Subjects

Subjects are epilepsy patients whose seizures are refractory to nonsurgical treatment and who undergo invasive seizure monitoring in an effort to determine whether they are suitable candidates for resection surgery.^5,6 Research protocols must be scrutinized and approved by the institutional review board where the research will be taking place according to the ethical guidelines of the institution’s governing bodies.⁷ In all cases, the plan for electrode placement is influenced exclusively by clinical criteria. Participation in this research does not change the risks associated with epilepsy surgery. The research plan is explained to research participants in detail, and informed consent for participation is obtained in advance. Particularly when chronic recordings are obtained over a period of days, this consent process is informally repeated before each experimental session. In most cases, patient-subjects wish to participate in these protocols but on certain days after surgery may elect to forgo testing. Because of this need for iterative informed consent and the practical considerations that accompany this requirement, most research of this type is carried out only with adult subjects.

The cognitive and behavioral functional status of each subject is evaluated extensively by a neuropsychologist before the electrode implantation surgery as part of the clinical diagnostic and treatment plan. It is desirable that the subject’s neuropsychological status fall within the normal limits of an age-matched control population. It is especially important to ensure that subjects do not have impairment in the cognitive functions of interest and that these functions be measured objectively and documented before surgery.

Electrodes

Several different types of clinical and combined clinical-research electrodes are available for invasive monitoring of seizure activity. Usually, the signals recorded from a given electrode contact can be split and used for both clinical monitoring and research purposes. This does not disrupt the clinical ECoG recording activity. There are two broad categories of intracranial electrodes: (1) subdural cortical surface electrodes in the form of either grids or strip electrodes and (2) depth electrodes (Fig. 59-1). The extent of coverage is decided solely by clinical necessity. Electrodes need to cover wide cortical surface areas and deep structures sufficiently to diagnose the seizure foci accurately. The specific implantation strategies used by different groups across the United States and elsewhere in the world to achieve this objective vary widely. Some programs use surface grids and strips almost exclusively, whereas other highly respected programs (e.g., Paris and Grenoble, France) use depth electrodes exclusively and implant more than 10 penetrating depth electrodes in a single hemisphere in many cases. There is no evidence proving the clinical superiority of any of these specific strategies, and in practice institutions have evolved to adopt a range of safe and effective approaches.

FIGURE 59-1 A, A photograph taken during electrode implantation surgery shows a standard clinical grid electrode with an intercontact distance of 1 cm (left upper) and a high-density custom grid electrode with an intercontact distance of 5 mm (right lower). B, Lateral skull radiograph of the same subject as in A. C, A photograph shows a standard clinical depth electrode (top) and a custom depth electrode with multiple high-impedance microcontacts on the electrode shaft (bottom). Arrows indicate positions of microcontacts.

(Courtesy of Ad-Tech Medical Instrument Corporation, Racine, WI.)

Many epilepsy patients who undergo invasive monitoring are suspected of having a temporal lobe focus. Standard preoperative evaluation typically includes video EEG monitoring with scalp electrodes, positron emission tomography, structural MRI, identification of clinical seizure semiology, and neuropsychological testing. Preoperative investigation may not lead to a conclusive site of seizure originfor example, the laterality of origination may be in question or the seizure focus may have been vaguely narrowed down to the temporal lobe of one hemisphere but the exact location of origin within that temporal lobe (i.e., medial structures versus lateral cortex) remains in question. In such cases, it is then necessary to extensively cover the surface and deep structures of the temporal lobe on the side that the seizure focus is likely to be located and also to have limited coverage of the contralateral temporal lobe. Contralateral coverage is usually achieved through a modified bur-hole exposure and placement of a small number of strip and depth electrodes. Such extensive recording from the temporal lobes provides an invaluable opportunity to investigate human brain functions that involve the temporal lobe and perisylvian brain regions.

In addition to standard clinical electrodes, a variety of specially modified electrodes are available that can collect research data in addition to clinical ECoG data. Some manufacturers make customized electrodes to suit each researcher’s need (e.g., Ad Tech Corporation, Racine WI). Most clinical grid or strip electrodes are constructed with a center-to-center intercontact distance of 1 cm. High-density electrodes with less than 5 mm of interelectrode distance provide better spatial resolution and can be fabricated without altering the clinical risk profile of the grid.⁸ Custom depth electrodes have several high-impedance microwire contacts in addition to clinical low-impedance contacts (see Fig. 59-1).^9–11 These high-impedance wires make it possible to record unit activity from the human brain. Some of the custom electrodes have more electrode contacts and lead cables attached to them than standard clinical electrodes do. The single-tailed electrode cables that some manufacturers provide can reduce the number of cables by combining multiple lead cables (up to 64 channels) into a single bundle, thus reducing the number of penetrations through the scalp.

