Circuit-Wide Structural and Functional Measures Predict Ventromedial Prefrontal Cortex Fear Generalization: Implications for Generalized Anxiety Disorder

Abstract

The ventromedial prefrontal cortex (vmPFC) plays a critical role in a number of evaluative processes, including risk assessment. Impaired discrimination between threat and safety is considered a hallmark of clinical anxiety. Here, we investigated the circuit-wide structural and functional mechanisms underlying vmPFC threat-safety assessment in humans. We tested patients with generalized anxiety disorder (GAD; n ϭ 32, female) and healthy controls (n ϭ 25, age-matched female) on a task that assessed the generalization of conditioned threat during fMRI scanning. The task consisted of seven rectangles of graded widths presented on a screen; only the midsize one was paired with mild electric shock [conditioned stimulus (CS)], while the others, safety cues, systematically varied in width by Ϯ20, 40, and 60% [generalization stimuli (GS)] compared with the CS. We derived an index reflecting vmPFC functioning from the BOLD reactivity on a continuum of threat (CS) to safety (GS least similar to CS); patients with GAD showed less discrimination between threat and safety cues, compared with healthy controls (Greenberg et al., 2013b). Using structural, functional (i.e., resting-state), and diffusion MRI, we measured vmPFC thickness, vmPFC functional connectivity, and vmPFC structural connectivity within the corticolimbic systems. The results demonstrate that all three factors predict individual variability of vmPFC threat assessment in an independent fashion. Moreover, these neural features are also linked to GAD, most likely via an vmPFC fear generalization. Our results strongly suggest that vmPFC threat processing is closely associated with broader corticolimbic circuit anomalies, which may synergistically contribute to clinical anxiety.

Neural Correlates of Aggression in Medication-Naive Children with ADHD: Multivariate Analysis of Morphometry and Tractography

“…Such circuit-wide (i.e., grey and white matter) MRI measures of aggression are analogous to the multiple MRI measures that account for OFC dysregulation in pathological anxiety (Cha et al, 2014). Our findings underscore the importance of coupling multi-modal MRI and multivariate statistical modeling to examine circuit-wide contributions to complex behaviors such as aggression.…”

“…This is true when studying not only aggression, but any psychiatric symptom or condition thought to arise from "brain circuits," rather than discrete lesions (Insel et al, 2010). For example, grey and white matter measures each account for dysregulation of the OFC in pathological anxiety, and combining these measures provides a more comprehensive account of the pathophysiology (Cha et al, 2014).…”

Neural basis of impaired safety signaling in Obsessive Compulsive Disorder

“…As fear extinction relies on revaluation of threatening stimuli as safe, it is critical to address how the brain processes the safety of stimuli in the environment. The ventromedial prefrontal cortex (vmPFC) is known to play a multifaceted role in integrating affective evaluative processes while mediating flexible behavior and is implicated in fear learning and anxiety-related disorders (1)(2)(3)(4)(5)(6)(7). Prefrontal inflexibility in Obsessive Compulsive Disorder (OCD) suggests rigidity in threat estimation alongside a persistent urge to perform compulsive behaviors, yet only one study has examined the neural correlates of fear learning and extinction in this disorder, implicating a maladaptive vmPFC (8).…”

Fear Generalization as Threat Prediction: Adaptive Changes in Facial Exploration Strategies revealed by Fixation-Pattern Similarity Analysis

“…neuronal or behavioral) are tested along a single dimension, this results in smoothly decaying response amplitudes with increasing dissimilarity to the adversity predicting stimulus. These generalization profiles can provide important clues about the selectivity of aversive representations [10] and may help understanding cognitive impairments such as anxiety disorders characterized by less selective generalization profiles [47][48][49]. However, the different hypotheses we could test here are difficult to be distinguished based on univariate generalization profiles, as they all predict monotonously decaying generalization profiles with increasing dissimilarity to the CS+.…”