Distributed neural representations of conditioned threat in the human brain.

Detecting and responding to threat engages several neural nodes including the amygdala, hippocampus, insular cortex, and medial prefrontal cortices. Recent propositions call for the integration of more distributed neural nodes that process sensory and cognitive facets related to threat. Integrative, sensitive, and reproducible distributed neural decoders for the detection and response to threat and safety have yet to be established. We combine functional MRI data across varying threat conditioning and negative affect paradigms from 1465 participants with multivariate pattern analysis to investigate distributed neural representations of threat and safety. The trained decoders sensitively and specifically distinguish between threat and safety cues across multiple datasets. We further show that many neural nodes dynamically shift representations between threat and safety. Our results establish reproducible decoders that integrate neural circuits, merging the well-characterized 'threat circuit' with sensory and cognitive nodes, discriminating threat from safety regardless of experimental designs or data acquisition parameters.

Mindfulness training and exercise differentially impact fear extinction neurocircuitry.

BACKGROUND: The ability to extinguish a maladaptive conditioned fear response is crucial for healthy emotional processing and resiliency to aversive experiences. Therefore, enhancing fear extinction learning has immense potential emotional and health benefits. Mindfulness training enhances both fear conditioning and recall of extinguished fear; however, its effects on fear extinction learning are unknown. Here we investigated the impact of mindfulness training on brain mechanisms associated with fear-extinction learning, compared to an exercise-based program. METHODS: We investigated BOLD activations in response to a previously learned fear-inducing cue during an extinction paradigm, before and after an 8-week mindfulness-based stress reduction program (MBSR, n = 49) or exercise-based stress management education program (n = 27). RESULTS: The groups exhibited similar reductions in stress, but the MBSR group was uniquely associated with enhanced activation of salience network nodes and increased hippocampal engagement. CONCLUSIONS: Our results suggest that mindfulness training increases attention to anticipatory aversive stimuli, which in turn facilitates decreased aversive subjective responses and enhanced reappraisal of the memory.

Aberrant resting-state functional connectivity of the globus pallidus interna in first-episode schizophrenia.

BACKGROUND: The striatal-pallidal pathway plays an important role in cognitive control and modulation of behaviors. Globus pallidus interna (GPi), as a primary output structure, is crucial in modulating excitation and inhibition. Studies of GPi in psychiatric illnesses are lacking given the technical challenges of examining this small and functionally diverse subcortical structure. METHODS: 71 medication-naïve first episode schizophrenia (FES) participants and 73 healthy controls (HC) were recruited at the Shanghai Mental Health Center. Clinical symptoms and imaging data were collected at baseline and, in a subset of patients, 8 weeks after initiating treatment. Resting-state functional connectivity of sub-regions of the GP were assessed using a novel mask that combines two atlases to create 8 ROIs in the GP. RESULTS: Baseline imaging data from 63 FES patients and 55 HC met quality standards and were analyzed. FES patients exhibited less negative connectivity and increased positive connectivity between the right anterior GPi and several cortical and subcortical areas at baseline compared to HC (PFWE < 0.05). Positive functional connectivity between the right anterior GPi and several brain areas, including the right dorsal anterior cingulate gyrus, was associated with severity of positive symptoms (PFWE < 0.05) and predicted treatment response after 8 weeks (n = 28, adjusted R2 = 0.486, p < 0.001). CONCLUSIONS: Our results implicate striatal-pallidal-thalamic pathways in antipsychotic efficacy. If replicated, these findings may reflect failure of neurodevelopmental processes in adolescence and early adulthood that decrease functional connectivity as an index of failure of the limbic/associative GPi to appropriately inhibit irrelevant signals in psychosis.

A proof-of-concept study of vicarious extinction learning and autonomic synchrony in parent-child dyads and posttraumatic stress disorder.

