Seizure-onset regions demonstrate high inward directed connectivity during resting-state: An SEEG study in focal epilepsy

Abstract

Objective: In patients with medically refractory focal epilepsy, stereotactic-electroencephalography (SEEG) can aid in localizing epileptogenic regions for surgical treatment. SEEG, however, requires long hospitalizations to record seizures, and ictal interpretation can be incomplete or inaccurate. Our recent work showed that non-directed resting-state analyses may identify brain regions as epileptogenic or uninvolved. Our present objective is to map epileptogenic networks in greater detail and more accurately identify seizure-onset regions using directed resting-state SEEG connectivity.

Methods: In 25 patients with focal epilepsy who underwent SEEG, 2 minutes of resting-state, artifact-free, SEEG data were selected and functional connectivity was estimated. Using standard clinical interpretation, brain regions were classified into four categories: ictogenic, early propagation, irritative, or uninvolved. Three non-directed connectivity measures (mutual information [MI] strength, and imaginary coherence between and within regions) and four directed measures (partial directed coherence [PDC] and directed transfer function [DTF], inward and outward strength) were calculated. Logistic regression was used to generate a predictive model of ictogenicity.

Results: Ictogenic regions had the highest and uninvolved regions had the lowest MI strength. Although both PDC and DTF inward strengths were highest in ictogenic regions, outward strengths did not differ among categories. A model incorporating directed and nondirected connectivity measures demonstrated an area under the receiver-operating characteristic (ROC) curve (AUC) of 0.88 in predicting ictogenicity of individual regions. The AUC of this model was 0.93 when restricted to patients with favorable postsurgical seizure outcomes.

Significance: Directed connectivity measures may help identify epileptogenic networks without requiring ictal recordings. Greater inward but not outward connectivity in ictogenic regions at rest may represent broad inhibitory input to prevent seizure generation.

Keywords: focal epilepsy; functional connectivity; intracranial EEG; localization; prediction.

FIGURE 1

Brain regions with greater epileptogenicity demonstrate higher mutual information (MI) strength. A, MI strength in epileptogenic regions (mean ± standard deviation) (0.40 ± 0.14) is higher than in nonepileptogenic structures (0.24 ± 0.07), using a dichotomized classification scheme of epileptogenicity (paired-sample t test). B, MI strength was compared between regions using four categories of epileptogenicity using a one-way analysis of variance (ANOVA) with Tukey’s honest significant difference criterion (THSDC) post hoc. MI strength of ictogenic regions (0.45 ± 0.20) was higher than irritative (0.31 ± 0.17) and uninvolved (0.22 ± 0.07) regions. In both panels, the central red line represents the median, and the top and bottom lines indicate the 75th and 25th percentiles, respectively. The red dots represent outliers, and the whiskers visualize the extremes of the data. (N = 25 focal epilepsy patients.) *P < .05, **P < .01, ***P < .001 with Bonferroni-Holm correction for multiple comparisons for t tests, where applicable

FIGURE 2

Mutual information (MI) strength maps in two example patients. A, Patient 1 is a right-handed, 29-year-old woman with 8 y duration of epilepsy. The ictogenic regions (red) are the left and right hippocampi. The early propagation region (orange)is the right amygdala, and the irritative region (green) is the left parahippocampal gyrus. In this patient, ictogenic regions demonstrate highest MI strength. B, Patient 2 is a right-handed, 24-year-oldman with 10 y duration of epilepsy. The ictogenic regions (red) are the right inferior frontal gyrus and middle frontal gyrus. The early propagation regions (orange) are the right insula, frontal operculum cortex, hippocampus, and middle temporal gyrus. The irritative regions (green) are the right precentral gyrus and superior frontal gyrus. In this patient, no clear relationship was seen between epileptogenicity and MI strength. In both panels, the size of the spheres is proportional to MI strength of the region. A full list of the regions sampled are listed in Figure 4 legend. A = anterior, L = left, P = posterior, R = right

FIGURE 3

Ictogenic regions demonstrate higher inward but not outward directed connectivity. Strengths of PDC inward (A), PDC outward (B), DTF inward (C), and DTF outward (D) are shown across all patients. Ictogenic regions demonstrate higher inward strength (A, C) but not outward strength (B, D) using both directed connectivity measures. The PDC inward strength values (mean ± standard deviation) are: ictogenic (0.47 ± 0.17), early propagation (0.28 ± 0.19), irritative (0.24 ± 0.12), and uninvolved (0.25 ± 0.11). The DTF inward strength values are: ictogenic (0.43 ± 0.16), early propagation (0.35 ± 0.12), irritative (0.32 ± 0.11), and uninvolved (0.30 ± 0.10). In all four panels, the central red line represents the median, and the top and bottom lines indicate the 75th and 25th percentiles, respectively. The red dots represent outliers, and the whiskers visualize the extremes of the data. (N = 25 patients.) *P < .05, **P < .01, ***P < .001, one-way ANOVA with THSDC post hoc. DTF = directed transfer function, PDC = partial directed coherence

FIGURE 4

Directed connectivity maps in two example patients. PDC matrices (A, C) and the DTF matrices(B, D) are shown in two example patients, where arrows represent the directionality of the connection and line thickness is proportional to thresholded, rescaled PDC and DTF values. In both patients, structures with greater epileptogenicity, particularly ictogenic regions, demonstrated a larger number of high-magnitude inward connections compared to uninvolved areas. Patients1 and 2 correspond to the same patients shown in Figure 2. R = right, L = left; AC = anterior cingulate gyrus, Amy = amygdala, COpC = central operculum cortex, DTF = directed transfer function, FG = anterior temporal fusiform gyrus, FOpC = frontal operculum cortex, FP = frontal pole, Hip = hippocampus, IFG = inferior frontal gyrus, Ins = insular cortex, MFG = middle frontal gyrus, MTG = middle temporal gyrus, OrFC = frontal orbital cortex, PDC = partial directed coherence, PHG = parahippocampal gyrus, PreG = precentral gyrus, SFG = superior frontal gyrus, SMA = supplementary motor area, STG = superior temporal gyrus

FIGURE 5

A model incorporating directed and nondirected connectivity measures may help predict ictogenicity of individual brain regions. Receiver-operating characteristic (ROC) curves demonstrate the true-positive and false-positive rates in predicting ictogenicity of 357 total individual brain regions across all 25 patients. Five individual connectivity measures (A, B) and a model (C) that combines these measures with a binary logistic regression analysis are shown. The area under the curve (AUC) values of the nondirected measures (A) varies between 0.64 and 0.77. The AUC values for PDC inward strength and DTF inward strength (B) are 0.84 and 0.72, respectively. The AUC for the summary model (C) is 0.88. The dotted red lines indicate the sensitivity (79.4%) and specificity (81.9%) of the model in predicting ictogenic vs nonictogenic brain regions at maximum sensitivity plus specificity. DTF = directed transfer function, ImCoh = imaginary coherence (alpha-band), PDC = partial directed coherence