Major stress in early childhood strengthens the association between peripheral inflammatory activity and corticostriatal responsivity to reward.

BACKGROUND: Severe, chronic stress during childhood accentuates vulnerability to mental and physical health problems across the lifespan. To explain this phenomenon, the neuroimmune network hypothesis proposes that childhood stressors amplify signaling between peripheral inflammatory cells and developing brain circuits that support processing of rewards and threats. Here, we conducted a preliminary test of the basic premises of this hypothesis. METHODS: 180 adolescents (mean age = 19.1 years; 68.9 % female) with diverse racial and ethnic identities (56.1 % White; 28.3 % Hispanic; 26.1 % Asian) participated. The Childhood Trauma Interview was administered to quantify early adversity. Five inflammatory biomarkers were assayed in antecubital blood - C-reactive protein, tumor necrosis factor-a, and interleukins-6, -8, and -10 - and were averaged to form a composite score. Participants also completed a functional MRI task to measure corticostriatal responsivity to the anticipation and acquisition of monetary rewards. RESULTS: Stress exposure and corticostriatal responsivity interacted statistically to predict the inflammation composite. Among participants who experienced major stressors in the first decade of life, higher inflammatory activity covaried with lower corticostriatal responsivity during acquisition of monetary rewards. This relationship was specific to participants who experienced major stress in early childhood, implying a sensitive period for exposure, and were evident in both the orbitofrontal cortex and the ventral striatum, suggesting the broad involvement of corticostriatal regions. The findings were independent of participants' age, sex, racial and ethnic identity, family income, and depressive symptoms. CONCLUSIONS: Collectively, the results are consistent with hypotheses suggesting that major stress in childhood alters brain-immune signaling.

Risk and protective factors for new-onset binge eating, low weight, and self-harm symptoms in >35,000 individuals in the UK during the COVID-19 pandemic.

OBJECTIVE: The disruption caused by the COVID-19 pandemic has been associated with poor mental health, including increases in eating disorders and self-harm symptoms. We investigated risk and protective factors for the new onset of these symptoms during the pandemic. METHOD: Data were from the COVID-19 Psychiatry and Neurological Genetics study and the Repeated Assessment of Mental health in Pandemics Study (n = 36,715). Exposures were socio-demographic characteristics, lifetime psychiatric disorder, and COVID-related variables, including SARS-CoV-2 infection/illness with COVID-19. We identified four subsamples of participants without pre-pandemic experience of our outcomes: binge eating (n = 24,211), low weight (n = 24,364), suicidal and/or self-harm ideation (n = 18,040), and self-harm (n = 29,948). Participants reported on our outcomes at frequent intervals (fortnightly to monthly). We fitted multiple logistic regression models to identify factors associated with the new onset of our outcomes. RESULTS: Within each subsample, new onset was reported by: 21% for binge eating, 10.8% for low weight, 23.5% for suicidal and/or self-harm ideation, and 3.5% for self-harm. Shared risk factors included having a lifetime psychiatric disorder, not being in paid employment, higher pandemic worry scores, and being racially minoritized. Conversely, infection with SARS-CoV-2/illness with COVID-19 was linked to lower odds of binge eating, low weight, and suicidal and/or self-harm ideation. DISCUSSION: Overall, we detected shared risk factors that may drive the comorbidity between eating disorders and self-harm. Subgroups of individuals with these risk factors may require more frequent monitoring during future pandemics. PUBLIC SIGNIFICANCE: In a sample of 35,000 UK residents, people who had a psychiatric disorder, identified as being part of a racially minoritized group, were not in paid employment, or were more worried about the pandemic were more likely to experience binge eating, low weight, suicidal and/or self-harm ideation, and self-harm for the first time during the pandemic. People with these risk factors may need particular attention during future pandemics to enable early identification of new psychiatric symptoms.

Sociodemographic, mental health, and physical health factors associated with participation within re-contactable mental health cohorts: an investigation of the GLAD Study.