Though threat-extinction models continue to inform scientific study of traumatic stress, knowledge of learning and extinction as mechanisms linking exposure to psychopathology remains critically limited among youth. This proof-of-concept study advances the study of threat-extinction in youth by determining feasibility of electrodermal stimulation (EDS), vicarious extinction learning via their parent, and social threat learning in pediatric PTSD (pPTSD). Typically developing (TD) and PTSD-diagnosed youth in 45 mother-child dyads completed an extinction learning paradigm. The use of EDS was first investigated in a cohort of TD youth (n = 20) using a 2-day paradigm without vicarious extinction, while direct (for TD and pPTSD) and vicarious (for pPTSD) extinction were investigated in a 3-day paradigm (n = 25). Threat acquisition and extinction were monitored using skin-conductance response (SCR) and behavioral expectations of EDS. Using Bayesian modeling to accommodate this pilot sample, our results demonstrate: (1) EDS-conditioning to be highly feasible and well-tolerated across TD and trauma-exposed youth, (2) Successful direct and vicarious extinction learning in trauma-exposed youth, and (3) PTSD-associated patterns in extinction learning and physiological synchrony between parent-child dyads. In summary, these novel approaches have the potential to advance translational studies in the mechanistic understanding of parent-child transmission of risk and youth psychopathology.

Contemporary Approaches Toward Neuromodulation of Fear Extinction and Its Underlying Neural Circuits.

Neuroscience and neuroimaging research have now identified brain nodes that are involved in the acquisition, storage, and expression of conditioned fear and its extinction. These brain regions include the ventromedial prefrontal cortex (vmPFC), dorsal anterior cingulate cortex (dACC), amygdala, insular cortex, and hippocampus. Psychiatric neuroimaging research shows that functional dysregulation of these brain regions might contribute to the etiology and symptomatology of various psychopathologies, including anxiety disorders and post traumatic stress disorder (PTSD) (Barad et al. Biol Psychiatry 60:322-328, 2006; Greco and Liberzon Neuropsychopharmacology 41:320-334, 2015; Milad et al. Biol Psychiatry 62:1191-1194, 2007a, Biol Psychiatry 62:446-454, b; Maren and Quirk Nat Rev Neurosci 5:844-852, 2004; Milad and Quirk Annu Rev Psychol 63:129, 2012; Phelps et al. Neuron 43:897-905, 2004; Shin and Liberzon Neuropsychopharmacology 35:169-191, 2009). Combined, these findings indicate that targeting the activation of these nodes and modulating their functional interactions might offer an opportunity to further our understanding of how fear and threat responses are formed and regulated in the human brain, which could lead to enhancing the efficacy of current treatments or creating novel treatments for PTSD and other psychiatric disorders (Marin et al. Depress Anxiety 31:269-278, 2014; Milad et al. Behav Res Ther 62:17-23, 2014). Device-based neuromodulation techniques provide a promising means for directly changing or regulating activity in the fear extinction network by targeting functionally connected brain regions via stimulation patterns (Raij et al. Biol Psychiatry 84:129-137, 2018; Markovic et al. Front Hum Neurosci 15:138, 2021). In the past ten years, notable advancements in the precision, safety, comfort, accessibility, and control of administration have been made to the established device-based neuromodulation techniques to improve their efficacy. In this chapter we discuss ten years of progress surrounding device-based neuromodulation techniques-Electroconvulsive Therapy (ECT), Transcranial Magnetic Stimulation (TMS), Magnetic Seizure Therapy (MST), Transcranial Focused Ultrasound (TUS), Deep Brain Stimulation (DBS), Vagus Nerve Stimulation (VNS), and Transcranial Electrical Stimulation (tES)-as research and clinical tools for enhancing fear extinction and treating PTSD symptoms. Additionally, we consider the emerging research, current limitations, and possible future directions for these techniques.

Gray matter associations with extinction-induced neural activation in patients with anxiety disorders.

The relationship between structural characteristics and extinction-induced brain activations in anxiety disorders (ANX) remains a space for greater exploration. In this study, we assessed gray matter volume (GMV) and its associated functional activations during fear extinction memory recall in an ANX cohort. We performed voxel-based morphometry analysis to examine GMVs from ANX (n = 92) and controls (n = 73). We further examined the correlation between GMVs and extinction-induced neural activations during recall across groups. In the patients' group, we observed decreased GMV in the anterior hippocampus and increased GMV in the dorsolateral prefrontal cortex (dlPFC). Hippocampal volume was positively correlated with ventromedial prefrontal cortex activation in healthy controls, while it was negatively correlated with dorsal anterior cingulate cortex (dACC) activation in ANX. The dlPFC volume was positively correlated with activations of dACC, pre- and post-central gyrus, and supramarginal gyrus only in healthy controls. Therefore, the link between structural and functional imbalance within the hippocampus and dlPFC might contribute to the pathophysiology of ANX. In the controls, the relationship between structural variance in the hippocampus and dlPFC and extinction-induced neural activations is consistent with a greater ability to regulate fear responding; associations that were absent in the ANX cohort. Furthermore, our findings of structure-function abnormalities within key nodes of emotional homeostasis in ANX point to dlPFC as a potential neural node to target using neuromodulation tools.

