Cortico-cortical evoked potential (CCEP) refers to the average potential response recorded at the site near the stimulating electrode and/or at the distal site in a time-locked relationship to the electrical stimulation by stimulating the local brain area with the help of intracranial electrodes. Currently, CCEP is mainly used in the study of epilepsy-related networks, and it can be used to determine the relationship between the stimulation site and the recording site, and then to trace the connections between different regions of the human brain and the electrical stimulation in vivo. In this paper, we introduce the role of CCEP, its functions, and the role of the network. In this paper, we present the role, advantages and shortcomings of CCEP and its future development, and review the value of this technique in epilepsy-related research.
I. Role of CCEP
Studies based on white matter fiber connections, such as intercortical connections and cortico-subcortical connections, are almost always performed in animals using a range of invasive tracing techniques. The combined application of non-invasive examination tools such as magnetic resonance diffusion tensor imaging (DTI) and invasive functional localization of cortical/subcortical electrical stimulation provides similar information on the relationship between cortical-subcortical networks, but the relationship between cortical functional areas and white matter fiber ends cannot yet be characterized, and the CCEP technique offers a possibility to track connectivity between different brain regions. Greenlee et al. investigated the functional connectivity within the inferior frontal gyrus using CCEP and showed that stimulation of a site in one subgyrus of the inferior frontal gyrus (orbit, triangle, or insula) elicited a CCEP in the distal part of the same or adjacent subgyrus, providing preliminary evidence of a functional connection between the site of stimulation and the site where the CCEP was recorded. Conner et al. used DTI in conjunction with CCEP to study the anatomical and electrophysiological connections of the language system and found that the amplitude and latency of CCEP were significantly correlated with the number of DTI pathways connecting the stimulation site to the recording site. With the help of CCEP, we can determine the relationship between stimulation sites and recording sites, and then track in vivo the connections between different brain regions and the networks associated with seizures in humans.
1. In vivo tracking of functional connectivity between different brain regions in the hemisphere
Matsumoto et al. found that stimulation of the anterior language area (i.e., the language area located in front of the central sulcus and above the lateral fissure) elicited a CCEP in the posterior language area (i.e., the language area located in the lateral convexity of the temporal and parietal lobes) and the base of the temporal lobe; stimulation of the posterior language area elicited a CCEP in the anterior language area and the base of the temporal lobe. Enatsu et al. used CCEP to study the functional reorganization of the posterior language area (i.e., the damaged language area is compensated for by the ipsilateral neighbor or transferred to the contralateral homologous area) and found that the relationship between the CCEP distribution and the posterior language area showed two patterns, i.e., the posterior language area identified by functional localization of electrical stimulation was either wholly or partially located within the CCEP distribution area. They suggested that the reorganization of the posterior language area might be related to its functional transfer from the end connecting the anterior-posterior language area (manifested as the recording site of CCEP) to the surrounding cortex, and indicated that the language area could be identified outside the recording site of CCEP.
Matsumoto et al. found that stimulation of the medial motor area (MMC) elicited CCEP in the lateral motor area (LMC) and vice versa, while regression analysis showed a close correlation between the stimulation site at the MMC and the site of recording to the CCEP maximum at the LMC and vice versa, according to the positional relationship between the stimulation site and the CCEP recording site; functionally, stimulation of the positive MMC motor area elicited CCEP in homologous areas of the somatocortical localization area of the LMC and vice versa. This study directly demonstrates the existence of an intercortical network in human motor areas that interactively connects anatomically homologous areas of LMC and MMC along a specific gradient and homologous areas of their somatocortical localization areas.
With the help of CCEP, Matsumoto et al. found that the parietal-extra-lateral network (consisting of parietal and frontal brain regions such as the premotor area, precentral gyrus, postcentral gyrus, and posterior parietal lobe) is a mirror-symmetrical structure from near to near and from far to far across the central sulcus and preserves the dorsal-ventral structure (i.e., inferior parietal lobule to ventral premotor area and superior parietal lobule to dorsal premotor area).Enatsu et al. used Kubota et al. investigated the connectivity of the human limbic system with the help of CCEP and demonstrated that the hippocampus has functional connections with the posterior cingulate gyrus, the posterior parahippocampal gyrus, the middle superior frontal gyrus, and the frontal orbital gyrus. They also hypothesized that a bidirectional network through the cingulate gyrus connects the hippocampus to the posterior cingulate gyrus.
