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

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

Jumping to attributions during social evaluation

Social learning is crucial for human relationships and well-being. Self- and other- evaluations are universal experiences, playing key roles in many psychiatric disorders, particularly anxiety and depression. We aimed to deepen our understanding of the computational mechanisms behind social learning, which have been implicated in internalizing conditions like anxiety and depression. We built on prior work based on the Social Evaluation Learning Task (SELT) and introduced a new computational model to better explain rapid initial inferences and progressive refinement during serial social evaluations. The Social Evaluation Learning Task-Revised (SELT-R) was improved by stakeholder input, making it more engaging and suitable for adolescents. A sample of 130 adults from the UK completed the SELT-R and questionnaires assessing symptoms of depression and anxiety. ‘Classify-refine’ computational models were compared with previously successful Bayesian models. The ‘classify-refine’ models performed better, providing insight into how people infer the attributes and motives of others. Parameters of the best fitting model from the SELT-R were correlated with Anxiety factor scores, with higher symptoms associated with greater decision noise and higher (less flexible) policy certainty. Our results replicate findings regarding the classify-refine process and set the stage for future investigations into the cognitive mechanisms of self and other evaluations in internalizing disorders

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

Associations between life-course-persistent antisocial behaviour and brain structure in a population-representative longitudinal birth cohort

BACKGROUND Studies with behavioural and neuropsychological tests have supported the developmental taxonomy theory of antisocial behaviour, which specifies abnormal brain development as a fundamental aspect of life-course-persistent antisocial behaviour, but no study has characterised features of brain structure associated with life-course-persistent versus adolescence-limited trajectories, as defined by prospective data. We aimed to determine whether life-course-persistent antisocial behaviour is associated with neurocognitive abnormalities by testing the hypothesis that it is also associated with brain structure abnormalities. METHODS We used structural MRI data collected at 45 years of age from participants in the Dunedin Study, a population-representative longitudinal birth cohort of 1037 individuals born between April 1, 1972, and March 31, 1973, in Dunedin, New Zealand, who were resident in the province and who participated in the first assessment at 3 years of age. Participants underwent MRI, and mean global cortical surface area and cortical thickness were extracted for each participant. Participants had been previously subtyped as exhibiting life-course-persistent, adolescence-limited, or no history of persistent antisocial behaviour (ie, a low trajectory group) based on informant-reported and self-reported conduct problems from the ages of 7 years to 26 years. Study personnel who processed the MRI images were masked to antisocial group membership. We used linear estimated ordinary least squares regressions to compare each antisocial trajectory group (life-course persistent and adolescence limited) with the low trajectory group to examine whether antisocial behaviour was related to abnormalities in mean global surface area and mean cortical thickness. Next, we used parcel-wise linear regressions to identify antisocial trajectory group differences in surface area and cortical thickness. All results were controlled for sex and false discovery rate corrected. FINDINGS Data from 672 participants were analysed, and 80 (12%) were classified as having life-course-persistent antisocial behaviour, 151 (23%) as having adolescence-limited antisocial behaviour, and 441 (66%) as having low antisocial behaviour. Individuals on the life-course-persistent trajectory had a smaller mean surface area (standardised β=–0·18 [95% CI −0·24 to −0·11]; p<0·0001) and lower mean cortical thickness (standardised β=–0·10 [95% CI −0·19 to −0·02]; p=0·020) than did those in the low group. Compared with the low group, the life-course-persistent group had reduced surface area in 282 of 360 anatomically defined parcels and thinner cortex in 11 of 360 parcels encompassing circumscribed frontal and temporal regions associated with executive function, affect regulation, and motivation. Widespread differences in brain surface morphometry were not observed for the adolescence-limited group compared with either non-antisocial behaviour or life-course-persistent groups. INTERPRETATION These analyses provide initial evidence that differences in brain surface morphometry are associated with life-course-persistent, but not adolescence-limited, antisocial behaviour. As such, the analyses are consistent with the developmental taxonomy theory of antisocial behaviour and highlight the importance of using prospective longitudinal data to define different patterns of antisocial behaviour development. FUNDING US National Institute on Aging, Health Research Council of New Zealand, New Zealand Ministry of Business, Innovation and Employment, UK Medical Research Council, Avielle Foundation, and Wellcome Trust

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

The effects of acute fluoxetine administration on temporal discounting in youth with ADHD

Serotonin is under-researched in attention deficit hyperactivity disorder (ADHD), despite accumulating evidence for its involvement in impulsiveness and the disorder. Serotonin further modulates temporal discounting (TD), which is typically abnormal in ADHD relative to healthy subjects, underpinned by reduced fronto-striato-limbic activation. This study tested whether a single acute dose of the selective serotonin reuptake inhibitor (SSRI) fluoxetine up-regulates and normalizes reduced fronto-striato-limbic neurofunctional activation in ADHD during TD. Twelve boys with ADHD were scanned twice in a placebo-controlled randomized design under either fluoxetine (between 8 and 15 mg, titrated to weight) or placebo while performing an individually adjusted functional magnetic resonance imaging TD task. Twenty healthy controls were scanned once. Brain activation was compared in patients under either drug condition and compared to controls to test for normalization effects. Repeated-measures whole-brain analysis in patients revealed significant up-regulation with fluoxetine in a large cluster comprising right inferior frontal cortex, insula, premotor cortex and basal ganglia, which further correlated trend-wise with TD performance, which was impaired relative to controls under placebo, but normalized under fluoxetine. Fluoxetine further down-regulated default mode areas of posterior cingulate and precuneus. Comparisons between controls and patients under either drug condition revealed normalization with fluoxetine in right premotor-insular-parietal activation, which was reduced in patients under placebo. The findings show that a serotonin agonist up-regulates activation in typical ADHD dysfunctional areas in right inferior frontal cortex, insula and striatum as well as down-regulating default mode network regions in the context of impulsivity and TD

Neural dysfunction during temporal discounting in paediatric Attention-Deficit/Hyperactivity Disorder and Obsessive-Compulsive Disorder

Both Attention-Deficit/Hyperactivity Disorder (ADHD) and Obsessive-Compulsive Disorder (OCD) are associated with choice impulsivity, i.e. the tendency to prefer smaller immediate rewards over larger delayed rewards. However, the extent to which this impulsivity is mediated by shared or distinct underlying neural mechanisms is unclear. Twenty-six boys with ADHD, 20 boys with OCD and 20 matched controls (aged 12–18) completed an fMRI version of an individually adjusted temporal discounting (TD) task which requires choosing between a variable amount of money now or £100 in one week, one month or one year. Activations to immediate and delayed reward choices were compared between groups using a three-way ANCOVA. ADHD patients had steeper discounting rates on the task relative to controls. OCD patients did not differ from controls or patients with ADHD. Patients with ADHD and OCD showed predominantly shared activation deficits during TD in fronto-striato-insular-cerebellar regions responsible for self-control and temporal foresight, suggesting that choice impulsivity is mediated by overlapping neural dysfunctions in both disorders. OCD patients alone showed dysfunction relative to controls in right orbitofrontal and rostrolateral prefrontal cortex, extending previous findings of abnormalities in these regions in OCD to the domain of choice impulsiveness

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