Neural Substrates of Decision-Making in Anxiety

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.

1 R01 MH075792-01 (Stein, Murray) 07/01/2006-06/31/2009

PharmacofMRI to Identify New Anxiolytics/A Human Bioassay

This proposal utilizes methods and approaches from behavioral pharmacology, neuroscience, magnetic resonance imaging and drug development to outline a series of studies aimed at determining whether pharmaco-fMRI can be used as an innovative bioassay for the development of novel anxiolytic drugs. We propose to use blood oxygen dependent (BOLD) and arterial spin labeling (ASL) functional magnetic resonance imaging (fMRI) to examine whether brain activations during emotion processing tasks can be used to predict anxiolytic efficacy of standard anxiolytic agents. Anxiety disorders are the most prevalent category of mental illness in the United States (Kessler et al 2005) as well as in other countries (Demyttenaere et al 2004).

Numerous pharmacotherapeutic options are available for the treatment of anxiety disorders (Stein 2005) including benzodiazepines and selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRIs and SNRIs). But, over half of patients with anxiety disorders who are treated with an adequate course of antidepressants fail to fully improve (Stein and Seedat 2004). Although several promising anxiolytic compounds have emerged from preclinical development and are currently being tested in humans (e.g., CRH-1 antagonists; mGluR2 and mGluR5 agonists; NK1 antagonists) (Kent et al 2002), there is a substantial time lag from the discovery of novel compounds in animal models of anxiety to the demonstration of anxiolytic efficacy in humans, and many promising compounds fail altogether in early human Phase II studies.

The U.S. Food and Drug Administration (FDA) has referred to this “pipeline problem” as a significant challenge to drug development in the 21st century (US Department of Health and Human Services. and Food & Drug Administration 2004). Among the recommendations from this FDA white paper is the need to invent new drug development tools to enhance the movement along the “critical path” from Phase I to Phase III. The development and refinement of effective biomarkers may overcome the dearth of interim steps in the anxiolytic drug development pipeline to bridge the gap between preclinical promise and Phase II/III success. For example, human in vivo screens for pharmacodynamic efficacy could be used as predictive tests to select compounds and design dosing regimens with a high likelihood of success. However, there are no short cuts for developing fMRI as a bioassay for anxiolytic drug development. Instead, what is needed are: (1) placebocontrolled, dose-response studies of standard anxiolytic and other psychopharmacological drugs to demonstrate feasibility, sensitivity, reliability, and predictive validity; (2) comparison of the sensitivity, reliability, predictive validity of this approach in anxiety disorder populations or in highly anxious individuals. Thus, the purpose of this application is to determine whether pharmacological testing combined with functional magnetic resonance imaging (pharmaco-fMRI) can be used as a human in vivo bioassay to identify drugs with anxiolytic properties in humans. The intent is to validate paradigms that could be implemented widely as a routine step in the anxiolytic drug development process; as such, fMRI is strongly preferred for this purpose over other neuroimaging techniques such as positron emission tomography (PET), which are much more costly, have greater risk to subjects (and thus limit repeat testing), and can be conducted in relatively few centers. We have completed several fMRI studies which provide evidence of the feasibility and potential utility of this approach. Specifically, we have shown that a known anxiolytic drug (lorazepam) reduces activity in a dose-dependent fashion in the amygdala (Paulus et al 2005), which is considered a critical target brain region for the mediation of anxiety (Rauch et al 2003).

1 R01 MH071916-01 (Perry, William) 07/1/04 - 06/30/09:

Inhibitory Deficits in Mania and Hyperdopaminergic Mice

Inhibitory deficits are characteristic of the mania of Bipolar Disorder (BD) and provide a behavioral target for translational research. The primary focus of this translational project is to assess deficits in three domains of inhibition in manic BD patients and in parallel animal models based on pharmacological challenges and gene engineering technology. Extensive animal data as well as recent findings linking a BD to alterations in the genetic sequence in the vicinity of the dopamine transporter (DAT) gene support the basic hypothesis that the manic state involves a dysregulation of dopaminergic systems. This project uses and further develops cross-species measures that reflect abnormalities in dopaminergic systems to further our understanding of BD and its treatment. The design involves parallel studies in manic BD patients and in mice in which the DAT has been manipulated either pharmacologically (amphetamine) or genetically (DAT knockdown and knockout mice). Specifically, inhibitory deficits in three domains will be assessed: 1. Impaired sensorimotor inhibition using prepulse inhibition of startle; 2. Motor hyperactivity in a novel environment using species-appropriate ambulatory monitoring devices; and, 3. Perseveration using innovative non-linear analyses of spatial and temporal patterns of motor responses. Manic BD inpatients will be studied at hospital admission, when highly symptomatic, and longitudinally during treatment with antimanic and/or atypical antipsychotic drugs. Normal comparison subjects will also be studied longitudinally, although in the absence of treatment. An important innovative aspect of this application is the development of an explicit human analog of the open field, the classic rodent behavioral paradigm used to assess dopaminergic psychostimulant effects. Experiments with mice will test the hypothesis that mutant mice lacking the normal complement of DAT might serve as a model of the inhibitory deficits in BD and that DAT-deficient mice might provide an animal model with predictive validity for the identification of antimanic agents. The parallel characterization of core features of BD across species will enable objective measures of mania that can be used to monitor treatment efficacy in BD patients and facilitate the validation of homologous predictive models of BD in rodents. Such preclinical models, and the human measures essential to their validation, are critical to the future discovery of novel treatments of this condition.

Home Lab MRI-information Recruitment Publications Tasks Other Interests

last edited: 12/02/2007