Prefrontal-amygdala connectivity in trait anxiety and generalized anxiety disorder: Testing the boundaries between healthy and pathological worries

Highlights

• GAD participants presented an increased resting-state functional connectivity between left basolateral amygdala and vmPFC.

• Non-GAD participants with low and high tendency to worry did not differ in amygala-vmPFC connectivity.

• Cognitive anxiety sensitivity was a significant predictor of this circuit connectivity, above the effect of GAD diagnosis.

• Our data suggest a categorical differentiation, at a neural level, between pathological and healthy worries.

Abstract

Background

Current brain-based theoretical models of generalized anxiety disorder (GAD) suggest a dysfunction of amygdala-ventromedial prefrontal cortex emotional regulatory mechanisms. These alterations might be reflected by an altered resting state functional connectivity between both areas and could extend to vulnerable non-clinical samples such as high worriers without a GAD diagnosis. However, there is a lack of information in this regard.

Methods

We investigated differences in resting state functional connectivity between the basolateral amygdala and the ventromedial prefrontal cortex (amygdala-vmPFC) in 28 unmedicated participants with GAD, 28 high-worriers and 28 low-worriers. We additionally explored selected clinical variables as predictors of amygdala-vmPFC connectivity, including anxiety sensitivity.

Results

GAD participants presented higher left amygdala-vmPFC connectivity compared to both groups of non-GAD participants, and there were no differences between the latter two groups. In our exploratory analyses, concerns about the cognitive consequences of anxiety (the cognitive dimension of anxiety sensitivity) were found to be a significant predictor of the left amygdala-vmPFC connectivity.

Limitations

The cross-sectional nature of our study preclude us from assessing if functional connectivity measures and anxiety sensitivity scores entail an increased risk of GAD.

Conclusions

These results suggest a neurobiological qualitative distinction at the level of the amygdala-vmPFC emotional-regulatory system in GAD compared to non-GAD participants, either high- or low-worriers. At this neural level, they question previous hypotheses of continuity between high worries and GAD development. Instead, other anxiety traits such as anxiety sensitivity might confer a greater proneness to the amygdala-vmPFC connectivity alterations observed in GAD.

Introduction

Generalized Anxiety Disorder (GAD) is a prevalent condition (5% lifetime prevalence in high-income countries) with a significant impact on quality of life and role functioning (Ruscio et al., 2017). It is characterized by excessive and uncontrollable anxiety and worry, associated with somatic symptoms such as muscle tension and autonomic hyperarousal (American Psychiatric Association, 2013a). In an accepted theoretical model of GAD (Emotional Dysregulation Model, Mennin et al., 2005), excessive worry is presented as a persistent and ineffective strategy that is used by GAD patients to cope with unpleasant emotions and anxiety, serving as a perpetuator of underlying deficits in emotion regulation.

At a neural level, adaptive emotion regulation mechanisms have been suggested to rely on the interaction between regions involved in emotional responses and regions linked to emotion regulation. One of the most studied systems is the one comprised of the amygdala (Pessoa and Adolphs, 2010) and the ventromedial prefrontal cortex (vmPFC), which is involved in amygdalar regulation (Diekhof et al., 2011; Fullana et al., 2018) through the connections with the basolateral subregion of the amygdala (BLA) (Kim et al., 2011b; Nuss, 2015; SAH et al., 2003). In anxiety–related disorders, alterations in this BLA-prefrontal system have been suggested to rely on a hyperactive amygdala which would be less effectively controlled by the vmPFC (Coombs et al., 2014; Delli Pizzi et al., 2017). Alterations in the connectivity within the amygdala-prefrontal circuitry, either in task-based or in resting state studies, have been found in anxiety-related disorders such as obsessive-compulsive disorder (Paul et al., 2018), posttraumatic stress disorder (Brown et al., 2014; Stevens et al., 2013) and social anxiety disorder (Liao et al., 2010; Young et al., 2017). The same hypothesis of miscommunication between these two regions has also been tested in GAD (Hilbert et al., 2014), finding an increased functional connectivity in both task-based studies (Etkin et al., 2010; Etkin and Schatzberg, 2011; Gold et al., 2016) and during resting state (Etkin et al., 2009). The latter study, while being the sole study evaluating resting state in an adult sample of GAD participants, included patients with depression or in pharmacological treatment, factors that have been shown to modulate amygdala-prefrontal connectivity (Davey et al., 2015; McCabe and Mishor, 2011). Thus, and despite its relevance to the understanding of a hypothesised miscommunication between amygdala and vmPFC, resting state studies in adult GAD are scarce and have not ruled out the effects of comorbid diagnoses or pharmacological treatment.

In healthy individuals, it is considered that a high tendency to worry (Hirsch and Mathews, 2012), negative emotionality (Spinhoven et al., 2017), subthreshold anxiety symptoms (Kanuri et al., 2015) as well as mood disorders such as depression (Goldstein-Piekarski et al., 2016; Moscati et al., 2016) are predisposing factors to the development of GAD. Furthermore, subthreshold GAD and increased worry tendency are linked to an increased functional impairment and health care use, implying human and economic burden (Haller et al., 2014; Kertz and Woodruff-Borden, 2011). However, it remains open to debate whether there exists a symptomatic continuum between the intensity and frequency of worries and the emergence of GAD (Kertz et al., 2014; Olatunji et al., 2010). At the neural level, a dysfunction of the amygdala-vmPFC connectivity has been correlated to anxiety-related vulnerability traits (Baeken et al., 2014; Kim et al., 2011a) in a similar pattern to what has been observed in GAD (Etkin et al., 2009). It is worth mentioning this pathway is recruited during worry induction by both GAD and healthy participants (Mohlman et al., 2017). All together, we hypothesized a common neurobiological alteration in this circuit in both vulnerable subjects and GAD participants. However, a formal comparison of these alterations in a group of vulnerable subjects-high tendency to worry- compared to a group of GAD has not yet been conducted.

In this study, we aimed at testing the hypothesis that there is a similar neurobiological alteration in the emotional regulatory cortico-limbic circuit in participants with GAD and non-GAD participants with high tendency to worry. To do so, we examined the nature of amygdala-vmPFC resting state functional connectivity in a group of medication-free participants with GAD with no comorbid depression, a group of non-GAD participants with a high tendency to worry (high-worriers) and a group of healthy participants with a low tendency to worry (low-worriers). We predicted that GAD participants and high-worriers would show an amygdala-vmPFC hyperconnectivity compared to low-worriers. Additionally, we explored the association between worry and other anxiety traits and amygdala-vmPFC connectivity in all participants.