Aberrant thalamic GABA-network coupling as a neural signature of insomnia severity in major depressive disorder

Insomnia is one of the most common and debilitating symptoms of major depressive disorder (MDD), with its severity closely associated with both the onset and course of the illness. However, its underlying neurobiological mechanisms remain poorly understood. This study employed a multimodal neuroimaging approach, combining magnetoencephalography and magnetic resonance spectroscopy, to separately examine the associations between insomnia severity and both thalamic functional connectivity (FC) with large-scale brain networks in the gamma frequency band, and thalamic gamma-aminobutyric acid (GABA) concentrations. Hierarchical regression analyses revealed a group-specific neurobiological mechanism, marked by opposing associations of insomnia severity with thalamic FC with large-scale brain networks and GABA⁺ levels between patients with MDD and healthy controls (HCs). Furthermore, the intrinsic coupling between thalamic GABA⁺ and thalamic-default mode network FC was reversed between groups, as evidenced by a negative association in HCs that trended toward a positive association in MDD patients. These findings indicate that insomnia in MDD constitutes a distinct pathological state, in which elevated thalamic GABA⁺ levels may represent a compensatory yet maladaptive response that disrupts thalamic GABA-network coupling. Our results provide a novel neurobiological framework for MDD-related insomnia and highlight the potential of therapies aimed at restoring thalamic neurochemical-functional coordination.