Targeting a Modifiable GABAergic Deficit in the Left DLPFC for Preemptive Intervention in At-Risk Individuals with High Trait Anxiety

Trait anxiety, characterized by a stable predisposition to perceive environmental stimuli as threatening, represents a significant vulnerability factor for anxiety disorders in non-clinical populations.

Neurobiological models posit that impaired inhibitory control within the dorsolateral prefrontal cortex (DLPFC) underlies anxiety symptomatology, though the specific neurochemical correlates in individuals with high trait anxiety, a non-clinical vulnerability phenotype, remain elusive.

Here, we utilized ultra-high-field 7-Tesla magnetic resonance imaging to systematically compare neurochemical and brain function profiles between individuals with high and low trait anxiety. We identified a specific reduction in γ-aminobutyric acid (GABA) concentration within the left DLPFC in the high trait anxiety group, while glutamate levels and the GABA/glutamate ratio remained unaltered. This impairment in GABAergic neurotransmission was accompanied by aberrant local spontaneous neural activity. Furthermore, correlation analysis across the full anxiety spectrum revealed a significant negative relationship between GABA levels and anxiety scores—a continuous relationship that was obscured when examining the restricted ranges within separate high- and low-anxiety groups, thus supporting GABA as a continuous neurochemical substrate of anxiety vulnerability.

Critically, a subsequent transcranial direct current stimulation intervention targeting the left DLPFC in high trait anxiety individuals demonstrated a trend toward increased GABA concentration alongside improved anxiety symptoms, suggesting the potential malleability of this identified neurochemical deficit. Our study provides the first in vivo evidence of a specific GABAergic deficit in the left DLPFC in high trait anxiety, independent of glutamatergic function. These findings not only establish localized inhibitory dysfunction as a key neural mechanism underlying trait anxiety but also offer empirical support for its plasticity, thereby identifying a promising target for early non-invasive neuromodulation strategies in at-risk populations.

Yuyang Li is a Direct-Entry PhD candidate in the Department of Brain Science and Brain Medicine at Zhejiang University School of Medicine. Her research focuses on the neurobiological mechanisms of emotion regulation and the application of neuromodulation techniques, with a particular interest in trait anxiety and related neural circuitry.