Intolerance of uncertainty as a predictor of anxiety severity and trajectory during the COVID-19 pandemic.

BACKGROUND: Efforts to identify risk and resilience factors for anxiety severity and course during the COVID-19 pandemic have focused primarily on demographic rather than psychological variables. Intolerance of uncertainty (IU), a transdiagnostic risk factor for anxiety, may be a particularly relevant vulnerability factor. METHOD: N = 641 adults with pre-pandemic anxiety data reported their anxiety, IU, and other pandemic and mental health-related variables at least once and up to four times during the COVID-19 pandemic, with assessments beginning in May 2020 through March 2021. RESULTS: In preregistered analyses using latent growth models, higher IU at the first pandemic timepoint predicted more severe anxiety, but also a sharper decline in anxiety, across timepoints. This finding was robust to the addition of pre-pandemic anxiety and demographic predictors as covariates (in the full sample) as well as pre-pandemic depression severity (in participants for whom pre-pandemic depression data were available). Younger age, lower self/parent education, and self-reported history of COVID-19 illness at the first pandemic timepoint predicted more severe anxiety across timepoints with strong model fit, but did not predict anxiety trajectory. CONCLUSIONS: IU prospectively predicted more severe anxiety but a sharper decrease in anxiety over time during the pandemic, including after adjustment for covariates. IU therefore appears to have unique and specific predictive utility with respect to anxiety in the context of the COVID-19 pandemic.

Periaqueductal gray matter and medial prefrontal cortex reflect negative prediction errors during differential conditioning.

Computational models of associative learning posit that negative prediction errors (PEs) arising from the omission of aversive outcomes weaken aversive Pavlovian associations during differential conditioning and extinction. It is possible that negative PEs may underlie exaggerated conditioned responses to the conditioned stimulus not paired with an aversitve outcome (CS-) during differential conditioning and to the conditioned stimulus originally paired with a aversive outcome (CS+) during extinction in patients with clinical anxiety disorders. Although previous research has demonstrated that manipulations of the periaqueductal gray matter (PAG) interfere with extinction learning in animals, the role of the PAG in processing negative PEs within the human brain is presently unclear. We set out to investigate how PAG responses and connectivity are impacted by negative PEs using ultra-high-field (7 T) functional magnetic resonance imaging and hierarchical Bayesian analysis. During differential conditioning, negative PEs were associated with larger responses within the lateral and dorsolateral PAG and increased connectivity between the dorsolateral PAG and medial areas of Brodmann area 9. Collectively, these results shed light on the association between activity within the PAG and medial prefrontal cortex and the omission of aversive outcomes during Pavlovian learning.

The novel vasopressin receptor (V1aR) antagonist SRX246 reduces anxiety in an experimental model in humans: a randomized proof-of-concept study.

RATIONALE: Arginine vasopressin (AVP) is a neuropeptide that modulates both physiological and emotional responses to threat. Until recently, drugs that target vasopressin receptors (V1a) in the human central nervous system were unavailable. The development of a novel V1a receptor antagonist, SRX246, permits the experimental validation of vasopressin's role in the regulation of anxiety and fear in humans. OBJECTIVES: Here, we examined the effects of SRX246 in a proof-of-concept translational paradigm of fear (phasic response to imminent threat) and anxiety (prolonged response to potential threat). METHODS: Healthy volunteers received both SRX246 and placebo in a randomized, double-blind, counter-balanced order separated by a 5-7-day wash-out period. Threat consisted of unpleasant electric shocks. The "NPU" threat test probed startle reactivity during predictable threat (i.e., fear-potentiated startle) and unpredictable threat (i.e., anxiety-potentiated startle). RESULTS: As predicted, SRX246 decreased anxiety-potentiated startle independent of fear-potentiated startle. CONCLUSIONS: As anxiety-potentiated startle is elevated in anxiety and trauma-associated disorders and decreased by traditional anxiolytics such as SSRIs and benzodiazepines, the V1a receptor is a promising novel treatment target.

Neural Substrates of Overgeneralized Conditioned Fear in PTSD.

OBJECTIVE: Heightened generalization of fear from an aversively reinforced conditioned stimulus (CS+, a conditioned danger cue) to resembling stimuli is widely accepted as a pathogenic marker of posttraumatic stress disorder (PTSD). Indeed, a distress response to benign stimuli that "resemble" aspects of the trauma is a central feature of the disorder. To date, the link between overgeneralization of conditioned fear and PTSD derives largely from clinical observations, with limited empirical work on the subject. This represents the first effort to examine behavioral and brain indices of generalized conditioned fear in PTSD using systematic methods developed in animals known as generalization gradients: the gradual decline in conditioned responding as the presented stimulus gradually differentiates from CS+. METHOD: Gradients of conditioned fear generalization were assessed using functional MRI and behavioral measures in U.S. combat veterans who served in Iraq or Afghanistan and had PTSD (N=26), subthreshold PTSD (N=19), or no PTSD (referred to as trauma control subjects) (N=17). Presented stimuli included rings of graded size, with extreme sizes serving as CS+ (paired with shock) and as a nonreinforced conditioned stimulus (CS-, a conditioned safety cue), and with intermediate sizes forming a continuum of similarity between CS+ and CS-. Generalization gradients were assessed as response slopes from CS+, through intermediate ring sizes, to CS-, with less steep slopes indicative of stronger generalization. RESULTS: Relative to trauma control subjects, PTSD patients showed stronger conditioned generalization, as evidenced by less steep generalization gradients in both behavioral risk ratings and brain responses in the left and right anterior insula, left ventral hippocampus, dorsolateral and dorsomedial prefrontal cortex, and caudate nucleus. Severity of PTSD symptoms across the three study groups was positively correlated with levels of generalization at two such loci: the right anterior insula and left ventral hippocampus. CONCLUSIONS: The results point to evidence of brain-based markers of overgeneralized fear conditioning related to PTSD. These findings provide further understanding of a central yet understudied symptom of trauma-related psychopathology.