Interictal Connectivity Revealed by Granger Analysis of Stereoelectroencephalography: Association With Ictal Onset Zone, Resection, and Outcome.

BACKGROUND: Stereoelectroencephalography (sEEG) facilitates electrical sampling and evaluation of complex deep-seated, dispersed, and multifocal locations. Granger causality (GC), previously used to study seizure networks using interictal data from subdural grids, may help identify the seizure-onset zone from interictal sEEG recordings. OBJECTIVE: To examine whether statistical analysis of interictal sEEG helps identify surgical target sites and whether surgical resection of highly ranked nodes correspond to favorable outcomes. METHODS: Ten minutes of extraoperative recordings from sequential patients who underwent sEEG evaluation were analyzed (n = 20). GC maps were compared with clinically defined surgical targets using rank order statistics. Outcomes of patients with focal resection/ablation with median follow-up of 3.6 years were classified as favorable (Engel 1, 2) or poor (Engel 3, 4) to assess their relationship with the removal of highly ranked nodes using the Wilcoxon rank-sum test. RESULTS: In 12 of 20 cases, the rankings of contacts (based on the sum of outward connection weights) mapped to the seizure-onset zone showed higher causal node connectivity than predicted by chance ( P ≤ .02). A very low aggregate probability ( P < 10 -18 , n = 20) suggests that causal node connectivity predicts seizure networks. In 8 of 16 with outcome data, causal connectivity in the resection was significantly greater than in the remaining contacts ( P ≤ .05). We found a significant association between favorable outcome and the presence of highly ranked nodes in the resection ( P < .05). CONCLUSION: Granger analysis can identify seizure foci from interictal sEEG and correlates highly ranked nodes with favorable outcome, potentially informing surgical decision-making without reliance on ictal recordings.

Posterior quadrant disconnection for refractory epilepsy: how I do it.

BACKGROUND: Posterior quadrant disconnection (PQD) is intended to interrupt the propagation of intractable unilateral temporo-parieto-occipital epilepsy. METHOD: An enhanced operative video presents the illustrative case of a total PQD indicated for a 15-year-old boy with Sturge-Weber syndrome suffering from seizure recurrence after a partial PQD. We describe the surgical procedure with emphasis on relevant anatomy and multimodal intraoperative guidance in three steps: (i) parieto-occipital disconnection, (ii) posterior callosotomy, and (iii) temporal disconnection/resection. Pearls and pitfalls of surgical management are discussed. CONCLUSION: PQD is a less invasive surgical option to typical hemispherotomy and hemispherectomy for selected indications of posterior multilobar epilepsy.

Complete Corpus Callosotomy for Refractory Epilepsy in Children.

Corpus callosotomy is an interhemispheric disconnection by callosal commissural fiber ablation. Its rationale is the disruption of ictal spread to prevent seizure generalization. The objective pursued is alleviation of intractable, debilitating, and injurious manifestations of generalized epilepsy.1 Eight decades of experience support this procedure's safety and effectiveness for appropriately selected patients with drug-resistant epilepsy not amenable to optimal resection; particularly, favorable outcomes for tonic or atonic seizures with drop attacks have been reported.2,3 Children may benefit more than adults from callosotomy for improved daily function, psychosocial adjustment, and family satisfaction.4 A meta-analysis found a better seizure reduction from total than partial callosotomy (88.2% vs. 58.6% of worthwhile reduction) comprising drop-attacks (77.8% vs. 45.4%) with an increased but transient (i.e., resolution within 6 weeks) risk of significant disconnection syndromes (12.5% vs. none).5 Here, we present the illustrative case of a 4-year-old boy with Lennox-Gastaut syndrome who underwent open single-stage complete callosotomy. Video 1 shows the microscope-assisted interhemispheric approach aided by stereotactic navigation. We showcase critical steps such as dissection of cingulate gyri and anterior and then posterior callosotomy while highlighting crucial anatomic landmarks. This procedure may be accessible for epilepsy surgeons worldwide in resource-constrained environments6 while serving as a basis for promising high-technology development (e.g., endoscopic, radiosurgical, laser interstitial thermal therapy, or magnetic resonance-guided focused ultrasound callosotomies). In this video article, we aim to provide a streamlined and stepwise approach to this rare but important epilepsy surgery.

