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Belonging is a basic human need, with social isolation signaling a threat to biological fitness. Sensitivity to ostracism varies across individuals and the lifespan, peaking in adolescence. Government-imposed restrictions upon social interactions during COVID-19 may therefore be particularly detrimental to young people and those most sensitive to ostracism. Participants ( N = 2367; 89.95% female, 11–100 years) from three countries with differing levels of government restrictions (Australia, UK, and USA) were surveyed thrice at three-month intervals (May 2020 – April 2021). Young people, and those living under the tightest government restrictions, reported the worst mental health, with these inequalities in mental health remaining constant throughout the study period. Further dissection of these results revealed that young people high on social rejection sensitivity reported the most mental health problems at the final assessment. These findings help account for the greater impact of enforced social isolation on young people’s mental health, and open novel avenues for intervention.

Individuals vary in their ability to tolerate uncertainty. High intolerance of uncertainty (the tendency to react negatively to uncertain situations) is a known risk factor for mental health problems. In the current study we examined the degree to which intolerance of uncertainty predicted depression and anxiety symptoms and their interrelations across the first year of the COVID-19 pandemic. We examined these associations across three time points (May 2020 – April 2021) in an international sample of adults ( N  = 2087, Mean age = 41.13) from three countries (UK, USA, Australia) with varying degrees of COVID-19 risk. We found that individuals with high and moderate levels of intolerance of uncertainty reported reductions in depression and anxiety symptoms over time. However, symptom levels remained significantly elevated compared to individuals with low intolerance of uncertainty. Individuals with low intolerance of uncertainty had low and stable levels of depression and anxiety across the course of the study. Network analyses further revealed that the relationships between depression and anxiety symptoms became stronger over time among individuals with high intolerance of uncertainty and identified that feeling afraid showed the strongest association with intolerance of uncertainty. Our findings are consistent with previous work identifying intolerance of uncertainty as an important risk factor for mental health problems, especially in times marked by actual health, economic and social uncertainty. The results highlight the need to explore ways to foster resilience among individuals who struggle to tolerate uncertainty, as ongoing and future geopolitical, climate and health threats will likely lead to continued exposure to significant uncertainty.

Alterations in reward-related brain activity have been linked to response to psychological treatment in adolescents with anxiety disorders. However, it remains unknown whether these effects are driven by reward anticipation or feedback, which reflect different functional roles in motivated behavior, or whether brain activity changes as a function of treatment response. The current study investigated these questions in the context of a randomized controlled trial of cognitive-behavioral therapy (CBT) for anxiety disorders in adolescents. This study used an fMRI paradigm to investigate reward-related brain activity in youth aged 9–14 with anxiety disorders (ANX; N = 133; 57 female) before and after 16 weeks of CBT or an active comparison (child-centered therapy, CCT). Age- and sex-matched healthy comparison (HC) youth (N = 38; 17 female) completed scans on a similar timeline. A subset of ANX youth completed a 2-year follow-up assessment of depressive symptoms. At pretreatment, ANX compared to HC youth demonstrated reduced brain activity in reward-related regions (e.g. dorsal striatum, thalamus) during reward anticipation, and elevated activity in angular gyrus, PCC and inferior frontal gyrus during reward feedback. Reduced pretreatment activation in the precuneus/cuneus and pre-to-post reductions in left angular gyrus corresponded with treatment response. Finally, pre-to-post increases in posterior cingulate cortex (PCC) corresponded with increased depressive symptoms at 2 years. Our results suggest that reward-related brain activity outside of striatal reward regions, including PCC, precuneus and angular gyrus, plays a role in treatment response in youth with anxiety disorders. Trial registration: ClinicalTrials.gov NCT00774150.

Several mental disorders emerge during childhood or adolescence and are often characterized by socioemotional difficulties, including alterations in emotion perception. Emotional facial expressions are processed in discrete functional brain modules whose connectivity patterns encode emotion categories, but the involvement of these neural circuits in psychopathology in youth is poorly understood. This study examined the associations between activation and functional connectivity patterns in emotion circuits and psychopathology during development. We used task-based fMRI data from the Philadelphia Neurodevelopmental Cohort (PNC, N  = 1221, 8–23 years) and conducted generalized psycho-physiological interaction (gPPI) analyses. Measures of psychopathology were derived from an independent component analysis of questionnaire data. The results showed positive associations between identifying fearful, sad, and angry faces and depressive symptoms, and a negative relationship between sadness recognition and positive psychosis symptoms. We found a positive main effect of depressive symptoms on BOLD activation in regions overlapping with the default mode network, while individuals reporting higher levels of norm-violating behavior exhibited emotion-specific lower functional connectivity within regions of the salience network and between modules that overlapped with the salience and default mode network. Our findings illustrate the relevance of functional connectivity patterns underlying emotion processing for behavioral problems in children and adolescents.