BACKGROUND: The Genetic Links to Anxiety and Depression (GLAD) Study is a large cohort of individuals with lifetime anxiety and/or depression, designed to facilitate re-contact of participants for mental health research. At the start of the pandemic, participants from three cohorts, including the GLAD Study, were invited to join the COVID-19 Psychiatry and Neurological Genetics (COPING) study to monitor mental and neurological health. However, previous research suggests that participation in longitudinal studies follows a systematic, rather than random, process, which can ultimately bias results. Therefore, this study assessed participation biases following the re-contact of GLAD Study participants. METHODS: In April 2020, all current GLAD Study participants (N = 36,770) were invited to the COPING study. Using logistic regression, we investigated whether sociodemographic, mental, and physical health characteristics were associated with participation in the COPING baseline survey (aim one). Subsequently, we used a zero-inflated negative binomial regression to examine whether these factors were also related to participation in the COPING follow-up surveys (aim two). RESULTS: For aim one, older age, female gender identity, non-binary or self-defined gender identities, having one or more physical health disorders, and providing a saliva kit for the GLAD Study were associated with an increased odds of completing the COPING baseline survey. In contrast, lower educational attainment, Asian or Asian British ethnic identity, Black or Black British ethnic identity, higher alcohol consumption at the GLAD sign-up survey, and current or ex-smoking were associated with a reduced odds. For aim two, older age, female gender, and saliva kit provision were associated with greater COPING follow-up survey completion. Lower educational attainment, higher alcohol consumption at the GLAD Study sign-up, ex-smoking, and self-reported attention deficit hyperactivity disorder had negative relationships. CONCLUSIONS: Participation biases surrounding sociodemographic and physical health characteristics were particularly evident when re-contacting the GLAD Study volunteers. Factors associated with participation may vary depending on study design. Researchers should examine the barriers and mechanisms underlying participation bias in order to combat these issues and address recruitment biases in future studies.

Individual differences in threat and reward neural circuitry activation: Testing dimensional models of early adversity, anxiety and depression.

Altered functioning of the brain's threat and reward circuitry has been linked to early life adversity and to symptoms of anxiety and depression. To date, however, these relationships have been studied largely in isolation and in categorical-based approaches. It is unclear to what extent early life adversity and psychopathology have unique effects on brain functioning during threat and reward processing. We examined functional brain activity during a face processing task in threat (amygdala and ventromedial prefrontal cortex) and reward (ventral striatum and orbitofrontal cortex) regions of interest among a sample (N = 103) of young adults (aged 18-19 years) in relation to dimensional measures of early life adversity and symptoms of anxiety and depression. Results demonstrated a significant association between higher scores on the deprivation adversity dimension and greater activation of reward neural circuitry during viewing of happy faces, with the largest effect sizes observed in the orbitofrontal cortex. We found no significant associations between the threat adversity dimension, or symptom dimensions of anxiety and depression, and neural activation in threat or reward circuitries. These results lend partial support to theories of adversity-related alterations in neural activation and highlight the importance of testing dimensional models of adversity and psychopathology in large sample sizes to further our understanding of the biological processes implicated.

Risk factors for developing COVID-19: a population-based longitudinal study (COVIDENCE UK).

BACKGROUND: Risk factors for severe COVID-19 include older age, male sex, obesity, black or Asian ethnicity and underlying medical conditions. Whether these factors also influence susceptibility to developing COVID-19 is uncertain. METHODS: We undertook a prospective, population-based cohort study (COVIDENCE UK) from 1 May 2020 to 5 February 2021. Baseline information on potential risk factors was captured by an online questionnaire. Monthly follow-up questionnaires captured incident COVID-19. We used logistic regression models to estimate multivariable-adjusted ORs (aORs) for associations between potential risk factors and odds of COVID-19. RESULTS: We recorded 446 incident cases of COVID-19 in 15 227 participants (2.9%). Increased odds of developing COVID-19 were independently associated with Asian/Asian British versus white ethnicity (aOR 2.28, 95% CI 1.33 to 3.91), household overcrowding (aOR per additional 0.5 people/bedroom 1.26, 1.11 to 1.43), any versus no visits to/from other households in previous week (aOR 1.31, 1.06 to 1.62), number of visits to indoor public places (aOR per extra visit per week 1.05, 1.02 to 1.09), frontline occupation excluding health/social care versus no frontline occupation (aOR 1.49, 1.12 to 1.98) and raised body mass index (BMI) (aOR 1.50 (1.19 to 1.89) for BMI 25.0-30.0 kg/m2 and 1.39 (1.06 to 1.84) for BMI >30.0 kg/m2 versus BMI <25.0 kg/m2). Atopic disease was independently associated with decreased odds (aOR 0.75, 0.59 to 0.97). No independent associations were seen for age, sex, other medical conditions, diet or micronutrient supplement use. CONCLUSIONS: After rigorous adjustment for factors influencing exposure to SARS-CoV-2, Asian/Asian British ethnicity and raised BMI were associated with increased odds of developing COVID-19, while atopic disease was associated with decreased odds. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04330599).

