Volume 2, Number 4, October 2022
A brief summary of the articles in this issue of Biological Psychiatry: Global Open Science.
Review: Imaging Transcriptomics of Brain Disorders
Developments in anatomically comprehensive gene expression atlases that map the expression of thousands of genes across the brain open new opportunities for investigating the genetic underpinnings of brain organization. By relating such transcriptional maps to changes observed in brain disorders, some of the putative mechanisms contributing to disease can be evaluated. Here, Arnatkeviciute et al. (pages 319–331) overview the methods used in such imaging transcriptomics studies and outline their application for understanding brain disorders of neurodevelopment, adulthood, and neurodegeneration.
Review: Thalamic Connectivity in Psychiatric Disorders
Thalamic connectivity appears disrupted in multiple psychiatric disorders. Here, Hwang et al. (pages 332–340) review the current knowledge of thalamic connectivity system deficits in psychiatric disorders. The most commonly observed deficits are reduced thalamo-prefrontal connectivity in schizophrenia and increased thalamo-temporal connectivity in major depressive disorder and autism spectrum disorder. Furthermore, evidence suggests increased thalamo-somatomotor/parietal connectivity, observed across multiple psychiatric illnesses, as a possible marker of general psychiatric illness, and the mediodorsal nucleus as a state marker of psychosis.
Review: Distinguishing Fear Versus Anxiety
While fear and anxiety are frequently seen as fundamentally distinct, Daniel-Watanabe and Fletcher (pages 341–349) review evidence at the neural, physiological, and behavioral level and suggest that there are a number of inconsistencies and unsupported assumptions that call into question a clear-cut distinction. The authors conclude that drawing such a distinction is a simplification that has proven useful but should not be strictly followed given the limitations that it places on future research.
Review: Task-Based Connectivity in ADHD
Attention-deficit/hyperactivity disorder (ADHD) is frequently associated with atypical brain activation and altered functional connections across brain areas at rest. However, there is growing interest in exploring changes in brain interactions in response to task demands. In this review, Kowalczyk et al. (pages 350–367) appraise studies that have investigated task-based functional connectivity in ADHD and the impact of pharmacotherapy on the identified dysfunctional networks.
Neuropsychiatry: Understanding Genetic Risk
The factors that may influence the age of onset of anorexia nervosa (AN), a highly heritable eating disorder, are unclear. In this genome-wide association study, Watson et al. (pages 368–378) found that common genetic variants contribute to the age at which AN first begins. The authors then identified distinct genetic correlation patterns for early- versus typical-onset AN. Early-onset AN showed a genetic relationship with younger age at menarche, whereas typical-onset AN had a genetic relationship with anthropometric traits. This work suggests that age of onset of AN may have a genetic basis and may also inform differential genetic associations.
Polygenic risk scores (PRSs) are used to quantify the genetic vulnerability to a disorder. In this work, Nurnberger et al. (pages 379–388) analyzed the use of an alcohol-related PRS plus clinical data in the prediction of alcohol problems in young people at risk for alcohol use disorder (AUD). The authors report that clinical data were best for overall prediction, but the PRS helped identify subgroups at very high risk, suggesting that PRS may ultimately help aid prediction of outcome in individuals at the highest risk.
Externalizing behaviors are common, but the neurobiological processes underlying development of such behaviors remain unclear. Here, Baselmans et al. (pages 389–399) examined the genetic correlations of multiple externalizing behaviors and found evidence for 2 subtypes, one characterized by disruptive behaviors (aggression, anger, irritability, ADHD) and the other by risk-taking behaviors (risk tolerance, antisocial behavior, substance use, number of sexual partners). Bioinformatic analyses of the genetic signals of each subtype supported this classification and identified related biological mechanisms; gene-brain mappings were generally similar.
Stressful life events and genetic risk may be interacting factors in the etiology of depression. To investigate this hypothesis, Suppli et al. (pages 400–410) conducted a genome-wide by environment interaction study to test for interactions between individual genetic variants and a time-varying measure of stressful life events as risk factors for hospital-treated depression. The authors identified three potential loci, but none replicated in an independent sample. Future research in this area will require sample sizes large enough to detect variants with small effect sizes.
