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Obsessive-compulsive disorder (OCD), like other illnesses with prominent anxiety, may involve abnormal fear regulation and consolidation of safety memories. Impaired fear extinction memory (extinction recall, ER) has been shown in individuals with current symptoms of OCD [1]. However, contrary to expectations, the only previous study investigating this phenomenon showed a positive correlation between extinction recall abilities and OCD symptomology (i.e., as OCD symptoms worsened, extinction memory improved). The purpose of the current study was to determine if patients with a lifetime diagnosis of OCD (not necessarily currently symptomatic) also demonstrate impairments in extinction memory, and the relationship between OCD symptomology and extinction memory in this type of sample. In addition, we also examined fear renewal, which has never been investigated in an OCD sample. We enrolled 37 patients with OCD, the majority of whom were on serotonin reuptake inhibitors, and 18 healthy control participants in a 2-day paradigm assessing fear conditioning and extinction (Day 1) and extinction retention and renewal (Day 2). Skin conductance responses (SCRs) were the dependent measure. Results, as in the prior study, indicated that the only between-group difference was impaired ER in OCD patients relative to controls. Contrary to our prediction, OCD symptom severity was not correlated with the magnitude of extinction recall. There were no differences in fear renewal between OCD patients and controls.

Trauma type moderates the impact of trauma exposure on clinical symptomatology; however, the impact of trauma type on the neural correlates of emotion regulation is not as well understood. This study examines how violent and nonviolent trauma differentially influence the neural correlates of conditioned fear and extinction. We aggregated psychophysiological and fMRI data from three studies; we categorized reported trauma as violent or nonviolent, and subdivided violent trauma as sexual or nonsexual. We examined skin conductance responses (SCR) during a fear conditioning and extinction paradigm. For fMRI data analyses, we conducted region-specific and whole-brain analyses. We examined associations between beta weights from specific brain regions and CAPS scores. The group exposed to violent trauma showed significantly higher SCR during extinction recall. Those exposed to nonviolent trauma showed significantly higher functional activation during late extinction learning. The group exposed to violent trauma showed higher functional connectivity within the default mode network (DMN) and between the DMN and frontoparietal control network. For secondary analyses of sexual vs nonsexual trauma, we did not observe any between-group differences in SCR. During late extinction learning, the group exposed to sexual trauma showed significantly higher activation in the prefrontal cortex and precuneus. During extinction recall, the group exposed to nonsexual trauma showed significantly higher activation in the insular cortex. Violent trauma significantly impacts functional brain activations and connectivity in brain areas important for perception and attention with no significant impact on brain areas that modulate emotion regulation. Sexual trauma impacts brain areas important for internal perception., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Ltd.)

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., (© 2024. The Author(s).)

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.

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., (© 2023. Springer Nature Limited.)

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., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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; Marković 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., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

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., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

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., (© 2022 Wen et al.; Published by Cold Spring Harbor Laboratory Press.)

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.

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., (© 2022. The Author(s).)

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., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© 2021. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Fear is an adaptive emotion that serves to protect an organism against potential dangers. It is often studied using classical conditioning paradigms where a conditioned stimulus is paired with an aversive unconditioned stimulus to induce a threat response. Less commonly studied is a phenomenon that is related to this form of conditioning, known as latent inhibition. Latent inhibition (LI) is a paradigm in which a neutral cue is repeatedly presented in the absence of any aversive associations. Subsequent pairing of this pre-exposed cue with an aversive stimulus typically leads to reduced expression of a conditioned fear/threat response. In this article, we review some of the theoretical basis for LI and its behavioral and neural mechanisms. We compare and contrast LI and fear/threat extinction-a process in which a previously conditioned cue is repeatedly presented in the absence of aversive outcomes. We end with highlighting the potential clinical utility of LI. Particularly, we focus on how LI application could be useful for enhancing resilience, especially for individuals who are more prone to continuous exposure to trauma and stressful environments, such as healthcare workers and first responders. The knowledge to be gained from advancing our understanding of neural mechanisms in latent inhibition could be applicable across psychiatric disorders characterized by exaggerated fear responses and impaired emotion regulation., (© 2022 Miller et al.; Published by Cold Spring Harbor Laboratory Press.)

