Since the time of Freud, the distinction between fear and anxiety has been a hallmark of influential models of emotion and emotional illness, including the Diagnostic and Statistical Manual of Mental Disorders and Research Domain Criteria. Fear and anxiety disorders are common, debilitating, and challenging to treat, underscoring the importance of developing accurate models of the underlying neurobiology. Although there is consensus that the extended amygdala (EA) plays a central role in orchestrating responses to threat, the respective contributions of its two major subdivisions-the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST)-remain contentious. To help adjudicate this debate, we performed a harmonized mega-analysis of fMRI data acquired from 295 adults as they completed a well-established threat-anticipation paradigm. Contrary to popular double-dissociation models, results demonstrated that the Ce responds to temporally uncertain threat and the BST responds to certain threat. In direct comparisons, the two regions showed statistically indistinguishable responses, with strong Bayesian evidence of regional equivalence. In contrast, frontocortical regions responded preferentially to uncertain-threat anticipation. Together, these observations underscore the need to reformulate conceptual models that posit a strict segregation of temporally certain and uncertain threat processing in the EA.

Background and Hypothesis Among individuals living with psychotic disorders, social impairment is common, debilitating, and challenging to treat. While the roots of this impairment are undoubtedly complex, converging lines of evidence suggest that social motivation and pleasure (MAP) deficits play a central role. Yet most neuroimaging studies have focused on monetary rewards, precluding decisive inferences.Study Design Here we leveraged parallel social and monetary incentive delay functional magnetic resonance imaging paradigms to test whether blunted reactivity to social incentives in the ventral striatum-a key component of the distributed neural circuit mediating appetitive motivation and hedonic pleasure-is associated with more severe MAP symptoms in a transdiagnostic adult sample enriched for psychosis. To maximize ecological validity and translational relevance, we capitalized on naturalistic audiovisual clips of an established social partner expressing positive feedback.Study Results Although both paradigms robustly engaged the ventral striatum, only reactivity to social incentives was associated with clinician-rated MAP deficits. This association remained significant when controlling for other symptoms, binary diagnostic status, or striatal reactivity to monetary incentives. Follow-up analyses suggested that this association predominantly reflects diminished activation during the presentation of social reward.Conclusions These observations provide a neurobiologically grounded framework for conceptualizing the social-anhedonia symptoms and social impairments that characterize many individuals living with psychotic disorders and underscore the need to develop targeted intervention strategies.

OBJECTIVE:Childhood inhibited temperament (cIT) is associated with an increased risk for developing internalizing psychopathology. Neurobiological characteristics identified by structural magnetic resonance imaging (MRI) may elucidate the neural substrates for cIT, but studies are scarce and often focus on particular regions of interest. Moreover, current findings lack replication. This preregistered analysis from the ENIGMA-Anxiety Working Group examined structural brain characteristics associated with cIT using a comprehensive whole-brain approach. METHOD:Temperament assessments (behavioral observations, parent/teacher reports or self-reports on cIT before age 13 years) and MRI data (age at scan, 6-25 years) from international research sites (Europe, North America, South America) were pooled for mega-analysis. Following image processing and quality control, associations between cIT and brain structure were examined in 3,803 participants. Subcortical volumes, cortical thickness, and surface area (main analyses) and detailed subcortical characteristics (eg, subnuclei, subfields, partial volume effects; exploratory analyses) were considered. RESULTS:In the full sample, cIT showed no relation with brain structure, either as a main effect or in interactions with sex or age. Subgroup analyses (based on cIT assessment type) revealed cIT by sex interactions on mean cortical thickness (pMC-FWER = .037) and thickness of the right superior parietal region (pMC-FWER = .029) in youth with parent/teacher reports on cIT levels. Exploratory analyses revealed findings in the hippocampus, putamen, and caudate, but most did not survive statistical correction for multiple testing. CONCLUSION:This mega-analysis found no consistent associations between cIT and regional brain structure, although the role of parietal regions warrants further investigation. Future studies should consider brain function in cIT, preferably using longitudinal designs. PLAIN LANGUAGE SUMMARY:Inhibited temperament during childhood is a risk factor for the development of anxiety and depression later in life. A preregistered study from the international ENIGMA-Anxiety Working Group investigated whether characteristics of brain structure are associated with the level of childhood inhibited temperament, using brain scans and data on temperamental traits from participants aged 6 to 25 years, which have been previously acquired at research sites worldwide (total sample > 3,800 subjects). Analyses revealed no consistent correlations between brain structure and inhibited temperament. STUDY REGISTRATION INFORMATION:Structural Brain Correlates of Childhood Inhibited Temperament: An ENIGMA-Anxiety Mega-analysis. https://www.jaacap.org/article/S0890-8567(22)00299-4/fulltext.

