A New Use for Cortico-Cortical Evoked Potentials: Mapping Brain Connectivity

By Dileep R. Nair, MD, and John C. Mosher, PhD

The need for mapping the human brain is now a widely recognized priority — even at the world’s highest levels of power. Indeed, the importance of this quest is underscored by the NIH’s Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative laid out by President Barack Obama in 2013. The initiative’s aim is to help researchers uncover mysteries of various brain disorders by facilitating a more dynamic understanding of brain function.

Cleveland Clinic’s Epilepsy Center is proud to be contributing to those efforts through an NIH-funded brain mapping project that uses the invasive monitoring technique known as cortico-cortical evoked potentials in a novel way. This article outlines the rationale behind that project and looks ahead to its potential clinical payoffs.

Limits to traditional studies of white matter connectivity

Current understanding of neuroscience relates mostly to cortical function, i.e., the regions of cortex associated with different functional tasks. This understanding has come from a variety of methods that include studying the impact of neurologic deficits from ischemic lesions, observations on the effect of cortical stimulation on occurrence of observable symptoms, and functional MRI during specific tasks. We’ve only recently begun to understand how the white matter connections of various brain regions play a role in cognitive tasks.

Much of the knowledge comes from either invasive tracer studies of cadavers or diffuse tractography. Each has its disadvantages: Tracer studies represent anatomic pathways without much information gained on functional relevance, and diffuse tractography yields in vivo information but has difficulty differentiating regions where there is a tortuous or complex crossing of fibers. Studies using resting-state functional MRI have also resulted in additional advances in the understanding of functional brain connectivity.

What the CCEP technique brings to the table

In 2004, Cleveland Clinic’s Epilepsy Center published the first of several articles based on a technique — cortico-cortical evoked potentials (CCEPs) — pioneered by our neurophysiology lab using low-frequency electrical stimulation of electrodes implanted in patients undergoing invasive monitoring for epilepsy surgery. The first two articles published by our group (both in Brain, the first in 2004 and the second in 2007) showed how regions of language and motor functions could be mapped using this technique.

The CCEP technique is unique and different from the better-known method of standard cortical stimulation, which uses high-frequency direct cortical stimulation (25 to 50 Hz) to observe elicitation of an impairment or production of a behavioral response. In contrast, low-frequency cortical stimulation (1 Hz) is used in CCEP recordings to determine which other brain regions respond by observing a measurable evoked signal in distant or nearby cortical regions (Figure). The response, we believe, travels through white matter via cortico-cortical tracts or cortico-thalamo-cortical pathways.

Since those initial publications, our group has published several articles in the peer-reviewed literature reporting studies of various functional and epileptic networks in the human brain. Meanwhile, the CCEP technique has gained acceptance and been adopted by various academic centers in the U.S. and around the world.

Figure. A patient’s CCEP responses are depicted as waveforms on the left with response estimates depicted by scaled colors (white is strongest) in the MRI scans on the right. Brain currents were estimated using a standard “minimum energy” constraint that restricts the currents to the vicinity of the electrodes to generate a useful estimate of brain dynamics.

Next step: A single brain atlas from hundreds of patients

The strength of CCEP research findings to date has attracted an R01 grant from the National Institute of Neurological Disorders and Stroke, with Cleveland Clinic’s Epilepsy Center serving as a principal investigative site along with the University of Southern California. The five-year grant is funding a study to develop a brain map of CCEP responses from across hundreds of patients who have undergone epilepsy surgery using the invasive technique of stereoelectroencephalography (SEEG).

The benefits of SEEG are that it minimizes distortion of the brain through placement of depth electrodes. This allows for easy co-registration and thus warping of analogous cortical regions onto a single brain atlas. The clear benefit of this research is that it promises to overcome a major disadvantage of the SEEG technique or any other invasive mapping of the brain — i.e., lack of resolution of coverage of different brain regions. Since not all major brain regions are implanted with electrodes in an individual patient, the ability to systematically co-register hundreds of patients onto a single brain atlas will, over time, give a much clearer picture of the complete and complex interactions of brain regions that can be elicited using CCEP studies.

Current published reports of brain interactions determined by CCEPs have been able to address questions of language organization, motor organization, limbic system connections and epileptic regions within small groups of patients. The objective now is to see how these findings correlate with larger groups of patients with more complete coverage of brain regions and to reveal the dynamic changes that can occur within and across different age groups, different epilepsies, different mood disorders, different stimulation parameters and different pathologies. We hope to be able to find noninvasive surrogates, such as in resting-state MRI or resting-state magnetoencephalography, that can identify these cortico-cortical pathways.

The study is currently at the point where we are reviewing and processing retrospective data into a common brain atlas and developing new techniques for calculating and displaying connectivity from these data.

Insights may be broadly applicable

If we can understand brain connectivity in a more complete fashion, we stand to gain considerable insights that may extend beyond epilepsy and apply to a host of other neurological conditions, including autism, traumatic brain injury, Alzheimer disease and various mood disorders.

Dr. Nair is Section Head of Adult Epilepsy in Cleveland Clinic’s Epilepsy Center. Dr. Mosher is a research scientist in Cleveland Clinic’s Epilepsy Center.