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., (© 2021. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

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., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

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., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: We assessed the impact of total and partial sleep loss on neural correlates of fear conditioning, extinction learning, and extinction recall in healthy young adults., Methods: Participants (56.3% female, age 24.8 ± 3.4 years) were randomized to a night of normal sleep (NS) (n = 48), sleep restriction (SR) (n = 53), or sleep deprivation (SD) (n = 53). All completed fear conditioning and extinction learning phases the following morning. Extinction recall was tested in the evening of the same day. Task-based contrasts were modeled at the beginning of, at the end of, and across the fear conditioning and extinction learning phases, and at the beginning of extinction recall. These contrasts were compared among the 3 groups by means of analysis of variance. Nonparametric permutation corrected analyses using a cluster-determining threshold of p < .005 and a familywise error of p < .05., Results: At the end of fear conditioning, NS activated medial prefrontal regions, SR activated motor areas, and participants in the SD group showed no significant activations. Across extinction learning, only NS activated both salience (fear) and extinction (regulatory) areas. For extinction recall, SD activated similar regions as NS across extinction learning, while SR activated salience and motor areas. During early fear conditioning, compared with NS, SD activated more medial prefrontal and SR activated more salience network areas. For extinction recall, NS activated more prefrontal areas and SD activated more of both salience- and extinction-related areas than SR., Conclusions: Relative to NS, SR may enhance fear-related and diminish extinction-related activity, whereas SD may delay engagement of extinction learning. Findings may have clinical implications for populations and occupations in which sleep loss is common., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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.

Observational fear learning can contribute to the development of fear-related psychopathologies, such as anxiety disorders and post-traumatic stress disorder. Observational fear learning is especially relevant during childhood. Parent-child attachment and anxiety sensitivity modulate fear reactions and fear learning but their impact on observational fear learning has not been investigated. This study investigated how these factors contribute to observational fear learning in children. We examined this question among 55 healthy parent-child dyads. Children (8-12 years old) watched a video of their parent undergoing a direct fear conditioning protocol, where one stimulus (CS+Parent) was paired with a shock and one was not (CS-), and a video of a stranger for whom a different stimulus was reinforced (CS+Stranger). Subsequently, all stimuli were presented to children (without shocks) while skin conductance responses were recorded to evaluate fear levels. Our results showed that children more sensitive to anxiety and who had lower father-child relationship security levels exhibited higher skin conductance responses to the CS+Parent. Our data suggest that the father-child relationship security influences vicarious fear transmission in children who are more sensitive to anxiety. This highlights the importance of the father-child relationship security as a potential modulator of children's vulnerability to fear-related psychopathologies., (Copyright © 2020 Bilodeau-Houle, Bouchard, Morand-Beaulieu, Herringa, Milad and Marin.)

The biological mechanisms involved in fear transmission within families have been scarcely investigated in humans. Here we studied (1) how children acquired conditioned fear from observing their parent, or a stranger, being exposed to a fear conditioning paradigm, and (2) the subsequent fear extinction process in these children. Eighty-three child-parent dyads were recruited. The parent was filmed while undergoing a conditioning procedure where one cue was paired with a shock (CS + Parent) and one was not (CS -). Children (8 to 12 years old) watched this video and a video of an adult stranger who underwent conditioning with a different cue reinforced (CS + Stranger). Children were then exposed to all cues (no shocks were delivered) while skin conductance responses (SCR) were recorded. Children exhibited higher SCR to the CS + Parent and CS + Stranger relative to the CS -. Physiological synchronization between the child's SCR during observational learning and the parent's SCR during the actual process of fear conditioning predicted higher SCR for the child to the CS + Parent. Our data suggest that children acquire fear vicariously and this can be measured physiologically. These data lay the foundation to examine observational fear learning mechanisms that might contribute to fear and anxiety disorders transmission in clinically affected families.

