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In this study we dissect the heterogeneity that underlies traditional group-level analyses, and determine how individualised patterns of predicted activation relate to age, sex, and variations in acquisition parameters and task design choices. To this end we take advantage of six large open-access/shared datasets and collate a large representative sample of over 7500 participants from which we build a normative of task-evoked activation during a widely used emotional reactivity task, the Emotional Face Matching Task. This enables us to bind heterogeneous datasets to a common reference model and enables meaningful comparisons between them. We then apply this model to the naturalistic and clinically realistic MIND-Set cohort, which is a heterogeneous and highly comorbid sample containing individuals with one or more current diagnosis (affective and anxiety disorders, autism spectrum disorders and/or attention deficit hyperactivity disorder). This enables us to determine whether, and if so how, participants with mental illness and/or neurodivergence differ from the reference cohort, both at the group level and at the level of the individual and in terms of cross-diagnostic symptom domains in addition to diagnosis. We show that patients have, on average, a higher frequency of extreme deviations, and have unique spatial distributions depending on the DSM-IV diagnosis and the number of co-occurring diagnoses when models are constructed using the face>shapes task contrast. Models built using the face>baseline task contrast, have, by comparison, greater predictive value for individuals’ functioning across four transdiagnostic domains. We demonstrate the application of the normative modelling framework to task-based functional neuroimaging data, discuss its potential to further our understanding of individual differences in brain function within reference populations, and further validate the clinical relevance of these models.

BackgroundCurrent behavioural treatment of obsessive-compulsive disorder (OCD) is informed by fear conditioning and involves iteratively re-evaluating previously threatening stimuli as safe. However, there is limited research investigating the neurobiological response to conditioning and reversal of threatening stimuli in individuals with OCD.MethodsA clinical sample of individuals with OCD (N=45) and matched healthy controls (N=45) underwent functional Magnetic Resonance Imaging (fMRI). While in the scanner, participants completed a well-validated fear reversal task and a resting-state scan.ResultsWe found no evidence for group differences in task-evoked brain activation or functional connectivity in OCD. Multivariate analyses encompassing all participants in the clinical and control groups suggested that subjective appraisal of threatening and safe stimuli were associated with a larger difference in brain activity than the contribution of OCD symptoms. In particular, we observed a brain-behaviour continuum whereby heightened affective appraisal was related to increased bilateral insula activation during the task (r = 0.39, pFWE = 0.001).ConclusionsThese findings suggest that changes in conditioned threat-related processes may not be a core neurobiological feature of OCD and encourage further research on the role of subjective experience in fear conditioning.

The brain’s “default mode network” (DMN) enables flexible switching between internally and externally focused cognition. Precisely how this modulation occurs is not well understood, although it may involve key subcortical mechanisms, including hypothesized influences from the basal forebrain (BF) and mediodorsal thalamus (MD). Here, we used ultra-high field (7 T) functional magnetic resonance imaging to examine the involvement of the BF and MD across states of task-induced DMN activity modulation. Specifically, we mapped DMN activity suppression (“deactivation”) when participants transitioned between rest and externally focused task performance, as well as DMN activity engagement (“activation”) when task performance was internally (i.e., self) focused. Consistent with recent rodent studies, the BF showed overall activity suppression with DMN cortical regions when comparing the rest to external task conditions. Further analyses, including dynamic causal modeling, confirmed that the BF drove changes in DMN cortical activity during these rest-to-task transitions. The MD, by comparison, was specifically engaged during internally focused cognition and demonstrated a broad excitatory influence on DMN cortical activation. These results provide the first direct evidence in humans of distinct BF and thalamic circuit influences on the control of DMN function and suggest novel mechanistic avenues for ongoing translational research.

ObjectiveIdentifying brain differences associated with suicidal thoughts and behaviors (STBs) in young people is critical to understanding their development and generating effective approaches to early intervention and prevention. The ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium analyzed neuroimaging data harmonized across sites to examine brain morphology associated with STBs in youth.MethodsFirst, we examined associations among regional brain structure and STBs, which were assessed in six samples of youth with mood disorders, using the Columbia Suicide Severity Rating Scale (C-SSRS;N=577). Second, we combined this sample with a larger sample (total 21 sites) in which STBs were assessed using various instruments. MRI metrics were compared among healthy controls without STBs (HC;N=688), clinical controls without STBs (CC;N=648), and young people with psychiatric diagnoses and current suicidal ideation (N=406). In separate analyses, MRI metrics were compared among HCs (N=335), CCs (N=768), and suicide attempters (N=254).ResultsIn the homogeneous C-SSRS sample, surface area of the frontal pole was lower in young people with mood disorders and history of actual suicide attempts (N=163) than those without (N=394; FDR-pd=.334). When expanding to more clinically heterogeneous samples, we also found lower surface area of the frontal pole in those with a history of suicide attempts (Cohen’sd=.22).ConclusionsLower frontal pole surface area may represent a vulnerability for a suicide attempt; however, more research is needed to understand the nature of its relationship to suicide risk.

