Authors :
Presenting Author: Masaya Togo, MD, PhD – Stanford University
Dian Lyu, PhD – Stanford University
Weichen Huang, PhD – Stanford University
Sofia Pantis, BS – Stanford University
Robert Fisher, MD, PhD – Stanford University
Riki Matsumoto, MD, PhD – Kyoto University Graduate School of Medicine.
Vivek Buch, MD – Stanford University
Josef Parvizi, MD, PhD – Stanford University School of Medicine
Rationale:
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 mPLV versus ANT within the same brains and between the two thalamic structures.
Methods:
We investigated 41 patients with simultaneous depth electrodes implanted in the HPC, ANT, and mPLV. Repeated single-pulse electrical stimulations were applied to compare the effective causal connectivity of these regions within the same individuals. The stimulation protocol involved a 0.5 Hz biphasic pulse with a stimulus intensity of 4-6 mA and a pulse-width of 0.2 ms. We identified early-latency evoked responses (F1) based on recently reported features of power and inter-trial phase coherence (Lyu et al. 2025). The strength and the latency of evoked responses were calculated.Results:
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 a clear anterio-posterior gradient of connectivity between HPC and mPLV. We show robust bilateral and bidirectional connectivity between the ANT and the mPLV. Stimulation of either nucleus elicited strong responses in the other, including within the contralateral thalamus.Conclusions:
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.Funding:
This work was supported by research grants from the US National Institute of Neurological Disorders and Stroke (R01NS078396 and R21NS113024), US National Institute of Mental Health (1R01MH109954, and P50MH109429) and US National Science Foundation (BCS1358907) and US National Science Foundation (BCS1358907 and BCS1850938) to JP, and Japan International Medical Research Foundation to MT.