Single-stage resection of bottom-of-a-sulcus dysplasia involving eloquent cortex using navigated transcranial magnetic stimulation and intraoperative modalities.

BACKGROUND: Focal cortical dysplasia (FCD) is a common etiology of refractory epilepsy, particularly in children. Surgical management is potentially curative, but poses the challenge of distinguishing the border between ictogenic regions of dysplasia and functionally critical brain tissue. Bottom-of-a-sulcus dysplasia (BOSD) amplifies this challenge, due to difficulties in physiologic mapping of the deep tissue. METHODS: We report a one-stage resection of a dysplasia-associated seizure focus abutting and involving the hand and face primary motor cortex. In doing so, we describe our surgical planning integrating neuronavigated transcranial magnetic stimulation (nTMS) for functional motor mapping, combined with intraoperative ultrasonography, intracranial electroencephalography, and magnetic resonance imaging (MRI). A 5-year-old girl with intractable focal epilepsy was referred to our comprehensive epilepsy program. Despite attentive pharmacotherapy, she experienced status epilepticus and up to 70 seizures per day, accompanied by multiple side effects from her antiseizure medication. A right frontal BOSD in close proximity to the hand motor area of the precentral gyrus was identified on MRI. Postoperatively, she is seizure-free for over 1 year with no hand deficit. CONCLUSION: Although technically complex, single-stage resection taking advantage of comprehensive surgical planning with optimized fusion of functional mapping and intraoperative modalities merits consideration given the invasiveness of a two-stage approach for limited added value. Integrated pre-surgical nTMS allowed for mapping of eloquent cortex without invasive electrocortical stimulation.

Diagnostic Accuracy of Non-Invasive Thermal Evaluation of Ventriculoperitoneal Shunt Flow in Shunt Malfunction: A Prospective, Multi-Site, Operator-Blinded Study.

BACKGROUND: Thermal flow evaluation (TFE) is a non-invasive method to assess ventriculoperitoneal shunt function. Flow detected by TFE is a negative predictor of the need for revision surgery. Further optimization of testing protocols, evaluation in multiple centers, and integration with clinical and imaging impressions prompted the current study. OBJECTIVE: To compare the diagnostic accuracy of 2 TFE protocols, with micropumper (TFE+MP) or without (TFE-only), to neuro-imaging in patients emergently presenting with symptoms concerning for shunt malfunction. METHODS: We performed a prospective multicenter operator-blinded trial of a consecutive series of patients who underwent evaluation for shunt malfunction. TFE was performed, and preimaging clinician impressions and imaging results were recorded. The primary outcome was shunt obstruction requiring neurosurgical revision within 7 d. Non-inferiority of the sensitivity of TFE vs neuro-imaging for detecting shunt obstruction was tested using a prospectively determined a priori margin of -2.5%. RESULTS: We enrolled 406 patients at 10 centers. Of these, 68/348 (20%) evaluated with TFE+MP and 30/215 (14%) with TFE-only had shunt obstruction. The sensitivity for detecting obstruction was 100% (95% CI: 88%-100%) for TFE-only, 90% (95% CI: 80%-96%) for TFE+MP, 76% (95% CI: 65%-86%) for imaging in TFE+MP cohort, and 77% (95% CI: 58%-90%) for imaging in the TFE-only cohort. Difference in sensitivities between TFE methods and imaging did not exceed the non-inferiority margin. CONCLUSION: TFE is non-inferior to imaging in ruling out shunt malfunction and may help avoid imaging and other steps. For this purpose, TFE only is favored over TFE+MP.

Identification of Heterodera glycines (Tylenchida; Heteroderidae) Using qPCR.

