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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.

Active avoidance is a core behavior for human coping, and its excess is common across psychiatric diseases. The decision to actively avoid a threat is influenced by cost and reward. Yet, threat, avoidance, and reward have been studied in silos. We discuss behavioral and brain circuits of active avoidance and the interactions with fear and threat. In addition, we present a neural toggle switch model enabling fear-to-anxiety transition and approaching reward vs. avoiding harm decision. To fully comprehend how threat, active avoidance, and reward intersect, it is paramount to develop one shared experimental approach across phenomena and behaviors, which will ultimately allow us to better understand human behavior and pathology. How do threat, reward, and active avoidance intersect? This Perspective proposes the existence of a toggle switch that allows the organism to change, responding from threat to active avoidance.

Neuroimaging-based subtyping is increasingly used to explain heterogeneity in psychiatric disorders. However, the clinical utility of these subtyping efforts remains unclear, and replication has been challenging. Here we examined how the choice of neuroimaging measures influences the derivation of neuro-subtypes and the consequences for clinical delineation. On a clinically heterogeneous dataset (total n  = 566) that included controls ( n  = 268) and cases ( n  = 298) of psychiatric conditions, including individuals diagnosed with post-traumatic stress disorder (PTSD), traumatic brain injury (TBI), and comorbidity of both (PTSD&TBI), we identified neuro-subtypes among the cases using either structural, resting-state, or task-based measures. The neuro-subtypes for each modality had high internal validity but did not significantly differ in their clinical and cognitive profiles. We further show that the choice of neuroimaging measures for subtyping substantially impacts the identification of neuro-subtypes, leading to low concordance across subtyping solutions. Similar variability in neuro-subtyping was found in an independent dataset ( n  = 1642) comprised of major depression disorder (MDD, n  = 848) and controls ( n  = 794). Our results suggest that the highly anticipated relationships between neuro-subtypes and clinical features may be difficult to discover.

Systematic reviews are increasingly used to inform health policy-making. The conflicts of interest (COI) of the authors of systematic reviews may bias their results and influence their conclusions. This may in turn lead to misguided public policies and systems level decisions. In order to mitigate the adverse impact of COI, scientific journals require authors to disclose their COIs. The objective of this study was to assess the frequency and different types of COI that authors of systematic reviews on health policy and systems research (HSPR) report. We conducted a cross sectional survey. We searched the Health Systems Evidence (HSE) database of McMaster Health Forum for systematic reviews published in 2015. We extracted information regarding the characteristics of the systematic reviews and the associated COI disclosures. We conducted descriptive analyses. Eighty percent of systematic reviews included authors' COI disclosures. Of the 160 systematic reviews that included COI disclosures, 15% had at least one author reporting at least one type of COI. The two most frequently reported types of COI were individual financial COI and individual scholarly COI (11% and 4% respectively). Institutional COIs were less commonly reported than individual COIs (3% and 15% respectively) and non-financial COIs were less commonly reported than financial COIs (6% and 14% respectively). Only one systematic review reported the COI disclosure by editors, and none reported disclosure by peer reviewers. All COI disclosures were in the form of a narrative statement in the main document and none in an online document. A fifth of systematic reviews in HPSR do not include a COI disclosure statement, highlighting the need for journals to strengthen and/or better implement their COI disclosure policies. While only 15% of identified disclosure statements report any COI, it is not clear whether this indicates a low frequency of COI versus an underreporting of COI, or both.

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.

Conflicts of interest (COIs) are increasingly recognized as important to disclose and manage in health research. The objective of this study was to assess the reporting of both financial and nonfinancial COI by authors of randomized controlled trials published in a representative sample of clinical journals. We searched Ovid Medline and included a random sample of 200 randomized controlled trials published in 2015 in one of the 119 Core Clinical Journals. We classified COI using a comprehensive framework that includes the following: individual COIs (financial, professional, scholarly, advocatory, personal) and institutional COIs (financial, professional, scholarly, and advocatory). We conducted descriptive and regression analyses. Of the 200 randomized controlled trials, 188 (94%) reported authors' COI disclosures that were available in the main document (92%) and as International Committee of Medical Journal Editors forms accessible online (12%). Of the 188 trials, 57% had at least one author reporting at least one COI; in all these trials, at least one author reported financial COI. Institutional COIs (11%) and nonfinancial COIs (4%) were less commonly reported. References to COI disclosure statements for editors (1%) and medical writers (0%) were seldom present. Regression analyses showed positive associations between reporting individual financial COI and higher journal impact factor (odds ratio [OR] = 1.06, 95% confidence interval [CI] = 1.02–1.10), larger number of authors (OR = 1.10, 95% CI 1.02–1.20), affiliation with an institution from a high-income country (OR = 16.75, 95% CI 3.38–82.87), and trials reporting on pharmacological interventions (OR = 2.28, 95% CI 1.13–4.62). More than half of published randomized controlled trials report that at least one author has a COI. Trial authors report financial COIs more often than nonfinancial COIs and individual COIs more frequently than institutional COIs.

Abstract Background Conflicts of interest (COI) are increasingly recognised as important to disclose and manage in health research. The objective of this study was to assess the reporting of both financial and non-financial COI by authors of randomised controlled trials published in a representative sample of clinical journals. Methods We searched Ovid Medline and included a random sample of 200 randomised controlled trials published in 2015 in one of the 119 Core Clinical Journals. We classified COI using a comprehensive framework that includes: individual COIs (financial, professional, scholarly, advocatory, personal) and institutional COIs (financial, professional, scholarly, and advocatory). We conducted descriptive and regression analyses. Results Of the 200 randomised controlled trials, 188 (94%) reported authors’ COI disclosures that were available in the main document (92%) and as ICMJE forms accessible online (12%). Of the 188 trials, 57% had at least one author reporting at least one COI; in all these trials at least one author reported financial COI. Institutional COIs (11%) and non-financial COIs (4%) were less commonly reported. References to COI disclosure statements for editors (1%) and medical writers (0%) were seldom present. Regression analyses showed positive associations between reporting individual financial COI and higher journal impact factor (OR=1.06, 95% CI=1.02-1.10), larger number of authors (OR=1.10, 95% CI 1.02-1.20), affiliation with an institution from a high income country (OR=16.75, 95% CI 3.38-82.87), and trials reporting on pharmacological interventions (OR=2.28, 95% CI 1.13-4.62). Conclusion More than half of published randomised controlled trials report that at least one author has a COI. Trial authors report financial COIs more often than non-financial COIs and individual COIs more frequently than institutional COIs.