Uncertainty and anticipation in anxiety: an integrated neurobiological and psychological perspective

Abstract

Uncertainty about a possible future threat disrupts our ability to avoid it or to mitigate its negative impact and thus results in anxiety. Here, we focus the broad literature on the neurobiology of anxiety through the lens of uncertainty. We identify five processes that are essential for adaptive anticipatory responses to future threat uncertainty and propose that alterations in the neural instantiation of these processes result in maladaptive responses to uncertainty in pathological anxiety. This framework has the potential to advance the classification, diagnosis and treatment of clinical anxiety.

Figure 1. Neural regions and circuitry implicated in the UAMA

A. Inflated estimates of threat cost and probability reflect disruptions to the dorsomedial prefrontal cortex (dmPFC), rostral cingulate (rCing), orbitofrontal cortex (OFC), ventral striatum (VS), and anterior insula (AI). B. Elevated amygdala (Amyg) activity leads to increased basal forebrain (BF) modulation of visual and other sensory input [Au: could we label the region that the arrow from BF points to ‘sensory cortex’?] and heightened threat attention. Interactions between the amygdala, OFC, and VS further increase threat expectancies and threat attention. C. Deficient safety learning reflects disrupted inhibitory ventromedial PFC (vmPFC)-amygdala circuitry. D. Behavioral and cognitive avoidance reflects interactions between the amygdala and circuitry involved in decision-making and action selection, including the OFC, dorsolateral PFC (dlPFC), striatum, anterior mid-cingulate cortex (aMCC), and anterior insula. E. Hyperactivity of the bed nucleus of the stria terminalis (BNST) and amygdala in response to sustained, unpredictable threat modulate defensive responding as mediated by the hypothalamus (Hy), pons, periaqueductal gray (PAG), and other midbrain/brainstem structures. Anterior insula dysfunction is associated with elevated intolerance of uncertainty and further contributes to BNST and amygdala hyperactivity. F. Dysfunction of the aMCC, or disrupted structural connectivity between the aMCC and interconnected regions, prevents individuals from identifying and executing adaptive responses to uncertainty and contributes to the disruptions highlighted in A–E. Lateral cortical regions are shown in blue, medial cortical regions in green, and subcortical regions in orange. The functional pathways in A–E are indicated with red arrows (excitatory) and blue arrows (inhibitory). The known structural connections in F are indicated with purple arrows (directionality indicated by arrowheads). ST=spinothalamic tract; VTA=ventral tegmental area.

Figure 2. Altered anticipatory processes in response to threat uncertainty in anxiety

Dynamic interactions among five key psychological processes (in purple) allow for anticipatory responses to uncertainty about future threat. The UAMA posits that alterations to these processes and associated core brain circuitry (see Figure 1) are responsible for maladaptive cognitive, behavioral, and affective responses to uncertainty in highly anxious individuals. At the core of UAMA are heightened expectancies about the probability and cost of future threat (in blue). These elevated expectancies are the result of alterations in the calculation of expected value and aversive prediction error signaling (A), increased threat attention and hypervigilance (B), and deficient safety learning or an inability to inhibit anxious responding in the presence of safety (C). These heightened expectancies and an inability to identify safety in situations of uncertainty contribute to elevated cognitive and behavioral avoidance (D), which leads to further difficulties in identifying safety and reducing threat expectancies. Heightened threat expectancies and an inability to identify safety signals contribute to exaggerated physiological and behavioral reactivity under conditions of uncertainty (E), and this heightened reactivity to uncertainty leads to further avoidance of such conditions.