Background:Anxiety, depression, and related internalizing illnesses are a leading burden on global public health, and often emerge during times of stress. Yet the underlying neurobiology has remained enigmatic, hindering treatment development. Methods:Here we used a combination of tools-including a well-established threat-anticipation fMRI paradigm and longitudinal assessments of internalizing symptoms and negative life events (NLEs)-to identify the neural systems associated with future internalizing illness in a risk-enriched sample of 224 emerging adults followed for 2.5 years. We performed parallel analyses in an overlapping sample of 209 participants who completed a popular threat-related faces paradigm. Results:Here we show that heightened reactivity to uncertain-threat anticipation in the bed nucleus of the stria terminalis and the periaqueductal gray is associated with a worsening longitudinal course of broadband internalizing symptoms among individuals with low levels of NLE exposure. These associations were specific to uncertain threat and generally remained significant when controlling for concurrent measures of threat-elicited distress or psychophysiological arousal, highlighting the added value of the neuroimaging measures. Symptom trajectories were unrelated to amygdala and frontocortical reactivity to anticipated threat. Contrary to past research, amygdala reactivity to threat-related faces was unrelated to future symptoms. Conclusions:These observations provide a novel neurobiological framework for conceptualizing transdiagnostic internalizing risk and lay the groundwork for mechanistic and therapeutics research. A racially diverse, risk-enriched sample and pre-registered, best-practices approach enhance confidence in the robustness and translational relevance of these results.

Temporal dynamics play a central role in models of emotion: "fear" is widely conceptualized as a phasic response to certain-and-imminent danger, whereas "anxiety" is a sustained response to uncertain-or-distal harm. Yet the underlying neurobiology remains contentious. Leveraging a translationally relevant fMRI paradigm and theory-driven modeling approach in 220 adult humans, we demonstrate that certain- and uncertain-threat anticipation recruit a shared circuit that encompasses the central extended amygdala (EAc), periaqueductal gray, midcingulate, and anterior insula. This circuit exhibits persistently elevated activation when threat is uncertain and distal and transient bursts of activation just before certain encounters with threat. Although there is agreement that the EAc plays a critical role in orchestrating responses to threat, confusion persists about the respective contributions of its major subdivisions, the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce). Here we used anatomical regions of interest to demonstrate that the BST and Ce exhibit statistically indistinguishable threat dynamics. Both regions exhibited activation dynamics that run counter to popular models, with the Ce (and BST) showing sustained responses to uncertain-and-distal threat and the BST (and Ce) showing phasic responses to certain-and-imminent threat. For many scientists, feelings are the hallmark of fear and anxiety. Here we used an independently validated multivoxel brain "signature" to covertly probe the moment-by-moment dynamics of anticipatory distress for the first time. Results mirrored the dynamics of neural activation. These observations provide fresh insights into the neurobiology of threat-elicited emotions and set the stage for more ambitious clinical and mechanistic research.

Pavlovian fear conditioning is a fundamental process in both health and disease. We investigate its neural correlates and sources of variability using harmonized functional magnetic resonance imaging data from 2199 individuals across nine countries, including 1888 healthy individuals and 311 with anxiety-related or depressive disorders. Using mega-analysis and normative modeling, we show that fear conditioning consistently engages brain regions within the "central autonomic-interoceptive" or "salience" network. Several task variables strongly modulate activity in these regions, contributing to variability in neural responses. Additionally, brain activation patterns differ between healthy individuals and those with anxiety-related or depressive disorders, with distinct profiles characterizing specific disorders such as post-traumatic stress disorder and obsessive-compulsive disorder. While the neural correlates of fear conditioning are highly generalizable at the population level, variability arises from differences in task design and clinical status, highlighting the importance of methodological diversity in capturing fear learning mechanisms.