Different trajectories of depression, anxiety and anhedonia symptoms in the first 12 months of the COVID-19 pandemic in a UK longitudinal sample.

BACKGROUND: While studies from the start of the COVID-19 pandemic have described initial negative effects on mental health and exacerbating mental health inequalities, longer-term studies are only now emerging. METHOD: In total, 34 465 individuals in the UK completed online questionnaires and were re-contacted over the first 12 months of the pandemic. We used growth mixture modelling to identify trajectories of depression, anxiety and anhedonia symptoms using the 12-month data. We identified sociodemographic predictors of trajectory class membership using multinomial regression models. RESULTS: Most participants had consistently low symptoms of depression or anxiety over the year of assessments (60%, 69% respectively), and a minority had consistently high symptoms (10%, 15%). We also identified participants who appeared to show improvements in symptoms as the pandemic progressed, and others who showed the opposite pattern, marked symptom worsening, until the second national lockdown. Unexpectedly, most participants showed stable low positive affect, indicating anhedonia, throughout the 12-month period. From regression analyses, younger age, reporting a previous mental health diagnosis, non-binary, or self-defined gender, and an unemployed or a student status were significantly associated with membership of the stable high symptom groups for depression and anxiety. CONCLUSIONS: While most participants showed little change in their depression and anxiety symptoms across the first year of the pandemic, we highlight the divergent responses of subgroups of participants, who fared both better and worse around national lockdowns. We confirm that previously identified predictors of negative outcomes in the first months of the pandemic also predict negative outcomes over a 12-month period.

Sleep quality is associated with emotion experience and adaptive regulation of positive emotion: An experience sampling study.

Poor sleep patterns have been strongly linked to disrupted emotional experiences. Emotion regulation, defined as the capacity to manage one's own emotional responses, comprises strategies to increase, maintain, or decrease the intensity, duration, and trajectory of positive and negative emotions. Poor sleep has been identified as a risk factor for emotional dysregulation, but most of the focus has been on negative emotion regulation. We therefore asked whether natural variations in sleep are associated with the experience and regulation of both positive and negative emotion. Young adults, aged between 18-24 years (N = 101), completed 7 days of ecological momentary assessments using a smartphone application. Duration and quality of the previous night's sleep was reported each morning. Levels of positive and negative emotions, and strategies used to regulate emotions, were measured at pseudorandom timepoints four times a day. Multilevel modelling indicated that higher self-reported sleep quality was significantly associated with increased intensity and duration of positive emotion, and decreased intensity of negative emotion. There were no statistically significant associations between sleep duration and emotion intensity or duration. Sleep quality, and not sleep duration, was also associated with the reported use of positive emotion regulation strategies. For negative emotion regulation strategy use, we found no associations with sleep quality or duration. Naturally occurring fluctuations in daily sleep quality may be important for the experience and regulation of positive emotion in young adults. These findings emphasise the need to examine both positive and negative emotion, and emotion regulation to understand the links between sleep and mood.

Large-scale remote fear conditioning: Demonstration of associations with anxiety using the FLARe smartphone app.

OBJECTIVES: We aimed to examine differences in fear conditioning between anxious and nonanxious participants in a single large sample. MATERIALS AND METHODS: We employed a remote fear conditioning task (FLARe) to collect data from participants from the Twins Early Development Study (n = 1,146; 41% anxious vs. 59% nonanxious). Differences between groups were estimated for their expectancy of an aversive outcome towards a reinforced conditional stimulus (CS+) and an unreinforced conditional stimulus (CS-) during acquisition and extinction phases. RESULTS: During acquisition, the anxious group (vs. nonanxious group) showed greater expectancy towards the CS-. During extinction, the anxious group (vs. nonanxious group) showed greater expectancy to both CSs. These comparisons yielded effect size estimates (d = 0.26-0.34) similar to those identified in previous meta-analyses. CONCLUSION: The current study demonstrates that remote fear conditioning can be used to detect differences between groups of anxious and nonanxious individuals, which appear to be consistent with previous meta-analyses including in-person studies.

