Two Decades of Anxiety Neuroimaging Research: New Insights and a Look to the Future.

Abstract

Anxiety is widely conceptualized as a state of heightened distress, arousal, and vigilance that can be elicited by potential threat (1, 2). When extreme or pervasive, anxiety can be debilitating (3). Anxiety disorders are among the leading cause of years lived with disability, afflicting ;300 million individuals annually (3). In the United States, nearly 1 in 3 individuals will experience an anxiety disorder in their lifetime, diagnoses and service utilization are surging among young people, and direct health care costs exceed $40 billion annually (3–6). Yet existing treatments are inconsistently effective or are associated with significant adverse effects, underscoring the urgency of developing a clearer understanding of the underlying neurobiology (7, 8). Perturbation and recording studies in rodents and monkeys have begun to reveal the specific molecules and microcircuits that control defensive responses to a variety of threats (9), but the relevance of these discoveries to the complexities of the human brain and human anxiety is unclear. Human neuroimaging research provides an opportunity to address this translational conundrum. Clinical studies of anxiety have leveraged a variety of experimental challenges—from aversive photographs and other symptom provocations to threat conditioning and trauma recall paradigms—to identify aspects of brain function that discriminate individuals with pathological anxiety from control subjects. Preclinical human studies of anxiety have taken a different tack and narrowly focused on tracing the circuits normatively engaged by the anticipation of potential threat in nominally healthy samples. Preclinical studies are essential for understanding how anxiety normally works, free from the confounders, comorbidities, andsequelaeofpsychiatricdisease and treatment. They provide a translational bridge to mechanistic studies in animals, which also tend to focus on adaptive behavioral responses (e.g., freezing) to threat.Andbecause they capture symptoms and intermediate phenotypes—such as subjective feelings of anxiety—that cut acrossdisorders, human preclinical studies provide a unique opportunity to develop transdiagnostic biomarkers (10, 11). While clinical and preclinical studies both provide valuable clues about the neural underpinnings of anxiety, as the literature has grown, it has become increasingly difficult to integrate the two veins of research into a unified conceptual framework. In this issue of the Journal, Chavanne and Robinson (12) provide the most comprehensive coordinate-based metaanalysis of anxiety-related functional neuroimaging research in over a decade (13), focusing on studies of emotion perception and provocation (156 studies with 693 preclinical participants, 2,554 case subjects, and 2,348 control subjects). Their clinical meta-analyses included patients with generalized anxiety disorder, social anxiety disorder, specific phobia, panic disorder, posttraumatic stress disorder, and mixed anxiety diagnoses. Preclinical analyses included coordinates culled from a variety of unpredictable or uncertain threat studies (e.g., threat of shock).Notably, the authorshave made their rawdata (https://osf.io/9s32h) andmeta-analytic maps (https://neurovault.org/collections/6012) freelyavailable, facilitating a range of applications by other investigators. The publication of Chavanne and Robinson’s report provides an opportunemoment to take stock ofwhatwehave learned from 20 years of anxiety-related neuroimaging research and to identify the most fruitful next steps. Chavanne and Robinson show that clinical anxiety is associatedwith heightened reactivity in an extended subcorticocortical circuit. Subcortically, this encompasses several regions implicated in animal models of anxiety, including regions of the amygdala, anterior hippocampus, and periaqueductal gray (9). The bed nucleus of the stria terminalis (BST)—another key player in animal models of anxiety that has only recently begun to attract the attention of the psychiatric imaging community (9, 14)—was also evident in secondary analyses that excluded medicated patients. In the cortex, Chavanne and Robinson show that clinical anxiety is associated with elevated reactivity in the dorsolateral prefrontal cortex, pregenual anterior cingulate cortex,midcingulate cortex, and anterior insula. Collectively, these observations replicate and extend Etkin and Wager’s influential 2007 neuroimaging meta-analysis (13), which identified heightened amygdala and insula reactivity as a potential “final common pathway” for pathological anxiety. A key feature of Chavanne and Robinson’s report is the systematic analysis of preclinical studies of anxiety. This revealed a circuit encompassing many of the regions identified Chavanne and Robinson provide the most comprehensive coordinatebased meta-analysis of anxiety-related functional neuroimaging research in over a decade, focusing on studies of emotion perceptionandprovocation.