Electrophysiological connections linking medial pulvinar, anterior nuclei of the thalamus and the hippocampus

The Papez circuit traditionally highlights the anterior nuclei of the thalamus (ANT) as the main relay of hippocampal (HPC) output to the cortex, a view that has shaped neuromodulation strategies in temporal lobe epilepsy (TLE). However, recent studies suggest that the medial subregion of the pulvinar (mPLV)— a thalamic nucleus that has undergone significant evolutionary expansion throughout the mammalian brain evolution— also forms functional connections with medial temporal lobe (MTL) structures, including the hippocampus (HPC). To date, however, there is a lack of causal evidence directly comparing the connectivity between the HPC and the two thalamic nuclei (mPLV and ANT) and between the two thalamic structures within the same brains. In this study, we investigated 41 patients with medial (mTLE, N=22) and non-medial temporal lobe epilepsy (non-mTLE, N=19) implanted with simultaneous depth electrodes in the HPC, ANT, and mPLV. Repeated single-pulse electrical stimulations were applied to compare the causal electrophysiological connectivity of these regions within the same individuals. Our intra-subject analysis revealed that anterior HPC stimulation evoked strong responses in both ANT and mPLV, with mPLV responses occurring significantly later than those in the ANT [linear mixed-effect model (LMM), Mean: 10.19ms, 95% CI [1.78, 18.59], (FDR corrected P = 0.040)]. In contrast, stimulation of the posterior HPC resulted in stronger (and a trend for earlier) responses in mPLV compared to ANT [LMM: Mean: 0.117, 95% CI [0.033, 0.201] (FDR corrected P = 0.012)]. This finding suggests anterio-posterior gradient of HPC connectivity. Furthermore, we found robust bilateral and bidirectional connectivity between ANT and mPLV. Stimulation of either elicited responses in the other, including contralateral thalamus. This represents clear evidence for both intra-thalamic and inter-thalamic connectivity within the human brain. Our findings offer new insights about the connectivity of human HPC with the thalamus and strong intra-thalamic exchange of electrophysiological activity within the human brain.