Cognitive flexibility and resilience measured through a residual approach.

BACKGROUND AND OBJECTIVES: Resilience refers to the process through which individuals show better outcomes than what would be expected based on the adversity they experienced. Several theories have proposed that variation in resilience is underpinned by cognitive flexibility, however, no study has investigated this using an outcome-based measure of resilience. DESIGN: We used a residual-based approach to index resilience, which regresses a measure of mental health difficulties onto a measure of adversity experienced. The residuals obtained from this regression constitute how much better or worse someone is functioning relative to what is predicted by the adversity they have experienced. METHODS: A total of 463 undergraduate participants completed questionnaires of mental health difficulties and adversity, as well as a number-letter task-switching task to assess cognitive flexibility. RESULTS: Multiple regression analyses showed that better cognitive flexibility was not associated with greater resilience. CONCLUSIONS: Our findings do not support theoretical models that propose the existence of a relationship between cognitive flexibility and resilience. Future research may serve to refine the residual-based approach to measure resilience, as well as investigate the contribution of "hot" rather than "cold" cognitive flexibility to individual differences in resilience.

Contamination fear and attention bias variability early in the COVID-19 pandemic.

The onset of the COVID-19 pandemic resulted in a dramatic increase in the salience and importance of information relating to both the risk of infection, and factors that could mitigate against such risk. This is likely to have contributed to elevated contamination fear concerns in the general population. Biased attention for contamination-related information has been proposed as a potential mechanism underlying contamination fear, though evidence regarding the presence of such biased attention has been inconsistent. A possible reason for this is that contamination fear may be characterised by variability in attention bias that has not yet been examined. The current study examined the potential association between attention bias variability for both contamination-related and mitigation-related stimuli, and contamination fear during the early stages of the COVID-19 pandemic. A final sample of 315 participants completed measures of attention bias and contamination fear. The measure of average attention bias for contamination-related stimuli and mitigation-related stimuli was not associated with contamination fear (r = 0.055 and r = 0.051, p > 0.10), though both attention bias variability measures did show a small but statistically significant relationship with contamination fear (r = 0.133, p < 0.05; r = 0.147, p < 0.01). These attention bias variability measures also accounted for significant additional variance in contamination fear above the average attention bias measure (and controlling for response time variability). These findings provide initial evidence for the association between attention bias variability and contamination fear, underscoring a potential target for cognitive bias interventions for clinical contamination fear.

Assessing anxiety-linked impairment in attentional control without eye-tracking: The masked-target antisaccade task.

Contemporary cognitive theories of anxiety and attention processing propose that heightened levels of anxiety vulnerability are associated with a decreasing ability to inhibit the allocation of attention towards task-irrelevant information. Existing performance-based research has most often used eye-movement assessment variants of the antisaccade paradigm to demonstrate such effects. Critically, however, eye-movement assessment methods are limited by expense, the need for expert training in administration, and limited mobility and scalability. These barriers have likely led to researchers' use of suboptimal methods of assessing the relationship between attentional control and anxiety vulnerability. The present study examined the capacity for a non-eye-movement-based variant of the antisaccade task, the masked-target antisaccade task (Guitton et al., 1985), to detect anxiety-linked differences in attentional control. Participants (N = 342) completed an assessment of anxiety vulnerability and performed the masked-target antisaccade task in an online assessment session. Greater levels of anxiety vulnerability predicted poorer performance on the task, consistent with findings observed from eye-movement methods and with cognitive theories of anxiety and attention processing. Results also revealed the task to have high internal reliability. Our findings indicate that the masked-target antisaccade task provides a psychometrically reliable, low-cost, mobile, and scalable assessment of anxiety-linked differences in attentional control.

Development and psychometric evaluation of a scrambled sentences test specifically for worry in individuals with generalised anxiety disorder.

The tendency to draw negative conclusions from ambiguous information (interpretation bias) is prevalent across emotional disorders and plays a key role in the development and maintenance of pathological worry and anxious mood. Assessing interpretation bias using valid and reliable measures is central to empirical research. A commonly used measure of interpretation bias is the scrambled sentences test (SST), originally relating to depression. Given the association between interpretation bias and worry, we aimed to develop and psychometrically evaluate a new version of the SST with items pertaining to common worry domains for use in worry and anxiety research. In Studies 1-3 (analogue samples, combined N = 288), the new worry SST showed excellent construct validity (moderate-to-strong associations with worry and anxiety-related measures), and reliability (split-half and test-retest reliability). We confirmed construct validity in Study 4 (N = 215 individuals with generalised anxiety disorder). Furthermore, we demonstrated version specificity in analogue and clinical samples: the worry SST was associated with trait worry but not trait rumination, while the original depression SST largely showed the opposite pattern. Overall, the new worry SST is a psychometrically robust measure that may be especially useful for research into cognitive processes underpinning worry and anxiety.