Emotional content impacts how executive function ability relates to willingness to wait and to work for reward.

Research has demonstrated that better value-based decision making (e.g., waiting or working for rewards) relates to greater executive function (EF) ability. However, EF is not a static ability, but is influenced by the emotional content of the task. As such, EF ability in emotional contexts may have unique associations with value-based decision making, in which costs and benefits are explicit. Participants (N = 229) completed an EF task (with both negative and neutral task conditions) and two value-based decision-making tasks. Willingness to wait and to work were evaluated in separate path models relating the waiting and working conditions to the EF conditions. Willingness to wait and willingness to work showed distinct relationships with EF ability: Greater EF ability on a negative, but not on a neutral, EF task was related to a willingness to wait for a reward, whereas greater EF ability across both EF tasks was related to a greater willingness to work for a reward. EF ability on a negative EF task showed an inverted-U relationship to willingness to wait for reward, and was most related to willingness to wait at a 6-month delay. Greater EF, regardless of whether the task was negative or neutral, was related to a greater willingness to work when reward was uncertain (50%) or was likely (88%), but not when reward was unlikely (12%). This study suggests that the emotional content of value-based decisions impacts the relationship between EF ability and willingness to wait or to work for reward.

Experimental manipulation of infant temperament affects amygdala functional connectivity.

In this functional magnetic resonance imaging (fMRI) study we examined neural processing of infant faces associated with a happy or a sad temperament in nulliparous women. We experimentally manipulated adult perception of infant temperament in a probabilistic learning task. In this task, participants learned about an infant's temperament through repeated pairing of the infant face with positive or negative facial expressions and vocalizations. At the end of the task, participants were able to differentiate between "mostly sad" infants who cried often and "mostly happy" infants who laughed often. Afterwards, brain responses to neutral faces of infants with a happy or a sad temperament were measured with fMRI and compared to brain responses to neutral infants with no temperament association. Our findings show that a brief experimental manipulation of temperament can change brain responses to infant signals. We found increased amygdala connectivity with frontal regions and the visual cortex, including the occipital fusiform gyrus, during the perception of infants with a happy temperament. In addition, amygdala connectivity was positively related to the post-manipulation ratings of infant temperament, indicating that amygdala connectivity is involved in the encoding of the rewarding value of an infant with a happy temperament.

Evidence for a Caregiving Instinct: Rapid Differentiation of Infant from Adult Vocalizations Using Magnetoencephalography.

Crying is the most salient vocal signal of distress. The cries of a newborn infant alert adult listeners and often elicit caregiving behavior. For the parent, rapid responding to an infant in distress is an adaptive behavior, functioning to ensure offspring survival. The ability to react rapidly requires quick recognition and evaluation of stimuli followed by a co-ordinated motor response. Previous neuroimaging research has demonstrated early specialized activity in response to infant faces. Using magnetoencephalography, we found similarly early (100-200 ms) differences in neural responses to infant and adult cry vocalizations in auditory, emotional, and motor cortical brain regions. We propose that this early differential activity may help to rapidly identify infant cries and engage affective and motor neural circuitry to promote adaptive behavioral responding, before conscious awareness. These differences were observed in adults who were not parents, perhaps indicative of a universal brain-based "caregiving instinct."

Effects of Infant Cleft Lip on Adult Gaze and Perceptions of "Cuteness".

