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 the 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 the 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.

Causal Cortical and Thalamic Connections in the Human Brain

“…This issue is even more pressing when waveforms from subcortical structures such as the thalamus are included. Therefore, in line with recent attempts by other investigators 7,8 , we felt it was imperative to employ a multivariate and unbiased approach for sorting the distinct profiles of connectivity across cortical and thalamic sites.…”

“…This method has been traditionally referred to as the study of cortico-cortical evoked potentials 4 (CCEPs) since it has primarily been used to study causal electrophysiological connectivity between pairs of cortical regions. Similar studies of thalamocortical and corticothalamic connections have been rarely conducted since direct recordings from and stimulations in the human thalamus are extremely rare in human neuroscience research [5][6][7] . As a result, it remains unknown if stimulation of the thalamus will have a different, or the same, effect on other regions of the brain.…”

“…As a result, it remains unknown if stimulation of the thalamus will have a different, or the same, effect on other regions of the brain. Moreover, with a few exceptions 7,8 , previous studies have been largely reliant on simple univariate measures detecting large peaks or the time-to-peak in the evoked signals, and limit responses to fixed windows of interest. These traditional methods are not able to capture the complex dynamics of physiological responses generated by electrical stimulations (Figure 1); and they can vary significantly depending on the chosen cutoff z-scores for determining an effect, current intensity and the distance between stimulating and recording electrode contacts 9 .…”

Canonical Response Parameterization: Quantifying the structure of responses to single-pulse intracranial electrical brain stimulation

“…We know for example that, for the divergent paradigm, evoked potentials may arrive with smoothly varying latency, duration, or polarity along adjacent sites in an sEEG lead traversing a natural axis in a brain structure (e.g. the body of the hippocampus in response to stimulation [18]).…”