What's Worrying Our Students? Increasing Worry Levels over Two Decades and a New Measure of Student Worry Frequency and Domains.

BACKGROUND: The frequency and severity of mental health problems in student populations have been a growing cause for concern worldwide, and studies have identified measures of a number of mental health symptoms that have been steadily increasing in frequency and intensity over the past 20-25 years. METHODS: In two studies we investigate the levels and domains of pathological worrying in university student participants. Study 1 is a retrospective study of Penn State Worry Questionnaire (PSWQ) data collected between 2001 and 2019. Study 2 describes the development of the Student Worry Questionnaire, a short and easily delivered measure of student worrying that identifies both frequency of worry as well as the student-relevant domains across which worrying occurs. RESULTS: Study 1 revealed a steady increase in student worry scores of around 20% between 2001 and 2019, with a significant positive correlation between year of data collection and mean PSWQ score. The domain scores in Study 2 indicated that academic work was a significantly higher worry than any of the other domains, and worries about intimate relationships and 'what people think of me' were also worries that scored higher than either financial or health worries. CONCLUSIONS: The present studies indicate that pathological worrying can be added to the list of anxiety- and stress-related symptoms that have been shown to be on the increase in student populations in recent decades, and we discuss whether these increases represent a greater willingness to report symptoms or a genuine increase in experienced symptoms over time.

Internet-delivered interpretation training reduces worry and anxiety in individuals with generalized anxiety disorder: A randomized controlled experiment.

Objective: Generalized anxiety disorder (GAD) is a debilitating condition, characterized by negative interpretations about ambiguous situations. This study tested whether entirely internet-delivered interpretation training [cognitive bias modification (CBM)] versus control promotes positive interpretations and reduces worry and anxiety in individuals with GAD, with or without depression. Method: A two-arm (CBM; control) parallel-group randomized controlled experiment. Assessments were preintervention (T0), postintervention (T1), 1-month (T2) postintervention, and 3-month (T3) postintervention. Participants with GAD (with or without comorbid depression) were randomly allocated to either CBM (n = 115) or control (n = 115). Participants, but not researchers, were blind to allocated condition. Participants completed up to 10 online CBM or control sessions across 1 month. Interpretation bias [coprimary outcomes: scrambled sentence test (SST), recognition test (RT)], and number of negative thought intrusions during a breathing focus task were measured at T0 and T1. Self-reported levels of worry [Penn State Worry Questionnaire-trait (PSWQ trait); Penn State Worry Questionnaire-past week (PSWQ weekly)], anxiety [Generalized Anxiety Disorder scale (GAD-7)], depression [Patient Health Questionnaire (PHQ-9)], rumination [Ruminative Response Scale (RRS)], and repetitive negative thinking [RNT; Repetitive Thinking Questionnaire-trait (RTQ-trait)] were assessed at T0-T3. Results: The per-protocol analyses included N = 186 participants (CBM n = 94; control n = 92). As predicted, we found moderate-to-large training effects on the primary outcome of interpretation bias at T1. Secondary outcomes of negative thought intrusions at T1 and self-reported symptoms at T2 were all significantly lower in the CBM versus control condition. All but one effect (trait RNT) were sustained at T3. Conclusions: In this randomized controlled study, we found that fully online interpretation training ameliorated core features of GAD in individuals with or without comorbid depression up to 3 months posttraining. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Looking on the Bright Side Reduces Worry in Pregnancy: Training Interpretations in Pregnant Women.