OBJECTIVE: Early mother-infant interactions are impaired in the context of infant cleft lip and are associated with adverse child psychological outcomes, but the nature of these interaction difficulties is not yet fully understood. The aim of this study was to explore adult gaze behavior and cuteness perception, which are particularly important during early social exchanges, in response to infants with cleft lip, in order to investigate potential foundations for the interaction difficulties seen in this population. METHODS: Using an eye tracker, eye movements were recorded as adult participants viewed images of infant faces with and without cleft lip. Participants also rated each infant on a scale of cuteness. RESULTS: Participants fixated significantly longer on the mouths of infants with cleft lip, which occurred at the expense of fixation on eyes. Severity of cleft lip was associated with the strength of fixation bias, with participants looking even longer at the mouths of infants with the most severe clefts. Infants with cleft lip were rated as significantly less cute than unaffected infants. Men rated infants as less cute than women overall but gave particularly low ratings to infants with cleft lip. CONCLUSIONS: Results demonstrate that the limited disturbance in infant facial configuration of cleft lip can significantly alter adult gaze patterns and cuteness perception. Our findings could have important implications for early interactions and may help in the development of interventions to foster healthy development in infants with cleft lip.

The bonnie baby: experimentally manipulated temperament affects perceived cuteness and motivation to view infant faces.

Attractive individuals are perceived as having various positive personality qualities. Positive personality qualities can in turn increase perceived attractiveness. However, the developmental origins of the link between attractiveness and personality are not understood. This is important because infant attractiveness ('cuteness') elicits caregiving from adults, and infant personality ('temperament') shapes caregiving behaviour. While research suggests that adults have more positive attitudes towards cuter infants, it is not known whether positive infant temperament can increase the perception of infant cuteness. We investigated the impact of experimentally established infant temperament on adults' perception of cuteness and desire to view individual faces. Ataseline, adults rated the cuteness of, and keypressed to view, images of unfamiliar infants with neutral facial expressions. Training required adults to learn about an infant's 'temperament', through repeated pairing of the neutral infant face with positive or negative facial expressions and vocalizations. Adults then re-rated the original neutral infant faces. Post-training, there were significant changes from baseline: infants who were mostly happy were perceived as cuter and adults expended greater effort to view them. Infants who were mostly sad were not perceived as cuter and adults expended less effort to view them. Our results suggest that temperament has clear consequences for how adults perceive 'bonnie' babies. Perception of infant cuteness is not based on physical facial features alone, and is modifiable through experience.

Anhedonia is associated with overgeneralization of conditioned fear during late adolescence and early adulthood.

BACKGROUND: Pavlovian fear paradigms involve learning to associate cues with threat or safety. Aberrances in Pavlovian fear learning correlate with psychopathology, especially anxiety disorders. This study evaluated symptom dimensions of anxiety and depression in relation to Pavlovian fear acquisition and generalization. METHODS: 256 participants (70.31 % female) completed a Pavlovian fear acquisition and generalization paradigm at ages 18-19 and 21-22 years. Analyses focused on indices of learning (self-reported US expectancy, skin conductance). Multilevel models tested associations with orthogonal symptom dimensions (Anhedonia-Apprehension, Fears, General Distress) at each timepoint. RESULTS: All dimensions were associated with weaker acquisition of US expectancies at each timepoint. Fears was associated with overgeneralization only at age 21-22. General Distress was associated with overgeneralization only at age 18-19. Anhedonia-Apprehension was associated with overgeneralization at ages 18-19 and 21-22. CONCLUSIONS: Anhedonia-Apprehension disrupts Pavlovian fear acquisition and increases overgeneralization of fear. These effects may emerge during adolescence and remain into young adulthood. General Distress and Fears also contribute to overgeneralization of fear, but these effects may vary as prefrontal mechanisms of fear inhibition continue to develop during late adolescence. Targeting specific symptom dimensions, particularly Anhedonia-Apprehension, may decrease fear generalization and augment interventions built on Pavlovian principles, such as exposure therapy.

Transdiagnostic symptom of depression and anxiety associated with reduced gray matter volume in prefrontal cortex.

