novel target-selection strategy based on pre-therapy cortical connectivity. Guided by principles of homeostatic plasticity, we tested whether stimulating the cortical site with the lowest pre-therapy global connectivity would be more effective than two active comparators: stimulating the site with the ...

Rare Mendelian disorders affect 300-400 million people globally. Although genetic testing has become widely adopted, gene-specific evidence for tailored variant interpretation remains scattered across resources. We present Gene Portals, a framework for gene-centered multimodal knowledge bases that co-localize expert-harmonized clinical data, functional assays, population variation, structural annotations and gene-specific ACMG/AMP specifications within a single resource. A modular interface inte...

Tumour typing from whole-genome sequencing is increasingly accurate, yet molecular subtyping from somatic variants remains challenging because of tumour heterogeneity and inconsistent clinical annotations. Here, we present Mutation-Attention Dual-Task (MuAt2), a Transformer model that jointly classifies histological tumour types and subtypes directly from somatic single-nucleotide variants, indels and structural variants. MuAt2 leverages encoders pre-trained on 2,587 pan-cancer whole genomes, an...

BackgroundA coronary artery calcium (CAC) score of 0 is widely considered to indicate low short- to intermediate-term risk for coronary artery disease (CAD) and is frequently used to defer lipid-lowering therapy. However, a subset of individuals with CAC=0 still experience events, highlighting residual risk not captured by imaging alone. Polygenic risk scores (PRS) quantify lifelong inherited susceptibility, but conventional approaches rely on predefined ancestry labels despite human genetic div...

Type 2 diabetes (T2D) affects 11.1% of the global population, underscoring the need for biomarkers that inform treatment response and glycemic outcomes. We evaluated the association between the FTO variant rs9939609-A and glycemic control in a Mexican population. A total of 174 individuals living with T2D from Merida and Sisal, Yucatan, were included, of whom 85% were receiving oral hypoglycemic agents as main treatment. Glycemic control was defined cross-sectionally as good ([≤]130 mg/dL, n=...