Temporal order of signal propagation within and across intrinsic brain networks

We studied the temporal dynamics of activity within and across functional MRI (fMRI)–derived nodes of intrinsic resting-state networks of the human brain using intracranial electroencephalography (iEEG) and repeated single-pulse electrical stimulation (SPES) in neurosurgical subjects implanted with intracranial electrodes. We stimulated and recorded from 2,133 and 2,372 sites, respectively, in 29 subjects. We found that N1 and N2 segments of the evoked responses are associated with intra- and internetwork communications, respectively. In a separate cognitive experiment, evoked electrophysiological responses to visual target stimuli occurred with less temporal separation across pairs of electrodes that were located within the same fMRI-defined resting-state networks compared with those located across different resting-state networks. Our results suggest intranetwork prior to internetwork information processing at the subsecond timescale.

It has been known for a while that certain regions of the brain have correlated activity, forming “intrinsic networks” that can be identified while people are resting (SI Appendix, Table S1). These correlated activities were first discovered by measuring blood-oxygenation level–dependent (BOLD) signals and later confirmed with measures of electrophysiological activity (1–10). In a series of studies, we and others have shown that distinct sites of the cerebral cortex that are part of a functional MRI (fMRI)–defined intrinsic network become coactivated during an experimental task and are connected at rest via slow fluctuations of their local high-frequency broadband (HFB) power (5–10).Much of what we know about the resting-state intrinsic networks has been gleaned from studies that have relied on neural data within a slow temporal domain. As a result, the temporal dynamics of activity within and across these intrinsic networks remain almost entirely unknown. Such information may provide core mechanistic information about the functional architectural design of our brains.To address this unknown, we collected information from a relatively large number of recording sites in a group of human subjects implanted with intracranial electrodes as part of their clinical diagnostic workup. In each subject, repeated single electrical pulses were delivered intracranially in specific electrode sites while we recorded evoked responses from hundreds of other intracranial electrodes as routinely performed in clinical centers (11). This method, known as single-pulse electrical stimulation or corticocortical evoked potential (CCEP), allows one to explore the presence or absence of signal flow and its timing between a stimulated region and hundreds of target areas (i.e., those implanted with recording electrodes). The high temporal resolution of this method combined with precise anatomical information about the sites of stimulation and recording allows for measurements down to the millisecond timescale and millimeter precision (12). Also, because the source of the signal and time of evoked responses are known, this method provides indirect information about possible directionality of the propagation of electrophysiological signals within the brain. The prevailing current hypothesis is that direct anatomical connectivity between the seed and target regions will evoke sharper and faster responses while second-order connections are thought to evoke slower and dispersed responses (13, 14).     

The effectiveness of cortico-cortical evoked potential in detecting seizure onset zones

Objective The aim of the study was to evaluate the parameters for localizing the seizure onset zone in refractory epilepsy patients using cortico-cortical evoked potentials (CCEP).

Methods Fifteen patients (nine females) with medically refractory partial epilepsy underwent stereo electro encephalography (SEEG) in Tsinghua University Yu-Quan Hospital from 2015 to 2016. Clinical semiology and, scalp electroencephalography (EEG) findings were analyzed during phase I preoperative evaluation. During phase II evaluation, localization of seizure onset zone (SOZ) was analyzed using SEEG by experienced epileptologists. Meanwhile, the cortico-cortical evoked potential (CCEP) paradigm was tested in all patients in phase II. The value of root-mean-square (RMS) of CCEPs amplitude from 7 ms to 300 ms after stimulation was analyzed to quantify the response.

Results RMS of CCEPs amplitude in SOZ was higher than in seizure propagation zone (SPZ) (P < 0.05) and non-seizure onset zone (NSOZ) (P < 0.05). RMS of CCEPs amplitude in SOZ was higher than in NSOZ in epilepsy patients with secondary generalized tonic-clonic seizures (SGTCS) (N = 6, P < 0.05); The RMS of CCEPs amplitude in SOZ was strikingly higher than SPZ in the repetitive spiking (RS) onset pattern, and the difference was significant (N = 5, P < 0.01).

Conclusions This data indicated that CCEP response is enhanced in SOZ despite different seizure types (with or without SGTCS). CCEP may be an effective method to locate SOZ.     

Epileptogenic high-frequency oscillations skip the motor area in children with multilobar drug-resistant epilepsy

Objective

Subtotal hemispherectomy involves the resection of multiple lobes in children with drug-resistant epilepsy, skipping the motor area (MA). We determined epileptogenicity using the occurrence rate (OR) of high-frequency oscillations (HFOs) and the modulation index (MI), demonstrating strength of coupling between HFO and slow wave. We hypothesized that epileptogenicity increased over the multiple lobes but skipped the MA.