Introduction: Mindfulness meditation has successfully been applied to cultivate skills in self-regulation of emotion, as it employs the unbiased present moment awareness of experience. This heightened attention to and awareness of sensory experience has been postulated to create an optimal therapeutic exposure condition and thereby improve extinction learning. We recently demonstrated increased connectivity in hippocampal circuits during the contextual retrieval of extinction memory following mindfulness training., Methods: Here, we examine the role of structural changes in hippocampal subfields following mindfulness training in a randomized controlled longitudinal study using a two-day fear-conditioning and extinction protocol., Results: We demonstrate an association between mindfulness training-related increases in subiculum and decreased hippocampal connectivity to lateral occipital regions during contextual retrieval of extinguished fear. Further, we demonstrate an association between decreased connectivity and decreases in self-reported anxiety following mindfulness training., Conclusions: The results highlight the role of the subiculum in gating interactions with contextual stimuli during memory retrieval and, also, the mechanisms through which mindfulness training may foster resilience., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Study Objectives: Formation and maintenance of fear-extinction memories are disrupted in post-traumatic stress disorder (PTSD) and anxiety disorders. Sleep contributes to emotional memory consolidation and emotion regulation. Insomnia disorder (ID) is characterized by persistent sleep disturbance as well as rapid eye movement (REM) sleep abnormalities and often precedes or develops in parallel with PTSD and anxiety disorders. Here, we explore the impact of chronic poor sleep and sleep immediately following fear conditioning and extinction learning on preservation of extinction memories., Methods: Twenty-four ID age- and sex-matched to 24 healthy, good sleeper controls (GS) completed up to 2 weeks of habitual sleep monitoring with daily sleep-wake diaries and actigraphy, and then participated in a two-session fear conditioning, extinction learning and extinction recall procedure. Fear Conditioning and Extinction Learning occurred during session 1, followed by Extinction Recall approximately 24 hours later. Skin-conductance responses (SCR) and shock expectancies were recorded throughout all experimental phases to evaluate associative learning and memory. Overnight sleep between sessions 1 and 2 was recorded using ambulatory polysomnography., Results: ID showed greater physiological reactivity during Fear Conditioning. REM sleep physiology was associated with poorer extinction memory in ID but better extinction memory in GS., Conclusion: REM sleep physiology may differentially support emotional memory retention and expression in ID and GS. In the former, REM may enhance retention of fear memories, while in the later, REM may enhance the expression of extinction memories., (© Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Importance: The Research Domain Criteria project of the National Institute of Mental Health aims to guide neuropsychiatry toward precision medicine. Its inception was partly in response to the overlap of clinical manifestations between different DSM-IV diagnoses within a category. For example, anxiety disorders comprise a DSM-IV category that includes diagnoses that differ from each other but are all characterized by dysregulated fear levels. Whether DSM-IV-based and Research Domain Criteria-based analytic approaches provide distinct or similar information with regard to the fear circuitry of individuals with anxiety disorders has not been directly tested., Objective: To use a threat conditioning and extinction protocol to conduct categorical (DSM-IV-based) and dimensional (Research Domain Criteria-based) assessments of psychophysiological, neural, and psychometric responses in individuals with and without anxiety disorders., Design, Setting, and Participants: This cross-sectional study was conducted at the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital in Boston between March 2013 and May 2015. Functional magnetic resonance imaging was used to assess psychophysiological, neural, and psychometric responses among adults aged 18 to 65 years with specific phobia, generalized anxiety disorder, social anxiety disorder, and panic disorder as well as a control group of adults without anxiety disorders. Data were analyzed between May 2018 and April 2019., Exposures: A 2-day threat conditioning and extinction protocol., Main Outcomes and Measures: Skin conductance responses and blood oxygenated level-dependent responses were measured during the threat and extinction protocol. The categorical analysis was performed by grouping participants based on their primary DSM-IV diagnosis. The dimensional analysis was performed by regrouping participants, irrespective of their diagnoses, based on their skin conductance responses to shock delivery during threat conditioning., Results: This cross-sectional study of 114 adults aged 18 to 65 years included 93 participants (34 men and 59 women; mean [SD] age, 29.7 [11.1] years) with at least 1 anxiety disorder (specific phobia, generalized anxiety disorder, social anxiety disorder, or panic disorder) and 21 participants (11 men and 10 women) without an anxiety disorder. The categorical DSM-IV-based approach indicated that all anxiety disorder groups exhibited hypoactivation in the ventromedial prefrontal cortex during extinction recall (ηp2 = 0.15; P = .004). The Research Domain Criteria-based approach revealed that higher arousal to the unconditioned stimulus was associated with higher threat responses during extinction recall (for skin conductance responses, ηp2 = 0.21; P = .01 and in functional magnetic resonance imaging results, ηp2 = 0.12; P = .02). The direct comparison of DSM-IV-based vs Research Domain Criteria-based results did not yield significant findings (ηp2 values ranged from 0.02 to 0.078; P values ranged from .09 to .98), suggesting no overlap between the approaches., Conclusions and Relevance: The data obtained from both approaches indicated complementary yet distinct findings. The findings highlight the validity and importance of using both categorical and dimensional approaches to optimize understanding of the etiology and treatment of anxiety symptoms.