Understanding neurobiological characteristics of cognitive dysfunction in distinct psychiatric disorders remains challenging. In this secondary data analysis, we examined neurobiological differences in brain response during working memory updating among individuals with bipolar disorder (BD), those with unipolar depression (UD), and healthy controls (HC). Individuals between 18–45 years of age with BD ( n  = 100), UD ( n  = 109), and HC ( n  = 172) were scanned using fMRI while performing 0-back (easy) and 2-back (difficult) tasks with letters as the stimuli and happy, fearful, or neutral faces as distractors. The 2( n -back) × 3(groups) × 3(distractors) ANCOVA examined reaction time (RT), accuracy, and brain activation during the task. HC showed more accurate and faster responses than individuals with BD and UD. Difficulty-related activation in the prefrontal, posterior parietal, paracingulate cortices, striatal, lateral occipital, precuneus, and thalamic regions differed among groups. Individuals with BD showed significantly lower difficulty-related activation differences in the left lateral occipital and the right paracingulate cortices than those with UD. In individuals with BD, greater difficulty-related worsening in accuracy was associated with smaller activity changes in the right precuneus, while greater difficulty-related slowing in RT was associated with smaller activity changes in the prefrontal, frontal opercular, paracingulate, posterior parietal, and lateral occipital cortices. Measures of current depression and mania did not correlate with the difficulty-related brain activation differences in either group. Our findings suggest that the alterations in the working memory circuitry may be a trait characteristic of reduced working memory capacity in mood disorders. Aberrant patterns of activation in the left lateral occipital and paracingulate cortices may be specific to BD.

A recently developed risk calculator for bipolar disorder (BD) accounts for clinical and parental psychopathology. Yet, it is understood that both familial predisposition and early life adversity contribute to the development of BD. How the interplay between these two factors influence emotion and reward processing networks in youth at risk for BD remains unclear. In this exploratory analysis, offspring of BD parents performed emotion and reward processing tasks while undergoing a fMRI scan. Risk calculator score was used to assess risk for developing BD in the next 5 years. Environmental risk was tabulated using the Stressful Life Events Schedule (SLES). Emotion and reward processing networks were investigated for genetic and/or environment interactions. Interaction effects were found between risk calculator scores, negative SLES score and activity in right amygdala and bilateral fusiform gyri during the emotion processing task, as well as activity in the fronto-, striatal, and parietal regions during the reward processing task. Our findings are preliminary; however, they support the unique and interactive contributions of both familial and environmental risk factors on emotion and reward processing within OBP. They also identify potential neural targets to guide development of interventions for youth at greatest risk for psychiatric disorders.

There are no known biological measures that accurately predict future development of psychiatric disorders in individual at-risk adolescents. We investigated whether machine learning and fMRI could help to: 1. differentiate healthy adolescents genetically at-risk for bipolar disorder and other Axis I psychiatric disorders from healthy adolescents at low risk of developing these disorders; 2. identify those healthy genetically at-risk adolescents who were most likely to develop future Axis I disorders. 16 healthy offspring genetically at risk for bipolar disorder and other Axis I disorders by virtue of having a parent with bipolar disorder and 16 healthy, age- and gender-matched low-risk offspring of healthy parents with no history of psychiatric disorders (12-17 year-olds) performed two emotional face gender-labeling tasks (happy/neutral; fearful/neutral) during fMRI. We used Gaussian Process Classifiers (GPC), a machine learning approach that assigns a predictive probability of group membership to an individual person, to differentiate groups and to identify those at-risk adolescents most likely to develop future Axis I disorders. Using GPC, activity to neutral faces presented during the happy experiment accurately and significantly differentiated groups, achieving 75% accuracy (sensitivity = 75%, specificity = 75%). Furthermore, predictive probabilities were significantly higher for those at-risk adolescents who subsequently developed an Axis I disorder than for those at-risk adolescents remaining healthy at follow-up. We show that a combination of two promising techniques, machine learning and neuroimaging, not only discriminates healthy low-risk from healthy adolescents genetically at-risk for Axis I disorders, but may ultimately help to predict which at-risk adolescents subsequently develop these disorders.

