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

Reduced capacity to cognitively regulate emotional responses is a common impairment across major neuropsychiatric disorders. Brain systems supporting one such strategy, cognitive reappraisal of emotion, have been investigated extensively in the healthy population, a research focus that has led to influential meta-analyses and literature reviews. However, the emerging literature on neural substrates underlying cognitive reappraisal in clinical populations is yet to be systematically reviewed. Therefore, the goal of the current review was to summarize the literature on cognitive reappraisal and highlight common and distinct neural correlates of impaired emotion regulation in clinical populations. We performed a two-stage systematic literature search, selecting 32 studies on cognitive reappraisal in individuals with mood disorders (n=12), anxiety disorders (n=14), addiction (n=2), schizophrenia (n=2), and personality disorders (n=5). Comparing findings across these disorders allowed us to determine underlying mechanisms that were either disorder-specific or common across disorders. Results showed that across clinical populations, individuals consistently demonstrated reduced recruitment of the ventrolateral prefrontal cortex (vlPFC) and dorsolateral prefrontal cortex (dlPFC) during downregulation of negative emotion, indicating that there may be a core deficit in selection, manipulation and inhibition during reappraisal. Further, in individuals with mood disorders, amygdala responses were enhanced during downregulation of emotion, suggesting hyperactive bottom-up responses or reduced modulatory capacity. In individuals with anxiety disorders, however, emotion regulation revealed reduced activity in the dorsal anterior cingulate cortex (dACC) and inferior/superior parietal cortex, possibly indicating a deficit in allocation of attention. The reviewed studies thus provide evidence for both disorder-specific and common deficits across clinical populations. These findings highlight the role of distinct neural substrates as targets for developing/assessing novel therapeutic approaches that are geared towards cognitive regulation of emotion, as well as the importance of transdiagnostic research to identify both disorder specific and core mechanisms.

Assessing psychophysiological responses of emotion regulation is a cost-efficient way to quantify emotion regulation and to complement subjective report that may be biased. Previous studies have revealed inconsistent results complicating a sound interpretation of these findings. In the present study, we summarized the existing literature through a systematic search of articles. Meta-analyses were used to evaluate effect sizes of instructed downregulation strategies on common autonomic (electrodermal, respiratory, cardiovascular, and pupillometric) and electromyographic (corrugator activity, emotion-modulated startle) measures. Moderator analyses were conducted, with moderators including study design, emotion induction, control instruction and trial duration. We identified k = 78 studies each contributing multiple sub-samples and performed 23 meta-analyses for combinations of emotion regulation strategy and psychophysiological measure. Overall, results showed that effects of reappraisal and suppression on autonomic measures were highly inconsistent across studies with rather small mean effect sizes. Electromyography (startle and corrugator activity) showed medium effect sizes that were consistent across studies. Our findings highlight the diversity as well as the low level of standardization and comparability of research in this area. Significant moderation of effects by study design, trial duration, and control condition emphasizes the need for better standardization of methods. In addition, the small mean effect sizes resulting from our analyses on autonomic measures should be interpreted with caution. Findings corroborate the importance of multi-channel approaches.

ObjectiveDrugs targeting the N-Methyl-D-aspartic acid (NMDA) system and the ability to learn new associations have been proposed as potential adjunct treatments to boost the success of exposure therapy for anxiety disorders. However, the effects of the NMDA partial agonist d-cycloserine on psychological treatment have been mixed. We investigated potential neurocognitive mechanisms underlying the clinical effects of d-cycloserine-augmented exposure, to inform the optimal combination of this and similar agents with psychological treatment.MethodsUnmedicated patients with panic disorder were randomised to single-dose d-cycloserine (250mg; N=17) or matching placebo (N=16) 2hrs before one session of exposure therapy. Neurocognitive markers were assessed one day after treatment, including reaction-time based threat bias for fearful faces and amygdala response to threat. Clinical symptom severity was measured using self-report and clinician-rated scales the day before and after treatment, and at 1- and 6-months follow-up. Analysis was by intention-to-treat.ResultsOne day after treatment, threat bias for fearful faces and amygdala threat response were attenuated in the drug compared to the placebo group. Lower amygdala magnitude predicted greater clinical improvement during follow-up across groups. D-cycloserine led to greater clinical recovery at 1-month follow-up (d-cycloserine 71% versus placebo 25%).DiscussionD-cycloserine-augmented single-session exposure therapy reduces amygdala threat response, and this effect predicts later clinical response. These findings highlight a neurocognitive mechanism by which d-cycloserine may exert its augmentative effects on psychological treatment and bring forward a marker that may help understand and facilitate future development of adjunct treatments with CBT for anxiety disorders. (D-cycloserine Augmented CBT for Panic Disorder; clinicaltrials.gov;NCT01680107)