The role of prefrontal–subcortical circuitry in negative bias in anxiety: Translational, developmental and treatment perspectives

Anxiety disorders are the most common cause of mental ill health in the developed world, but our understanding of symptoms and treatments is not presently grounded in knowledge of the underlying neurobiological mechanisms. In this review, we discuss accumulating work that points to a role for prefrontal–subcortical brain circuitry in driving a core psychological symptom of anxiety disorders – negative affective bias. Specifically, we point to converging work across humans and animal models, suggesting a reciprocal relationship between dorsal and ventral prefrontal–amygdala circuits in promoting and inhibiting negative bias, respectively. We discuss how the developmental trajectory of these circuits may lead to the onset of anxiety during adolescence and, moreover, how effective pharmacological and psychological treatments may serve to shift the balance of activity within this circuitry to ameliorate negative bias symptoms. Together, these findings may bring us closer to a mechanistic, neurobiological understanding of anxiety disorders and their treatment

Loss aversion and 5HTT gene variants in adolescent anxiety

Loss aversion, a well-documented behavioral phenomenon, characterizes decisions under risk in adult populations. As such, loss aversion may provide a reliable measure of risky behavior. Surprisingly, little is known about loss aversion in adolescents, a group who manifests risk-taking behavior, or in anxiety disorders, which are associated with risk-avoidance. Finally, loss aversion is expected to be modulated by genotype, particularly the serotonin transporter (SERT) gene variant, based on its role in anxiety and impulsivity. This genetic modulation may also differ between anxious and healthy adolescents, given their distinct propensities for risk taking. The present work examines the modulation of loss aversion, an index of risk-taking, and reaction-time to decision, an index of impulsivity, by the serotonin-transporter-gene-linked polymorphisms (5HTTLPR) in healthy and clinically anxious adolescents. Findings show that loss aversion (1) does manifest in adolescents, (2) does not differ between healthy and clinically anxious participants, and (3), when stratified by SERT genotype, identifies a subset of anxious adolescents who are high SERT-expressers, and show excessively low loss-aversion and high impulsivity. This last finding may serve as preliminary evidence for 5HTTLPR as a risk factor for the development of comorbid disorders associated with risk-taking and impulsivity in clinically anxious adolescents

Comparative Multimodal Meta-analysis of Structural and Functional Brain Abnormalities in Autism Spectrum Disorder and Obsessive-Compulsive Disorder

BACKGROUND: Autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD) share inhibitory control deficits possibly underlying poor control over stereotyped and repetitive and compulsive behaviors, respectively. However, it is unclear whether these symptom profiles are mediated by common or distinct neural profiles. This comparative multimodal meta-analysis assessed shared and disorder-specific neuroanatomy and neurofunction of inhibitory functions. METHODS: A comparative meta-analysis of 62 voxel-based morphometry and 26 functional magnetic resonance imaging (fMRI) studies of inhibitory control was conducted comparing gray matter volume and activation abnormalities between patients with ASD (structural MRI: 911; fMRI: 188) and OCD (structural MRI: 928; fMRI: 247) and control subjects. Multimodal meta-analysis compared groups across voxel-based morphometry and fMRI. RESULTS: Both disorders shared reduced function and structure in the rostral and dorsomedial prefrontal cortex including the anterior cingulate. OCD patients had a disorder-specific increase in structure and function of left basal ganglia (BG) and insula relative to control subjects and ASD patients, who had reduced right BG and insula volumes versus OCD patients. In fMRI, ASD patients showed disorder-specific reduced left dorsolateral-prefrontal activation and reduced posterior cingulate deactivation, whereas OCD patients showed temporoparietal underactivation. CONCLUSIONS: The multimodal comparative meta-analysis shows shared and disorder-specific abnormalities. Whereas the rostrodorsomedial prefrontal cortex was smaller in structure and function in both disorders, this was concomitant with increased structure and function in BG and insula in OCD patients, but a reduction in ASD patients, presumably reflecting a disorder-specific frontostriatoinsular dysregulation in OCD in the form of poor frontal control over overactive BG, and a frontostriatoinsular maldevelopment in ASD with reduced structure and function in this network. Disorder-differential mechanisms appear to drive overlapping phenotypes of inhibitory control abnormalities in patients with ASD and OCD

Using genetic algorithms to uncover individual differences in how humans represent facial emotion

Emotional facial expressions critically impact social interactions and cognition. However, emotion research to date has generally relied on the assumption that people represent categorical emotions in the same way, using standardized stimulus sets and overlooking important individual differences. To resolve this problem, we developed and tested a task using genetic algorithms to derive assumption-free, participant-generated emotional expressions. One hundred and five participants generated a subjective representation of happy, angry, fearful and sad faces. Population-level consistency was observed for happy faces, but fearful and sad faces showed a high degree of variability. High test-retest reliability was observed across all emotions. A separate group of 108 individuals accurately identified happy and angry faces from the first study, while fearful and sad faces were commonly misidentified. These findings are an important first step towards understanding individual differences in emotion representation, with the potential to reconceptualize the way we study atypical emotion processing in future research

Association of subcortical gray-matter volumes with life-course-persistent antisocial behavior in a population-representative longitudinal birth cohort

Neuropsychological evidence supports the developmental taxonomy theory of antisocial behavior, suggesting that abnormal brain development distinguishes life-course-persistent from adolescence-limited antisocial behavior. Recent neuroimaging work confirmed that prospectively-measured life-course-persistent antisocial behavior is associated with differences in cortical brain structure. Whether this extends to subcortical brain structures remains uninvestigated. This study compared subcortical gray-matter volumes between 672 members of the Dunedin Study previously defined as exhibiting life-course-persistent, adolescence-limited or low-level antisocial behavior based on repeated assessments at ages 7-26 years. Gray-matter volumes of 10 subcortical structures were compared across groups. The life-course-persistent group had lower volumes of amygdala, brain stem, cerebellum, hippocampus, pallidum, thalamus, and ventral diencephalon compared to the low-antisocial group. Differences between life-course-persistent and adolescence-limited individuals were comparable in effect size to differences between life-course-persistent and low-antisocial individuals, but were not statistically significant due to less statistical power. Gray-matter volumes in adolescence-limited individuals were near the norm in this population-representative cohort and similar to volumes in low-antisocial individuals. Although this study could not establish causal links between brain volume and antisocial behavior, it constitutes new biological evidence that all people with antisocial behavior are not the same, supporting a need for greater developmental and diagnostic precision in clinical, forensic, and policy-based interventions

Altered structural brain asymmetry in autism spectrum disorder in a study of 54 datasets

Altered structural brain asymmetry in autism spectrum disorder (ASD) has been reported. However, findings have been inconsistent, likely due to limited sample sizes. Here we investigated 1,774 individuals with ASD and 1,809 controls, from 54 independent data sets of the ENIGMA consortium. ASD was significantly associated with alterations of cortical thickness asymmetry in mostly medial frontal, orbitofrontal, cingulate and inferior temporal areas, and also with asymmetry of orbitofrontal surface area. These differences generally involved reduced asymmetry in individuals with ASD compared to controls. Furthermore, putamen volume asymmetry was significantly increased in ASD. The largest case-control effect size was Cohen’s d = −0.13, for asymmetry of superior frontal cortical thickness. Most effects did not depend on age, sex, IQ, severity or medication use. Altered lateralized neurodevelopment may therefore be a feature of ASD, affecting widespread brain regions with diverse functions. Large-scale analysis was necessary to quantify subtle alterations of brain structural asymmetry in ASD