2. Functional connectivity between different brain regions in the interhemispheric somatic tracking
Terada et al. found that stimulation of the motor area on one side resulted in the recording of a CCEP in the motor area of the contralateral hemisphere, and that the greatest CCEP amplitude was recorded around the electrode of the same name located in the motor area of the contralateral hemisphere to the stimulating electrode, whereas no CCEP was elicited in the motor area of the contralateral hemisphere when the stimulation site was not in the motor area. This study provides direct evidence for the existence of interhemispheric functional connections originating from cortical motor areas. Furthermore, they observed a mirror image distribution of evoked potentials in the bilateral hemispheres, suggesting that motor coordination of the bilateral soma is at least partially controlled at the level of the motor cortex. In another study, Terada et al. found that stimulation of the facial motor area (f-MA) or non-facial motor area (nf-MA) elicited more CCEP than stimulation of sensory or non-functional areas; stimulation of f-MA versus nf-MA elicited more CCEP in the contralateral f-MA than in the contralateral nf-MA or other sites; stimulation of sensory area (SA) elicited almost no CCEP elicited; stimulation of the f-MA recorded the largest CCEP wave amplitude in the contralateral f-MA. This study found an asymmetrical feature between sensory-motor areas in the left and right hemispheres: there were strong interhemispheric connections between facial motor areas, non-facial motor areas and contralateral facial motor areas, while there may be no or only minimal direct connections between sensory areas and contralateral motor or sensory areas. kikuchi et al. found that stimulation of intrinsic supplementary motor areas (SMA) elicited: contralateral upper and lower limb To elicit MEP in the upper extremity, stimulation of the SMA requires higher stimulation intensity and a significantly longer latency period for this MEP. This study demonstrates the effect of bilateral asymmetry in the human intrinsic supplementary motor area on the corticospinal pathway, which may be conveyed through the direct downstream pathway, and in addition, they suggest that the CCEP is useful for clinically differentiating the supplementary motor area from the primary motor area.
Umeoka et al. found that stimulation of the base of the temporal lobe on one side resulted in a CCEP recorded at the corresponding site in its contralateral hemisphere, and that the speech area of the temporal floor in all subjects studied was associated with at least 1 CCEP, which could be located at the stimulation site or at the recording site. This study confirmed the existence of a neural connection at the base of the temporal lobe bilaterally. Koubeissi et al. found that stimulation of the posterior left superior temporal gyrus resulted in a CCEP recorded at the bilateral temporal base, while stimulation of either temporal base elicited a CCEP at the posterior left superior temporal gyrus. this study is the first to demonstrate the existence of a functional connection between the posterior left superior temporal gyrus and the bilateral temporal base in humans. This study demonstrated for the first time that there is a functional connection between the posterior left superior temporal gyrus and the bilateral temporal base in humans.
Greenlee et al. reported that electrical stimulation of the inferior frontal gyrus elicited CCEP in the bilateral hemispheric motor areas, including the orofacial motor areas, and stimulation of the orofacial motor areas also elicited a corresponding response in the inferior frontal gyrus. This study confirms the functional connection between the inferior frontal gyrus and the orofacial motor area in humans.
3. In vivo tracking of seizure-related networks
Matsumoto et al. applied CCEP to a patient with epilepsy with focal cortical dysplasia. The patient was found to have an enhanced intrinsic epileptogenic network during seizure formation. This is the first report of the application of CCEP to track seizure-related networks.
Iwasaki et al. compared the CCEP in the vicinity of the seizure onset area with the CCEP in the adjacent neocortical area that was not associated with the seizure EEG, and found that the CCEP was stronger in the vicinity of the seizure onset area.
With the help of CCEP, Enatsu et al. found that preictal excitability was stronger at sites showing a pattern of repeated spike wave delivery than at sites showing a pattern of paroxysmal fast wave delivery, confirming in a novel way that changes in cortical excitability are dependent on seizure onset patterns. In another study, they investigated the relationship between seizure propagation and evoked potentials by CCEP and found that continuous propagation was significantly faster than discontinuous propagation, which could be explained by enhanced excitability at sites around the seizure onset area.
Matsuzaki et al. found that CCEPs generated in higher-order visual cortices were significantly larger than those generated in lower-order visual cortices. Electrical stimulation of lower-order visual cortex elicited increased γ-activity in higher-order visual cortex, which appeared after the previous CCEP was attenuated. They suggested that these findings may have implications for future clinical applications of CCEP and preoperative evaluation in epilepsy surgery.
Enatsu et al. combined clinical symptoms, scalp EEG, stereotactic EEG, and CCEP to characterize the clinical and neurophysiological features of posterior cingulate epilepsy. This study revealed that both the network from the posterior cingulate gyrus and the alteration of posterior cingulate gyrus epileptic symptoms depend on the seizure propagation pattern.
II. Strengths and weaknesses of CCEP and future directions
Wrench et al. pointed out that compared with DTI, CCEP can track physiological connections between different brain regions and can provide directional and temporal information. They concluded that CCEP has a strong clinical utility because it enables (1) a convenient short online averaging technique that takes less than 1 or 2 minutes per stimulation site, (2) does not require patient cooperation, and (3) has a low chance of inducing seizures. The CCEP technique is currently immature in clinical application, and its related studies have only been conducted in a few overseas epilepsy centers, which still need to be explored in practice. In addition to the aforementioned shortcomings, the author believes that CCEP is an invasive examination tool that requires intracranial electrode embedding, and the depth and breadth of electrode embedding may affect the investigator’s overall judgment of the study results.
Wrench et al. concluded that CCEP will continue to be used in the future for in vivo tracking of connections between different brain regions and networks associated with seizures in humans, and that CCEP combined with DTI is a major direction for its future development. They also suggest that changes in CCEP potentials during task performance can be used to study in vivo the changes in intercortical connectivity during physiological activity in humans. The author believes that CCEP for predicting postoperative conductive aphasia and exploring the functional composition of different brain regions in combination with f-MRI, TMS and MEG may be possible in the near future.