Implantation Surgery

The surgical procedure to implant electrodes for a research participant is basically the same as that for a standard clinical epilepsy case. It is necessary to carefully plan placement of the electrodes in the optimal position so that the cables do not disturb each other or compress or displace the cortex. Displacement of cortex by grids or cables may occur because of the stiffness of the base plate of the electrodes and cables. Compression of the cortical surface can be minimized by making careful cuts on the base plate of the grid electrodes and meticulously looping cables to avoid undue torsion on the grid or strip electrodes. It is also important to pay careful attention to prevent leakage of cerebrospinal fluid (CSF) by placing a tight purse-string suture at each cable exit site on the scalp. It is not unusual to see CSF leakage around cable exit sites several days after the implantation surgery. This delayed leakage is probably due to subsidence of postoperative swelling of the scalp or breakdown of tissue around cable sutures that makes previously tight seals around cables loose enough to allow leakage of CSF. As soon as a CSF leak is noticed, the source of the leak should be identified and terminated by placing additional sutures at leak sites to reduce the risk for infection. In a series of approximately 200 patients who underwent implantation with chronic intracranial electrodes at the University of Iowa over a 15-year period, there was no significant difference in the infection rates of patients who were research participants and those who were not.

Accumulation of blood in the subdural space either beneath or above the grid electrodes sometimes occurs.^6,12–15 Although the exact mechanism of such blood accumulation is unknown, it is presumed that direct contact between the base plate of the grid electrodes and the dura mater may disturb normal hemostatic and resorptive processes. At our institution, we perform the following procedures in an effort to prevent accumulation of blood in the subdural space:

Verification of Electrode Placement

It is important to localize electrodes accurately in relation to surrounding brain structures to correctly interpret research data. Preimplantation and postimplantation computed tomography (CT), MRI, and photographs taken during both implantation and removal surgery are the three main tools used to localize the position of electrodes. Intracranially implanted electrodes create substantial artifact and distortion of images on CT and MRI, so extra caution is required when interpreting postimplantation imaging studies. The location of electrode contacts on a grid is best documented by photographs taken at the time of both implantation and explantation surgery. By matching the details of gyral and pial vessel anatomy, it is possible to localize surface contact locations with approximately millimeter accuracy. The position of electrodes is mapped onto a three-dimensional rendering of the brain surface drawn from each subject’s preoperative thin-slice MRI studies by referencing to a pattern of gyri and sulci on the cortical surface (Fig. 59-2).

FIGURE 59-2 Positions of subdural contacts are mapped on a three-dimensional surface rendering of a preoperative magnetic resonance image. The color on each contact represents the magnitude of electroencephalographic response in a high gamma band (approximately 70 to 150 Hz) to visual stimulation of static faces.

Localizing electrodes on the ventral surface of the brain is a difficult challenge because these electrodes cannot be viewed directly during surgery; as a consequence, electrodes in this location are not amenable to documentation by photography. MRI is also poorly suited for localizing ventral brain surface electrode contacts because of the susceptibility artifact created by brain-skull base bony structures interface. On thin-slice CT, metal contacts create such large amounts of artifact that it is impossible to observe brain parenchyma around a contact; however, each electrode contact and its relationship to the outline of the skull can be seen by adjusting the level and width of the display window. Therefore, it is possible to determine the position of contacts in relation to skull base bony structures. Images from CT and MRI are coregistered according to mutual voxel similarity. Finally, the position of electrodes can then be mapped onto the surface rendering of the preoperative brain image.

Electrode contacts on a depth electrode can be localized in relation to surrounding brain structures by postimplantation MRI. Only the larger, low-impedance contacts can be clearly delineated on postimplantation MRI, but with knowledge of the spacing of microwires positioned between these contacts, it is possible to depict accurately where these recording sites are within the brain, and these locations can be depicted on the preimplantation MRI study.^8,16,17

Recording of Electrical Activity

It is technically feasible to obtain massive amounts of ECoG recording data from hundreds of electrode contacts implanted in each surgical patient. Modern signal processing methods also enable investigators to use a wide range of analytic methods to discern what physiologic events are relevant to the cognitive functions being investigated. The practical challenge is to carefully plan and execute experimental protocols so that the results are interpretable and the limitations of the methods used are appropriately recognized. The key practical data collection issues are reviewed and discussed subsequently.

Modern clinical EEG recording equipment converts EEG potentials to digital signals and has the capability of recording more than 100 channels with high sampling rates. Although it is possible to use clinically recorded EEG signal for cognition research, it is better to have dedicated research recording equipment kept separately from the clinical EEG recording system because research recording can be performed more flexibly without disturbing the clinical EEG recording. In addition, the higher sampling rates used for research recordings enable investigators to study high-frequency brain activity that is not captured with standard clinical sampling rates. It is ideal to use battery-driven head stages and optical isolation of the EEG signal from the research amplifier-recording system to minimize the chance of injuring subjects by accidental leakage of current. Most institutional review boards and hospital biomedical engineers require this level of electrical isolation for the patient. This typically requires adaptation of research equipment designed for use in experimental animals, in which this level of isolation is not required. Almost all modern neurophysiologic recording systems have a digital recording design. Recorded data can be stored on digital recording media such as hard disk drives or optical recording media. Stored data can be analyzed offline with various commercially available or custom-made software. Because data are shared among many researchers, it is important to separate a subject’s identifiable information, such as name, initials, medical record number, or birthday, from the data recorded by replacing such information with unique research identifiers pursuant to regulations for the protection of personal health information.