Stress is widely acknowledged as a risk factor for various negative health outcomes. Therefore, assessing everyday stress through longitudinal research has gained interest, with a focus on capturing stress and its components using intra-individual approaches and ecological momentary assessment (EMA). Building on the proposal of Smyth et al. [1], our study aims to investigate the relationship between different operationalizations of stress components with two relevant constructs: declining mental health and trait anxiety. Over a 6-month period, we conducted a longitudinal study involving 165 adults (84 females; mean age = 24.91, SD = 4.61 years) with varying anxiety levels. We assessed retrospective stressor evaluations using a life history calendar (LHC) and prospective stress responses via EMA. Our LHC surveyed forty events representing significant changes in the participant´s environment across thirteen domains. EMA anxiety scores were derived from weekly averages of four items measuring anxiety symptoms. After defining three different baselines, we computed indices of pileup, average stress reactivity, and average stressor recovery for each participant, employing various operationalizations. Subsequently, we examined the relationship between these operationalizations and symptom changes using hierarchical multiple regression analyses. After data cleaning from 89100 potential notifications (165 retained participants × 180 days × three notifications per day), participants responded to 68554 (77%) of them. Every participant reported experiencing at least one event from the LHC list during the study. Interestingly, different stress reactivity baselines influenced both the total count of stressor episodes for the whole sample (239 with local baseline 1, 176 with local baseline 2, and 228 for cumulative baseline) and the number of stressor episodes per person (local baseline 1, M=1.45, SD=.74; local baseline 2, M=1.07, SD=.25; cumulative baseline, M=1.41, SD=.78). Only a few stress components operationalizations showed the expected associations with increased internalizing symptoms or trait anxiety. When defining a stressor as an event with increased stress reactivity and operationalizing pileup using either local (one week) or cumulative baseline, there was a correlation observed between pileup and stress scores. Additionally, two operationalizations of average stress reactivity correlated with anxiety and stress scores. Moreover, the operationalization using cumulative recovery and the local baseline 2 significantly predicted stress symptoms at follow-up. Finally, only one operationalization, which used the number of weeks with stressors, supported the expected association of trait anxiety with pileup (r=.17, P=.03). Our results underscore the importance of selecting appropriate intra-individual baselines for capturing stress dynamics in everyday life. To our knowledge, this is the first study to combine LHC for retrospective stressor assessment with prospective longitudinal assessment of stress responses using EMA. Future research can benefit from these insights by utilizing the most effective operationalizations identified here and investigating alternative methodologies.

To effectively address the staggering burden of mental illness, clinical psychological science will need to face some uncomfortable truths about current training practices. In a commentary authored by 23 current or recent trainees, Palitsky and colleagues (2022) highlighted a number of urgent challenges facing today's clinical interns. They provid a thoughtful framework for reform with specific recommendations and guiding questions for a broad spectrum of stakeholders. Key suggestions are applicable to the entire sequence of clinical training, including doctoral studies that occur prior to internship. Although there is cause for cautious optimism, overcoming these systemic barriers will require a coordinated, all-hands approach and a more collaborative approach to policymaking.

Graduate students are a vital component of the academic enterprise. They produce research, teach, mentor, and provide healthcare and other critical services. Evidence suggests that a large proportion of graduate students experience high levels of depression and anxiety, attracting the attention of policy makers. Yet past work has relied on cross-sectional surveys and samples that are small, non-representative, and lack appropriate benchmarks. Consequently, it remains unclear whether this apparent crisis is abating or worsening, and whether it is specific to graduate students or simply reflects surging levels of distress among young adults. We leveraged data acquired from 187,054 U.S. students between 2008 and 2019 to demonstrate that emotional distress, psychiatric illness, suicidality, and poor general health are disturbingly common and that these metrics have steadily deteriorated. We used data collected from 443,894 U.S. adults over the same 11-year period to show that graduate students are significantly more likely to experience mental illness, suicidality, and poor general health compared to their demographically matched non-student peers and the general public. These observations provide the first comprehensive analysis of the state of graduate student mental health in the U.S. and some of the strongest evidence that graduate training confers heightened risk for mental illness and suicide.

