Anxiety Patients Show Reduced Working Memory Related dlPFC Activation During Safety and Threat

Abstract

Background: Anxiety patients exhibit deficits in cognitive tasks that require prefrontal control of attention, including those that tap working memory (WM). However, it is unclear whether these deficits reflect threat-related processes or symptoms of the disorder. Here, we distinguish between these hypotheses by determining the effect of shock threat versus safety on the neural substrates of WM performance in anxiety patients and healthy controls.

Methods: Patients, diagnosed with generalized and/or social anxiety disorder, and controls performed blocks of an N-back WM task during periods of safety and threat of shock. We recorded blood-oxygen-level dependent (BOLD) activity during the task, and investigated the effect of clinical anxiety (patients vs. controls) and threat on WM load-related BOLD activation.

Results: Behaviorally, patients showed an overall impairment in both accuracy and reaction time compared to controls, independent of threat. At the neural level, patients showed less WM load-related activation in the dorsolateral prefrontal cortex, a region critical for cognitive control. In addition, patients showed less WM load-related deactivation in the ventromedial prefrontal cortex and posterior cingulate cortex, which are regions of the default mode network. Most importantly, these effects were not modulated by threat.

Conclusions: This work suggests that the cognitive deficits seen in anxiety patients may represent a key component of clinical anxiety, rather than a consequence of threat.

Trial registration: ClinicalTrials.gov NCT00047853.

Keywords: GAD/generalized anxiety disorder; anxiety/anxiety disorders; cognition; functional MRI; stress.

Figure 1. Schematic of experimental design and statistical comparisons

A) Subjects tracked the location of a red asterisk on the corners of a black diamond (up, down, right, left), and had to indicate whether the location of the current stimulus (*) matched the location of the target. In the 0-back condition, the subject indicated whether the stimulus was located at the top of the diamond (target-up position). B) We performed a general linear model with the following factors: 1) patients vs. controls, 2) threat vs. safe, and 3) load. We modeled the load factor using the three orthogonal planned comparisons depicted.

Figure 2. Accuracy and reaction time performance for the N-back task

A) As WM load increases, accuracy decreases (A) and reaction time increases (B). Across all levels of load patients are slower and less accurate than controls. (Bars represent the mean ± SEM)

Figure 3. The effects of WM load and threat on BOLD activation

A) Thresholded t-map for the 0- vs. 1-, 2-, 3-back comparison. B) Thresholded t-map for the 1- vs. 2-, 3-back comparison. C) Thresholded t-map for the 2- vs. 3-back comparison. (Warm colors represent WM load-related increases in BOLD activity. Cool colors represent WM load-related decreases in BOLD activity.) D) Thresholded t-map for the safe vs. threat comparison. (Warm colors represent threat related increases in BOLD activity. Cool colors represent threat related decreases in BOLD activity.)

Figure 4. The effect of Diagnosis on WM load-related activity

A, B, C, G, H, I ) Thresholded t-maps for the Diagnosis x Load 1 (0- vs. 1-, 2-, 3-back) interaction. (Warm colors represent decreases in task-positive activity as a function of diagnosis. Cool colors represent decreases in task-negative activity as a function of diagnosis. Crosshairs depict the location of the voxel with the peak activation for a given cluster. Coordinates are reported in Table 3. Insets depict the WM load-related effect at the corresponding location.) D, E, F, J, K, L ) Pattern of activity seen in the clusters depicted in the above panels. (Bars represent the mean ± SEM.)

Figure 5. The effect of Threat on WM load-related activity

A, B, C ) Thresholded t-maps for the Threat x Load 2 (1- vs. 2-, 3-back) interaction. (Warm colors represent decreases in task-positive activity as a function of threat. Cool colors represent decreases in task-negative activity as a function of threat. Crosshairs depict the location of the voxel with the peak activation for a given cluster. Coordinates are reported in Table 3. Insets depict the WM load-related effect at the corresponding location.) D, E, F ) Pattern of activity seen in the clusters depicted in the above panels. (Bars represent the mean ± SEM.)