This proposal is the competing renewal of our ongoing work into the neural substrates of anxiety. In a natural progression of this work, we now propose to test key aspects of a neural circuit model for anxiety disorders. We will use BOLD fMRI in conjunction with emotion processing tasks to compare healthy controls subjects (HC) to patients with panic disorder (PD) and generalized anxiety disorder (GAD), who will be studied before and after cognitive behavioral treatment (CBT). This proposal brings together methods and approaches from behavioral and cognitive neuroscience, functional neuroimaging imaging, and psychological clinical therapeutics to outline a series of studies with the long-term objective of delineating the neural substrates of anxiety disorders. The principal objective of this competitive renewal is to build on the applicants' previously accomplished work in non-clinical individuals with anxiety proneness and apply this to patients with anxiety disorders with the following specific aims: (1) To develop a basic systems neuroscience endophenotype for anxiety disorders. Based on our prior work, we hypothesize that, compared to healthy controls (HC), patients with GAD or PD will show increased activation of the anterior insula during various types of emotion processing that engage interoceptive systems. Moreover, we hypothesize that there is less functional coupling between the insular cortex and both the amygdala and the medial prefrontal cortex (mPFC) in patients with anxiety disorders. (2) To evaluate effects of CBT on the neural systems hypothesized to be dysfunctional in patients with anxiety disorders. We expect that successful treatment will be associated with attenuation of insular cortex activity and increased coupling between insula and both amygdala and mPFC, respectively. In the case of GAD, we also expect to see a reduction in task-related dorsolateral prefrontal cortex (DLPFC) activity. Anxiety disorders are early onset, prevalent, serious conditions that impact adversely on individual and societal functioning. Improved understanding of the neural circuitry of anxiety disorders will inform diagnostic conceptualizations and enable the more directed development and testing of novel therapies that are based on a more thorough understanding of pathophysiology, thereby conveying new therapeutic options to the many patients with anxiety disorders for whom existing treatments are inadequate. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH065413-06
Application #
7435379
Study Section
Adult Psychopathology and Disorders of Aging Study Section (APDA)
Program Officer
Kozak, Michael J
Project Start
2002-04-01
Project End
2012-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
6
Fiscal Year
2008
Total Cost
$312,863
Indirect Cost
Name
University of California San Diego
Department
Psychiatry
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Fonzo, Gregory A; Ramsawh, Holly J; Flagan, Taru M et al. (2014) Cognitive-behavioral therapy for generalized anxiety disorder is associated with attenuation of limbic activation to threat-related facial emotions. J Affect Disord 169:76-85
Ball, Tali M; Stein, Murray B; Ramsawh, Holly J et al. (2014) Single-subject anxiety treatment outcome prediction using functional neuroimaging. Neuropsychopharmacology 39:1254-61
Ball, T Manber; Ramsawh, H J; Campbell-Sills, L et al. (2013) Prefrontal dysfunction during emotion regulation in generalized anxiety and panic disorders. Psychol Med 43:1475-86
Acheson, Dean T; Stein, Murray B; Paulus, Martin P et al. (2012) Effects of anxiolytic treatment on potentiated startle during aversive image anticipation. Hum Psychopharmacol 27:419-27
Ball, Tali Manber; Sullivan, Sarah; Flagan, Taru et al. (2012) Selective effects of social anxiety, anxiety sensitivity, and negative affectivity on the neural bases of emotional face processing. Neuroimage 59:1879-87

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