EEG microstates and dynamic functional connectivity reveal stage-specific brain networks in subjective tinnitus.

Prolonged or repeated exposure to physical and psychological stress is a major risk factor for emotional disorders, including major depressive disorder (MDD) (, , , ). Although traditional antidepressants are widely used, they typically require weeks to months to achieve therapeutic efficacy, and approximately one-third of patients fail to respond adequately to treatment (). A landmark study by Berman et al. demonstrated that a single subanaesthetic dose of intravenous ketamine (0.5 mg/kg infused for 40 min) exerted rapid antidepressant effects in patients with depression (). Since then, accumulating evidence confirmed that a single low dose of ketamine induces rapid antidepressant effects within hours that can persist for approximately one week (, , ). Given ketamine’s short elimination half-life and its clearance from the body within 24 h (, ), these sustained antidepressant effects are particularly remarkable and have generated considerable interest in the underlying neurobiological mechanisms. Ketamine was initially considered as a non-competitive N-methyl--aspartate receptor (NMDAR) antagonist and has long been used as an anaesthetic agent (, ). Activation of the ventral hippocampus (vHip)-medial prefrontal cortex (mPFC) circuit is necessary and sufficient for ketamine’s antidepressant effects (). However, recent studies suggest that ketamine may have multiple molecular targets (), including the widely expressed NMDAR (). Owing to its pharmacological promiscuity, ketamine likely modulates neural activity across many brain regions and cell types, including neurons and glial cells (, ). In addition, ketamine exerts sustained antidepressant-like effects through the facilitation of GABA function in the mPFC and hippocampus (, ), as evidenced by increased GABA levels in the mPFC of patients diagnosed with MDD following ketamine treatment (, ). Both intracellular and extracellular proteins are involved in brain function over time (, ). Many intracellular proteins exhibit relatively rapid turnover, with synthesis and degradation occurring over hours to several days (, ). In contrast, extracellular matrix (ECM) molecules are considerably more stable and are largely protected from intracellular ubiquitin-mediated and enzymatic degradation processes (, ). Therefore, it is reasonable to speculate that the ECM may play a role in the sustained antidepressant effects of ketamine (). However, compared with the well-characterised role of intracellular mechanisms, the role of ECM in mediating ketamine’s antidepressant actions remains poorly understood. A better understanding of the ECM-related mechanisms underlying this condition may contribute to the discovery of novel therapeutic targets that can produce rapid and sustained antidepressant effects.