Background: Recent evidence suggests that anxiety is more common than depression in the perinatal period, however there are few interventions available to treat perinatal anxiety. Targeting specific processes that maintain anxiety, such as worry, may be one potentially promising way to reduce anxiety in this period. Given evidence that negative interpretation bias maintains worry, we tested whether interpretation bias could be modified, and whether this in turn would lead to less negative thought (i.e., worry) intrusions, in pregnant women with high levels of worry. Method: Participants (N = 49, at least 16 weeks gestation) were randomly assigned to either an interpretation modification condition (CBM-I) which involved training in accessing positive meanings of emotionally ambiguous scenarios, or an active control condition in which the scenarios remained ambiguous and unresolved. Results: Relative to the control condition, participants in the CBM-I condition generated significantly more positive interpretations and experienced significantly less negative thought intrusions. Conclusions: Our findings indicate that worry is a modifiable risk factor during pregnancy, and that it is possible to induce a positive interpretation bias in pregnant women experiencing high levels of worry. Although preliminary, our findings speak to exciting clinical possibilities for the treatment of worry and the prevention of perinatal anxiety.

Cortical thickness and resting-state cardiac function across the lifespan: A cross-sectional pooled mega-analysis.

Understanding the association between autonomic nervous system [ANS] function and brain morphology across the lifespan provides important insights into neurovisceral mechanisms underlying health and disease. Resting-state ANS activity, indexed by measures of heart rate [HR] and its variability [HRV] has been associated with brain morphology, particularly cortical thickness [CT]. While findings have been mixed regarding the anatomical distribution and direction of the associations, these inconsistencies may be due to sex and age differences in HR/HRV and CT. Previous studies have been limited by small sample sizes, which impede the assessment of sex differences and aging effects on the association between ANS function and CT. To overcome these limitations, 20 groups worldwide contributed data collected under similar protocols of CT assessment and HR/HRV recording to be pooled in a mega-analysis (N = 1,218 (50.5% female), mean age 36.7 years (range: 12-87)). Findings suggest a decline in HRV as well as CT with increasing age. CT, particularly in the orbitofrontal cortex, explained additional variance in HRV, beyond the effects of aging. This pattern of results may suggest that the decline in HRV with increasing age is related to a decline in orbitofrontal CT. These effects were independent of sex and specific to HRV; with no significant association between CT and HR. Greater CT across the adult lifespan may be vital for the maintenance of healthy cardiac regulation via the ANS-or greater cardiac vagal activity as indirectly reflected in HRV may slow brain atrophy. Findings reveal an important association between CT and cardiac parasympathetic activity with implications for healthy aging and longevity that should be studied further in longitudinal research.

Repetitive Negative Thinking and Interpretation Bias in Pregnancy.

Background: Repetitive negative thinking (RNT; e.g., worry about the future, rumination about the past) and the tendency to interpret ambiguous information in negative ways (interpretation bias) are cognitive processes that play a maintaining role in anxiety and depression, and recent evidence has demonstrated that interpretation bias maintains RNT. In the context of perinatal mental health, RNT has received minimal research attention (despite the fact that it predicts later anxiety and depression), and interpretation bias remains unstudied (despite evidence that it maintains depression and anxiety which are common in this period). Method: We investigated the relationship between RNT, interpretation bias and psychopathology (depression, anxiety) in a pregnant sample (n = 133). We also recruited an age-matched sample of non-pregnant women (n = 104), to examine whether interpretation bias associated with RNT emerges for ambiguous stimuli regardless of its current personal relevance (i.e., pregnancy or non-pregnancy-related). Results: As predicted, for pregnant women, negative interpretation bias, RNT, depression and anxiety were all positively associated. Interpretation bias was evident to the same degree for material that was salient (pregnancy-related) and non-salient (general), and pregnant and non-pregnant women did not differ. RNT was associated with interpretation bias for all stimuli and across the full sample. Conclusion: Our findings highlight the need to further investigate the impact of interpretation bias in pregnant women, and test the effectiveness of interventions which promote positive interpretations in reducing RNT in the perinatal period.

tDCS increases anxiety reactivity to intentional worry.

While considerable experimental research has examined the impact of transcranial direct current stimulation (tDCS) on a range of cognitive processes associated with emotional pathology, the impact of tDCS on worry has been comparatively neglected. Given that anxiety pathology is characterised by motivated engagement in worry, and that frontal tDCS has the capacity to enhance goal-oriented cognition, it is important to examine whether tDCS would increase or ameliorate the cognitive and emotional effects of worry. In the current study we examined how tDCS influenced the anxiety response to worry, and the frequency of negative intrusive thoughts. We additionally examined whether stimulation delivered in isolation, or in combination with a mindful-focus task would augment the effects of tDCS. Ninety-seven (75 female) healthy participants received either active or sham anodal tDCS to the left dorsolateral prefrontal cortex, delivered either in isolation or concurrently with a mindful task (four conditions). The frequency of negative thought intrusions was assessed before and after a period of instructed worry, and state anxiety was assessed across the study. Active tDCS was associated with significantly greater elevation in anxiety in response to the worry induction. No effects were observed on the frequency of negative thought intrusions, and the combined delivery of tDCS with the concurrent mindful task did not alter the pattern of observed effects. While inviting replication in a high anxious sample, the present results highlight the possibility that tDCS may interact with motivated engagement in negative patterns of cognition, such as worry, to produce greater emotional reactivity.