The soybean cyst nematode, Heterodera glycines, is a major plant-parasitic nematode that has caused important economic losses to Korea's soybean production. Four species of cyst nematodes, H. schachtii, H. glycines, H. trifolii, and H. sojae, all belong to schachtii group are coexist in field soil in Korea. The rapid identification of the nematode is crucial for preventing crop damage and in decision making for controlling this nematode. This study aimed to develop a species-specific primer set for quantitative PCR (qPCR) assay of H. glycines. The specific primer set (HGF1 and HGR1) for H. glycines was designed based on the cytochrome c oxidase subunit I (COI) sequence of mitochondrial DNA. After optimization, it is possible to identify the H. glycines using a qPCR assay with DNA extracted from a single cyst and single second-stage juvenile (J2). The specificity was confirmed by the absence of SYBR fluorescent signals of three other Heterodera species. A serial dilution of DNA extracted from a single cyst was obtained for the sensitivity test. The result showed that the standard curve of the test had a highly significant linearity between DNA concentration and Ct value (R 2 = 0.996, slope = -3.49) and that the detection limit concentration of DNA of the primer set was 10 pg of DNA per reaction. Our findings suggested that H. glycines could be distinguished from H. sojae and other Heterodera species when a qPCR assay is used with a specific primer set.

Surgical resection of ripple onset predicts outcome in pediatric epilepsy.

OBJECTIVE: In patients with medically refractory epilepsy (MRE), interictal ripples (80-250Hz) are observed in large brain areas whose resection may be unnecessary for seizure freedom. This limits their utility as epilepsy biomarkers for surgery. We assessed the spatiotemporal propagation of interictal ripples on intracranial electroencephalography (iEEG) in children with MRE, compared it with the propagation of spikes, identified ripples that initiated propagation (onset-ripples), and evaluated their clinical value as epilepsy biomarkers. METHODS: Twenty-seven children who underwent epilepsy surgery were studied. We identified propagation sequences of ripples and spikes across multiple iEEG contacts and calculated each ripple or spike latency from the propagation onset. We classified ripples and spikes into categories (ie, onset, spread, and isolated) based on their spatiotemporal characteristics and correlated their mean rate inside and outside resection with outcome (good outcome, Engel 1 versus poor outcome, Engel≥2). We determined, as onset-zone, spread-zone, and isolated-zone, the areas generating the corresponding ripple or spike category and evaluated the predictive value of their resection. RESULTS: We observed ripple propagation in all patients and spike propagation in 25 patients. Mean rate of onset-ripples inside resection predicted the outcome (odds ratio = 5.37; p = 0.02) and correlated with Engel class (rho = -0.55; p = 0.003). Resection of the onset-ripple-zone was associated with good outcome (p = 0.047). No association was found for the spread-ripple-zone, isolated-ripple-zone, or any spike-zone. INTERPRETATION: Interictal ripples propagate across iEEG contacts in children with MRE. The association between the onset-ripple-zone resection and good outcome indicates that onset-ripples are promising epilepsy biomarkers, which estimate the epileptogenic tissue better than spread-ripples or onset-spikes. Ann Neurol 2018;84:331-346.

Granger Causality Analysis of Interictal iEEG Predicts Seizure Focus and Ultimate Resection.

BACKGROUND: A critical conceptual step in epilepsy surgery is to locate the causal region of seizures. In practice, the causal region may be inferred from the set of electrodes showing early ictal activity. There would be advantages in deriving information about causal regions from interictal data as well. We applied Granger's statistical approach to baseline interictal data to calculate causal interactions. We hypothesized that maps of the Granger causality network (or GC maps) from interictal data might inform about the seizure network, and set out to see if "causality" in the Granger sense correlated with surgical targets. OBJECTIVE: To determine whether interictal baseline data could produce GC maps, and whether the regions of high GC would statistically resemble the topography of the ictally active electrode (IAE) set and resection. METHODS: Twenty-minute interictal baselines obtained from 25 consecutive patients were analyzed. The "GC maps" were quantitatively compared to conventionally constructed surgical plans, by using rank order and Cartesian distance statistics. RESULTS: In 16 of 25 cases, the interictal GC rankings of the electrodes in the IAE set were lower than predicted by chance (P < .05). The aggregate probability of such a match by chance alone is very small (P < 10-20) suggesting that interictal GC maps correlated with ictal networks. The distance of the highest GC electrode to the IAE set and to the resection averaged 4 and 6 mm (Wilcoxon P < .001). CONCLUSION: GC analysis has the potential to help localize ictal networks from interictal data.

