Goal Directed Worry Rules Are Associated with Distinct Patterns of Amygdala Functional Connectivity and Vagal Modulation during Perseverative Cognition

Abstract

Excessive and uncontrollable worry is a defining feature of Generalized Anxiety Disorder (GAD). An important endeavor in the treatment of pathological worry is to understand why some people are unable to stop worrying once they have started. Worry perseveration is associated with a tendency to deploy goal-directed worry rules (known as “as many as can” worry rules; AMA). These require attention to the goal of the worry task and continuation of worry until the aims of the “worry bout” are achieved. This study examined the association between the tendency to use AMA worry rules and neural and autonomic responses to a perseverative cognition induction. To differentiate processes underlying the AMA worry rule use from trait worry, we also examined the relationship between scores on the Penn State Worry Questionnaire (PSWQ) and neural and autonomic responses following the same induction. We used resting-state functional magnetic resonance brain imaging (fMRI) while measuring emotional bodily arousal from heart rate variability (where decreased HRV indicates stress-related parasympathetic withdrawal) in 19 patients with GAD and 21 control participants. Seed-based analyses were conducted to quantify brain changes in functional connectivity (FC) with the amygdala. The tendency to adopt an AMA worry rule was associated with validated measures of worry, anxiety, depression and rumination. AMA worry rule endorsement predicted a stronger decrease in HRV and was positively associated with increased connectivity between right amygdala and locus coeruleus (LC), a brainstem noradrenergic projection nucleus. Higher AMA scores were also associated with increased connectivity between amygdala and rostral superior frontal gyrus. Higher PSWQ scores amplified decreases in FC between right amygdala and subcallosal cortex, bilateral inferior frontal gyrus, middle frontal gyrus, and areas of parietal cortex. Our results identify neural mechanisms underlying the deployment of AMA worry rules. We propose that the relationship between AMA worry rules and increased connectivity between the amygdala and prefrontal cortex (PFC) represents attempts by high worriers to maintain arousal and distress levels in order to feel prepared for future threats. Furthermore, we suggest that neural mechanisms associated with the PSWQ represent effortful inhibitory control during worry. These findings provide unique information about the neurobiological processes that underpin worry perseveration.

The neurobiology of interoception in health and disease

“…Fatigue is a disorder that is characterized in the ICD-10 as a long-term condition that includes severe and constant feelings of tiredness, trouble concentrating and carrying out daily activities, generalized aches and pains, fever, and sleep disturbances. 95 It can be part of SBs, and as such have adaptive effects in that it prioritizes rest to save resources and may facilitate the role of fever in fighting off infections. 96 Fatigue can also appear on its own as a chronic condition (chronic fatigue syndrome), 97 which affects approximately 20% of the general population.…”

“…102 Fatigue is strongly associated with depression, 103 and listed in both DSM-5 and ICD-10 as a core criterion for major depression. 95,104 Fatigue is a multidimensional construct that involves impairment of motor and cognitive processes, the subjective experience of fatigue, and behavioral changes affecting every day activities. 105 Research on fatigue emphasizes approaches that associate the condition with peripheral inflammation and its influence on brain structures involved in steering immunological responses.…”

Cortical morphometric predictors of autonomic dysfunction in generalized anxiety disorder

“…The present study is based on a secondary analysis of baseline data from a subsample of volunteers enrolled in a larger longitudinal functional magnetic resonance imaging (fMRI) by public advertisement (Makovac et al, 2016a;2016b;2016c;Meeten et al, 2016;Ottaviani et al, 2016). In order to decrease inter-individual variation, we considered only female participants (n = 37) as they represented the large majority of the initial sample.…”

Response time as a proxy of ongoing mental state: A combined fMRI and pupillometry study in Generalized Anxiety Disorder

“…The current study presents data from the follow-up component of a larger multilevel longitudinal investigation of the neurobiological correlates of perseverative cognition in GAD (see Makovac et al 2016a,b,c;Makovac et al, 2018a,b;Meeten et al 2016;Ottaviani et al 2016b for time 0 and longitudinal resting state functional connectivity analyses).…”

“…Studies suggest that unlike the more common patterns of mind-wandering seen in the general population, perseverative cognition is characterized by reduced parasympathetic drive to the heart for a meta-analysis), which contributes to another pervasive symptom of GAD, the feelings of physiological arousal (e.g., Andor et al, 2008). Recent work combining peripheral physiological monitoring with functional magnetic resonance imaging (fMRI) has highlighted the neural processes that shape aberrant cognitions in anxiety through their bidirectional interaction with autonomic bodily states of arousal (e.g., Makovac et al, 2018;Meeten et al, 2016). Increased self-reported levels of worry following an induction of perseverative cognition leads to decreases in heart rate variability (an index of parasympathetic nervous control of the heart) and in prefrontalamygdala functional connectivity in GAD patients and controls (Makovac et al, 2016b).…”