At the University of Iowa we use custom-built connecting cables with a signal breakout box to split the ECoG signal picked up from the subject simultaneously to both a clinical ECoG recording device and a research recording device. These cables make it possible to conduct research recordings without disrupting clinical EEG monitoring. Researchers can use dedicated research recording equipment, and research cables can be disconnected for subjects’ convenience when research activity is not being performed. Depending on the specific research question being addressed, research recordings may require a wider frequency bandwidth.

Frequently, contamination by ambient electronic noise can become a problem, more so for the research recordings than for the clinical EEG recordings. Among various sources of noise, power line noise is typically the most disruptive and requires the greatest attention to eliminate. Although notch filtering may effectively reduce power line noise, such filtering distorts the EEG waveform and may affect the result of frequency analysis. Therefore, every possible effort must be taken to reduce noise contamination at its source. At our institution, research participants are housed in a specially constructed, electromagnetically shielded room in the National Institutes of Health–funded General Clinical Research Center. A significant amount of medical and nonmedical equipment is necessary for both the medical treatment and the convenience of the subjects, who spend up to 2 weeks in the room. It is useful to unplug as many power cords as possible when research recording is being performed. If any equipment can be run on battery power, it should be turned to battery mode. Shielding EEG connecting cables can reduce the extent of noise contamination. If some equipment has to be powered by alternating current, careful attention has to be paid to keep the power cords away from the ECoG recording equipment and connecting cables. Hospital-grade power cords must be used for all equipment, if possible, not only to reduce the noise level but also to reduce the chance of injuring the patient by leakage of current.

Cognitive Task

In properly selected patients with chronic intracranial electrodes, almost any test of cognitive function can be performed while ECoG recordings are under way. These tasks include those involving language functions and complex social behavior such as ethical decision making, as well as economic or financial decision making. Because these cognitive functions have been highly developed in humans, many of these functions cannot be studied in a substantive way in nonhuman animals. Emotion is another complex cognitive function that offers potential advantages for study in humans rather than other species because investigators can directly ask subjects how they are feeling and what kinds of emotions they are experiencing when they are exposed to experimental manipulations.

The following points must be considered carefully when a cognitive task is designed: (1) factors of interest and nuisance factors, (2) timing of stimulus delivery and response, (3) generation and recording of the timing signal, (4) order of stimulus presentation or response, and (5) number of trials.

The factors of interest must be defined clearly. After defining them, it should be determined how many levels each factor has and which nuisance, or confounding, factors need to be controlled. A randomized block design is often used to control contamination with nuisance factors. For example, the development of fatigue or fluctuation of attention level can be problematic in many cognitive tasks. When the effect of conditions A and B is to be compared, if experimental sessions are conducted sequentially by delivering condition A in the first session and condition B in the second session, it is likely that levels of fatigue and attention will not be the same between these sessions. If some difference is found in EEG measurement, it is difficult to assess whether these distinctions were due to differences in experimental conditions or differences in fatigue or attention level. In such cases, randomly interleaving the experimental conditions makes it possible to effectively equalize time-dependent nuisance factors (e.g., fatigue and attention level) between conditions A and B.

The timing of experiments must be planned carefully when the researcher wishes to detect correlations between the cognitive function of interest and EEG responses. Decisions on the interstimulus or intertrial interval should be based on considerations of what cognitive function is of interest and which region of the brain is being studied. For example, for investigation of lower level sensory cognition in a primary sensory cortex, the interstimulus interval can be shorter than that required for investigation of highly complicated cognitive function in the higher order cortex in the temporal or frontal lobe.

The sequence of stimulus presentations needs to be considered carefully to avoid unwanted effects on the EEG response that are related to stimulus order. When more than two stimuli are presented or more than two different responses are required, the order of their occurrence should be randomized, and the frequency of occurrence should also ideally be equalized.

It is necessary to conduct a sufficient number of trials to obtain robust statistical power. This issue is particularly important and challenging for experiments performed on epilepsy surgery patients. In most instances, these patients can maintain a high level of attention and fully participate in complex behavior tasks for less than 30 minutes per experimental block. This limitation has to be considered carefully when deciding how to balance the tradeoff between a large number of different stimuli or a large number of presentations of a smaller number of stimuli. The smaller the effect of experimental manipulation on the ECoG response, the larger the number of trials that are needed to detect and characterize the response induced.