Biological Psychiatry

BackgroundTo personalize the diagnosis and treatment of anxiety, there is a need to identify biological constructs that underlie self-reported symptoms. Notably, physiological responses and altered levels of arousal are constituents of anxiety and have widespread ("global") effects on fMRI signals across the brain. Therefore, fMRI signatures of global cortical arousal and autonomic physiological responses may provide valuable neuroimaging biomarkers of anxiety. Additionally, these effects may al...

Mental illness is often characterised by a maladaptive sense of self. The neurobiological basis of Self-Other distinction may provide targets for therapeutic interventions. Psychedelics alter the experience of selfhood, but the neurocomputational mechanism is unclear. We used a computationally-informed behavioural assay to investigate whether psychedelics disrupt Self-Other boundaries in belief formation. In a double-blind, crossover design, 22 participants received placebo, psilocybin or 2C-B (...

Somatic awareness is a fundamental practice for novice mindfulness practitioners. It has been proposed that mindfulness meditation training enhances brain function through somatic awareness in both non-clinical and clinical populations. However, the neural signatures underlying this mechanism remain poorly understood. In our study, we conducted single-blind mindfulness interventions in both healthy and depressed populations and examined whether somatomotor network (SMN)-related edge-centric func...

Genetically informed drug development and repurposing is an attractive prospect for improving outcomes in patients with psychiatric illness; however, the effectiveness of these endeavours can be confounded by heterogeneity. In this study, we propose a novel approach that links interventions implicated by disorder-associated genetic risk, at the population level, to a framework that can target these compounds to individuals. Specifically, results from genome-wide association studies are integrate...

Impulsivity is a complex psychological construct that represents a core feature of many psychiatric and neurological conditions. Here, we used multivariate methods to formally model the genetic architecture of impulsivity in humans, advancing genomic discovery and revealing pervasive pleiotropy that largely counters theories of impulsivity as a unitary construct. We identified 18 loci and 93 genes with diverse effects in GWAS and TWAS analyses, respectively, including a hotspot at 17q21.31 that ...

Understanding the mechanisms underlying the response to antipsychotic medications is critical for refining targets for new interventions and predicting clinical outcomes. This study presents a mega-analysis of individual participant data (N = 1,189) from 18 {superscript 1}H-MRS datasets to examine differences in neurometabolites in antipsychotic non-responsive compared to antipsychotic-responsive psychosis, accompanied by complementary meta-analyses across the wider published literature (23 stud...

Preclinical evidence suggests that modulating neural excitation through diazepam administration, a positive allosteric modulator of GABAA receptors, can prevent the emergence of behavioural and neurobiological alterations relevant to psychosis in adulthood. Here, we examined this neurochemical mechanism in individuals at clinical high-risk for psychosis (CHRp) in a randomised, double-blind, placebo-controlled crossover study. Twenty-four individuals aged 18-35 were scanned twice using proton mag...

Self-agency is being aware of oneself as the agent of ones thoughts and actions. Self-agency is necessary for successful interactions with the outside world (reality-monitoring). Prior research has shown that the medial superior prefrontal gyri (mPFC/SFG) may represent one neural correlate underlying self-agency judgments. However, the causal relationship remains unknown. Here, we applied high-frequency 10Hz repetitive transcranial magnetic stimulation (rTMS) to modulate the excitability of the ...

BackgroundPreclinical evidence suggests that diazepam enhances hippocampal {gamma}-aminobutyric acid (GABA) signalling and normalises a psychosis-relevant cortico-limbic-striatal circuit. Hippocampal network dysconnectivity, particularly from the CA1 subfield, is evident in people at clinical high-risk for psychosis (CHR-P), representing a potential treatment target. This study aimed to forward-translate this preclinical evidence. MethodsIn this randomised, double-blind, placebo-controlled stud...

BackgroundCannabidiol (CBD) is being studied as a potential intervention for the people at clinical high risk for psychosis (CHR), though the mechanisms underlying its effects are not fully understood. Previous studies indicate that a single dose of CBD can normalize alterations in memory-related brain activation and modulate hippocampal glutamate levels in the early stages of psychosis. This study aimed to examine the acute effects of CBD on the coupling between hippocampal glutamate levels and...

