The Hippocampus and Amygdala Are Integrators of Neocortical Influence: A CorticoCortical Evoked Potential Study

Brain stimulation is increasingly viewed as an effective approach to treat neuropsychiatric disease. The brain's organization in distributed networks suggests that the activity of a remote brain structure could be modulated by stimulating cortical areas that strongly connect to the target. Most connections between cerebral areas are asymmetric, and a better understanding of the relative direction of information flow along connections could improve the targeting of stimulation to influence deep brain structures. The hippocampus and amygdala, two deep-situated structures that are crucial to memory and emotions, respectively, have been implicated in multiple neurological and psychiatric disorders. We explored the directed connectivity between the hippocampus and amygdala and the cerebral cortex in patients implanted with intracranial electrodes using corticocortical evoked potentials (CCEPs) evoked by single-pulse electrical stimulation. The hippocampus and amygdala were connected with most of the cortical mantle, either directly or indirectly, with the inferior temporal cortex being most directly connected. Because CCEPs assess the directionality of connections, we could determine that incoming connections from cortex to hippocampus were more direct than outgoing connections from hippocampus to cortex. We found a similar, although smaller, tendency for connections between the amygdala and cortex. Our results support the roles of the hippocampus and amygdala to be integrators of widespread cortical influence. These results can inform the targeting of noninvasive neurostimulation to influence hippocampus and amygdala function.