Signatures of electrical stimulation driven network interactions in the human limbic system

Abstract

Stimulation-evoked signals are starting to be used as biomarkers to indicate the state and health of brain networks. The human limbic network, often targeted for brain stimulation therapy, is involved in emotion and memory processing. Previous anatomical, neurophysiological and functional studies suggest distinct subsystems within the limbic network (Rolls, 2015). Previous studies using intracranial electrical stimulation, however, have emphasized the similarities of the evoked waveforms across the limbic network. We test whether these subsystems have distinct stimulation-driven signatures. In seven patients with drug-resistant epilepsy we stimulated the limbic system with single pulse electrical stimulation (SPES). Reliable cortico-cortical evoked potentials (CCEPs) were measured between hippocampus and the posterior cingulate cortex (PCC) and between the amygdala and the anterior cingulate cortex (ACC). However, the CCEP waveform in the PCC after hippocampal stimulation showed a unique and reliable morphology, which we term the limbic H-wave. This limbic H-wave was visually distinct and separately decoded from the amygdala to ACC waveform. Diffusion MRI data show that the measured endpoints in the PCC overlap with the endpoints of the parolfactory cingulum bundle rather than the parahippocampal cingulum, suggesting that the limbic H-wave may travel through fornix, mammillary bodies and the anterior nucleus of the thalamus (ANT). This was further confirmed by stimulating the ANT, which evoked the same limbic H-wave but with a shorter latency. Limbic subsystems have unique stimulation evoked signatures that may be used in the future to help develop stimulation therapies. Significance StatementThe limbic system is often compromised in diverse clinical conditions, such as epilepsy or Alzheimers disease, and it is important to characterize its typical circuit responses. Stimulation evoked waveforms have been used in the motor system to diagnose circuit pathology. We translate this framework to limbic subsystems using human intracranial stereo EEG (sEEG) recordings that measure deeper brain areas. Our sEEG recordings describe a stimulation evoked waveform characteristic to the memory and spatial subsystem of the limbic network that we term the limbic H-wave. The limbic H-wave follows anatomical white matter pathways from hippocampus to thalamus to the posterior cingulum and shows promise as a distinct biomarker of signaling in the human brain memory and spatial limbic network.