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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.

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.

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.

BACKGROUND: Repetitive transcranial magnetic stimulation (TMS) therapy can modulate pathological neural network functional connectivity in major depressive disorder (MDD). Posttraumatic stress disorder (PTSD) is often comorbid with MDD, and symptoms of both disorders can be alleviated with TMS therapy. This is the first study to evaluate TMS-associated changes in connectivity in patients with comorbid PTSD and MDD. METHODS: Resting state functional connectivity magnetic resonance imaging was acquired before and after TMS therapy in 33 adult outpatients in a prospective open trial. 5Hz TMS was delivered, in up to 40 daily sessions, to left dorsolateral prefrontal cortex (DLPFC). Analyses used a priori seeds relevant to TMS, PTSD or MDD (subgenual anterior cingulate cortex (sgACC), DLPFC, hippocampus, and basolateral amygdala) to identify imaging predictors of response and to evaluate clinically relevant changes in connectivity after TMS, followed by leave-one-out cross validation. Imaging results were explored using data-driven multivoxel pattern activation (MVPA). RESULTS: More negative pretreatment connectivity between sgACC and default mode network (DMN) predicted clinical improvement, as did more positive amygdala-to-ventromedial prefrontal cortex connectivity. After TMS, symptom reduction was associated with reduced connectivity between sgACC and DMN, DLPFC, and insula, and reduced connectivity between hippocampus and salience network (SN). MVPA confirmed seed-based predictors and correlates of treatment outcomes. CONCLUSIONS: These results highlight the central role of the sgACC, DMN and SN as predictors of TMS response, and suggest their involvement in mechanisms of action. Furthermore, this work indicates there may be network-based biomarkers of clinical response relevant to these commonly comorbid disorders. (5Hz Repetitive Transcranial Magnetic Stimulation for Posttraumatic Stress Disorder Comorbid With Major Depressive Disorder; ClinicalTrials.gov; )

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.

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.

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 (η(p)(2) = 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, η(p)(2) = 0.21; P = .01 and in functional magnetic resonance imaging results, η(p)(2) = 0.12; P = .02). The direct comparison of DSM-IV–based vs Research Domain Criteria–based results did not yield significant findings (η(p)(2) 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.