Impact of imagery-enhanced interpretation training on offline and online interpretations in worry.

Worry and rumination are forms of repetitive negative thinking (RNT) that are maintained by negative interpretations and a predominance of abstract, verbal thinking. Hence, facilitating more positive interpretations and imagery-based thinking in combination may reduce RNT. Study 1 administered interpretation training with and without enhanced imagery, and an active control condition (designed not to change interpretations), in individuals with high levels of RNT (worry and/or rumination). Combining interpretation training with sustained imagery resulted in the highest levels of positive interpretation bias using an offline test of interpretation bias (when individuals have time to reflect). Study 2 investigated whether imagery-enhanced interpretation training influences online interpretations when ambiguous information is first encountered, indexed by reaction times and amplitude of the N400 event-related potential, as well as enhances offline positive interpretations in high worriers. It also examined whether imagery-enhanced interpretation training reduces negative thought intrusions associated with worry. Both online (reaction time) and offline interpretations were more positive following imagery-enhanced interpretation training, and negative thoughts were reduced, compared to the active control. However, no differences emerged on neurophysiological markers during the online task. Hence, brief interpretation training encompassing sustained imagery modifies online and offline interpretations, but further training may be required to impact upon neurophysiological measures.

Using event-related potential and behavioural evidence to understand interpretation bias in relation to worry.

The tendency to interpret ambiguous information in a consistent (e.g., negative) manner (interpretation bias) may maintain worry. This study explored whether high and low worriers generate different interpretations and examined at which stages of information processing these interpretations can occur. Participants completed interpretation assessment tasks yielding behavioural and N400 event-related potential indices, which index whether a given interpretation was generated. High worriers lacked the benign interpretation bias found in low worriers. This was evident for early "online" interpretations (reflected in reaction times to relatedness judgments and lexical decisions, as well as at a neurophysiological level, N400, for lexical decisions only), to later "offline" interpretations (observed at a behavioural level on the scenario task and recognition task) when participants had time for reflection. Results suggest that a benign interpretation bias may be a protective factor for low worriers, and that these interpretations remain active across online and offline stages of processing.

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

In Generalized Anxiety Disorder (GAD), fluctuations in ongoing thoughts (i.e., mind-wandering) often take the form of rigid and intrusive perseverative cognition, such as worry. Here, we sought to characterise the neural correlates of mind-wandering and perseverative cognition, alongside autonomic nervous system indices of central arousal, notably pupil dilation. We implemented a protocol incorporating the dynamic delivery of thought-probes within a functional neuroimaging task. Sixteen individuals with GAD and sixteen matched healthy controls (HC) underwent functional magnetic resonance imaging with concomitant pupillometry. Participants performed a series of low-demand tracking tasks, responding to occasional changes in a target stimulus. Such a task is typically accompanied by self-generated, off-task thinking. Thought-probes were triggered based on an individual's response time (RT) when responding to the change in the target. Subjective reports showed that long RT predicted off-task thinking/mind-wandering. Moreover, long RT and mind-wandering were also associated with larger pupil diameter. This effect was exaggerated in GAD patients during perseverative cognition. Within brain, during both pre-target periods and target events, there were distinct neural correlates for mind-wandering (e.g., anterior cingulate and paracingulate activation at target onset) and perseverative cognition (e.g., opposite patterns of activation in posterior cingulate and cerebellum at target onset in HC and GAD). Results suggest that not only attention systems but also sensory-motor cortices are important during off-task states. Interestingly, changes across the 'default mode network' also tracked fluctuations in pupillary size. Autonomic expression in pupillary changes mirrors brain activation patterns that occur during different forms of repetitive thinking.

Cortical morphometric predictors of autonomic dysfunction in generalized anxiety disorder.

