Anxiety disorders affect approximately 1 in 5 (18%) Americans within a given 1 year period, placing a substantial burden on the national health care system. Therefore, there is a critical need to understand the neural mechanisms mediating anxiety symptoms. We used unbiased, multimodal, data-driven, whole-brain measures of neural activity (magnetoencephalography) and connectivity (fMRI) to identify the regions of the brain that contribute most prominently to sustained anxiety. We report that a single brain region, the intraparietal sulcus (IPS), shows both elevated neural activity and global brain connectivity during threat. The IPS plays a key role in attention orienting and may contribute to the hypervigilance that is a common symptom of pathological anxiety. Hyperactivation of this region during elevated state anxiety may account for the paradoxical facilitation of performance on tasks that require an external focus of attention, and impairment of performance on tasks that require an internal focus of attention.DOI: http://dx.doi.org/10.7554/eLife.23608.001

One of the hallmarks of anxiety disorders is impaired cognitive control, affecting working memory (WM). The dorsolateral prefrontal cortex (dlPFC) is critical for WM, however it is still unclear how dlPFC activity relates to WM impairments in patients. Forty-one healthy volunteers and 32 anxiety (general and/or social anxiety disorder) patients completed the Sternberg WM paradigm during safety and unpredictable shock threat. On each trial a series of letters was presented, followed by brief retention and response intervals. On low and high load trials, subjects retained the series (5 and 8 letters, respectively) in the original order, while on sort trials subjects rearranged the series (5 letters) in alphabetical order. We sampled BOLD activity during retention using a bilateral anatomical dlPFC mask. Compared to controls, patients showed increased reaction time during high load, greater right dlPFC activity, and reduced dlPFC activity during threat. These results suggest that WM performance for patients and controls may rely on distinct patterns of dlPFC activity with patients requiring bilateral dlPFC activity. These results are consistent with reduced efficiency of WM in anxiety patients. This reduced efficiency may be due to an inefficient allocation of dlPFC resources across hemispheres or a decreased overall dlPFC capacity.

It has long been established that individuals with anxiety disorders tend to overgeneralize attributes of fearful stimuli to nonfearful stimuli, but there is little mechanistic understanding of the neural system that supports overgeneralization. To address this gap in our knowledge, this study examined effect of experimentally induced anxiety in humans on generalization using the behavioral pattern separation (BPS) paradigm. Healthy subjects of both sexes encoded and retrieved novel objects during periods of safety and threat of unpredictable shocks while we recorded brain activity with fMRI. During retrieval, subjects were instructed to differentiate among new, old, and altered images. We hypothesized that the hippocampus and dorsolateral prefrontal cortex (dlPFC) would play a key role in the effect of anxiety on BPS. The dlPFC, but not the hippocampus, showed increased activity for altered images compared with old images when retrieval occurred during periods of threat compared with safety. In addition, accuracy for altered items retrieved during threat was correlated with dlPFC activity. Together, these results suggest that overgeneralization in anxiety patients may be mediated by an inability to recruit the dlPFC, which mediates the cognitive control needed to overcome anxiety and differentiate between old and altered items during periods of threat. Anxiety and posttraumatic stress disorder patients generalize fear to nonfearful fear stimuli, making it difficult to regulate anxiety. Understanding how anxiety affects generalization is key to understanding the overgeneralization experienced by these patients. We examined this relationship in healthy subjects by studying how threat of shock affects neural responses to previously encountered stimuli. Although previous studies point to hippocampal involvement, we found that threat affected activity in the dorsolateral prefrontal cortex (dlPFC), rather than the hippocampus, when subjects encountered slightly altered versions of the previously encountered items. Importantly, this dlPFC activity predicted performance for these items. Together, these results suggest that the dlPFC is important for discrimination during elevated anxiety and that overgeneralization may reflect a deficit in dlPFC-mediated cognitive control.