Consensus design of a calibration experiment for human fear conditioning.

Fear conditioning is a widely used laboratory model to investigate learning, memory, and psychopathology across species. The quantification of learning in this paradigm is heterogeneous in humans and psychometric properties of different quantification methods can be difficult to establish. To overcome this obstacle, calibration is a standard metrological procedure in which well-defined values of a latent variable are generated in an established experimental paradigm. These intended values then serve as validity criterion to rank methods. Here, we develop a calibration protocol for human fear conditioning. Based on a literature review, series of workshops, and survey of N = 96 experts, we propose a calibration experiment and settings for 25 design variables to calibrate the measurement of fear conditioning. Design variables were chosen to be as theory-free as possible and allow wide applicability in different experimental contexts. Besides establishing a specific calibration procedure, the general calibration process we outline may serve as a blueprint for calibration efforts in other subfields of behavioral neuroscience that need measurement refinement.

Revisiting sex differences in the acquisition and extinction of threat conditioning in humans.

Findings pertaining to sex differences in the acquisition and extinction of threat conditioning, a paradigm widely used to study emotional homeostasis, remain inconsistent, particularly in humans. This inconsistency is likely due to multiple factors, one of which is sample size. Here, we pooled functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) data from multiple studies in healthy humans to examine sex differences during threat conditioning, extinction learning, and extinction memory recall. We observed increased functional activation in males, relative to females, in multiple parietal and frontal (medial and lateral) cortical regions during acquisition of threat conditioning and extinction learning. Females mainly exhibited higher amygdala activation during extinction memory recall to the extinguished conditioned stimulus and also while responding to the unconditioned stimulus (presentation of the shock) during threat conditioning. Whole-brain functional connectivity analyses revealed that females showed increased connectivity across multiple networks including visual, ventral attention, and somatomotor networks during late extinction learning. At the psychophysiological level, a sex difference was only observed during shock delivery, with males exhibiting higher unconditioned responses relative to females. Our findings point to minimal to no sex differences in the expression of conditioned responses during acquisition and extinction of such responses. Functional MRI findings, however, show some distinct functional activations and connectivities between the sexes. These data suggest that males and females might use different neural mechanisms, mainly related to cognitive processing, to achieve comparable levels of acquired conditioned responses to threating cues.

Temporally and anatomically specific contributions of the human amygdala to threat and safety learning.

Neural plasticity in subareas of the rodent amygdala is widely known to be essential for Pavlovian threat conditioning and safety learning. However, less consistent results have been observed in human neuroimaging studies. Here, we identify and test three important factors that may contribute to these discrepancies: the temporal profile of amygdala response in threat conditioning, the anatomical specificity of amygdala responses during threat conditioning and safety learning, and insufficient power to identify these responses. We combined data across multiple studies using a well-validated human threat conditioning paradigm to examine amygdala involvement during threat conditioning and safety learning. In 601 humans, we show that two amygdala subregions tracked the conditioned stimulus with aversive shock during early conditioning while only one demonstrated delayed responding to a stimulus not paired with shock. Our findings identify cross-species similarities in temporal- and anatomical-specific amygdala contributions to threat and safety learning, affirm human amygdala involvement in associative learning and highlight important factors for future associative learning research in humans.

Abnormal dynamic functional connectivity during fear extinction learning in PTSD and anxiety disorders.