Impaired pulsation absorber mechanism in idiopathic normal pressure hydrocephalus: laboratory investigation.

OBJECT: The pathophysiology of normal pressure hydrocephalus (NPH), and the related problem of patient selection for treatment of this condition, have been of great interest since the description of this seemingly paradoxical condition nearly 50 years ago. Recently, Eide has reported that measurements of the amplitude of the intracranial pressure (ICP) can both positively and negatively predict response to CSF shunting. Specifically, the fraction of time spent in a "high amplitude" (> 4 mm Hg) state predicted response to shunting, which may represent a marker for hydrocephalic pathophysiology. Increased ICP amplitude might suggest decreased brain compliance, meaning a static measure of a pressure-volume ratio. Recent studies of canine data have shown that the brain compliance can be described as a frequency-dependent function. The normal canine brain seems to show enhanced ability to absorb the pulsations around the heart rate, quantified as a cardiac pulsation absorbance (CPA), with properties like a notch filter in engineering. This frequency dependence of the function is diminished with development of hydrocephalus in dogs. In this pilot study, the authors sought to determine whether frequency dependence could be observed in humans, and whether the frequency dependence would be any different in epochs with high ICP amplitude compared with epochs of low ICP amplitude. METHODS: Systems analysis was applied to arterial blood pressure (ABP) and ICP waveforms recorded from 10 patients undergoing evaluations of idiopathic NPH to calculate a time-varying transfer function that reveals frequency dependence and CPA, the measure of frequency-dependent compliance previously used in animal experiments. The ICP amplitude was also calculated in the same samples, so that epochs with high (> 4 mm Hg) versus low (≤ 4 mm Hg) amplitude could be compared in CPA and transfer functions. RESULTS: Transfer function analysis for the more "normal" epochs with low amplitude exhibits a dip or notch in the physiological frequency range of the heart rate, confirming in humans the pulsation absorber phenomenon previously observed in canine studies. Under high amplitude, however, the dip in the transfer function is absent. An inverse relationship between CPA index and ICP amplitude is evident and statistically significant. Thus, elevated ICP amplitude indicates decreased performance of the human pulsation absorber. CONCLUSIONS: The results suggest that the human intracranial system shows frequency dependence as seen in animal experiments. There is an inverse relationship between CPA index and ICP amplitude, indicating that higher amplitudes may occur with a reduced performance of the pulsation absorber. Our findings show that frequency dependence can be observed in humans and imply that reduced frequency-dependent compliance may be responsible for elevated ICP amplitude observed in patients who respond to CSF shunting.

Alterations of pulsation absorber characteristics in experimental hydrocephalus.

