Neurobiology of Generalized Fear-Conditioning & Avoidance in Anxiety Disorders

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 transdiagnostic relevance to
anxiety pathology. 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 fMRI 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 transdiagnostic, psychometrically validated personality traits. 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.

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 CNS function including antidepressants,
benzodiazipines, anti-psychotics, moodstabilizers,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