A considerable number of previous studies have shown abnormalities in the processing of emotional faces in major depression. Fewer studies, however, have focused specifically on abnormal processing of neutral faces despite evidence that depressed patients are slow and less accurate at recognizing neutral expressions in comparison with healthy controls. The current study aimed to investigate whether this misclassification described behaviourally for neutral faces also occurred when classifying patterns of brain activation to neutral faces for these patients. TWO INDEPENDENT DEPRESSED SAMPLES: (1) Nineteen medication-free patients with depression and 19 healthy volunteers and (2) Eighteen depressed individuals and 18 age and gender-ratio-matched healthy volunteers viewed emotional faces (sad/neutral; happy/neutral) during an fMRI experiment. We used a new pattern recognition framework: first, we trained the classifier to discriminate between two brain states (e.g. viewing happy faces vs. viewing neutral faces) using data only from healthy controls (HC). Second, we tested the classifier using patterns of brain activation of a patient and a healthy control for the same stimuli. Finally, we tested if the classifier's predictions (predictive probabilities) for emotional and neutral face classification were different for healthy controls and depressed patients. Predictive probabilities to patterns of brain activation to neutral faces in both groups of patients were significantly lower in comparison to the healthy controls. This difference was specific to neutral faces. There were no significant differences in predictive probabilities to patterns of brain activation to sad faces (sample 1) and happy faces (samples 2) between depressed patients and healthy controls. Our results suggest that the pattern of brain activation to neutral faces in depressed patients is not consistent with the pattern observed in healthy controls subject to the same stimuli. This difference in brain activation might underlie the behavioural misinterpretation of the neutral faces content by the depressed patients.

Close proximity to an attachment figure, such as a caregiver, has been shown to attenuate threat-related activity in limbic regions such as the hypothalamus in healthy individuals. We hypothesized that such features might be similarly attenuated by proximity during a potentially stressful situation in a clinically anxious population of youths. Confirmation of this hypothesis could support the role of attachment figures in the management of anxiety among children and adolescents. Three groups were analyzed: anxious children and adolescents who requested that their caregiver accompany them in the scanner room, anxious children and adolescents without their caregiver in the scanner room and healthy controls (each of N = 10). The groups were matched for age and, among the two anxious groups, for diagnosis (mean age 9.5). The children and adolescents were exposed to physical threat words during an fMRI assessment. Results indicate that activity in the hypothalamus, ventromedial, and ventrolateral prefrontal cortex were significantly reduced in anxious children and adolescents who requested that their caregiver accompany them in the scanner room compared to those without their caregiver in the scanner room. Mean activity in these regions in anxious children and adolescents with their caregiver in the scanner room was comparable to that of healthy controls. These data suggest links between social contact and neural mechanisms of emotional reactivity; specifically, presence of caregivers moderates the increase in anxiety seen with stressful stimuli. Capitalizing on the ability of anxious youths to manifest low levels of anxiety-like information processing in the presence of a caregiver could help in modeling adaptive function in behavioral treatments.

Negative relationships with parents and peers are considered risk factors for depression in adolescence, yet not all adolescents perceiving negative social relationships develop depression. In line with neurobiological susceptibility to social context models, we examined how individual differences in neural processing of parental praise, a unique form of social reward, might explain variability in susceptibility to perceived maternal acceptance and peer victimization. During neuroimaging, 38 11- to 17-year-olds with a history of anxiety listened to audio clips of a parent (predominately mothers) providing personalized praise and neutral statements. Average activation during parental praise clips relative to neutral clips was extracted from several anatomically-defined reward-related regions-of-interest (ROIs): the subgenual anterior cingulate cortex, caudate nucleus, amygdala, nucleus accumbens, and insula. Moderation models included direct effects and interactions between neural activation to praise, peer victimization, and maternal acceptance at the time of scanning on depressive symptoms one year later. Results showed a significant three-way interaction for the bilateral caudate such that peer victimization was associated with depressive symptoms only for individuals with higher caudate response to praise who perceived maternal acceptance as low. Consistent with neurobiological susceptibility to social context models, caudate activation to social reward could represent a neural marker that helps explain variability in adolescent sensitivity to social contexts. High caudate activation to praise could reflect a history of negative experiences with parents and/or peers that places youth at greater risk for depressive symptoms. Findings suggest that interactions between neural response to reward and salient social contexts may help us understand changes in depressive symptoms during a period of development marked by significant biopsychosocial change.