Hyper-reactive human ventral tegmental area and aberrant mesocorticolimbic connectivity in overgeneralization of fear in generalized anxiety disorder.
The ventral tegmental area (VTA) has been primarily implicated in reward-motivated behavior. Recently, aberrant dopaminergic VTA signaling has also been implicated in anxiety-like behaviors in animal models. These findings, however, have yet to be extended to anxiety in humans. Here we hypothesized that clinical anxiety is linked to dysfunction of the mesocorticolimbic circuit during threat processing in humans; specifically, excessive or dysregulated activity of the mesocorticolimbic aversion circuit may be etiologically related to errors in distinguishing cues of threat versus safety, also known as "overgeneralization of fear." To test this, we recruited 32 females with generalized anxiety disorder and 25 age-matched healthy control females. We measured brain activity using fMRI while participants underwent a fear generalization task consisting of pseudo-randomly presented rectangles with systematically varying widths. A mid-sized rectangle served as a conditioned stimulus (CS; 50% electric shock probability) and rectangles with widths of CS ±20%, ±40%, and ±60% served as generalization stimuli (GS; never paired with electric shock). Healthy controls showed VTA reactivity proportional to the cue's perceptual similarity to CS (threat). In contrast, patients with generalized anxiety disorder showed heightened and less discriminating VTA reactivity to GS, a feature that was positively correlated with trait anxiety, as well as increased mesocortical and decreased mesohippocampal coupling. Our results suggest that the human VTA and the mesocorticolimbic system play a crucial role in threat processing, and that abnormalities in this system are implicated in maladaptive threat processing in clinical anxiety.
Program in Neuroscience, Stony Brook University, Stony Brook, New York 11794, Department of Psychiatry, Columbia University College of Physicians and Surgeons and the New York State Psychiatric Institute, New York, New York 10032, Department of Biomedical Engineering, Stony Brook University School of Medicine, Stony Brook, New York 11794, Department of Psychology, Northern Michigan University, Marquette, Michigan 49855, Department of Psychology, Stony Brook University, Stony Brook, New York 11794, and Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts 02129.
Jiook
J
Cha
Joshua M
JM
Carlson
Daniel J
DJ
Dedora
Tsafrir
T
Greenberg
Greg H
GH
Proudfit
Lilianne R
LR
Mujica-Parodi
D000293:Adolescent; D000328:Adult; D001007:Anxiety / Q000503:physiopathology; D001008:Anxiety Disorders / Q000503:physiopathology*; D001931:Brain Mapping; D005239:Fear / Q000502:physiology*; D005260:Female; D005793:Generalization, Psychological / Q000502:physiology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D009415:Nerve Net / Q000503:physiopathology*; D017557:Ventral Tegmental Area / Q000503:physiopathology*
anxiety disorder; dopaminergic aversion system; fear generalization; human fear conditioning; mesocorticolimbic system; ventral tegmental area