Dimensional models of psychopathology may provide insight into mechanisms underlying comorbid depression and anxiety and improve specificity and sensitivity of neuroanatomical findings. The present study is the first to examine neural structure alterations using the empirically derived Tri-level Model. Depression and anxiety symptoms of 269 young adults were assessed using the Tri-level Model dimensions: General Distress (transdiagnostic depression and anxiety symptoms), Anhedonia-Apprehension (relatively specific depression symptoms), and Fears (specific anxiety symptoms). Using structural MRI, gray matter volumes were extracted for emotion generation (amygdala, nucleus accumbens) and regulation (orbitofrontal, ventrolateral, and dorsolateral prefrontal cortex) regions, often implicated in depression and anxiety. Each Tri-level symptom was regressed onto each region of interest, separately, adjusting for relevant covariates. General Distress was significantly associated with smaller gray matter volumes in bilateral orbitofrontal cortex and ventrolateral prefrontal cortex, independent of Anhedonia-Apprehension and Fears symptom dimensions. These results suggests that prefrontal alterations are associated with transdiagnostic dysphoric mood common across depression and anxiety, rather than unique symptoms of these disorders. Additionally, no regions of interest were associated with Anhedonia-Apprehension or Fears, highlighting the importance of studying transdiagnostic features of depression and anxiety. This has implications for understanding mechanisms of and interventions for depression and anxiety.

Bridging the gap from medical to psychological safety assessment: consensus study in a digital mental health context.

BACKGROUND: Digital Mental Health Interventions (DMHIs) that meet the definition of a medical device are regulated by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK. The MHRA uses procedures that were originally developed for pharmaceuticals to assess the safety of DMHIs. There is recognition that this may not be ideal, as is evident by an ongoing consultation for reform led by the MHRA and the National Institute for Health and Care Excellence. AIMS: The aim of this study was to generate an experts' consensus on how the medical regulatory method used for assessing safety could best be adapted for DMHIs. METHOD: An online Delphi study containing three rounds was conducted with an international panel of 20 experts with experience/knowledge in the field of UK digital mental health. RESULTS: Sixty-four items were generated, of which 41 achieved consensus (64%). Consensus emerged around ten recommendations, falling into five main themes: Enhancing the quality of adverse events data in DMHIs; Re-defining serious adverse events for DMHIs; Reassessing short-term symptom deterioration in psychological interventions as a therapeutic risk; Maximising the benefit of the Yellow Card Scheme; and Developing a harmonised approach for assessing the safety of psychological interventions in general. CONCLUSION: The implementation of the recommendations provided by this consensus could improve the assessment of safety of DMHIs, making them more effective in detecting and mitigating risk.

Seeking help for mental health during the COVID-19 pandemic: A longitudinal analysis of adults' experiences with digital technologies and services.

The COVID-19 pandemic brought about dramatic changes in how patients access healthcare from its outset. Lockdown restrictions and remote working led to a proliferation of digital technologies and services, which also impacted mental health provisions. Against the backdrop of new and changing support services, along with an unprecedented emphasis on mental health, relatively little is known about how adults sought out and received support for their mental health during this period. With a sample of 27,574 adults assessed longitudinally online over 12 months of the pandemic in the UK, we analysed reports of help-seeking for mental health, as well as sources of treatment or support and the perceived helpfulness of treatments received. We observed that the proportions of participants who reported seeking help remained relatively consistent throughout the 12-month period (ranging from 12.6% to 17.0%). Online talking therapies were among the most frequently sought sources (15.3%), whereas online self-guided treatments were among the least frequently sought sources (5%). Telephone lines, both NHS and non-governmental, had marked treatment 'gaps'. These treatment gaps, where individuals sought treatment but did not receive it, were especially evident for men and older adults. Our findings underscore online talking therapies as being a widely-sought and helpful source of mental health support. This is important given the current global need for accessible treatment options.

Broadening the scope: Multiple functional connectivity networks underlying threat and safety signaling.

Introduction: Threat learning and extinction processes are thought to be foundational to anxiety and fear-related disorders. However, the study of these processes in the human brain has largely focused on a priori regions of interest, owing partly to the ease of translating between these regions in human and non-human animals. Moving beyond analyzing focal regions of interest to whole-brain dynamics during threat learning is essential for understanding the neuropathology of fear-related disorders in humans. Methods: 223 participants completed a 2-day Pavlovian threat conditioning paradigm while undergoing fMRI. Participants completed threat acquisition and extinction. Extinction recall was assessed 48 hours later. Using a data-driven group independent component analysis (ICA), we examined large-scale functional connectivity networks during each phase of threat conditioning. Connectivity networks were tested to see how they responded to conditional stimuli during early and late phases of threat acquisition and extinction and during early trials of extinction recall. Results: A network overlapping with the default mode network involving hippocampus, vmPFC, and posterior cingulate was implicated in threat acquisition and extinction. Another network overlapping with the salience network involving dACC, mPFC, and inferior frontal gyrus was implicated in threat acquisition and extinction recall. Other networks overlapping with parts of the salience, somatomotor, visual, and fronto-parietal networks were involved in the acquisition or extinction of learned threat responses. Conclusions: These findings help confirm previous investigations of specific brain regions in a model-free fashion and introduce new findings of spatially independent networks during threat and safety learning. Rather than being a single process in a core network of regions, threat learning involves multiple brain networks operating in parallel coordinating different functions at different timescales. Understanding the nature and interplay of these dynamics will be critical for comprehensive understanding of the multiple processes that may be at play in the neuropathology of anxiety and fear-related disorders.