The accumulating evidence regarding the impact of estradiol on learning and memory synergized studies to examine its influence on enhancing animal's ability to quell fear and anxiety. In this review, we first provide a foundational platform regarding the impact of oestradiol on cellular mechanisms of learning and memory and we review recent advances from rodent and human data showing that oestrogen enhances extinction learning across species. We then propose clinical application to these data. We discuss the potential role of oestradiol variance on the aetiology, maintenance and treatment for post-traumatic stress disorder. Specifically, we argue that the use of oestradiol as an adjunct to prolonged exposure (PE) therapy for PTSD may provide a new treatment approach for enhancing the efficacy of PE in women with PTSD. This could advance our understanding of the mechanisms of PTSD and help tailor sex-specific treatments for this disorder., (© 2019 British Society for Neuroendocrinology.)

Skin conductance response (SCR) is often used as an index of conditioned fear. SCR has been shown to be highly variable, and absence of SC reactivity is sometimes used as criteria for excluding data. It is, however, possible that low or no SC reactivity is the result of a distinct biological signature that underlies individual differences in SCR reactivity. This study examined neural correlates associated with the near absence of SCR conditionability. Archival data from 109 healthy adults aged 18-60 years were pooled. All individuals had participated in a fear conditioning protocol in a fMRI environment, during which two cues were partially reinforced (CS+) with a shock and a third cue was not (CS-). Using SCR to the conditioned stimuli and differential SCR (CS+ minus CS-), we created two groups of 30 individuals: low conditioners (defined as those showing the smallest SCR to the CS+ and smallest differential SCR) and high conditioners (defined as those showing the largest SCR to the CS+ and largest differential SCR). Our analyses showed differences in patterns of brain activations between these two groups during conditioning in the following regions: dorsal anterior cingulate cortex, amygdala, subgenual anterior cingulate cortex, and insular cortex. Our findings suggest that low or absent SCR conditionability is associated with hypoactivation of brain regions involved in fear learning and expression. This highlights the need to be cautious when excluding SCR nonconditioners and to consider the potential implications of such exclusion when interpreting the findings from studies of conditioned fear., (© 2019 Society for Psychophysiological Research.)

