Multivariate regression methods for estimating velocity of ictal discharges from human microelectrode recordings

Objective. Epileptiform discharges, an electrophysiological hallmark of seizures, can propagate across cortical tissue in a manner similar to traveling waves. Recent work has focused attention on the origination and propagation patterns of these discharges, yielding important clues to their source location and mechanism of travel. However, systematic studies of methods for measuring propagation are lacking. Approach. We analyzed epileptiform discharges in microelectrode array recordings of human seizures. The array records multiunit activity and local field potentials at 400-micron spatial resolution, from a small cortical site free of obstructions. We evaluated several computationally efficient statistical methods for calculating traveling wave velocity, benchmarking them to analyses of associated neuronal burst firing. Main results. Over 90% of discharges met statistical criteria for propagation across the sampled cortical territory. Detection rate, direction and speed estimates derived from a multiunit estimator were compared to four field potential-based estimators: negative peak, maximum descent, high gamma power, and cross-correlation. Interestingly, the methods that were computationally simplest and most efficient (negative peak and maximal descent) offer non-inferior results in predicting neuronal traveling wave velocities compared to the other two, more complex methods. Moreover, the negative peak and maximal descent methods proved to be more robust against reduced spatial sampling challenges. Using least absolute deviation in place of least squares error minimized the impact of outliers, and reduced the discrepancies between local field potential-based and multiunit estimators. Significance. Our findings suggest that ictal epileptiform discharges typically take the form of exceptionally strong, rapidly traveling waves, with propagation detectable across millimeter distances. The sequential activation of neurons in space can be inferred from clinically-observable EEG data, with a variety of straightforward computation methods available. This opens possibilities for systematic assessments of ictal discharge propagation in clinical and research settings

The ictal wavefront is the spatiotemporal source of discharges during spontaneous human seizures

The extensive distribution and simultaneous termination of seizures across cortical areas has led to the hypothesis that seizures are caused by large-scale coordinated networks spanning these areas. This view, however, is difficult to reconcile with most proposed mechanisms of seizure spread and termination, which operate on a cellular scale. We hypothesize that seizures evolve into self-organized structures wherein a small seizing territory projects high-intensity electrical signals over a broad cortical area. Here we investigate human seizures on both small and large electrophysiological scales. We show that the migrating edge of the seizing territory is the source of travelling waves of synaptic activity into adjacent cortical areas. As the seizure progresses, slow dynamics in induced activity from these waves indicate a weakening and eventual failure of their source. These observations support a parsimonious theory for how large-scale evolution and termination of seizures are driven from a small, migrating cortical area

Epileptogenic but MRI-normal perituberal tissue in Tuberous Sclerosis Complex contains tuber-specific abnormalities

Introduction: Recent evidence has implicated perituberal, MRI-normal brain tissue as a possible source of seizures in tuberous sclerosis complex (TSC). Data on aberrant structural features in this area that may predispose to the initiation or progression of seizures are very limited. We used immunohistochemistry and confocal microscopy to compare epileptogenic, perituberal, MRI-normal tissue with cortical tubers. Results: In every sample of epileptogenic, perituberal tissue, we found many abnormal cell types, including giant cells and cytomegalic neurons. The majority of giant cells were surrounded by morphologically abnormal astrocytes with long processes typical of interlaminar astrocytes. Perituberal giant cells and astrocytes together formed characteristic “microtubers”. A parallel analysis of tubers showed that many contained astrocytes with features of both protoplasmic and gliotic cells. Conclusions: Microtubers represent a novel pathognomonic finding in TSC and may represent an elementary unit of cortical tubers. Microtubers and cytomegalic neurons in perituberal parenchyma may serve as the source of seizures in TSC and provide potential targets for therapeutic and surgical interventions in TSC

Patient-Specific Metrics of Invasiveness Reveal Significant Prognostic Benefit of Resection in a Predictable Subset of Gliomas

Object Malignant gliomas are incurable, primary brain neoplasms noted for their potential to extensively invade brain parenchyma. Current methods of clinical imaging do not elucidate the full extent of brain invasion, making it difficult to predict which, if any, patients are likely to benefit from gross total resection. Our goal was to apply a mathematical modeling approach to estimate the overall tumor invasiveness on a patient-by-patient basis and determine whether gross total resection would improve survival in patients with relatively less invasive gliomas. Methods In 243 patients presenting with contrast-enhancing gliomas, estimates of the relative invasiveness of each patient's tumor, in terms of the ratio of net proliferation rate of the glioma cells to their net dispersal rate, were derived by applying a patient-specific mathematical model to routine pretreatment MR imaging. The effect of varying degrees of extent of resection on overall survival was assessed for cohorts of patients grouped by tumor invasiveness. Results We demonstrate that patients with more diffuse tumors showed no survival benefit (P = 0.532) from gross total resection over subtotal/biopsy, while those with nodular (less diffuse) tumors showed a significant benefit (P = 0.00142) with a striking median survival benefit of over eight months compared to sub-totally resected tumors in the same cohort (an 80% improvement in survival time for GTR only seen for nodular tumors). Conclusions These results suggest that our patient-specific, model-based estimates of tumor invasiveness have clinical utility in surgical decision making. Quantification of relative invasiveness assessed from routinely obtained pre-operative imaging provides a practical predictor of the benefit of gross total resection