A Multivoxel Pattern Analysis of Anhedonia During Fear Extinction: Implications for Safety Learning.

BACKGROUND: Pavlovian learning processes are central to the etiology and treatment of anxiety disorders. Anhedonia and related perturbations in reward processes have been implicated in Pavlovian learning. Associations between anhedonia symptoms and neural indices of Pavlovian learning can inform transdiagnostic associations among depressive and anxiety disorders. METHODS: Participants ages 18 to 19 years (67% female) completed a fear extinction (n = 254) and recall (n = 249) paradigm during functional magnetic resonance imaging. Symptom dimensions of general distress (common to anxiety and depression), fears (more specific to anxiety), and anhedonia-apprehension (more specific to depression) were evaluated. We trained whole-brain multivoxel pattern decoders for anhedonia-apprehension during extinction and extinction recall and tested the decoders' ability to predict anhedonia-apprehension in an external validation sample. Specificity analyses examined effects covarying for general distress and fears. Decoding was repeated within canonical brain networks to highlight candidate neurocircuitry underlying whole-brain effects. RESULTS: Whole-brain decoder training succeeded during both tasks. Prediction of anhedonia-apprehension in the external validation sample was successful for extinction (R2 = 0.047; r = 0.276, p = .002) but not extinction recall (R2 < 0.001, r = -0.063, p = .492). The extinction decoder remained significantly associated with anhedonia-apprehension covarying for fears and general distress (t121 = 3.209, p = .002). Exploratory results highlighted activity in the cognitive control, default mode, limbic, salience, and visual networks related to these effects. CONCLUSIONS: Results suggest that patterns of brain activity during extinction, particularly in the cognitive control, default mode, limbic, salience, and visual networks, can be predictive of anhedonia symptoms. Future research should examine associations between anhedonia and extinction, including studies of exposure therapy or positive affect treatments among anhedonic individuals.

Association between reward-related functional connectivity and tri-level mood and anxiety symptoms.

Depression and anxiety are associated with abnormalities in brain regions that process rewards including the medial orbitofrontal cortex (mOFC), the ventral striatum (VS), and the amygdala. However, there are inconsistencies in these findings. This may be due to past reliance on categorical diagnoses that, while valuable, provide less precision than may be required to understand subtle neural changes associated with symptoms of depression and anxiety. In contrast, the tri-level model defines symptom dimensions that are common (General Distress) or relatively specific (Anhedonia-Apprehension, Fears) to depression and anxiety related disorders, which provide increased precision. In the current study, eligibility was assessed by quasi-orthogonal screening questionnaires measuring reward and threat sensitivity (Behavioral Activation Scale; Eysenck Personality Questionnaire-Neuroticism). These participants were assessed on tri-level symptom severity and completed the Monetary Incentive Delay task during fMRI scanning. VS-mOFC and VS-amygdala connectivity were estimated during reward anticipation and reward outcome. Heightened General Distress was associated with lower VS-mOFC connectivity during reward anticipation (b = -0.064, p = 0.021) and reward outcome (b = -0.102, p = 0.014). Heightened Anhedonia-Apprehension was associated with greater VS-amygdala connectivity during reward anticipation (b = 0.065, p = 0.004). The present work has important implications for understanding the coupling between the mOFC and vS and the amygdala and the vS during reward processing in the pathophysiology of mood and anxiety symptoms and for developing targeted behavioral, pharmacological, and neuromodulatory interventions to help manage these symptoms.