Threat imminence reveals links among unfolding of anticipatory physiological response, cortical-subcortical intrinsic functional connectivity, and anxiety

Abstract

Excessive expression of fear responses in anticipation of threat occurs in anxiety, but understanding of underlying pathophysiological mechanisms is limited. Animal research indicates that threat-anticipatory defensive responses are dynamically organized by threat imminence and rely on conserved circuitry. Insight from basic neuroscience research in animals on threat imminence could guide mechanistic research in humans mapping abnormal function in this circuitry to aberrant defensive responses in pathological anxiety. 50 pediatric anxiety patients and healthy-comparisons (33 females) completed an instructed threat-anticipation task whereby cues signaled delivery of painful (threat) or non-painful (safety) thermal stimulation. Temporal changes in skin-conductance indexed anxiety effects on anticipatory responding as function of threat imminence. Multivariate network analyses of resting-state functional connectivity data from a subsample were used to identify intrinsic-function correlates of anticipatory-response dynamics, within a specific, distributed network derived from translational research on defensive responding. By considering threat imminence, analyses revealed specific anxiety effects. Importantly, pathological anxiety was associated with excessive deployment of anticipatory physiological response as threat, but not safety, outcomes became more imminent. Magnitude of increase in threat-anticipatory physiological responses corresponded with magnitude of intrinsic connectivity within a cortical-subcortical circuit. Moreover, more severe anxiety was associated with stronger associations between anticipatory physiological responding and connectivity that ventromedial prefrontal cortex showed with hippocampus and basolateral amygdala, regions implicated in animal models of anxiety. These findings link basic and clinical research, highlighting variations in intrinsic function in conserved defensive circuitry as a potential pathophysiological mechanism in anxiety.

Threat Vigilance and Intrinsic Amygdala Connectivity

“…Following hypothesis-testing we conducted a series of planned exploratory tests on a wider 'defensive response' network which included other subcortical and cortical regions implicated in anxiety and threat vigilance (Abend et al, 2022;Grupe & Nitschke 2013). Here, we detected a relationship between amygdala-periaqueductal gray connectivity and threat vigilance (but not self-report).…”

Threat vigilance and intrinsic amygdala connectivity

“…Human fMRI work has demonstrated an association between evoked anxiety and periaqueductal gray activation (Mobbs et al, 2007;Hur et al, 2020). One study in humans using an anxiety induction did not find interactions between functional connectivity of the periaqueductal gray and the degree of evoked anxiety or clinical diagnosis (Abend et al, 2022).…”

“…After hypothesis‐testing we conducted a series of planned exploratory tests on a wider “defensive response” network which included other subcortical and cortical regions implicated in anxiety and threat vigilance (Abend et al, 2022 ; Grupe & Nitschke 2013 ). Here, we detected a relationship between amygdala‐periaqueductal gray connectivity and threat vigilance (but not self‐report).…”

“…Human fMRI work has demonstrated an association between evoked anxiety and periaqueductal gray activation (Mobbs et al, 2007 ; Hur et al, 2020 ). One study in humans using an anxiety induction did not find interactions between functional connectivity of the periaqueductal gray and the degree of evoked anxiety or clinical diagnosis (Abend et al, 2022 ). Here, we provide evidence that, unlike amygdala‐prefrontal connections, individual differences in amygdala‐periaqueductal circuitry may be apparent at rest; specifically, this circuitry may be chronically engaged in hypervigilant individuals, even in the absence of threatening cues/anxiogenic stimuli.…”

“…We have now seen a plethora of anxiety research implicating this “defensive response network” spanning cortical and subcortical regions (Abend et al, 2022 ). However, despite a wide range of research establishing an association between anxiety and this network, our understanding of individual differences in this circuitry nonetheless remains limited.…”