Intrinsic excitation-inhibition imbalance in major depressive disorder

Major depressive disorder (MDD) ranks among the foremost contributors to disability worldwide, yet its neurophysiological mechanisms remain poorly understood. Excitation-inhibition (E/I) imbalance has been implicated in MDD pathophysiology, but cortex-wide E/I ratio and its molecular substrates in MDD remain unknown.

Resting-state functional magnetic resonance imaging data from 254 MDD patients and 451 healthy controls (HCs) across six sites were analyzed. The Hurst exponent, a biophysically confirmed proxy of E/I balance, was estimated using a fractionally integrated process framework. Neurobiological decoding analyses were performed to map the transcriptomic and neurochemical signatures of cortical E/I imbalance in MDD. An independent ketamine clinical trial dataset (32 treatment-resistant depression patients and 21 HCs) was used to examine ketamine-induced changes in cortical E/I balance.

Patients with MDD demonstrated significantly reduced Hurst exponent values, predominantly encompassing the parietal and prefrontal-cingulate cortices. Transcriptomic analysis identified enrichment for neuronal structural organization, nucleic acid metabolism, and mitochondrial function, with preferential overlap with excitatory and inhibitory neuron-specific gene sets. Neurochemically, Hurst exponent alterations were spatially associated with GABAergic, opioidergic, serotonergic, and synaptic density distributions. Divergent group-by-treatment effects were observed in the anterior cingulate and medial prefrontal cortices, with ketamine-induced increases in TRD patients.

These findings highlight that prefrontal-cingulate E/I imbalance, anchored to specific transcriptional and neurochemical substrates, may underlie the pathophysiology of MDD and the antidepressant effects of ketamine. The Hurst exponent offers a promising neuroimaging approach for probing E/I imbalance and identifying potential treatment targets in depression.