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

Recent developments in intracranial EEG (iEEG) allow direct recordings from the human thalamus, offering new insight into thalamocortical relationships in the human brain. In this study, we applied direct intracranial electrical stimulation (iES) to the mid-thalamus, within or close to the mediodorsal nucleus, to examine its impact on conscious experience and causal brain connectivity in 30 patients with focal epilepsy (10 females, 128 sites; 4±1 sites per patient). Applying 50Hz stimulations (iES HF ) in the mid-thalamus region elicited 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 seemingly obvious lateralization effect. Our connectivity analyses based on single pulse 0.5Hz stimulations (iES LF ), at the individual brain level, revealed strong electrophysiological connectivity between the mid-thalamus and the insula, anterior- and mid-cingulate, as well as the other prefrontal cortices (PFC) and medial temporal lobe structures. Notably, inflow signals from some of the sites to the mid-thalamus were significantly stronger than those in the reverse direction, indicating clear asymmetry in connectivity. These findings demonstrate that stimulation of the human thalamus modulates conscious experience and reveal an asymmetric electrophysiological relationship between the thalamus and human cerebral cortex. Significance statement Our findings provide a functional and causal map of the mid-thalamus 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.