Electrophysiological Brain Connectivity and Subjective States Evoked by Electrical Stimulation of the Human Mediodorsal Thalamus

Recent advances in human intracranial EEG (iEEG) have enabled new investigations into the role of the thalamus in human brain functions. In this study, we applied direct intracranial electrical stimulation (iES) to the mediodorsal (MD) subregion of the thalamus using both high-frequency (50 Hz, iESHF) and low-frequency (0.5 Hz, iESLF) procedures to examine its impact on conscious experience and causal brain connectivity in 30 patients with focal refractory epilepsy (128 electrode contacts; 4 {+/-} 1 MD sites per patient). iESHF of the MD elicited reportable changes in conscious experience in 11 of 12 patients (39 sites; 83 stimulations across 27 unique pairs) - predominantly in the visceral, emotional, or somatosensory domains and often described as unpleasant without any lateralization effect. Our connectivity analyses based on iESLF revealed that the cingulate and insular cortices produced stronger electrophysiological responses in the MD (inflow connectivity) than did the sites in the prefrontal cortex (PFC) within the same individuals. Moreover, MD stimulation showed its strongest outflow connectivity to the cingulate, insular, and PFC regions, all significantly stronger than to medial temporal lobe (MTL) structures. Notably, inflow from both MTL and insula sites to the MD were significantly stronger than their reverse directions, indicating clear asymmetry in connectivity. These findings provide direct evidence that stimulation of the human thalamus can modulate conscious experience. They also highlight the extensive bidirectional connectivity between the MD and cingulate and insular cortices along with asymmetric connectivity between the MD and MTL and insula sites in the human brain. SIGNIFICANCE STATEMENTOur findings provide a functional and causal map of the mediodorsal thalamus (MD) in the human brain. We provide direct evidence that stimulation of the human thalamus can modulate conscious experience. This study also holds clinical and translational value for identifying thalamic pathways involved in the propagation and generalization of seizures, especially seizures involving the medial temporal lobe, as well as for neuromodulation in epilepsy and other neuropsychiatric disorders, as MD stimulation may not be well-tolerated in human subjects.