Examining the neural circuits of fear/threat extinction advanced our mechanistic understanding of several psychiatric disorders, including anxiety disorders (AX) and posttraumatic stress disorder (PTSD). More is needed to understand the interplay of large-scale neural networks during fear extinction in these disorders. We used dynamic functional connectivity (FC) to study how FC might be perturbed during conditioned fear extinction in individuals with AX or PTSD. We analyzed neuroimaging data from 338 individuals that underwent a two-day fear conditioning and extinction paradigm. The sample included healthy controls (HC), trauma-exposed non-PTSD controls, and patients diagnosed with AX or PTSD. Dynamic FC during extinction learning gradually increased in the HC group but not in patient groups. The lack of FC change in patients was predominantly observed within and between the default mode, frontoparietal control, and somatomotor networks. The AX and PTSD groups showed impairments in different, yet partially overlapping connections especially involving the dorsolateral prefrontal cortex. Extinction-induced FC predicted ventromedial prefrontal cortex activation and FC during extinction memory recall only in the HC group. FC impairments during extinction learning correlated with fear- and anxiety-related clinical measures. These findings suggest that relative to controls, individuals with AX or PTSD exhibited widespread abnormal FC in higher-order cognitive and attention networks during extinction learning and failed to establish a link between neural signatures during extinction learning and memory retrieval. This failure might underlie abnormal processes related to the conscious awareness, attention allocation, and sensory processes during extinction learning and retrieval in fear- and anxiety-related disorders.

Mega-analysis methods in ENIGMA: The experience of the generalized anxiety disorder working group.

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses.

Impairment in acquisition of conditioned fear in schizophrenia.

Individuals with schizophrenia show impairments in associative learning. One well-studied, quantifiable form of associative learning is Pavlovian fear conditioning. However, to date, studies of fear conditioning in schizophrenia have been inconclusive, possibly because they lacked sufficient power. To address this issue, we pooled data from four independent fear conditioning studies that included a total of 77 individuals with schizophrenia and 74 control subjects. Skin conductance responses (SCRs) to stimuli that were paired (the CS + ) or not paired (CS-) with an aversive, unconditioned stimulus were measured, and the success of acquisition of differential conditioning (the magnitude of CS + vs. CS- SCRs) and responses to CS + and CS- separately were assessed. We found that acquisition of differential conditioned fear responses was significantly lower in individuals with schizophrenia than in healthy controls (Cohen's d = 0.53). This effect was primarily related to a significantly higher response to the CS- stimulus in the schizophrenia compared to the control group. Moreover, the magnitude of this response to the CS- in the schizophrenia group was correlated with the severity of delusional ideation (p = 0.006). Other symptoms or antipsychotic dose were not associated with fear conditioning measures. In conclusion, individuals with schizophrenia who endorse delusional beliefs may be over-responsive to neutral stimuli during fear conditioning. This finding is consistent with prior models of abnormal associative learning in psychosis.

Randomized controlled experimental study of hydrocortisone and D-cycloserine effects on fear extinction in PTSD.

Fear extinction underlies prolonged exposure, one of the most well-studied treatments for posttraumatic stress disorder (PTSD). There has been increased interest in exploring pharmacological agents to enhance fear extinction learning in humans and their potential as adjuncts to PE. The objective of such adjuncts is to augment the clinical impact of PE on the durability and magnitude of symptom reduction. In this study, we examined whether hydrocortisone (HC), a corticosteroid, and D-Cycloserine (DCS), an N-methyl-D-aspartate receptor partial agonist, enhance fear extinction learning and consolidation in individuals with PTSD. In a double-blind placebo-controlled 3-group experimental design, 90 individuals with full or subsyndromal PTSD underwent fear conditioning with stimuli that were paired (CS+) or unpaired (CS-) with shock. Extinction learning occurred 72 h later and extinction retention was tested one week after extinction. HC 25 mg, DCS 50 mg or placebo was administered one hour prior to extinction learning. During extinction learning, the DCS and HC groups showed a reduced differential CS+/CS- skin conductance response (SCR) compared to placebo (b = -0.19, CI = -0.01 to -37, p = 0.042 and b = -0.25, CI = -08 to -0.43, p = 0.005, respectively). A nonsignificant trend for a lower differential CS+/CS- SCR in the DCS group, compared to placebo, (b = -0.25, CI = 0.04 to -0.55, p = 0.089) was observed at retention testing, one week later. A single dose of HC and DCS facilitated fear extinction learning in participants with PTSD symptoms. While clinical implications have yet to be determined, our findings suggest that glucocorticoids and NMDA agonists hold promise for facilitating extinction learning in PTSD.

Associations of sleep measures with neural activations accompanying fear conditioning and extinction learning and memory in trauma-exposed individuals.

