Induction and Quantification of Excitability Changes in Human Cortical Networks

Abstract

How does human brain stimulation result in lasting changes in cortical excitability? Uncertainty on this question hinders the development of personalized brain stimulation therapies. To characterize how cortical excitability is altered by stimulation, we applied repetitive direct electrical stimulation in eight human subjects (male and female) undergoing intracranial monitoring. We evaluated single-pulse corticocortical-evoked potentials (CCEPs) before and after repetitive stimulation across prefrontal ( = 4), temporal ( = 1), and motor ( = 3) cortices. We asked whether a single session of repetitive stimulation was sufficient to induce excitability changes across distributed cortical sites. We found a subset of regions at which 10 Hz prefrontal repetitive stimulation resulted in both potentiation and suppression of excitability that persisted for at least 10 min. We then asked whether these dynamics could be modeled by the prestimulation connectivity profile of each subject. We found that cortical regions (1) anatomically close to the stimulated site and (2) exhibiting high-amplitude CCEPs underwent changes in excitability following repetitive stimulation. We demonstrate high accuracy (72-95%) and discriminability (81-99%) in predicting regions exhibiting changes using individual subjects' prestimulation connectivity profile, and show that adding prestimulation connectivity features significantly improved model performance. The same features predicted regions of modulation following motor and temporal cortices stimulation in an independent dataset. Together, baseline connectivity profile can be used to predict regions susceptible to brain changes and provides a basis for personalizing brain stimulation. Brain stimulation is increasingly used to treat neuropsychiatric disorders by inducing excitability changes at specific brain regions. However, our understanding of how, when, and where these changes are induced is critically lacking. We inferred plasticity in the human brain after applying electrical stimulation to the brain's surface and measuring changes in excitability. We observed excitability changes in regions anatomically and functionally closer to the stimulation site. Those in responsive regions were accurately predicted using a classifier trained on baseline brain network characteristics. Finally, we showed that the excitability changes can potentially be monitored in real-time. These results begin to fill basic gaps in our understanding of stimulation-induced brain dynamics in humans and offer pathways to optimize stimulation protocols.

Test–retest reliability of a stimulation‐locked evoked response to deep brain stimulation in subcallosal cingulate for treatment resistant depression

“…Future research comparing results across target and nontarget contacts is needed to infer which components of the evoked potential, if any, are therapeutically relevant. In the meantime, our descriptive evidence that the p40 feature may reflect forceps minor activation is consistent with empirical findings that link the stimulation evoked response (e.g., CCEP) to white matter activation (e.g., Conner et al, 2011; Keller et al, 2018; Ookawa et al, 2017, Yamao et al, 2017). Making this leap in the context of SCC-DBS may require more precise biophysical modeling of neural elements, further exploitation of invasive recording in the OR and utilization of animal models.…”

“…Both CCEP and TEP have been explored as a measure of effective connectivity, which refers to the causal influence between cortical regions and the propagation of electrical signal across large-scale brain networks (Entz et al, 2014; Keller et al, 2011, 2014; Massimini et al, 2005; Matsumoto et al, 2006; Miniussi & Thut, 2010). Importantly, a growing literature also links CCEP and TEP features to white matter integrity and structural connectivity (Conner et al, 2011; Keller et al, 2018; Ookawa et al, 2017; Yamao et al, 2017). …”

Intracortical dynamics underlying repetitive stimulation predicts changes in network connectivity

“…Repetitive stimulation paradigm. In order to examine cortical dynamics during and after stimulation, we applied focal 10Hz stimulation in a clinically-relevant manner, as previously described 17 . Each subject received 15 minutes of 10Hz direct electrical stimulation in a bipolar fashion (biphasic pulses at 100 µs/phase).…”

“…Prior to and immediately after repetitive stimulation, we applied bipolar electrical stimulation (biphasic pulses at 100 µs/phase) with a 1s inter-stimulation interval (ISI). This ISI was chosen to allow voltage deflections to return to baseline after ~500ms and to allow for sufficient trials to be collected within the expected time constraints in order to establish a stable pre-stimulation CCEP baseline 17 . A uniform random jitter (+/-200ms) was included in the ISI to avoid potential entrainment effects that could change baseline cortical excitability 17 .…”

“…Recent studies using direct electrical stimulation coupled with invasive EEG demonstrated evidence of entrainment to the stimulation frequency 14 , decrease in low-frequency power during high frequency stimulation (100Hz) 15 , and increased theta activity directly after a stimulation train 16 . We recently demonstrated that repeated 10Hz electrical stimulation resulted in post-stimulation excitability changes in regions functionally connected to the stimulation site 17 . Furthermore, tracking the first pulse across stimulation trains was useful in predicting these post-stimulation changes, suggesting a potential link between the induction period and maintenance effects.…”