Background: The role of hippocampus in context-dependent recall of extinction is well recognized. However, little is known about how intervention-induced changes in hippocampal networks relate to improvements in extinction learning. In this study, we hypothesized that mindfulness training creates an optimal exposure condition by heightening attention and awareness of present moment sensory experience, leading to enhanced extinction learning, improved emotion regulation, and reduced anxiety symptoms., Methods: We tested this hypothesis in a randomized controlled longitudinal study design using a 2-day fear conditioning and extinction protocol. The mindfulness training group included 42 participants (28 women) and the control group included 25 participants (15 women)., Results: We show that mindfulness training is associated with differential engagement of the right supramarginal gyrus as well as hippocampal-cortical reorganization. We also report enhanced hippocampal connectivity to the primary sensory cortex during retrieval of extinguished stimuli following mindfulness training., Conclusions: These findings suggest hippocampal-dependent changes in contextual retrieval as one plausible neural mechanism through which mindfulness-based interventions enhance fear extinction and foster stress resilience., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The neural mechanisms and durability of Δ9-tetrahydrocannabinol (THC) impact on threat processing in humans are not fully understood. Herein, we used functional MRI and psychophysiological tools to examine the influence of THC on the mechanisms of conditioned threat extinction learning, and the effects of THC on extinction memory retention when assessed 1 day and 1 week from learning. Healthy participants underwent threat conditioning on day 1. On day 2, participants were randomized to take one pill of THC or placebo (PBO) 2-h before threat extinction learning. Extinction memory retention was assessed 1 day and 1 week after extinction learning. We found that THC administration increased amygdala and ventromedial prefrontal cortex (vmPFC) activation during early extinction learning with no significant impact on skin conductance responses (SCR). When extinction memory retention was tested 24 h after learning, the THC group exhibited lower SCRs to the extinguished cue with no significant extinction-induced activations within the extinction network. When extinction memory retention was tested 1 week after learning, the THC group exhibited significantly decreased responses to the extinguished cues within the vmPFC and amygdala, but significantly increased functional coupling between the vmPFC, hippocampus, and dorsal anterior cingulate cortex during this extinction retention test. Our results are the first to report a long-term impact of one dose of THC on the functional activation of the threat extinction network and unveil a significant change in functional connectivity emerging after a week from engagement. We highlight the need for further investigating the long-term impact of THC on threat and anxiety circuitry.

Despite the exponential increase in fear research during the last years, few studies have included female subjects in their design. The need to include females arises from the knowledge gap of mechanistic processes underlying the behavioral and neural differences observed in fear extinction. Moreover, the exact contribution of sex and hormones in relation to learning and behavior is still largely unknown. Insights from this field could be beneficial as fear-related disorders are twice as prevalent in women compared to men. Here, we review an up-to-date summary of animal and human studies in adulthood that report sex differences in fear extinction from a structural and functional approach. Furthermore, we describe how these factors could contribute to the observed sex differences in fear extinction during normal and pathological conditions., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: We have previously demonstrated that pre-scan salivary cortisol is associated with attentuated frontal-subcortical brain activation during emotion processesing and semantic list-learning paradigms in depressed subjects. Additionally, altered functional connectivity is observed after remission of acute depression symptoms (rMDD). It is unknown whether cortisol also predicts altered functional connectivity during remission., Methods: Participants were 47 healthy controls (HC) and 73 rMDD, 18-30 years old who provided salivary cortisol samples before and after undergoing resting-state fMRI. We tested whether salivary cortisol by diagnosis interactions were associated with seed-based resting connectivity of the default mode (DMN) and salience and emotion (SN) networks using whole-brain, cluster-level corrected (p < .01) regression in SPM8., Results: Pre-scan cortisol predicted decreased (HC) and increased (rMDD) cross-network connectivity to the dorsal anterior cingulate, dorso-medial and lateral- prefrontal cortex, brain stem and cerebellum (all seeds) and precuneus (DMN seeds). By and large, pre/post-scan cortisol change predicted the same pattern of findings. In network analyses, cortisol predominantly predicted enhanced cross-network connectivity to cognitive control network regions in rMDD., Conclusions: The association of cortisol with connections of default and salience networks to executive brain networks differs between individuals with and without a history of depression. Further investigation is needed to better understand the role of cortisol and related stress hormones as a potential primary and interactive driver of network coherence in depression., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Connectomics is a framework that models brain structure and function interconnectivity as a network, rather than narrowly focusing on select regions-of-interest. MRI-derived connectomes can be structural, usually based on diffusion-weighted MR imaging, or functional, usually formed by examining fMRI blood-oxygen-level-dependent (BOLD) signal correlations. Recently, we developed a novel method for assessing the hierarchical modularity of functional brain networks-the probability associated community estimation (PACE). PACE uniquely permits a dual formulation, thus yielding equivalent connectome modular structure regardless of whether positive or negative edges are considered. This method was rigorously validated using the 1,000 functional connectomes project data set (F1000, RRID:SCR&#95;005361) (1) and the Human Connectome Project (HCP, RRID:SCR&#95;006942) (2, 3) and we reported novel sex differences in resting-state connectivity not previously reported. (4) This study further examines sex differences in regard to hierarchical modularity as a function of age and clinical correlates, with findings supporting a basal configuration framework as a more nuanced and dynamic way of conceptualizing the resting-state connectome that is modulated by both age and sex. Our results showed that differences in connectivity between men and women in the 22-25 age range were not significantly different. However, these same non-significant differences attained significance in both the 26-30 age group ( p = 0.003) and the 31-35 age group ( p < 0.001). At the most global level, areas of diverging sex difference include parts of the prefrontal cortex and the temporal lobe, amygdala, hippocampus, inferior parietal lobule, posterior cingulate, and precuneus. Further, we identified statistically different self-reported summary scores of inattention, hyperactivity, and anxiety problems between men and women. These self-reports additionally divergently interact with age and the basal configuration between sexes.

