A failed top-down control from the prefrontal cortex to the amygdala in generalized anxiety disorder: Evidence from resting-state fMRI with Granger causality analysis

AbstractObjectiveIn generalized anxiety disorder (GAD), abnormal top-down control from prefrontal cortex (PFC) to amygdala is a widely accepted hypothesis through which “emotional dysregulation model” may be explained. However, whether and how the PFC directly exerted abnormal top-down control on amygdala remained largely unknown. We aim to investigate the amygdala-based effective connectivity by using Granger causality analysis (GCA).MethodsThirty-five drug-naive patients with GAD and thirty-six healthy controls (HC) underwent resting-state functional MR imaging. We used seed-based Granger causality analysis to examine the effective connectivity between the bilateral amygdala and the whole brain. The amygdala-based effective connectivity was compared between the two groups.ResultsIn HC, the left middle frontal gyrus exerted inhibitory influence on the right amygdala, while in GAD group, this influence was disrupted (single voxel P < 0.001, Gaussian random field corrected with P < 0.01).ConclusionOur finding might provide new insight into the “insufficient top-down control” hypothesis in GAD.

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Functional dissection of neural connectivity in generalized anxiety disorder

10.1101/2022.01.09.475543 ◽

2022 ◽

Author(s):

Jonas L Steinhäuser ◽

Adam R Teed ◽

Obada Al-Zoubi ◽

René Hurlemann ◽

Gang Chen ◽

...

Keyword(s):

Prefrontal Cortex ◽

Anxiety Disorder ◽

Generalized Anxiety Disorder ◽

Resting State ◽

A Priori ◽

Resting State Fmri ◽

Brain Regions ◽

Generalized Anxiety ◽

Correlated Activity ◽

Dorsolateral Prefrontal

Differences in the correlated activity of networked brain regions have been reported in individuals with generalized anxiety disorder (GAD) but an overreliance on the null-hypothesis significance testing (NHST) framework limits the identification and characterization of disorder-relevant relationships. In this preregistered study, we applied a Bayesian statistical framework as well as NHST to the analysis of resting-state fMRI scans from females with GAD and demographically matched healthy comparison females. Eleven a-priori hypotheses about functional correlativity (FC) were evaluated using Bayesian (multilevel model) and frequentist (t-test) inference. Reduced FC between the ventromedial prefrontal cortex (vmPFC) and the posterior-mid insula (PMI) was confirmed by both statistical approaches. FC between the vmPFC-anterior insula, the amygdala-PMI, and the amygdala-dorsolateral prefrontal cortex (dlPFC) region pairs did not survive multiple comparison correction using the frequentist approach. However, the Bayesian model provided evidence for these region pairs having decreased FC in the GAD group. Leveraging Bayesian modeling, we demonstrate decreased FC of the vmPFC, insula, amygdala, and dlPFC in females with GAD. Exploiting the Bayesian framework revealed FC abnormalities between region pairs excluded by the frequentist analysis, as well as other previously undescribed regions, demonstrating the benefits of applying this statistical approach to resting state FC data.

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The Association Between Generalized Anxiety Disorder and Resting-State Prefrontal Cortex Oxygenation Is Modified by Self-Reported Physical Activity: Results From The Irish Longitudinal Study on Ageing

The Journals of Gerontology Series A ◽

10.1093/gerona/glab090 ◽

2021 ◽

Author(s):

Cillian P McDowell ◽

Louise Newman ◽

Derek C Monroe ◽

John D O’Connor ◽

Silvin P Knight ◽

...

Keyword(s):

Physical Activity ◽

Prefrontal Cortex ◽

Longitudinal Study ◽

Anxiety Disorder ◽

Generalized Anxiety Disorder ◽

Resting State ◽

Short Form ◽

Saturation Index ◽

World Health ◽

Generalized Anxiety

Abstract Individuals with anxiety disorders exhibit lower intrinsic functional connectivity between prefrontal cortical areas and subcortical regions. The prefrontal cortex (PFC) is sensitive to the acute and chronic effects of physical activity (PA), while the anxiolytic effects of PA are well known. The current study examined the association of generalized anxiety disorder (GAD) and its interaction with PA, with resting-state, left PFC oxygenation. This cross-sectional study used data from participants (N = 2444) from The Irish Longitudinal Study on Ageing, a nationally representative prospective study of community-living adults aged 50 and older in Ireland. The Composite International Diagnostic Interview Short-Form determined fulfillment of criteria for GAD. The short-form International Physical Activity Questionnaire determined adherence to the World Health Organization PA guidelines. Resting-state, left PFC oxygenation was continuously measured via a Portalite. Tissue saturation index (TSI) was calculated as the ratio of oxygenated hemoglobin to total tissue hemoglobin (expressed as a percentage) for the final minute of a 5-minute supine-rest period. Multivariable linear regression quantified associations of GAD with TSI in the total population and population stratified by PA status. Participants with GAD had lower TSI (b = −1.416, p = .008) compared to those without GAD. However, this association was modified by PA. Among participants who met the PA guidelines, TSI did not differ according to GAD status (b = −0.800, p = .398). For participants who did not meet the guidelines, TSI was significantly lower among those with GAD (b = −1.758, p = .004). These findings suggest that PA may help to protect brain health among older adults with GAD.

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