Causal and Directional Relationships of the Human Subgenual Cingulate Cortex Revealed Using Single Pulse Evoked Potentials

Introduction: Subgenual cingulate cortex (SCC) deep brain stimulation (DBS) is effective for treating patients with major depressive disorder (MDD). The SCC has extensive white matter connections with MDD brain networks, but the causality or directionality of these connections are not known. SCC single pulse evoked potentials (SPEPs) can highlight these relationships, which would elucidate how SCC DBS exerts its network-wide effects.

Methods: Fifteen patients with intracranial electrodes for the identification of epilepsy networks were recruited. 40-100 SCC SPEPs (1.5-4mA bipolar pulses, 0.2ms/phase, 3-second inter-SPEP interval) were performed. Activity was assessed in all gray matter contacts. Root-mean square responses (500ms post-SPEP) were used to describe direct connections from the SCC and granger causality (after modelling and removing the direct stimulation effects) was used to describe second-order, “ringing” relationships. Cortical contacts were categorized into Desikan-Killiany parcels.

Results: We assessed responses in 3269 cortical, 113 hippocampal, and 43 amygdala contacts. SCC SPEPs elicited significant direct activation of contacts in the medial and lateral orbitofrontal (OFC), rostral anterior cingulate, and superior frontal cortices (FDR-corrected p< 0.05), but no other cortical regions. After removing the direct effect of the stimulation, additional directional relationships were found arising from the OFC (both medial and lateral) to the middle and posterior cingulate cortices, amygdala, and medial frontal cortex (FDR-corrected p< 0.05).

Conclusion : SCC SPEPs reveal directional influence of the SCC to specific nodes of the MDD brain network. The OFC may represent a key region, as it receives direct influence from the SCC and, in turn, also exerts second-order effects that may function to recruit additional MDD network regions. Hence, the therapeutic benefit of SCC DBS may rely on both direct and second-order effects. Future studies may implement this SPEP-derived causal functional connectome to optimize SCC DBS or monitor network (or therapeutic) response over time.