Trait anxiety is an individual disposition marked by heightened anticipation of potential threats under uncertainty. It has been associated with allostatic load, the cumulative physiological cost of chronic stress, suggesting that enduring anxiety vulnerability emerges from brain-body interactions across multiple scales. Yet these domains have largely been examined separately and the temporal dynamics of brain activity remain underexplored. Using data from healthy young adults (LEMON cohort, N =...

The neuropeptides oxytocin and vasotocin are predominantly produced in the supraoptic and paraventricular nuclei of the anterior-inferior, anterior-superior and tubular-superior hypothalamic subunits. Evidence suggests that oxytocin and vasotocin signaling play a role in both physiology and behavior and that dysfunction of these signaling systems may contribute to the co-occurrence of metabolic and psychiatric conditions. The genetic pathways, however, that may underlie the connection between th...

1. ImportanceSchizophrenia is clinically and biologically heterogeneous, with marked variability in course and treatment response. Stratification of patients may advance individualized therapy and clarify underlying mechanisms. 2. ObjectiveTo identify, validate, and replicate genetic risk factors distinct to each other in schizophrenia patients using polygenic risk scores of large numbers of psychiatry-relevant phenotypes. 3. DesignWe analyzed genetic and phenotypic data from FinnGen (discover...

Our understanding of the interplay between positive and negative psychosis symptoms is constrained by reliance on retrospective assessments, which fail to capture dynamic, short-term symptom-context interactions. Ecological-Momentary-Assessment (EMA) offers real-time symptom tracking in naturalistic settings, but its validity and clinical utility remain uncertain. We address this using a recently developed Behavioral-Tractography approach in individuals with 22q11.2 Deletion Syndrome, a high-ris...

We have previously described how the DLPFC transcriptomes of schizophrenia patients can be used to define two patient groups: "Type 1" patients with a relatively normal DLPFC transcriptome and "Type 2" patients with hundreds of genes differentially expressed in the DLPFC at a statistical significance which survives Bonferroni correction. The biological significance of the distinction between Type 1 and Type 2 patients remains an open question. In the present report we examine the polygenic risk ...

We tested two metabotropic glutamate receptor 2/3 (mGluR2/3) agonist prodrugs - pomaglumetad (POMA) and TS-134 - including a high-dose of POMA that was four times the dose tested in the failed phase schizophrenia III trials - in two proof of mechanism, Phase Ib studies using identical pharmacoBOLD target-engagement methodology. The POMA study was a double-blind, NIMH-sponsored, 10-day study of 80 or 320 mg/d POMA or placebo (1:1:1 ratio), designed to detect d>0.8 sd between-group effect-size di...

Schizophrenia is a complex, polygenic disorder associated with subtle, distributed abnormalities in brain morphology. Here, we report large genetic overlap between schizophrenia and brain morphology, which enabled derivation of polygenic risk scores more predictive of schizophrenia diagnosis than the current state-of-the-art. Our results illustrate the potential of exploiting genetic overlap in imaging genetics studies, and how pleiotropy-enriched risk scores may improve prediction of polygenic ...

Schizophrenia (SCZ) is a highly heritable brain disorder marked by a wide range of changes throughout the central nervous system. These changes include alterations at the molecular and cellular levels, suggesting significant disruptions in synapse function, as well as modifications in brain structure and activity. However, it remains unclear, how changes in molecular synapse biology translate into neurophysiological and ultimately behavioral consequences across scales. Here, we narrow this trans...

Early detection of treatment-resistant schizophrenia (TRS) is of substantial clinical importance. While TRS is heritable, the associated genetic variants have been difficult to identify. Cigarette smoking is associated with non-response to antipsychotics, and smoking behavior and schizophrenia have a shared genetic basis. Thus, TRS may also have a shared genetic basis with smoking behavior. Here we aim to identify genetic variants associated with TRS, by leveraging overlapping genetic variants w...

Despite great progress on methods for case-control polygenic prediction (e.g. schizophrenia vs. control), there remains an unmet need for a method that genetically distinguishes clinically related disorders (e.g. schizophrenia (SCZ) vs. bipolar disorder (BIP) vs. depression (MDD) vs. control); such a method could have important clinical value, especially at disorder onset when differential diagnosis can be challenging. Here, we introduce a method, Differential Diagnosis-Polygenic Risk Score (DDx...