OBJECT: Analysis of waveform data in previous studies suggests that the pulsatile movement of CSF may play a role in attenuating strong arterial pulsations entering the cranium, and its effectiveness in attenuating these pulsations may be altered by changes in intracranial pressure (ICP). These findings were obtained in studies performed in canines with normal anatomy of the CSF spaces. How then would pulsation absorbance respond to changes in CSF movement under obstructive conditions such as the development of hydrocephalus? In the present study, chronic obstructive hydrocephalus was induced by the injection of cyanoacrylate gel into the fourth ventricle of canines, and pulsation absorbance was compared before and after hydrocephalus induction. METHODS: Five animals were evaluated with simultaneous recordings of ICP and arterial blood pressure (ABP) before and at 4 and 12 weeks after fourth ventricle obstruction by cyanoacrylate. To assess how the intracranial system responds to the arterial pulsatile component, ABP and ICP waveforms recorded in a time domain had to be analyzed in a frequency domain. In an earlier study the authors introduced a particular technique that allows characterization of the intracranial system in the frequency domain with sufficient accuracy and efficiency. This same method was used to analyze the relationship between ABP and ICP waveforms recorded during several acute states including hyperventilation as well as CSF withdrawal and infusion under conditions before and after inducing chronic obstructive hydrocephalus. Such a relationship is reflected in terms of a gain, which is a function of frequency. The cardiac pulsation absorbance (CPA) index, which is simply derived from a gain evaluated at the cardiac frequency, was used to quantitatively evaluate the changes in pulsation absorber function associated with the development of hydrocephalus within each of the animals, which did become hydrocephalic. To account for normal and hydrocephalic conditions within the same animal and at multiple time points, statistical analysis was performed by repeated-measures ANOVA. RESULTS: The performance of the pulsation absorber as assessed by CPA significantly deteriorated after the development of chronic hydrocephalus. In these animals the decrement in CPA was far more significant than other anticipated changes including those in ICP, compliance, or ICP pulse amplitude. CONCLUSIONS: To the extent that the free CSF movement acts as a buffer of arterial pulsation input to flow in microvessels, alterations in the pulsation absorber may play a pathophysiological role. One measure of alterations in the way the brain deals with pulsatile input-the CPA measurement-changes dramatically with the imposition of hydrocephalus. Results in the present study suggest that CPA may serve as a complementary metric to the conventional static measure of intracranial compliance in other experimental and clinical studies.

Potassium diffusive coupling in neural networks.

Conventional neural networks are characterized by many neurons coupled together through synapses. The activity, synchronization, plasticity and excitability of the network are then controlled by its synaptic connectivity. Neurons are surrounded by an extracellular space whereby fluctuations in specific ionic concentration can modulate neuronal excitability. Extracellular concentrations of potassium ([K(+)](o)) can generate neuronal hyperexcitability. Yet, after many years of research, it is still unknown whether an elevation of potassium is the cause or the result of the generation, propagation and synchronization of epileptiform activity. An elevation of potassium in neural tissue can be characterized by dispersion (global elevation of potassium) and lateral diffusion (local spatial gradients). Both experimental and computational studies have shown that lateral diffusion is involved in the generation and the propagation of neural activity in diffusively coupled networks. Therefore, diffusion-based coupling by potassium can play an important role in neural networks and it is reviewed in four sections. Section 2 shows that potassium diffusion is responsible for the synchronization of activity across a mechanical cut in the tissue. A computer model of diffusive coupling shows that potassium diffusion can mediate communication between cells and generate abnormal and/or periodic activity in small (section sign 3) and in large networks of cells (section sign 4). Finally, in section sign 5, a study of the role of extracellular potassium in the propagation of axonal signals shows that elevated potassium concentration can block the propagation of neural activity in axonal pathways. Taken together, these results indicate that potassium accumulation and diffusion can interfere with normal activity and generate abnormal activity in neural networks.

Intracranial pressure waves: characterization of a pulsation absorber with notch filter properties using systems analysis: laboratory investigation.

OBJECT: The relationship between the waveform of intracranial pressure (ICP) and arterial blood pressure can be quantitatively characterized using a newly developed technique in systems analysis, the time-varying transfer function. This technique considers the arterial blood pressure as an input signal composed of multiple frequencies represented in the output ICP according to the transfer function imposed by the intracranial system on the input signal. The transfer function can change with time and with physiological manipulations. The authors examined data obtained from canine experiments involving manipulations of ICP. METHODS: The authors analyzed 11 experiments from 3 normal mongrel dogs under conditions of normal ICP and with changes in ICP made by bolus injection, infusion, or withdrawal of cerebrospinal fluid by using time-varying transfer function. RESULTS: During normal ICP periods, the gain of the transfer function displayed a deep notch (> or = 1 log unit) centered at or near the cardiac frequency. In systems terms, the intracranial compartment under normal conditions appears to act as a notch filter attenuating the cardiac frequency input relative to other frequencies. Epochs of ICP elevation showed suppression of the notch, and the notch was restored when ICP returned to normal. CONCLUSIONS: The intracranial system in these animals could be considered to include a pulsation absorber for which the target frequency appears to be close to the cardiac frequency. One possible source for such an absorber mechanism might be the free movement of cerebrospinal fluid, implying that impairment of this motion may have important clinical implications in various neurological conditions such as hydrocephalus.