STUDY OBJECTIVES: Sleep disturbances increase risk of posttraumatic stress disorder (PTSD). Sleep effects on extinction may contribute to such risk. Neural activations to fear extinction were examined in trauma-exposed participants and associated with sleep variables. METHODS: Individuals trauma-exposed within the past 2 years (N = 126, 63 PTSD) completed 2 weeks actigraphy and sleep diaries, three nights ambulatory polysomnography and a 2-day fMRI protocol with Fear-Conditioning, Extinction-Learning and, 24 h later, Extinction-Recall phases. Activations within the anterior cerebrum and regions of interest (ROI) were examined within the total, PTSD-diagnosed and trauma-exposed control (TEC) groups. Sleep variables were used to predict activations within groups and among total participants. Family wise error was controlled at p < 0.05 using nonparametric analysis with 5,000 permutations. RESULTS: Initially, Fear Conditioning activated broad subcortical and cortical anterior-cerebral regions. Within-group analyses showed: (1) by end of Fear Conditioning activations decreased in TEC but not PTSD; (2) across Extinction Learning, TEC activated medial prefrontal areas associated with emotion regulation whereas PTSD did not; (3) beginning Extinction Recall, PTSD activated this emotion-regulatory region whereas TEC did not. However, the only between-group contrast reaching significance was greater activation of a hippocampal ROI in TEC at Extinction Recall. A greater number of sleep variables were associated with cortical activations in separate groups versus the entire sample and in PTSD versus TEC. CONCLUSIONS: PTSD nonsignificantly delayed extinction learning relative to TEC possibly increasing vulnerability to pathological anxiety. The influence of sleep integrity on brain responses to threat and extinction may be greater in more symptomatic individuals.

Cortical and subcortical brain structure in generalized anxiety disorder: findings from 28 research sites in the ENIGMA-Anxiety Working Group.

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5-90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.

Impact of exogenous estradiol on task-based and resting-state neural signature during and after fear extinction in healthy women.

Fluctuations of endogenous estrogen modulates fear extinction, but the influence of exogenous estradiol is less studied. Moreover, little focus has been placed on the impact of estradiol on broad network connectivity beyond the fear extinction circuit. Here, we examined the effect of acute exogenous estradiol administration on fear extinction-induced brain activation, whole-brain functional connectivity (FC) during the fear extinction task and post-extinction resting-state. Ninety healthy women (57 using oral contraceptives [OC], 33 naturally cycling [NC]) were fear conditioned on day 1. They ingested an estradiol or placebo pill prior to extinction learning on day 2 (double-blind design). Extinction memory was assessed on day 3. Task-based functional MRI data were ascertained on days 2 and 3 and resting-state data were collected post-extinction on day 2 and pre-recall on day 3. Estradiol administration significantly modulated the neural signature associated with fear extinction learning and memory, consistent with prior studies. Importantly, estradiol administration induced significant changes in FC within multiple networks, including the default mode and somatomotor networks during extinction learning, post-extinction, and during extinction memory recall. Exploratory analyses revealed that estradiol impacted ventromedial prefrontal cortex (vmPFC) activation and FC differently in the NC and OC women. The data implicate a more diffused and significant effect of acute estradiol administration on multiple networks. Such an effect might be beneficial to modulating attention and conscious processes in addition to engaging neural processes associated with emotional learning and memory consolidation.

Fear extinction learning modulates large-scale brain connectivity.

Exploring the neural circuits of the extinction of conditioned fear is critical to advance our understanding of fear- and anxiety-related disorders. The field has focused on examining the role of various regions of the medial prefrontal cortex, insular cortex, hippocampus, and amygdala in conditioned fear and its extinction. The contribution of this 'fear network' to the conscious awareness of fear has recently been questioned. And as such, there is a need to examine higher/multiple cortical systems that might contribute to the conscious feeling of fear and anxiety. Herein, we studied functional connectivity patterns across the entire brain to examine the contribution of multiple networks to the acquisition of fear extinction learning and its retrieval. We conducted trial-by-trial analyses on data from 137 healthy participants who underwent a two-day fear conditioning and extinction paradigm in a functional magnetic resonance imaging (fMRI) scanner. We found that functional connectivity across a broad range of brain regions, many of which are part of the default mode, frontoparietal, and ventral attention networks, increased from early to late extinction learning only to a conditioned cue. The increased connectivity during extinction learning predicted the magnitude of extinction memory tested 24 h later. Together, these findings provide evidence supporting recent studies implicating distributed brain regions in learning, consolidation and expression of fear extinction memory in the human brain.

