Reduced Structural Connectivity of a Major Frontolimbic Pathway in Generalized Anxiety Disorder
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CONTEXT: Emotion regulation deficits figure prominently in generalized anxiety disorder (GAD) and in other anxiety and mood disorders. Research examining emotion regulation and top-down modulation has implicated reduced coupling of the amygdala with prefrontal cortex and anterior cingulate cortex, suggesting altered frontolimbic white matter connectivity in GAD. OBJECTIVES: To investigate structural connectivity between ventral prefrontal cortex or anterior cingulate cortex areas and the amygdala in GAD and to assess associations with functional connectivity between those areas. DESIGN: Participants underwent diffusion-tensor imaging and functional magnetic resonance imaging. SETTING: University magnetic resonance imaging facility. PARTICIPANTS: Forty-nine patients with GAD and 39 healthy volunteer control subjects, including a matched subset of 21 patients having GAD without comorbid Axis I diagnoses and 21 healthy volunteers matched for age, sex, and education. MAIN OUTCOME MEASURES: The mean fractional anisotropy values in the left and right uncinate fasciculus, as measured by tract-based analysis for diffusion-tensor imaging data. RESULTS: Lower mean fractional anisotropy values in the bilateral uncinate fasciculus indicated reduced frontolimbic structural connectivity in patients with GAD. This reduction in uncinate fasciculus integrity was most pronounced for patients without comorbidity and was not observed in other white matter tracts. Across all participants, higher fractional anisotropy values were associated with more negative functional coupling between the pregenual anterior cingulate cortex and the amygdala during the anticipation of aversion. CONCLUSIONS: Reduced structural connectivity of a major frontolimbic pathway suggests a neural basis for emotion regulation deficits in GAD. The functional significance of these structural differences is underscored by decreased functional connectivity between the anterior cingulate cortex and the amygdala in individuals with reduced structural integrity of the uncinate fasciculus.
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Reduced grey matter volume in the mPFC and weaker integrity of the uncinate fasciculus have been reported in adults with anxious temperament and anxiety disorders.
“Structural abnormalities, such as reduced grey matter volume in the mPFC and weaker integrity of the uncinate fasciculus, have been reported in adults with anxious temperament and anxiety disorders24–28.”
From Multimodal evidence for delayed threat extinction learning in adolescence and young adulthood (2019) · cites this paper as [26]
Weaker structural integrity of the uncinate fasciculus has been found in populations with anxious temperament, suggesting that this tract may play a crucial role in anxiety aetiology.
“Notably, weaker structural integrity of the uncinate fasciculus has been found in populations with anxious temperament24–27,32, suggesting that this tract may play a crucial role in anxiety aetiology.”
From Multimodal evidence for delayed threat extinction learning in adolescence and young adulthood (2019) · cites this paper as [26]
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- Authors
- Tromp, D. P. M., Grupe, D. W., Oathes, D. J., McFarlin, D. R., Hernandez, P. J., Kral, T. R. A., Lee, J. E., Adams, M., Alexander, A. L., & Nitschke, J. B.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Nitschke, Jack B.
- ORCID
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2012-09-01
- Volume
- 69
- Issue
- 9
- Pages
- 925
- ISSN
- 0003-990X (ISSN-L)
- PMC
- PMC3566704
- OpenAlex
- W1992691945
- Cited by
- 184
- References
- 87
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 11 · 2023: 6 · 2022: 11 · 2021: 15 · 2020: 7 · 2019: 15 · 2018: 12 · 2017: 22 · 2016: 21 · 2015: 16 · 2014: 11 · 2013: 15 · 2012: 1
- FWCI
- 18.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5k02mh082130-05)
- National Institute of Mental Health (K02‑MH082130, R01MH074847, K08MH063984, P50MH084051, T32MH018931)
- National Institute of General Medical Sciences (R25GM083252, T32GM007507)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD003352)
- Topics
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- generalized anxiety disorder, uncinate fasciculus, structural connectivity, fractional anisotropy, amygdala, anterior cingulate cortex, prefrontal cortex, emotion regulation, functional connectivity, white matter integrity, comorbidities
- MeSH terms
- Adolescent, Adult, Amygdala, Anxiety Disorders, Arousal, Brain Mapping, Dominance, Cerebral, Emotions, Female, Frontal Lobe, Gyrus Cinguli, Humans, Image Interpretation, Computer-Assisted, Limbic System, Magnetic Resonance Imaging, Male, Neural Pathways, Reference Values, Temporal Lobe, Comorbidity, Imaging, Three-Dimensional, Diffusion Magnetic Resonance Imaging, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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