Social anxiety-which typically emerges in adolescence-lies on a continuum and, when extreme, can be devastating. Socially anxious individuals are prone to heightened fear, anxiety, and the avoidance of contexts associated with potential social scrutiny. Yet most neuroimaging research has focused on acute social threat. Much less attention has been devoted to understanding the neural systems recruited during the uncertain anticipation of potential encounters with social threat. Here we used a novel functional magnetic resonance imaging paradigm to probe the neural circuitry engaged during the anticipation and acute presentation of threatening faces and voices in a racially diverse sample of 66 adolescents selectively recruited to encompass a range of social anxiety and enriched for clinically significant levels of distress and impairment. Results demonstrated that adolescents with more severe social anxiety symptoms experience heightened distress when anticipating encounters with social threat, and reduced discrimination of uncertain social threat and safety in the bed nucleus of the stria terminalis, a key division of the central extended amygdala (EAc). Although the EAc-including the bed nucleus of the stria terminalis and central nucleus of the amygdala-was robustly engaged by the acute presentation of threatening faces and voices, the degree of EAc engagement was unrelated to the severity of social anxiety. Together, these observations provide a neurobiologically grounded framework for conceptualizing adolescent social anxiety and set the stage for the kinds of prospective-longitudinal and mechanistic research that will be necessary to determine causation and, ultimately, to develop improved interventions for this often-debilitating illness.

In psychosis, reward motivation and pleasure (MAP) symptoms are common, treatment resistant, and often manifest as deficits in social affiliation and interpersonal functioning. Yet most neuroimaging studies have focused on monetary rather than social reward.

Graduate students are a vital component of the academic enterprise. They produce research, teach, mentor, and provide healthcare and other critical services. Evidence suggests that a large proportion of graduate students experience high levels of depression and anxiety, attracting the attention of policy makers1-8. Yet past work has relied on cross-sectional surveys and samples that are small, non-representative, and lack appropriate benchmarks9-11. Consequently, it remains unclear whether this apparent crisis is abating or worsening, and whether it is specific to graduate students or simply reflects surging levels of distress among young adults12-16. We leveraged data acquired from 187,054 U.S. students between 2008 and 2019 to demonstrate that emotional distress, psychiatric illness, suicidality, and poor general health are disturbingly common and that these metrics have steadily deteriorated. We used data collected from 443,894 U.S. adults over the same 11-year period to show that graduate students are significantly more likely to experience mental illness, suicidality, and poor general health compared to their demographically matched non-student peers and the general public. These observations provide the first comprehensive analysis of the state of graduate student mental health in the U.S. and some of the strongest evidence that graduate training confers heightened risk for mental illness and suicide.

Neuroticism/negative emotionality (N/NE)—the tendency to experience anxiety, fear, and other negative emotions—is a fundamental dimension of temperament with profound consequences for health, wealth, and well-being. Elevated N/NE is associated with a panoply of adverse outcomes, from reduced socioeconomic attainment to psychiatric illness. Animal research suggests that N/NE reflects heightened reactivity to uncertain threat in the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce), but the relevance of these discoveries to humans has remained unclear. Here we used a novel combination of psychometric, psychophysiological, and neuroimaging approaches to test this hypothesis in an ethnoracially diverse, sex-balanced sample of 220 emerging adults selectively recruited to encompass a broad spectrum of N/NE. Cross-validated robust-regression analyses demonstrated that N/NE is preferentially associated with heightened BST activation during the uncertain anticipation of a genuinely distressing threat (aversive multimodal stimulation), whereas N/NE was unrelated to BST activation during certain-threat anticipation, Ce activation during either type of threat anticipation, or BST/Ce reactivity to threat-related faces. It is often assumed that different threat paradigms are interchangeable assays of individual differences in brain function, yet this has rarely been tested. Our results revealed negligible associations between BST/Ce reactivity to the anticipation of threat and the presentation of threat-related faces, indicating that the two tasks are nonfungible. These observations provide a framework for conceptualizing emotional traits and disorders; for guiding the design and interpretation of biobank and other neuroimaging studies of psychiatric risk, disease, and treatment; and for refining mechanistic research.