Hippocampal activation during contextual fear inhibition related to resilience in the early aftermath of trauma.

BACKGROUND: Impaired contextual fear inhibition is often associated with posttraumatic stress disorder (PTSD). Our previous work has demonstrated that more hippocampal activation during a response inhibition task after trauma exposure was related to greater resilience and fewer future PTSD symptoms. In the current study, we sought to extend our previous findings by employing a contextual fear conditioning and extinction paradigm to further determine the role of the hippocampus in resilience and PTSD in the early aftermath of trauma. METHODS: Participants (N = 28) were recruited in the Emergency Department shortly after experiencing a traumatic event. A contextual fear inhibition task was conducted in a 3 T MRI scanner approximately two months post-trauma. Measures of resilience (CD-RISC) at time of scan and PTSD symptoms three months post-trauma were collected. The associations between hippocampal activation during fear conditioning and during the effect of context during extinction, and post-trauma resilience and PTSD symptoms at three-months were assessed. RESULTS: During fear conditioning, activation of the bilateral hippocampal region of interest (ROI) correlated positively with resilience (r = 0.48, p = 0.01). During the effect of context during extinction, greater bilateral hippocampal activation correlated with lower PTSD symptoms three months post-trauma after controlling for baseline PTSD symptoms, age and gender (r=-0.59, p=0.009). CONCLUSIONS: Greater hippocampal activation was related to post-trauma resilience and lower PTSD symptoms three months post-trauma. The current study supports and strengthens prior findings suggesting the importance of hippocampus-dependent context processing as a mechanism for resilience versus PTSD risk, which could be a potential mechanistic target for novel early interventions.

Fear-induced brain activations distinguish anxious and trauma-exposed brains.

Translational models of fear conditioning and extinction have elucidated a core neural network involved in the learning, consolidation, and expression of conditioned fear and its extinction. Anxious or trauma-exposed brains are characterized by dysregulated neural activations within regions of this fear network. In this study, we examined how the functional MRI activations of 10 brain regions commonly activated during fear conditioning and extinction might distinguish anxious or trauma-exposed brains from controls. To achieve this, activations during four phases of a fear conditioning and extinction paradigm in 304 participants with or without a psychiatric diagnosis were studied. By training convolutional neural networks (CNNs) using task-specific brain activations, we reliably distinguished the anxious and trauma-exposed brains from controls. The performance of models decreased significantly when we trained our CNN using activations from task-irrelevant brain regions or from a brain network that is irrelevant to fear. Our results suggest that neuroimaging data analytics of task-induced brain activations within the fear network might provide novel prospects for development of brain-based psychiatric diagnosis.

Unconditioned response to an aversive stimulus as predictor of response to conditioned fear and safety: A cross-species study.

Safety signals predict the non-occurrence of an aversive event, thereby inhibiting fear responses. Previous research has shown that conditioned safety learning is impaired in patients suffering from post-traumatic stress disorder (PTSD). Using a translational approach, the present study aimed to investigate whether individual responses to an aversive unconditioned stimulus (US) in rats (basic science), non-traumatized (pre-clinical) or traumatized humans (clinical) predicts their response to a conditioned fear or safety stimulus. Using three different archival datasets, the unconditioned response (UCR) to the US during fear or safety conditioning was assessed in rats, non-traumatized humans, and trauma-exposed humans. The response to learned fear (CS+; context) and safety (CS-) was measured by the modulation of the startle response (rats, traumatized humans) or skin conductance response (non-traumatized humans). Our results showed that all groups with low UCR and those with high UCR from the rodent or non-traumatized human samples displayed lower fear response to the CS- than to the CS+ . Traumatized humans with high UCR showed similarly high responses to the CS+ and CS-. While all groups showed a positive association between the UCR and CS+ response, the UCR correlated positively with the CS- response in traumatized humans only. Our findings suggest that an elevated response to aversive stimuli predicts deficits in conditioned safety memory in those at risk for trauma-related disorders and confirms that impaired safety learning could be a valid biomarker for these diseases.