Brain substates induced by DMT relate to sympathetic output and meaningfulness of the experience

N,N-Dimethyltryptamine (DMT) is a serotonergic psychedelic, known to rapidly induce short-lasting alterations in conscious experience, characterized by a profound and immersive sense of physical transcendence alongside rich and vivid auditory distortions and visual imagery. Multimodal neuroimaging data paired with dynamic analysis techniques offer a valuable approach for identifying unique signatures of brain activity – and linked autonomic physiology – naturally unfolding during the altered state of consciousness induced by DMT. We leveraged simultaneous fMRI and EKG data acquired in 14 healthy volunteers prior to, during, and after intravenous administration of DMT, and, separately, placebo. fMRI data was preprocessed to derive individual dynamic activity matrices, reflecting the similarity of brain activity in time, and community detection algorithms were applied on these matrices to identify brain activity substates; EKG data was used to derive continuous heart rate. We identified a brain substate occurring immediately after DMT injection, characterized by increased superior temporal lobe activity, and hippocampal and medial parietal deactivations under DMT. Results revealed that hippocampus and medial parietal cortex hypoactivity correlated with scores of meaningfulness of the experience. During this first post-injection substate, increased heart rate under DMT correlated negatively with the meaningfulness of the experience and positively with hippocampus/medial parietal deactivation. These results suggest a chain of influence linking sympathetic regulation to hippocampal and medial parietal deactivations under DMT, which combined, may contribute to positive mental health outcomes related to self-referential processing following psychedelic administration. Significance Statement Human subjective experience entails an interaction between bodily awareness and higher-level self-referential processes. DMT is a fast-acting psychedelic that induces intense and short-lasting disruptions in subjective experience. We applied dynamic analysis techniques and graph theoretical approaches to multimodal fMRI/EKG data from a pharmacological study in healthy volunteers. We show that DMT injection is followed by a brain substate characterized by medial parietal and hippocampal hypoactivity, which correlated with meaningfulness of the psychedelic experience. These deactivations were also related to lower increases in heart rate under DMT, suggesting that sympathetic regulation and medial parietal/hippocampal deactivations are an important component of the DMT-induced altered state of consciousness. ### Competing Interest Statement The authors have declared no competing interest.