There is growing recognition that the composition of the gut microbiota influences behaviour, including responses to threat. The cognitive‐interoceptive appraisal of threat‐related stimuli relies on dynamic neural computations between the anterior insular (AIC) and the dorsal anterior cingulate (dACC) cortices. If, to what extent, and how microbial consortia influence the activity of this cortical threat processing circuitry is unclear. We addressed this question by combining a threat processing task, neuroimaging, 16S rRNA profiling and computational modelling in healthy participants. Results showed interactions between high‐level ecological indices with threat‐related AIC‐dACC neural dynamics. At finer taxonomic resolutions, the abundance of Ruminococcus was differentially linked to connectivity between, and activity within the AIC and dACC during threat updating. Functional inference analysis provides a strong rationale to motivate future investigations of microbiota‐derived metabolites in the observed relationship with threat‐related brain processes., There is convincing preclinical evidence demonstrating the effect of the gut microbiota in altering brain mechanisms supporting threat processing. However, there remains a large gap in understanding how microbiota consortia engenders variability in neural dynamics underpinning human threat processing. Our study supports distinct interactions between microbial abundance patterns—reflected across different taxonomic scales—with neural dynamics supporting threat learning and threat updating processes in healthy individuals.

Both clinicians and neuroscientists have been long interested in the topic of fear conditioning, with recent advances in neuroscience, in particular, igniting a shared interest in further translation between these domains. Here, we review some historical aspects of this relationship and the progress that has been made in translating the neuroscientific study of fear conditioning to the conceptualization and treatment of mental disorders, especially anxiety-related disorders. We also address some conceptual and methodological challenges faced by this research, and offer some suggestions to support future progress in the field.

Responding flexibly to sources of threat and safety is critical to the adaptive regulation of emotions, including fear. At a neural systems level, such flexibility is thought to rely on an extended neural circuitry involving the dorsal anterior cingulate cortex (dACC) and ventromedial prefrontal cortices (vmPFC), although precisely how this occurs remains unclear. Using a novel fear reversal task and functional magnetic resonance imaging (fMRI), we examined the neural correlates of threat and safety reversal learning and their associations with individual differences in anxious responding in a large sample of healthy adolescents and young adults. Overall, participants demonstrated successful threat and safety reversal learning, as indexed by subjective ratings. At a whole-brain level, threat reversal was associated with significant activation of the bilateral anterior insular cortex and dACC, in particular its rostral subregion. Conversely, safety reversal led to significant activation of the anterior vmPFC, together with posterior mid-line regions. Further analyses of regional responses suggested a more selective role for the rostral dACC in threat signal updating, as well as a direct association of its activity with participants’ change in subjective anxious arousal to the reversed threat. Taken together, our findings complement existing neurocircuitry models of human fear regulation, particularly regarding the importance of midline cortical regions, and provide further insights into their specific contribution to flexible threat-safety signal processing. In particular, our results suggest that rostral dACC function may be more centrally involved in regulating levels of anxious arousal when flexibility is required. They also raise important questions regarding the vmPFC’s role in safety learning, particularly involving its hypothesized subregional contributions to response inhibitory versus stimulus value processing functions.

Deficient safety learning has been implicated in the pathogenesis of anxiety disorders. Despite increased translational interest, there has been limited research on the basis of safety learning in humans. Here, we examined safety learning in seventy-three healthy participants via a modified Pavlovian conditioned inhibition paradigm, featuring a conditioned threat stimulus that was reinforced alone (A+), but not when combined with a second stimulus (the conditioned inhibitor, AX-). During a test phase, X and a control safety cue (C) were combined with a second threat stimulus to assess their inhibition of threat responses, measured via skin conductance (SCRs) and US-expectancy ratings. Both stimuli exhibited conditioned inhibition, but X suppressed ratings by a greater magnitude than C. Trait anxiety also predicted increased US-expectancy ratings of X. These findings suggest that a Pavlovian inhibitor accrues greater safety value than a merely unreinforced safety signal. Conditioned inhibition paradigms may have utility in the ongoing study of safety learning and its relevance to anxious psychopathology.

Social anxiety disorder (SAD) has been linked to maladaptive forms of fear regulation, including flexibly distinguishing between learned threat and safety signals. Few studies have examined this in young, unmedicated SAD patients, including its neural basis. We aimed to characterize the neural, subjective, and autonomic correlates of reversal learning in patients with SAD and compare them to matched patients with major depressive disorder and to healthy control participants. All participants completed a threat-safety reversal learning task during functional magnetic resonance imaging. Successful threat-safety updating was associated with significant activation of primary regions of interest (anterior cingulate, insula and ventromedial prefrontal cortex), however, no significant differences were observed between them, consistent with subjective reports of task-evoked anxiety and affect. Contrary to expectations, we did not observe threat and safety reversal learning to be significantly impaired in young people with SAD.