Study Objectives: Insomnia increases the risk for anxiety disorders that are also associated with fear-extinction deficits. We compared activation of fear and extinction networks between insomnia disorder (ID) without comorbidity and good sleepers (GS)., Methods: Twenty-three ID participants age- and sex-matched to 23 GS participants completed 14 days of actigraphy and diaries, three nights of ambulatory polysomnography and a 2-day fear conditioning and extinction paradigm. Fear conditioning and extinction learning occurred on the first day, followed 24 hours later by extinction recall. Blood-oxygen-level-dependent functional magnetic resonance imaging (fMRI) signal and skin conductance responses (SCR) were recorded. Nineteen participants per group produced usable fMRI data. Beta weights from areas where activation differed between groups were regressed against sleep and psychophysiological measures. SCR was compared between groups at various stages of the paradigm., Results: During fear conditioning, both ID (N = 19) and GS (N = 19) activated fear-related structures. Across extinction learning, ID (N = 19) demonstrated little change, whereas GS (N = 16) activated both fear and extinction-related areas, including the hippocampus, insula, dorsal anterior cingulate (dACC), and ventromedial prefrontal (vmPFC) cortices. During extinction recall, while GS (N = 17) demonstrated limited activation, ID (N = 16) activated regions similar to those previously activated in GS (vmPFC, dACC, insula). Sleep quality was predictive of activations seen at various stages of the paradigm. SCR data suggested ID were more physiologically reactive than GS., Conclusions: Across extinction learning, GS but not ID activated both fear and extinction-related networks. At extinction recall, ID engaged similar regions whereas GS no longer did so. Individuals with ID may show a delayed acquisition of fear extinction memories.