Generalized anxiety disorder (GAD) is associated with both autonomic dysfunction, notably decreased vagally-mediated heart rate variability (vmHRV), and neurostructural abnormalities. Regional differences in brain morphometry correlate with vmHRV in healthy individuals. Here, we tested the hypothesis that specific focal abnormalities in cortical structure in GAD underpin decreased vmHRV. Adult female patients with GAD (n = 17) and matched controls (n = 18) underwent structural magnetic resonance imaging after characterization of symptoms and quantification of resting vmHRV derived from continuous pulse oximetry. Cortical reconstruction was performed using the FreeSurfer image analysis suite. A priori analysis was conducted only within brain regions involved in vagal control of heart rate. Compared to controls, patients with GAD showed cortical thinning of the (i) left rostral anterior cingulate cortex, (ii) left medial orbitofrontal cortex, and (iii) right isthmus cingulate gyrus. Significant negative relationships were identified between the severity of anxiety symptoms and cortical thickness of the left medial orbitofrontal cortex and right isthmus cingulate gyrus. Compared to controls, patients with GAD showed decreased vmHRV at rest. In controls only, cortical thickness of the left caudal anterior cingulate cortex correlated positively with resting vmHRV. These results extend evidence in GAD for structural abnormalities within cortical areas implicated in emotion regulation and cognition. In addition, these findings may implicate abnormal integrity of anterior cingulate cortex in the psychophysiological expression of GAD and suggest that interventional targeting of this region may normalize autonomic function in GAD.

Computerized Exposure Therapy for Spider Phobia: Effects of Cardiac Timing and Interoceptive Ability on Subjective and Behavioral Outcomes.

OBJECTIVE: Spider phobia is a common form of anxiety disorder for which exposure therapy is an effective first-line treatment. Motivated by the observed modulation of threat processing by afferent cardiac signals, we tested the hypothesis that interoceptive information concerning cardiovascular arousal can influence the outcomes of computerized exposure therapy for spider phobia. METHOD: Fifty-three normal healthy participants with high spider phobia scores underwent one of the following three modified computerized exposure protocols, defined by the timing of exposure to brief spider stimuli within the cardiac cycle: systole (during afferent baroreceptor firing); diastole (during baroreceptor-quiescent interbeat interval); random (noncontingent on cardiac cycle). Outcomes were judged on phobic and anxiety measures and physiological data (skin conductance). Individuals were also rated on interoceptive accuracy. RESULTS: MANCOVA analysis showed that timing group affected the outcome measures (F(10,80) = 2.405, p = .015) and there was a group interaction with interoception ability (F(15,110) = 1.808, p = .045). Subjective symptom reduction was greatest in the systolic group relative to the other two groups (diastolic (t = 3.115, ptukey = .009); random (t = 2.438, ptukey = .048)), with greatest reductions in those participants with lower interoceptive accuracy. Behavioral aversion reduced more in cardiac-contingent groups than the noncontingent (random) group (diastolic (t = 3.295, ptukey = .005); systolic (t = 2.602, ptukey = .032)). Physiological (skin conductance response) responses remained strongest for spider stimuli presented at cardiac systole. CONCLUSIONS: Interoceptive information influences exposure benefit. The reduction in the subjective expression of fear/phobia is facilitated by "bottom-up" afferent signals, whereas improvement in the behavioral expression is further dependent on "top-down" representation of self-related physiology (heart rhythm). Individual interoceptive differences moderate these effects, suggesting means to personalize therapy.

Network abnormalities in generalized anxiety pervade beyond the amygdala-pre-frontal cortex circuit: Insights from graph theory.

Generalized anxiety disorder (GAD) has excessive anxiety and uncontrollable worry as core symptoms. Abnormal cerebral functioning underpins the expression and perhaps pathogenesis of GAD:. Studies implicate impaired communication between the amygdala and the pre-frontal cortex (PFC). Our aim was to longitudinally investigate whether such network abnormalities are spatially restricted to this circuit or if the integrity of functional brain networks is globally disrupted in GAD. We acquired resting-state functional magnetic resonance imaging data from 16 GAD patients and 16 matched controls at baseline and after 1 year. Using network modeling and graph-theory, whole-brain connectivity was characterized from local and global perspectives. Overall lower global efficiency, indicating sub-optimal brain-wide organization and integration, was present in patients with GAD compared to controls. The amygdala and midline cortices showed higher betweenness centrality, reflecting functional dominance of these brain structures. Third, lower betweenness centrality and lower degree emerged for PFC, suggesting weakened inhibitory control. Overall, network organization showed impairments consistent with neurobiological models of GAD (involving amygdala, PFC, and cingulate cortex) and further pointed to an involvement of temporal regions. Such impairments tended to progress over time and predict anxiety symptoms. A graph-analytic approach represents a powerful approach to deepen our understanding of GAD.