Diffusive coupling and network periodicity: a computational study.

Diffusive coupling (nearest-neighbor coupling) is the most common type of coupling present in many systems. Previous experimental and theoretical studies have shown that potassium lateral diffusion coupling (i.e., diffusive coupling) can be responsible for synchronization of neuronal activity. Recent in vivo experiments carried out with anesthetized rat hippocampus suggested that the extracellular potassium could play an important role in the generation of a novel type of epileptiform nonsynaptic activity. Yet, the role of potassium in the generation of seizures remains controversial. We tested the hypothesis that potassium lateral diffusion coupling is responsible for the coupling mechanisms for network periodicity in a nonsynaptic model of epilepsy in vivo using a CA1 pyramidal neuron network model The simulation results show that 1), potassium lateral diffusion coupling is crucial for establishing epileptiform activity similar to that generated experimentally; and 2), there exists a scaling relation between the critical coupling strength and the number of cells in the network. The results not only agree with the theoretical prediction, but strongly suggest that potassium lateral diffusion coupling, a physiological realization of the concept of diffusive coupling, can play an important role in entraining periodicity in a nonsynaptic neural network.

Role of potassium lateral diffusion in non-synaptic epilepsy: a computational study.

An increase of extracellular potassium ion concentration can result in neuronal hyperexcitability, and thus contribute to non-synaptic epileptiform activity. It has been shown that potassium lateral diffusion alone is sufficient for synchronization in the low-calcium epilepsy in-vitro model. However, it is not yet known whether the lateral diffusion can, by itself, induce seizure activity. We hypothesize that spontaneous sustained neuronal activity can be generated by potassium coupling between neurons. To test this hypothesis, neuronal simulations with 2-cell or 4-cell models were used. Each model neuron was embedded in a bath of K+ and surrounded by interstitial space. Interstitial potassium concentration was regulated by both K+-pump and glial buffer mechanisms. Simulations performed with two coupled neurons with parameter values within physiological range show that, without chemical and electrical synapses, potassium lateral diffusion alone can generate and synchronize zero-Ca2+ non-synaptic epileptiform activity. Simulations performed with a network of four zero-Ca2+ CA1 pyramidal neurons modeled in zero-calcium conditions also show that spontaneous sustained activity can propagate by potassium lateral diffusion alone with a velocity of approximately 0.93 mm/sec. This diffusion model used for the simulations is based on physiological parameters, is robust for various kinetics, and is able to reproduce both the spontaneous triplet bursting of non-synaptic activity and speed of propagation in low-Ca2+ non-synaptic epilepsy experiments. These simulations suggest that potassium lateral diffusion can play an important role in the synchronization and generation on non-synaptic epilepsy.

A model of the effects of applied electric fields on neuronal synchronization.

We examine the effects of applied electric fields on neuronal synchronization. Two-compartment model neurons were synaptically coupled and embedded within a resistive array, thus allowing the neurons to interact both chemically and electrically. In addition, an external electric field was imposed on the array. The effects of this field were found to be nontrivial, giving rise to domains of synchrony and asynchrony as a function of the heterogeneity among the neurons. A simple phase oscillator reduction was successful in qualitatively reproducing these domains. The findings form several readily testable experimental predictions, and the model can be extended to a larger scale in which the effects of electric fields on seizure activity may be simulated.

Self-induced slow-fast dynamics and swept bifurcation diagrams in weakly desynchronized systems.

In systems close to the state of phase synchronization, the fast timescale of oscillations interacts with the slow timescale of the phase drift. As a result, "fast" dynamics is subjected to a slow modulation, due to which an autonomous system under fixed parameter values can imitate repeated bifurcational transitions. We demonstrate the action of this general mechanism for a set of two coupled autonomous chaotic oscillators and for a chaotic system perturbed by a periodic external force. In both cases, the Poincaré sections of phase portraits resemble bifurcation diagram of a logistic mapping with time-dependent parameter.