Sleep modulates cortical connectivity and excitability in humans: Direct evidence from neural activity induced by single‐pulse electrical stimulation

Sleep‐induced changes in human brain connectivity/excitability and their physiologic basis remain unclear, especially in the frontal lobe. We investigated sleep‐induced connectivity and excitability changes in 11 patients who underwent chronic implantation of subdural electrodes for epilepsy surgery. Single‐pulse electrical stimuli were directly injected to a part of the cortices, and cortico‐cortical evoked potentials (CCEPs) and CCEP‐related high‐gamma activities (HGA: 100–200 Hz) were recorded from adjacent and remote cortices as proxies of effective connectivity and induced neuronal activity, respectively. HGA power during the initial CCEP component (N1) correlated with the N1 size itself across all states investigated. The degree of cortical connectivity and excitability changed during sleep depending on sleep stage, approximately showing dichotomy of awake vs. non‐rapid eye movement (REM) [NREM] sleep. On the other hand, REM sleep partly had properties of both awake and NREM sleep, placing itself in the intermediate state between them. Compared with the awake state, single‐pulse stimulation especially during NREM sleep induced increased connectivity (N1 size) and neuronal excitability (HGA increase at N1), which was immediately followed by intense inhibition (HGA decrease). The HGA decrease was temporally followed by the N2 peak (the second CCEP component), and then by HGA re‐increase during sleep across all lobes. This HGA rebound or re‐increase of neuronal synchrony was largest in the frontal lobe compared with the other lobes. These properties of sleep‐induced changes of the cortex may be related to unconsciousness during sleep and frequent nocturnal seizures in frontal lobe epilepsy. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc .     

A systematic exploration of parameters affecting evoked intracranial potentials in patients with epilepsy

BackgroundBrain activity is constrained by and evolves over a network of structural and functional connections. Corticocortical evoked potentials (CCEPs) have been used to measure this connectivity and to discern brain areas involved in both brain function and disease. However, how varying stimulation parameters influences the measured CCEP across brain areas has not been well characterized.ObjectiveTo better understand the factors that influence the amplitude of the CCEPs as well as evoked gamma-band power (70–150 Hz) resulting from single-pulse stimulation via cortical surface and depth electrodes.MethodsCCEPs from 4370 stimulation-response channel pairs were recorded across a range of stimulation parameters and brain regions in 11 patients undergoing long-term monitoring for epilepsy. A generalized mixed-effects model was used to model cortical response amplitudes from 5 to 100 ms post-stimulation.ResultsStimulation levels <5.5 mA generated variable CCEPs with low amplitude and reduced spatial spread. Stimulation at ≥5.5 mA yielded a reliable and maximal CCEP across stimulation-response pairs over all regions. These findings were similar when examining the evoked gamma-band power. The amplitude of both measures was inversely correlated with distance. CCEPs and evoked gamma power were largest when measured in the hippocampus compared with other areas. Larger CCEP size and evoked gamma power were measured within the seizure onset zone compared with outside this zone.ConclusionThese results will help guide future stimulation protocols directed at quantifying network connectivity across cognitive and disease states.     

Impact of volume-conducted potential in interpretation of cortico-cortical evoked potential: Detailed analysis of high-resolution electrocorticography using two mathematical approaches

Objective

Cortico-cortical evoked potential (CCEP) has been utilized to evaluate connectivity between cortices. However, previous reports have rarely referred to the impact of volume-conducted potential (VCP) which must be a confounding factor of large potential around the stimulation site. To address this issue, we challenged the null hypothesis that VCP accounts for the majority of the recorded potential, particularly around the stimulation site.

High frequency activity overriding cortico-cortical evoked potentials reflects altered excitability in the human epileptic focus

Objective

We aimed to clarify that high frequency activity (HFA) of cortico-cortical evoked potentials (CCEPs), elicited by single pulse electrical stimulation (SPES), reflects cortical excitability.

Considerations in performing and analyzing the responses of cortico‐cortical evoked potentials in stereo‐EEG

This review aims to highlight key considerations when performing cortico‐cortical evoked potentials (CCEPs) using stereo–electroencephalography (SEEG) for network mapping and show its clinical applicability to presurgical evaluations. The parameters for performing stimulation and safety aspects have been investigated in electrocorticography (ECoG) and deep brain stimulation (DBS), but not as extensively in SEEG. A review of current literature was performed, with an attempt made to emphasize practical insights from all modalities of intracranial stimulation. This paper reviews physical stimulation parameters, highlights safety limits, and considers the influence of changing common stimulation parameters. These factors are put into the context of CCEPs in SEEG. Given the paucity of direct research in this area, studies utilizing low frequency stimulation, DBS, and ECoG are incorporated along with the fundamental principles of electrical engineering. In addition, postprocessing considerations are reviewed, including electrode localization, application of digital filters, baseline selection, application of connectivity metrics, and higher order network analysis. The aim is to guide CCEP stimulation as well as to provide an understanding of the underlying principles of this technique. At present, there are few articles detailing the design of low‐frequency stimulation paradigms, especially in the setting of SEEG. Providing a review of the fundamentals and postprocessing considerations when performing CCEPs in SEEG will increase the accessibility of this technique.