Patient-Specific Simulations of Tumor Cell Distribution and Density for both a Relatively Diffuse and a Relatively Nodular Glioblastoma.

<p>T1Gd and T2 MRIs for two newly diagnosed glioblastoma patients, one relatively diffuse with a low ρ/D (a,c) and one more nodular with a high ρ/D (b,d). A simulation of the diffuse glioma extent predicted by the patient-specific simulation for the diffuse (low ρ/D) patient (e) and the more nodular (high ρ/D) patient (f) is overlayed on the T1Gd MRI with red and blue indicating high and low (but nonzero) glioma cell density, respectively. The effect of GTR is shown as a black region with a white outline and highlights the significant diffuse extent of glioma cells remaining post-GTR. In the more nodular (high ρ/D) case, GTR removes 75% of the pre-treatment glioma cells leaving 8.4e8 cells while in the diffusely invasive (low ρ/D) case, GTR removes only 27% of the pre-treatment glioma cells leaving 4.2e9 cells, an order of magnitude higher than the nodular case. The large number of tumor cells remaining after resection of a diffuse tumor drives recurrence.</p

Results of iterative Kaplan-Meier Analysis in each invasiveness cohort.

<p>Number of cells remaining was calculated for each patient, based on their ρ/D and measured residual enhancing disease. Each possible threshold was iterated through to separate the patients into large and small residual tumor cell population cohorts. White boxes correspond to thresholds separating patients into groups with significantly different (p<0.05) survival. White stars indicate tests with no p-value, as the threshold did not separate the patients in the given invasiveness cohort into two groups. Black asterisks indicate tests with p<0.05. Black bins with white x's indicate no the threshold did not separate the patients in the given invasiveness cohort into two groups. For example, for the diffuse case (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099057#pone-0099057-g003" target="_blank">Figure 3</a>, top row), the black bins with white x's represent the fact that even GTR was unable to achieve a remaining cell burden less than the cutoff (up to approximately 10⁹). Further, amongst the most diffuse gliomas, no threshold for a residual cells following resection was found to be significant of outcome represented visually as the lack of a white bar in the top row. Although less dramatic, the moderate cohort was unable to equate a GTR with <10^8.5 cells remaining represented by the black bars with white x's to the left on middle row of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099057#pone-0099057-g003" target="_blank">Figure 3</a>. While resection of tumors in the nodular cohort were able to attain residual disease burdens at all levels down to <10⁷ cells.</p

ρ/D Assessment.

<p>This figure presents an overview of how the “relative invasiveness,” or ρ/D, is obtained. Tumor volumes are segmented from T1Gd and T2 MRI. The measured volume is approximated with a sphere in order to obtain a radius. The T1Gd and T2 radii are associated with different levels of detection, with T2 at low tumor cell density and T1Gd abnormality associated with high tumor cell density. The relationship between these two radii describes the steepness of the tumor cell profile, or “relative invasiveness.”</p

Clinical Data Table.

<p>Median age and range, distribution of males and females, race (unknown, Caucasian, Asian, Hispanic, Black), median KPS and range, median XRT Dose and range, number of patients diagnosed in the 90's, number of patients diagnosed in 2000 or later, number receiving preoperative steroids, and number of patients who received concurrent Temozolomide with XRT are shown. Proportion chi-square tests were performed to compare steroid administration, concurrent TMZ, and proportion of patients who received GTR vs. STR/Bx between the three invasiveness cohorts. No statistical difference at the P = 0.05 significance level was found in any of these variables between cohorts. ANOVA tests were performed to compare KPS scores, age, and XRT doses between invasiveness cohorts. No difference at the P = 0.05 significance level was found in any of these variables between cohorts.</p><p>* - Indicates no significant difference (p≤0.05) between cohorts in this variable, per Proportion Chi-square test.</p><p>** - Indicates no significant difference (p≤0.05) between cohorts in this variable, per ANOVA test.</p><p>Clinical Data Table.</p