In a groundbreaking study published in the prestigious journal BMC Psychiatry, researchers have unveiled new insights into the potential of resting motor threshold (RMT) as a predictive biomarker for cognitive function in individuals diagnosed with major depressive disorder (MDD). This investigation focuses exclusively on drug-naive patients who have experienced their first episode of MDD, shedding light on the nuanced interplay between neurophysiological measures and cognitive performance in this vulnerable population. The research not only delves into the neurobiological underpinnings of cognitive deficits in depression but also highlights intriguing sex-specific differences that could revolutionize personalized treatment strategies.
Major depressive disorder is a pervasive and debilitating mental health condition characterized by persistent low mood and a constellation of cognitive impairments that impair daily functioning and social integration. These cognitive impairments often linger even after mood symptoms improve, posing a significant challenge for clinicians. Traditionally, cognitive evaluations rely on extensive neuropsychological testing batteries, which are time-intensive and susceptible to subjective bias. The present study pioneers the use of RMT—a quantitative measure of motor cortical excitability obtained via transcranial magnetic stimulation (TMS)—as an objective, potentially scalable tool to predict cognitive function.
The investigation enrolled a sizable cohort of 158 first-episode, drug-naive patients with MDD, assessed between August 2023 and April 2024. The participants underwent the MATRICS Consensus Cognitive Battery (MCCB), a comprehensive suite designed to evaluate multiple cognitive domains relevant to psychiatric conditions, alongside RMT measurement via TMS. Additionally, hormone assays were performed to control for the modulatory effects of endocrine factors on neurocognitive function. This robust methodological framework ensured that the findings reflect intrinsic brain physiology rather than medication effects or hormonal confounds.
The analysis included 138 patients who completed all assessments, comprising 41 males and 97 females with an average age of approximately 19 years, marking a young cohort at a critical developmental period. Statistical correlations revealed that in the total sample, higher right hemisphere RMT correlated positively with enhanced attention and vigilance, as measured by the Continuous Performance Test-Identical Pairs (CPT-IP). This suggests that greater motor cortex excitability in the right hemisphere might confer an advantage in sustaining attention among individuals with depression, a domain frequently impaired in MDD.
Intriguingly, when stratified by sex, the data exposed starkly divergent patterns. In male patients, a higher left hemisphere RMT was associated with poorer verbal learning performance, gauged by the Hopkins Verbal Learning Test-Revised (HVLT-R), while the right hemisphere RMT exhibited a protective effect, correlating positively with verbal learning outcomes. Such lateralized correlations intimate that hemispheric motor cortical excitability differentially influences cognitive faculties in males, potentially mediating the severity and profile of cognitive dysfunction in depression. Female patients, however, showed no significant association between RMT and the cognitive domains assessed, underscoring a critical sex-specific dissociation.
These results bear profound implications for the pathophysiology and treatment of MDD. RMT, as a non-invasive and reproducible neurophysiological index, may serve as a biomarker reflecting the integrity of cortical excitability and its modulation of cognitive processes. The distinct lateralization and sex-dependent associations revealed here emphasize the necessity of incorporating biological sex as a fundamental variable in both research paradigms and clinical protocols. This nuanced understanding could refine therapeutic approaches, particularly those employing repetitive transcranial magnetic stimulation (rTMS), which targets motor cortex excitability to alleviate both mood and cognitive symptoms in depression.
Notably, the study’s multiple regression analyses demonstrated that the relationships between RMT and cognitive outcomes were independent of confounders such as age, education level, and hormone concentrations. This underscores the direct relevance of motor cortical excitability to cognitive performance, rather than these associations being secondary to demographic or endocrine factors. Consequently, RMT may emerge as an objective biomarker that surpasses traditional cognitive testing in predictive power and clinical utility.
Despite its promising findings, this exploratory study invites caution and calls for replication and extension. The relatively young sample and the cross-sectional design limit the generalizability and causal inferences. Longitudinal research encompassing larger, more diverse populations is essential to validate the prognostic value of RMT and to elucidate the mechanistic pathways linking motor cortical excitability and cognitive function in depression across the lifespan.
Moreover, the absence of significant correlations in female patients raises complex questions about sex-specific neurobiological mechanisms in depression. Future investigations might explore hormonal fluctuations, neuroinflammatory profiles, or genetic modulators that differentially influence cortical excitability and cognitive networks in women. Such research could unravel tailored interventions optimized for sex-based neurocircuitry differences.
Importantly, the integration of RMT assessment into clinical practice could revolutionize the management of cognitive impairments in MDD. Non-invasive brain stimulation techniques, calibrated based on individual RMT profiles, hold the promise to modulate neural plasticity and restore cognitive functions impaired by depression. This personalized neurotherapeutic approach aligns with the broader precision psychiatry movement, aiming for interventions that address not only mood symptoms but also the often-neglected cognitive dimensions of mental illness.
In summary, this pioneering study leverages the intersection of neurophysiology and cognitive psychiatry to identify RMT as a potential objective marker for cognitive capacities in drug-naive individuals with major depressive disorder. The elucidation of sex-specific patterns enhances our understanding of depression’s heterogeneous neurobiology and advocates for sex-informed clinical strategies. As rTMS and related modalities gain traction, the use of RMT could inform both prognosis and individualized treatment planning, heralding a new era in the holistic care of patients battling depression.
Xu, L., He, J., Yang, L., and colleagues have set a compelling precedent for future research exploring the neurobiological determinants of cognitive dysfunction in MDD. Their work, published in BMC Psychiatry, not only advances scientific knowledge but also opens avenues for innovative clinical applications that may alleviate the cognitive burden borne by millions affected by this debilitating disorder.
Subject of Research: Utilization of resting motor threshold (RMT) as a neurophysiological predictor of cognitive function in drug-naive patients with major depressive disorder (MDD), with a focus on sex-specific differences.
Article Title: Utilizing resting motor threshold to predict cognitive function in drug-naive patients with major depressive disorder
Article References:
Xu, L., He, J., Yang, L. et al. Utilizing resting motor threshold to predict cognitive function in drug-naive patients with major depressive disorder. BMC Psychiatry 25, 1001 (2025). https://doi.org/10.1186/s12888-025-07393-z
DOI: https://doi.org/10.1186/s12888-025-07393-z
