Molecular Psychiatry

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...

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 ...

Background: Quantitative genome wide association studies (GWAS) primarily rely on additive linear models that compare average phenotypic differences between genotype groups. While effective for detecting common variants of moderate effect in large sample sizes, such approaches inherently reduce high resolution phenotypic data to summary statistics (group averages), potentially limiting the detection of subtle genotype phenotype relationships. Genomic Informational Field Theory (GIFT) is a recent...

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...

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...

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...

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...

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...

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...

OBJECTIVEUsing two cohorts and synthetic datasets, we estimated effects of prospectively reported alcohol use on memory outcomes across middle age. METHODSData were from National Longitudinal Study of Youth 1979 (NLSY79, n=7540, alcohol reports from ages 18-26), Health and Retirement Study (HRS age 50-56 at enrollment, n=13,090), and a synthetic cohort matching early life exposure information from 3,259 NLSY79 participants to later life memory information from 5,451 HRS participants. Covariate-...

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...

Background and ObjectivesAssociations of common infections with Alzheimer disease (AD) risk have been reported. A hypothesized mechanism to explain these is cerebral amyloid-beta (A{beta}) aggregation as a defence in response to infection, with subsequent tau accumulation. However, few studies have assessed associations of infections with tau and A{beta} pathology. We investigated associations of serological measures of several common infections with plasma p-tau217 and A{beta} status measured b...

Alzheimers disease and related dementias (ADRD)1 and Parkinsons disease and related disorders (PDRD)2 have substantial genetic contributions, yet the role of rare damaging coding variants remains incompletely characterized at population scale3-6. We performed gene-based burden testing of rare loss-of-function and deleterious missense variants using whole-genome sequencing data from large population biobanks combined with disease-specific sequencing cohorts, leveraging proxy phenotypes to maximiz...

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...

Background Whole-genome sequencing (WGS) has improved the diagnosis of rare genetic disorders, yet interpretation of non-coding variants that affect splicing remains challenging. In silico predictions alone are insufficient, and short-read RNA sequencing may fail to capture complex or low-abundance splicing events. Targeted amplicon-based long-read RNA sequencing (Amp-LRS) offers a cost-effective approach for functional validation of candidate splice-altering variants. Methods We applied Amp-LRS...

Introduction: Neurodegenerative diseases (NDDs) including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and non-AD dementias share chronic neuroinflammatory mechanisms that contribute to neuronal injury and disease progression. While anti-inflammatory therapies (AITs) are associated with reduced neurodegenerative disease risk, knowledge regarding the impact of biological sex and treatment duration across multiple NDDs remains li...

INTRODUCTIONAlzheimers disease (AD) diagnostic guidelines emphasize subjective cognitive decline (SCD) preceding mild cognitive impairment (MCI), implicitly assuming awareness of cognitive decline (ACD) is preserved in preclinical AD. This study aimed to evaluate associations of decreased ACD with multimodal core AD biomarkers in cognitively unimpaired (CU) individuals. METHODSWe analyzed data from CU individuals with baseline CSF biomarkers and 3-year longitudinal neuropsychological assessment...

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...

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 ...

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 ...