Background: Animal fear conditioning studies have illuminated neuronal mechanisms of learned associations between sensory stimuli and fear responses. In rats, brief electrical stimulation of the infralimbic cortex has been shown to reduce conditioned freezing during recall of extinction memory. Here, we translated this finding to humans with magnetic resonance imaging-navigated transcranial magnetic stimulation (TMS)., Methods: Subjects (N = 28) were aversively conditioned to two different cues (day 1). During extinction learning (day 2), TMS was paired with one of the conditioned cues but not the other. TMS parameters were similar to those used in rat infralimbic cortex: brief pulse trains (300 ms at 20 Hz) starting 100 ms after cue onset, total of four trains (28 TMS pulses). TMS was applied to one of two targets in the left frontal cortex, one functionally connected (target 1) and the other unconnected (target 2, control) with a human homologue of infralimbic cortex in the ventromedial prefrontal cortex. Skin conductance responses were used as an index of conditioned fear., Results: During extinction recall (day 3), the cue paired with TMS to target 1 showed significantly reduced skin conductance responses, whereas TMS to target 2 had no effect. Further, we built group-level maps that weighted TMS-induced electric fields and diffusion magnetic resonance imaging connectivity estimates with fear level. These maps revealed distinct cortical regions and large-scale networks associated with reduced versus increased fear., Conclusions: The results showed that spatiotemporally focused TMS may enhance extinction learning and/or consolidation of extinction memory and suggested novel cortical areas and large-scale networks for targeting in future studies., (Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Obsessive-compulsive disorder (OCD) is a neuropsychiatric condition that affects men and women equally, but with a sexually dimorphic pattern of development. Reproductive cycle events can influence symptom severity of OCD in females, indicating that ovarian hormones or their interaction with distinct neurotransmitter systems may play a role in OCD pathophysiology. Clinical studies and animal models have confirmed the importance of the serotonergic (5-HT) system in the neurobiology and treatment of OCD. Accordingly, the non-selective 5-HT2c agonist, meta-chlorophenylpiperazine (mCPP), exacerbates symptoms in untreated OCD patients. In rodents, it evokes repetitive behaviors that engage brain areas that are homologous with those found to be dysfunctional in OCD patients. These regions, including the medial prefrontal and anterior cingulate cortices, are also involved in fear inhibition, which is impaired in OCD. Here, we treated rats with mCPP (0.5 and 3.0 mg/kg) to evaluate its influence on self-grooming behavior and assess potential fear extinction retention deficits, taking into account sex differences and females' estrous cycle. We found that mCPP exacerbated grooming in male and female rats, irrespective of the estrous cycle phase. Fear extinction retention, however, was impaired only in females. Moreover, females undergoing fear extinction training during the metestrus/diestrus phases of the estrous cycle were more sensitive to the impairments induced by mCPP. Our results indicate that mCPP can induce OCD-like symptoms, exacerbating self-grooming and impairing fear extinction. It suggests that changes in 5-HT signaling through 5-HT2c receptors may have an important role in the OCD pathophysiology and that the influence of gonadal hormones in OCD should be further investigated., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Skin conductance (SC) is a psychophysiological measure of sympathetic nervous system activity that is commonly used in research to assess conditioned fear responses. A portion of individuals evidence very low or unmeasurable SC levels (SCL) and/or response (SCR) during fear conditioning, which precludes the use of their SC data. The reason that some individuals do not produce measurable SCL and/or SCR is not clear; some early research suggested that race may be an influencing factor. In the current article, archival data from five fear conditioning samples collected from four different laboratories were examined to explore SCL and SCR magnitude in African American (AA) and non-African American (non-AA) participants. Across studies, the aggregate group difference for exclusion due to unmeasurable SCL or no measurable SCR to an unconditioned stimulus reflected a significant medium effect size (d = 0.54). Furthermore, 24.3% (range: 0-48.3%) of AA participants met SC exclusion criteria versus 14.3% (range: 4.3-24.2%) of non-AA participants. AA participants also displayed significantly lower SCL during habituation (d = 0.58). The low SC levels and responses in AA individuals and the consequent exclusion of their contributions to fear conditioning study results impacts the generalizability of findings across races. Given higher rates of posttraumatic stress disorder (PTSD) and chronic anxiety in AA individuals, it is important that AA individuals not be excluded from fear conditioning research, which informs the treatment of anxiety and PTSD. Examination of the basis of very low SCL and/or SCR is a potentially informative direction for future research., (© 2017 Society for Psychophysiological Research.)

