A reliability-screened thalamocortical control-network phenotype tracks cocaine-use history in cocaine use disorder

A central goal in psychiatry is to move from symptom-defined diagnoses toward biologically interpretable and reliable phenotypes. In cocaine use disorder (CUD), many resting-state abnormalities have been reported, but few circuit-level findings have been explicitly screened for reliability. We tested whether prespecified thalamocortical features yield a reproducible phenotype in CUD and whether that phenotype reflects diagnosis, recent cocaine use, or longer-term illness history.

Discovery analyses used resting-state data from 105 participants (46 healthy controls, 59 CUD). From a 13-region thalamocortical circuit, we derived an HC-trained LEiDA state model, generated 11 prespecified features, and advanced only those meeting split-half reliability criteria (ICC[3,1] ≥0.40). A separate paired TMS sample (n=44) was used for extension analyses.

Five features survived reliability screening. Within CUD, longer duration since beginning cocaine use was associated with greater occupancy of a control-like state (standardized β=0.37, q=0.005) and stronger whole-thalamus connectivity with control frontoparietal cortex (standardized β=0.30, q=0.018). Neither days since last use nor CUD vs. healthy diagnosis were associated with any reliable feature after correction. Joint-history models indicated that the signal was better explained by longer-term use history than by recent use. Localization analyses indicated the connectivity effect was concentrated in dorsal thalamic regions. TMS-interaction and effective-connectivity follow-ups were null.

Reliability screening identified a thalamocortical control-network phenotype in CUD that tracks longer cocaine-use history rather than diagnosis or recent use. More broadly, this workflow offers a practical framework for screening candidate circuit-level psychiatric phenotypes for reliability.