Abstract
Objective: Anxiety disorders are collectively one of the most common mental illnesses. As a promising mechanism of pathological anxiety, over-generalization proliferates anxiety cues. In this study, we aimed to delineate the underlying neural circuitry using task fMRI, and multimodal MRI. We hypothesize that over-generalization of fear is associated with impaired threat-safety discrimination of the ventromedial prefrontal cortex (vmPFC) and the midbrain-based valence system.
Methods: 32 young females with generalized anxiety disorder (GAD; mean age = 22 ± 4.5) and 25 age-matched healthy controls were tested on a task assessing the degrees of generalization of conditioned stimulus (with electric shock) during functional MRI scanning; in parallel with fMRI, subjective ratings of stimuli and pupil size data were collected. Diffusion MRI was collected to measure anatomical connectivity of the prefrontal-limbic white matter pathway and microstructural integrity of the hippocampus and its subregions. Resting state functional MRI was collected to measure intrinsic functional connectivity within the prefrontal-limbic circuit. Effects of diagnosis on BOLD reactivity of the corticolimbic system during generalization task were assessed. Correlation of atypical BOLD reactivity with structural and functional connectivity was assessed.
Results: Controls showed increased reactivity as generalization stimuli (GS) were more similar to the CS in the widespread corticolimbic areas: the vmPFC, insula, anterior cingulate, right supplementary motor cortex, basal ganglia, and midbrain ventral tegmental area (VTA). On the contrary, individuals with GAD exhibited a indiscriminating response pattern in the vmPFC and the VTA. This indiscriminating response of the vmPFC and the VTA was associated with multiple measures of the corticolimbic circuitry: for vmPFC, vmPFC cortical thickness, vmPFC functional and structural connectivity with the prefrontal-limbic network; for VTA, VTA functional connectivity with corticostriatal putative “dopaminergic” valence network.
Conclusions: We demonstrate evidence for multiple neural substrates of over-generalization of conditioned stimulus in generalized anxiety disorder. Abnormal functioning of the corticolimbic system, such as the vmPFC and midbrain VTA, may underlie this mal-adaptive behavior. Multi-modal neuroimaging analyses suggest the functional abnormalities are associated with atypical brain circuit—grey matter atropy or functional/structural connectivity. This study indicates that the multiple circuit anomalies may synergistically contribute to fear generalization behavior and clinical anxiety.