Neurobiology of Generalized Fear-Conditioning & Avoidance in Anxiety Disorders

Neurobiology of Generalized Fear-Conditioning & Avoidance in Anxiety Disorders (Community Anxiety Response Study)

Anxiety disorders are among the most prevalent, costly, and disabling mental illnesses. One central, yet largely understudied, abnormality in anxiety disorders is the heightened tendency to display fear and avoidance in reaction to benign or safe events that resemble feared situations. The current project maps brain circuits associated with this abnormality in order to contribute to future brain-based diagnosis and treatments for clinical anxiety.

Study Overview

• Status: Completed
• Conditions: Anxiety Disorders
• Intervention / Treatment: Behavioral: Test of fear conditioning

Detailed Description

The objective of this project is to neurally, behaviorally, psychologically, and clinically characterize fundamental Pavlovian and instrumental dimensions of potential threat through which emotional and behavioral responses to threat cues generalize to resembling, safe stimuli. Such generalization is aligned with the potential threat construct due to the threat ambiguity, or uncertain threat value, inherent in these safe 'generalization' stimuli. The Pavlovian dimension of interest is generalization of conditioned fear: a fundamental Pavlovian process through which fear transfers, or generalizes, to safe stimuli resembling a conditioned threat-cue (CS+). The targeted instrumental dimension is generalized avoidance: active decisions to withdraw from safe stimuli resembling the CS+ that are motivationally prompted by Pavlovian generalization. Given lab-based findings have linked heightened Pavlovian generalization to a variety of traditional anxiety disorders, overgeneralization represents a promising dimension of potential threat with relevance across traditional anxiety disorders. One central aspect of this project is testing personality and psychiatric factors (e.g., trait fear, internalizing, externalizing) that may account for the relevance of generalization and its neurobiology across traditional anxiety disorders. A second key aspect, is studying neural processes by which Pavlovian generalization evokes instrumental generalized avoidance of benign stimuli (resembling danger cues), which, when excessive, is likely to impair day-to-day functioning in anxiety patients. Unfortunately, human fear-conditioning experiments in clinical samples, have focused almost exclusively on passive-emotional, Pavlovian conditioning, to the virtual exclusion of studying active-behavioral, instrumental avoidance. The current neuroimaging project fills this gap by applying a novel Pavlovian-instrumental generalization paradigm to neurally and behaviorally elucidate Pavlovian processes leading to generalized instrumental avoidance. Personality moderators (e.g., dispositional resilience) of relations between Pavlovian and instrumental generalization will also be examined. The studied adult samples will display a wide range of symptom severity across traditional anxiety disorders and will include anxiety-clinic patients and healthy comparisons (N=159). Central goals of this proposal include: 1) elucidating the neurobiology of Pavlovian and instrumental generalization and their interaction, 2) testing relations between neural substrates of Pavlovian and instrumental generalization and broad psychiatric dysfunction (Aims2-3); and 3) assessing the degree to which relations between these dimensions of generalization and broad dysfunction are driven by psychometrically validated personality traits relevant across traditional anxiety disorders. This third and final goal is critical to the project, because individual difference measures capturing empirically-validated psychological constructs will likely track relations between fundamental conditioning processes (e.g., generalization) and general dysfunction, better than traditional, polythetic, diagnostic entities, that, by and large, do not reflect any single coherent psychological process.

• Study Type: Observational
• Enrollment (Actual): 208

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 58 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Male and female adults presenting with anxiety symptoms at the Anxiety Disorders Clinic in the Department of Psychiatry at U of MN, as well as demographically matched healthy comparisons

Description

Inclusion Criteria:

A. Diagnosis: No psychiatric diagnosis is required, but recruitment will be guided by the goal of attaining a sample with wide-ranging levels of both anxiety symptom severity and individual differences in anxiety-related states and traits.

B. Caffeine and tobacco use: Participants will abstain from caffeine and tobacco one hour preceding testing

Exclusion Criteria:

A. Psychiatric health: Current or past history of any psychotic disorder, bipolar disorder, delirium, dementia, amnestic disorder, or mental retardation; comorbid depression if accompanied by current, significant suicide risk; substance use disorder presently or for the six months preceding testing.

B. Current use of any medication that alters central nervous system function including antidepressants, benzodiazepines, anti-psychotics, mood stabilizers,anti-parkinsonian agents, anti-convulsants, sleep medications, pain medications, and anti-hypertensives.

C. Medical health: Current or past medical illnesses which in the investigator's opinion may confound study results, or place the participant at risk.

D. Pregnancy status: Females who are, or may be, pregnant. Recruitment

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Anxiety Clinic Patients; Adult males and females being treated at the anxiety disorders clinic at the University of Minnesota predominantly for clinical anxiety.	Behavioral: Test of fear conditioning; Behavioral and brain correlates of conditioned fear generalization and avoidance will be assessed using fMRI and related to levels of anxiety related psychopathology.
Healthy Comparisons; Sex, age, and socioeconomically matched healthy controls	Behavioral: Test of fear conditioning; Behavioral and brain correlates of conditioned fear generalization and avoidance will be assessed using fMRI and related to levels of anxiety related psychopathology.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional magnetic resonance imaging	Blood oxygenation level dependent responses elicited during the fear conditioning paradigm	Years 1-4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Behavioral measures	Online behavioral responses elicited during the fear conditioning paradigm	Years 1-4

Collaborators and Investigators

• Sponsor: University of Minnesota
• Investigators: Principal Investigator: Shmuel Lissek, PhD, U of MN

Study record dates

Study Major Dates

• Study Start (Actual): July 17, 2017
• Primary Completion (Actual): August 1, 2021
• Study Completion (Actual): August 1, 2021

Study Registration Dates

• First Submitted: January 24, 2017
• First Submitted That Met QC Criteria: January 24, 2017
• First Posted (Estimate): January 26, 2017

Study Record Updates

• Last Update Posted (Actual): March 10, 2022
• Last Update Submitted That Met QC Criteria: March 9, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: fMRI; anxiety disorders; fear-conditioning; behavioral avoidance
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Disease; Anxiety Disorders
• Other Study ID Numbers: 1610M96641

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No