Effective emotion regulation strategies improve fMRI and ECG markers of psychopathology in panic disorder: implications for psychological treatment action

Abstract

Impairments in emotion regulation are thought to have a key role in the pathogenesis of anxiety disorders, but the neurobiological underpinnings contributing to vulnerability remain poorly understood. It has been a long-held view that exaggerated fear is linked to hyperresponsivity of limbic brain areas and impaired recruitment of prefrontal control. However, increasing evidence suggests that prefrontal-cortical networks are hyperactive during threat processing in anxiety disorders. This study directly explored limbic-prefrontal neural response, connectivity and heart-rate variability (HRV) in patients with a severe anxiety disorder during incidental versus intentional emotion regulation. During 3 Tesla functional magnetic resonance imaging, 18 participants with panic disorder and 18 healthy controls performed an emotion regulation task. They either viewed negative images naturally (Maintain), or they were instructed to intentionally downregulate negative affect using previously taught strategies of cognitive reappraisal (Reappraisal). Electrocardiograms were recorded throughout to provide a functional measure of regulation and emotional processing. Compared with controls, patients showed increased neural activation in limbic-prefrontal areas and reduced HRV during incidental emotion regulation (Maintain). During intentional regulation (Reappraisal), group differences were significantly attenuated. These findings emphasize patients' ability to regulate negative affect if provided with adaptive strategies. They also bring prefrontal hyperactivation forward as a potential mechanism of psychopathology in anxiety disorders. Although these results challenge models proposing impaired allocation of prefrontal resources as a key characteristic of anxiety disorders, they are in line with more recent neurobiological frameworks suggesting that prefrontal hyperactivation might reflect increased utilisation of maladaptive regulation strategies quintessential for anxiety disorders.

Figure 1

Whole-brain fMRI results. All images thresholded at Z>2.3, P<0.05, corrected. (a) Main effect of task: across both groups, Reappraisal (versus Maintain) led to greater BOLD signal response in bilateral dorsal anterior cingulate cortex, dorsomedial, dorsolateral, and ventrolateral PFC, orbitofrontal cortex, lateral occipital cortex, angular gyrus, cerebellum and occipital fusiform and inferior temporal gyri, and left middle temporal gyrus, and to a decrease in activation in bilateral precuneus ext. lingual gyrus. (b) Main effect of group: compared with controls, patients showed increased activation in prefrontal, temporal and occipital areas, including bilateral dorsomedial and dorsolateral PFC, left dorsal anterior cingulate cortex, right supplementary motor area, left inferior frontal and middle temporal gyri, left lateral occipital cortex and occipital fusiform gyrus, and left angular gyrus during picture blocks (versus fixation baseline block). (c) Group × task interaction: maintaining negative affect (versus Reappraisal) was associated with increased signal response in patients compared with controls in a right frontal pole cluster including the vlPFC, vmPFC and dmPFC (top panel), and a limbic cluster including parts of the right hippocampus, posterior cingulate cortex, precuneus and lingual gyrus (bottom panel). In controls, Maintain (versus Reappraisal) was related to decreased activation in this limbic cluster. For both clusters, BOLD% signal change during Maintain minus Reappraisal blocks was significantly correlated with symptom severity in patients. MNI coordinates 14,−42,−2. Error bars show s.e.m. *Significant difference between conditions or groups. dmPFC, dorsomedial PFC; ext., extending into; HC, healthy control; L, left; PD, panic disorder patient; PFC, prefrontal cortex; R, right; vlPFC, ventrolateral PFC; vmPFC, ventromedial PFC.

Figure 2

Whole-brain psychophysical interaction analysis with a right amygdala (a) and left amygdala (b) functional cluster (picture blocks versus baseline, across groups) as the seed region: patients showed higher connectivity of the right and left amygdala with left and right occipital pole, occipital fusiform gyrus, lateral occipital cortex and lingual gyrus. In patients, coupling between right amygdala seed and occipital cortex clusters and left amygdala seed and occipital cortex clusters was positively correlated with panic severity. Images thresholded at Z>2.3, P<0.05, corrected. *Significant difference between groups. Error bars show s.e.m. HC, healthy control; L, left; PD, panic disorder patient; R, right.

Figure 3

Psychophysiological interaction analyses exploring connectivity of activity within the right amygdala (a) and left amygdala (b) as seed regions and a right dorsomedial prefrontal cortex (R dmpfc) region of interest. The right amygdala showed a task × group interaction in connectivity with the dmpfc, with amygdala–dmpfc coupling being significantly greater in patients relative to controls during Maintain blocks. No such significant interaction was found for the left amygdala seed. In patients, higher right amygdala–dmpfc coupling, as well as higher left amygdala–dmpfc coupling during Maintain minus Reappraisal blocks were associated with higher panic severity. *Significant difference between groups. HC, healthy control; L, left; MNI, Montreal Neurological Institute; PD, panic disorder patient; R, right.