Obsessive-compulsive symptoms (OCSs) during childhood increase risk for later development of obsessive-compulsive disorder (OCD), but the underlying neurobiology remains unclear. In this study of healthy children, Suñol et al. (pages 411–420) report that an association between dynamic connectivity changes within cortico-striatal-thalamo-cortical circuits and OCSs was moderated by variations in glutamate-related genes. Similarly, an association between symmetry/ordering symptoms and dynamic connectivity changes in the superior parietal cortex was moderated by neural excitability genes. These findings provide insight into the neurogenetics of dynamic connectivity patterns associated with OCSs in healthy children.
Meta-analyses: Gray Matter in AUD and OCD
The neural underpinnings of compulsive behavior in AUD, which is commonly comorbid with OCD, are not fully understood. Here, Stevens et al. (pages 421–431) conducted and then compared separate meta-analyses of whole-brain voxel-based morphometry studies in AUD and OCD. Results identified decreased gray matter in the anterior cingulate cortex and insula in both disorders, suggesting that these regions may be involved in compulsive drinking associated with AUD.
Brain Controllability and Negative Affect
Negative affect in daily life naturally waxes and wanes, reflecting an adaptive capacity to respond to changing circumstances in the environment. Analyzing diffusion-weighted imaging data, McGowan et al. (pages 432–439) report that individuals with cingulo-insular systems that showed greater average controllability (the ability to distribute activity to other brain regions) showed greater fluctuations in negative affect. These data implicate the cingulo-insular system in the natural variability of negative affect in daily life.
Mother-Infant Transmission of Adversity
The effects of a history of childhood maltreatment (CM) extend beyond the affected individual, with children of affected mothers displaying increased risk for adverse developmental and health outcomes. Here, Khoury et al. (pages 440–449) found that maternal CM was associated with smaller infant total brain volume and gray matter volume in a community sample. In older infants, maternal CM was associated with lower volume in the right amygdala. This research highlights early biological factors that may be related to the intergenerational transmission of adversity.
Cerebellar Signaling in Autism Model
Autism spectrum disorder is often associated with motor deficits as well as enhanced sensitivity to sensory stimuli. Studying a mouse model for the human 15q11-13 duplication, a syndromic form of autism, Simmons et al. (pages 450–459) show that motor and sensory alterations may be related to aberrant signaling in the cerebellar cortex, providing insight into the synaptic mechanisms.
Mechanisms of Maladaptive Behaviors
Repetitive behavior is a feature of several neuropsychiatric disorders and has been linked to inhibitory interneurons in the dorsal striatum. Briones et al. (pages 460–469) examined mouse models of excessive repetitive behavior and found a larger proportion of striatal neurons surrounded by perineuronal nets, specialized extracellular matrix structures, than in control mice. Reduction of perineuronal nets in the striatum was associated with diminished repetitive behavior and alterations in synaptic transmission. These results suggest that extracellular abnormalities in the striatum may contribute to dysfunctional repetitive behavior.
While it is important to respond appropriately to threatening events in the environment, preoccupation with previous or potential future threatening events is maladaptive and a major pathology. In a series of neurobiological and behavioral experiments in rodent models, Adamcyzk et al. (pages 470–479) report that an agonist of the somatostatin SST4 receptor normalized stress-induced glutamate release, reduced aversion memory, and increased reward motivation. These data suggest that the SST4 receptor may be a potential therapeutic target for the treatment of stress-related disorders.
Hoarding and Sleep Impairment
Poor sleep is associated with a host of negative health and psychiatric outcomes. In this work, Nutley et al. (pages 480–488) examined the relationship between symptoms of hoarding disorder and impairment of sleep quality among adults. Findings indicated that individuals with hoarding symptoms are more likely to report poor sleep quality, disturbed sleeping patterns, and daytime fatigue than those without hoarding symptoms. Further, analyses implicated poor sleep as partially mediating the associations between hoarding problems and some adverse health outcomes, including poor cognitive functioning and reduced quality of life.
Functional Connectomics of Anxious Misery
Mapping transdiagnostic dimensions of psychopathology onto functional biological mechanisms is a challenging but important goal in the field. Analyzing data from participants experiencing symptoms of depression, anxiety, and trauma, Seok et al. (pages 489–499) demonstrated that different representations of the functional connectome varied in the extent to which they could reliably model different dimensions of psychopathology. Single connections failed to reproducibly model any symptom dimensions, a small subset of connections were sufficient to model insomnia and anxious arousal, and information from the entire connectome was necessary to model negative affect and ruminative thought.