Understanding the neurobiological mechanisms involved in psychopathology has been hindered by the limitations of categorical nosologies. The Hierarchical Taxonomy of Psychopathology (HiTOP) is an alternative dimensional system for characterizing psychopathology, derived from quantitative studies of covariation among diagnoses and symptoms. HiTOP provides more promising targets for clinical neuroscience than traditional psychiatric diagnoses and can facilitate cumulative integration of existing research. We systematically reviewed 164 human neuroimaging studies with sample sizes of 194 or greater that have investigated dimensions of psychopathology classified within HiTOP. Replicated results were identified for constructs at five different levels of the hierarchy, including the overarching p-factor, the externalizing superspectrum, the thought disorder and internalizing spectra, the distress subfactor, and the depression symptom dimension. Our review highlights the potential of dimensional clinical neuroscience research and the usefulness of HiTOP, while also suggesting limitations of existing work in this relatively young field. We discuss how HiTOP can be integrated synergistically with neuroscience-oriented, transdiagnostic frameworks developed by the National Institutes of Health, including the Research Domain Criteria (RDoC), Addictions Neuroclinical Assessment (ANA), and NIDA Phenotyping Assessment Battery (NIDA PhAB), and how researchers can use HiTOP to accelerate clinical neuroscience research in humans and other species.

In psychotic disorders, motivation and pleasure (MAP) deficits are associated with decreased affiliation and heightened functional impairment. We leveraged a transdiagnostic sample enriched for psychosis and a multimethod approach to test the hypothesis that MAP deficits undermine the stress-buffering benefits of affiliation. Participants completed the social-affiliation-enhancement task (SAET) to cultivate affiliation with an experimental partner. Although the SAET increased perceived affiliation and mood, individuals with greater negative symptoms derived smaller emotional benefits from the partners, as indexed by self-report and facial behavior. We then used the handholding functional MRI paradigm, which combines threat anticipation with affiliative physical contact, to determine whether MAP deficits undermine the social regulation of distress. Individuals with greater MAP deficits showed diminished neural "benefits"-reduced dampening of threat-elicited activation-from affiliative touch in key frontoparietal nodes of the dorsal attention network. In short, MAP symptoms disrupt the emotional and neuroregulatory benefits of affiliation.

Elevated levels of Neuroticism/Negative Emotionality (N/NE) and, less consistently, lower levels of Extraversion/Positive Emotionality (E/PE) confer risk for pathological depression and anxiety. To date, most prospective-longitudinal research has narrowly focused on traditional diagnostic categories, creating uncertainty about the precise nature of these prospective associations. Adopting an explicitly hierarchical-dimensional approach, we examined the association between baseline variation in personality and longitudinal changes in broad and narrow internalizing-symptom dimensions in 234 emerging adults followed for 2.5 years, during the transition from older adolescence to early adulthood. N/NE was uniquely associated with increases in broadband internalizing—the core cognitive and affective symptoms that cut across the emotional disorders—and unrelated to the narrower dimensions of positive affect and anxious arousal that differentiate specific internalizing presentations. Variation in E/PE and several other Big Five traits was cross-sectionally, but not prospectively, related to longitudinal changes in specific internalizing symptoms. Exploratory personality-facet-level analyses provided preliminary evidence of more granular associations between personality and longitudinal changes in internalizing symptoms. These observations enhance the precision of models linking personality to internalizing illness; highlight the centrality of N/NE to increases in transdiagnostic internalizing symptoms during a key developmental chapter; and set the stage for developing more effective prevention and treatment strategies.