Effective connectivity of the human claustrum: Triple networks, subcortical circuits, and psychedelic modulation

Decades of cross-species research highlight the claustrums extensive bidirectional connectivity with cortical and subcortical regions, implicating it in higher-order cognitive processes requiring synchronized brain states. Psychedelics may disrupt this synchrony by modulating claustro-cortical signaling, reflected by the dissolution of cortical network signatures. Using spectral dynamic causal modeling on resting-state fMRI data from the Human Connectome Project and PsiConnect datasets at 7T and 3T, we provide the first in vivo characterization of claustral effective connectivity with triple networks and subcortical regions in humans, both at rest and under the influence of psilocybin. Claustra displayed widespread bidirectional effective connectivity and a strong inhibitory influence on all target regions. Psilocybin enhanced claustral inhibition of cortical networks while disinhibiting subcortical areas, partially associated with psychedelic subjective effect scores. These findings are consistent with cellular and functional cross-species data, supporting the proposed mechanism of claustro-cortical inhibition in regulating network synchrony, while extending this influence to the subcortex, and revealing hierarchical and hemispheric asymmetries in claustral signaling modulation under psilocybin.