The learning principles that guide the acquisition and extinction of avoidance are not fully understood. We developed a novel paradigm to study the temporal dynamics of relief, a putative reinforcer of avoidance, and the recovery of fear and avoidance following extinction. During conditioning, the avoidance action canceled the aversive unconditional stimulus (US), without terminating the predictive conditional stimulus (CS). Relief pleasantness was rated after fixed CS offsets, when US omission occured. Avoidance was effective to one CS, but not to another, to track stimulus-specific avoidance learning. Fear was extinguished under response prevention in a separate context. Recovery tests took place 24 h later, in both contexts and with a monetary cost added to the avoidance action. We found that avoidance gradually became stimulus-specific during conditioning, but hardly recovered during delayed testing. Across all phases, initial omissions of the aversive US triggered relief that gradually declined over consecutive omissions, in line with a theoretical prediction error signal. Participants that scored low on distress tolerance, however, displayed sustained levels of relief over continuous omissions. We propose that such forms of sustained relief may produce over-reinforcement of foregoing avoidance actions and promote the development of pathological avoidance. The current paradigm represents an efficacious tool to study the temporal dynamics of relief across avoidance learning and fear extinction and to characterize relief dysregulations in relation to psychopathology., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Extinction of conditioned fear represents an important mechanism in the treatment of anxiety disorders. Return of fear after successful extinction or exposure therapy in patients with anxiety disorders might be linked to poor temporal or contextual generalization of extinction due to individual differences in brain structural connectivity. The goal of this magnetic resonance imaging study was therefore to investigate the association of context-dependent extinction recall with brain structural connectivity., Methods: Diffusion-tensor imaging was used to determine the fractional anisotropy as a measure of white matter structural integrity of fiber tracts connecting central brain regions of the fear and extinction circuit (uncinate fasciculus, cingulum). Forty-five healthy men participated in a two-day fear conditioning experiment with fear acquisition in context A and extinction learning in context B on the first day. Extinction recall in the extinction context as well as renewal in the acquisition context and a novel context C took place one day later., Results: Renewal of conditioned fear (skin conductance responses) in the acquisition context was associated with higher structural integrity of the hippocampal part of the cingulum., Conclusions: Enhanced structural integrity of the cingulum might be related to stronger hippocampal modulation of the dorsal anterior cingulate cortex, a region important for modulating conditioned fear output by excitatory projections to the amygdala. This finding underpins the crucial role of individual differences in the structural integrity of relevant fiber tracts for context-dependent extinction recall and return of fear after exposure therapy in anxiety disorders., (© 2017 Wiley Periodicals, Inc.)

Leuprolide acetate (LEU), also known as Lupron, is commonly used to treat prostate cancer in men. As a gonadotropin-releasing hormone (GnRH) receptor agonist, it initially stimulates the release of gonadal hormones, testosterone (T) and estradiol. This surge eventually suppresses these hormones, preventing the further growth and spread of cancer cells. Individuals receiving this treatment often report anxiety and cognitive changes, but LEU's effects on the neural mechanisms that are involved in anxiety during the trajectory of treatment are not well known. In this study, we examined the acute effects of LEU on fear extinction, hypothesizing that increased T levels following a single administration of LEU will facilitate extinction recall by altering neuronal activity within the fear extinction circuitry. Two groups of naïve adult male rats underwent a 3-day fear conditioning, extinction, and recall experiment. The delayed group (n=15) received a single injection of vehicle or LEU (1.2mg/kg) 3weeks before behavioral testing. The acute group (n=25) received an injection one day after fear conditioning, 30min prior to extinction training. Following recall, the brains for all animals were collected for c-fos immunohistochemistry. Blood samples were also collected and assayed for T levels. Acute administration of LEU increased serum T levels during extinction training and enhanced extinction recall 24h later. This enhanced extinction memory was correlated with increased c-fos activity within the infralimbic cortex and amygdala, which was not observed in the delayed group. These results suggest that the elevation in T induced by acute administration of LEU can influence extinction memory consolidation, perhaps through modification of neuronal activity within the infralimbic cortex and amygdala. This may be an important consideration in clinical applications of LEU and its effects on anxiety and cognition., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Sleep abnormalities are extremely common in anxiety disorders and may contribute to their development and persistence. Their shared pathophysiological mechanisms could thus serve as biomarkers or targets for novel therapeutics. Individuals with Primary Insomnia were age- and sex-matched to controls and to persons with Generalized Anxiety Disorder. All underwent fMRI resting-state scans at 3-T. In Primary Insomnia and controls, sleep was recorded for 2 weeks using diaries and actigraphy. All participants completed state-anxiety and neuroticism inventories. Whole-brain connectivity of 6 fear- and extinction-related seeds were compared between the 3 groups using ANOVA. The only significant between-group main effect was seen for connectivity between the left amygdala seed and a bilateral cluster in the rostral anterior cingulate cortex. The latter is believed to exert top-down control over amygdala activity and their interaction may thus constitute an emotion regulatory circuit. This connectivity was significantly greatest in controls while Primary Insomnia was intermediate between that of controls and Generalized Anxiety Disorder. Across Primary Insomnia and control subjects, mean connectivity decreased with poorer sleep. Across all 3 groups, connectivity decreased with greater neuroticism and pre-scan anxiety. Decreased top-down control of the amygdala may increase risk of developing an anxiety disorder with preexisting Primary Insomnia., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)