Functional magnetic resonance imaging networks induced by intracranial stimulation may help defining the epileptogenic zone

Abstract

Patients with medically intractable epilepsy often undergo invasive evaluation and surgery, with a 50% success rate. The low success rate is likely due to poor identification of the epileptogenic zone (EZ), the brain area causing seizures. This work introduces a new method using functional magnetic resonance imaging (fMRI) with simultaneous direct electrical stimulation of the brain that could help localize the EZ, performed in five patients with medically intractable epilepsy undergoing invasive evaluation with intracranial depth electrodes. Stimulation occurred in a location near the hypothesized EZ and a location away. Electrical recordings in response to stimulation were recorded and compared to fMRI. Multiple stimulation parameters were varied, like current and frequency. The brain areas showing fMRI response were compared with the areas resected and the success of surgery. Robust fMRI maps of activation networks were easily produced, which also showed a significant but weak positive correlation between quantitative measures of blood-oxygen-level-dependent (BOLD) activity and measures of electrical activity in response to direct electrical stimulation (mean correlation coefficient of 0.38 for all acquisitions that produced a strong BOLD response). For four patients with outcome data at 6 months, successful surgical outcome is consistent with the resection of brain areas containing high local fMRI activity. In conclusion, this method demonstrates the feasibility of simultaneous direct electrical stimulation and fMRI in humans, which allows the study of brain connectivity with high resolution and full spatial coverage. This innovative technique could be used to better define the localization and extension of the EZ in intractable epilepsies, as well as for other functional neurosurgical procedures.

Keywords: connectivity; direct intracranial stimulation; functional MRI; intracranial EEG; intracranial electrodes; intractable epilepsy.

FIG. 1.

Illustration of how cortico-cortical evoked potentials (CCEPs) were scored. The scalar CCEP score used for comparison against functional magnetic resonance imaging (fMRI) was the root-mean-square of the waveform in a 50-msec window (shaded region) following the end of the stimulus artifact. Other commonly used CCEP scores are the peak-to-peak amplitudes of the first and second deflections, also indicated in the figure.

FIG. 2.

Compilation of fMRI activation maps for all high-current stimulation trials (All MRI images in this and subsequent figures follow radiological convention, with the patient's left being in the right of the image.). The activation shown is of the t-statistic, above a threshold of |t|>2.6 (p<0.01). The site of stimulation in each panel is indicated by a color target; green represents the hypothesized epileptogenic zone (EZ), while magenta represents the control. The region outlined in white shows the area of the brain that was surgically resected. The patient's clinical information and stimulation parameters for each panel are summarized in Tables 1 and 2. P1, P2, P3, and P4: patients 1–4, respectively. Seizure freedom indicates whether or not the patient was free of seizures 6 months after resection. Color images available online at www.liebertpub.com/brain

FIG. 3.

Compilation of all low-current or low-frequency fMRI activation maps, for patients P2, P3, and P4 (image right=patient's left). Similar to Figure 2, the activation shown is the t-statistic, above a threshold of |t|>2.6 (p<0.01). The site of stimulation in each panel is indicated by a color target; green represents the hypothesized EZ, while magenta represents the control. The region outlined in white shows the area of the brain that was surgically resected. The patient's clinical information and stimulation parameters for each panel are summarized in Tables 1 and 2. Seizure freedom indicates whether or not the patient was free of seizures 6 months after resection. Color images available online at www.liebertpub.com/brain

FIG. 4.

Raw MR signals in patient P1. The thick red curve shows the MR signal averaged over the positively activated voxels of the limbic area in Figure 2A. The thin blue curve shows the MR signal averaged over the negatively activated voxels in the left motor strip in Figure 2A. Sections shaded in gray indicate the times when stimulation was on (15 mA, 20 Hz). Color images available online at www.liebertpub.com/brain

FIG. 5.

CCEP response versus fMRI response to stimulation. The CCEP score at each recording contact is plotted against the fMRI t-statistic in the coregistered voxel. Different colors represent different trials/patients. The trials included in the plot, along with a summary of the parameters used, are indicated in Table 2 by an asterisk (*). CCEP and fMRI scores are standardized for each trial to account for differences in the ranges of scores observed. Error bars represent the standard deviation of the CCEP recordings used to produce the average waveforms. The dashed line shows the least squares line of best fit. Color images available online at www.liebertpub.com/brain

FIG. 6.

CCEP response versus fMRI response to stimulation, using peak-to-peak scoring of CCEPs. The plots above show the same data as Figure 5, but the CCEPs are scored using peak-to-peak amplitudes rather than root-mean-square (see Fig. 1). The panel on the left uses the first peak-to-peak amplitude (r=0.43; p=2.6×10⁻¹⁶; n=326), while the panel on the right uses the second peak-to-peak amplitude (r=0.44; p=9.7×10⁻¹⁷; n=326). Color images available online at www.liebertpub.com/brain

FIG. 7.

Averaged positive blood-oxygen-level-dependent (BOLD) response in patient P2. Activation was generated at 4 mA (green, dashed) and 8 mA (blue, solid) stimulation. The y-axis shows the MR signal averaged over all voxels with t>3 in both low- and high-current runs. Sections shaded in gray represent the times when the stimulation was on. Color images available online at www.liebertpub.com/brain

FIG. 8.

Effect of anesthesia on CCEPs. Shown are CCEP recordings at two electrode contacts, taken from a trial on patient P2 without (blue, solid) and with (green, dashed) anesthesia. The contact on the left shows a small effect of anesthesia representative of most recording contacts (134/140). The panel on the right shows a larger effect of anesthesia, but this was observed in very few recording contacts (6/140). Color images available online at www.liebertpub.com/brain

FIG. 9.

Event versus block stimulation paradigm (image right=patient's left). The top panel (A) shows the event design applied a hypothesized EZ in the right anterior insula, using a stimulation lasting 2 sec (8 mA at 20 Hz), followed by 11 sec of rest. The bottom panel (B) shows images from the same patient with application of a corresponding block design, also at 8 mA and 20 Hz. In both cases there is a display threshold of t=3, and the maximum color is t=9. Only positive activation is shown for clarity. Color images available online at www.liebertpub.com/brain