The verbal nature of worry in generalized anxiety: Insights from the brain.

Background: The Cognitive Avoidance Theory of Worry argues that worry is a cognitive strategy adopted to control the physiological arousal associated with anxiety. According to this theory, pathological worry, as in Generalized Anxiety Disorder (GAD), is verbal in nature, negative and abstract, rather than concrete. Neuroimaging studies link the expression of worry to characteristic modes of brain functional connectivity, especially in relation to the amygdala. However, the distinctive features of worry (verbal, abstract, negative), and their relationship to physiological arousal, have not so far been mapped to brain function. Methods: We addressed this omission by undertaking a resting-state functional magnetic resonance neuroimaging study of 19 patients with GAD and 21 controls, before and after induction of perseverative cognitions, while measuring emotional bodily arousal from heart rate (HR). Seed-based analyses quantified brain changes in whole brain functional connectivity from the amygdala. Results: In GAD, the induction increased negative thoughts and their verbal content. In line with predictions, the verbal expression of worry in GAD was associated with higher HR at baseline and attenuated HR increases after induction of perseverative cognitions. Within brain, the increased use of words during worry, and the associated dampening of HR after induction were mediated by the strength of functional connectivity between the amygdala and default mode network 'hubs' and the opercular cortex. The negative content of worry was further related to functional communication between amygdala and cingulo-opercular and temporal cortices. Conclusions: Findings provide a neurobiological basis for the impact of verbal worry on HR in GAD.

'I had a sort of epiphany!' An exploratory study of group mindfulness-based cognitive therapy for older people with depression.

OBJECTIVES: Mindfulness-based cognitive therapy (MBCT) has been successful in reducing depressive symptoms in people with chronic-recurrent depression. However, the research evaluating the efficacy of this approach, and other innovative treatments for mood disorders, has mainly been with people under 65 years. This paper aims to help redress this imbalance by exploring older people's own reflections of their experience of MBCT. METHODS: A qualitative approach was used to explore 13 participants' experiences of MBCT; participants were interviewed pre and post-intervention and again after six months. To see whether the standard course requires any adaptations for older participants, the two MBCT course facilitators were interviewed post-intervention. RESULTS: Thematic analysis identified five overarching themes and showed that older people reported positive changes in their mental health and well-being and reported being 'released from the past'. The facilitators reported that they needed to be aware of later life issues, such as loneliness and potential physical limitations, but otherwise only minor adaptations were needed to the standard MBCT course for older people. CONCLUSION: MBCT is an acceptable approach for people aged 65 years and over and further research should explore potential mechanisms of change including changes in meta-cognitive awareness and self-compassion.

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

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.

Amygdala functional connectivity as a longitudinal biomarker of symptom changes in generalized anxiety.

Generalized anxiety disorder (GAD) is characterized by excessive worry, autonomic dysregulation and functional amygdala dysconnectivity, yet these illness markers have rarely been considered together, nor their interrelationship tested longitudinally. We hypothesized that an individual's capacity for emotion regulation predicts longer-term changes in amygdala functional connectivity, supporting the modification of GAD core symptoms. Sixteen patients with GAD (14 women) and individually matched controls were studied at two time points separated by 1 year. Resting-state fMRI data and concurrent measurement of vagally mediated heart rate variability were obtained before and after the induction of perseverative cognition. A greater rise in levels of worry following the induction predicted a stronger reduction in connectivity between right amygdala and ventromedial prefrontal cortex, and enhanced coupling between left amygdala and ventral tegmental area at follow-up. Similarly, amplified physiological responses to the induction predicted increased connectivity between right amygdala and thalamus. Longitudinal shifts in a distinct set of functional connectivity scores were associated with concomitant changes in GAD symptomatology over the course of the year. Results highlight the prognostic value of indices of emotional dysregulation and emphasize the integral role of the amygdala as a critical hub in functional neural circuitry underlying the progression of GAD symptomatology.