Transdiagnostic homogeneity, and diagnostic-specific biomarkers among major depressive disorder, bipolar disorder and schizophrenia during 40 Hz auditory steady-state response: a normative modeling analysis

J Affect Disord. 2025 Sep 4:120189. doi: 10.1016/j.jad.2025.120189. Online ahead of print.

ABSTRACT

BACKGROUND: Abnormal gamma-band auditory steady-state response (gamma-ASSR) power has been reported in major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ), but distinguishing between these disorders based solely on power remains challenging. Directed functional connectivity (DFC), which captures topological patterns of causal information flow, may provide more diagnostic-specific markers. However, conventional case-control framework often disregards the substantial individual heterogeneity, yielding unreliable biomarkers.

METHODS: An adapted framework integrating DFC heterogeneity with normative modeling was developed. 52 MDD, 33 BD, 39 SZ patients and 107 healthy controls (HC) participated in the 40 Hz-ASSR task. The normative model was established using data from 71 HC to define the population baseline. Thereafter, deviation Z-scores and the proportion of extreme deviations in DFC were calculated.

RESULTS: The DFC deviations showed high individual heterogeneity at most DFCs, with fewer than 2.6 % of individuals exhibiting extreme deviations at the same time point. However, a small proportion of DFC deviations with high overlap were embedded within common connectivity pathways in three disorders, particularly in the frontal and parietal regions. Furthermore, distinct diagnostic-specific patterns were identified: MDD mainly exhibited right temporal-frontal alterations, BD showed a parietal-driven temporo-occipital loop, and SZ presented a midline-centered pyramidal topology linking bilateral temporal-occipital regions. The Z-scores of DFC involved in these diagnostic-specific patterns achieved a maximum accuracy of 99.43 % with the K-nearest neighbors (KNN) algorithm.

CONCLUSIONS: These findings offer novel insights into gamma-ASSR alterations and provide a robust framework for transdiagnostic and disorder-specific identification across MDD, BD, and SZ.

PMID:40914528 | DOI:10.1016/j.jad.2025.120189