Faculty Bibliography

OBJECTIVE Somatic variants are a recognized cause of epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants may underlie a wider range of focal epilepsy, including non-lesional focal epilepsy (NLFE). Through genetic analysis of brain tissue, we evaluated the role of somatic variation in focal epilepsy with and without MCD. METHODS We identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequencing of DNA from epilepsy surgery specimens and leukocytes from 18 individuals with NLFE and 38 with focal MCD. RESULTS We observed somatic variants in five cases in SLC35A2, a gene associated with glycosylation defects and rare X-linked epileptic encephalopathies. Nonsynonymous variants in SLC35A2 were detected in resected brain, and absent from leukocytes, in 3/18 individuals (17%) with NLFE, one female and two males, with variant allele frequencies (VAFs) in brain-derived DNA of 2-14%. Pathologic evaluation revealed focal cortical dysplasia type Ia (FCD1a) in two of the three NLFE cases. In the MCD cohort, nonsynonymous variants in SCL35A2 were detected in the brains of two males with intractable epilepsy, developmental delay, and MRI suggesting FCD, with VAFs of 19-53%; FCD1a was not observed in either brain tissue specimen. INTERPRETATION We report somatic variants in SLC35A2 as an explanation for a substantial fraction of NLFE, a largely unexplained condition, as well as focal MCD, previously shown to result from somatic mutation but until now only in PI3K-AKT-mTOR pathway genes. Collectively, our findings suggest a larger role than previously recognized for glycosylation defects in the intractable epilepsies.

Sleep spindles are a cardinal feature in human NREM sleep and may be important for memory consolidation. We studied the intracortical organization of spindles in men and women by recording spontaneous sleep spindles from different cortical layers using linear microelectrode arrays. Two patterns of spindle generation were identified using visual inspection, and confirmed with factor analysis. Spindles (10-16Hz) were largest and most common in upper and middle channels, with limited involvement of deep channels. Many spindles were observed in only upper or only middle channels, but about half occurred in both. In spindles involving both middle and upper channels, the spindle envelope onset in middle channels led upper by ∼25-50ms on average. The phase relationship between spindle waves in upper and middle channels varied dynamically within spindle epochs, and across individuals. Current source density analysis demonstrated that upper and middle channel spindles were both generated by an excitatory supragranular current sink while an additional deep source was present for middle channel spindles only. Only middle channel spindles were accompanied by deep low (25-50Hz) and high (70-170Hz) gamma activity. These results suggest that upper channel spindles are generated by supragranular pyramids, and middle channel by infragranular. Possibly, middle channel spindles are generated by core thalamocortical afferents, and upper channel by matrix. The concurrence of these patterns could reflect engagement of cortical circuits in the integration of more focal (core) and distributed (matrix) aspects of memory. These results demonstrate that at least two distinct intracortical systems generate human sleep spindles.SIGNIFICANCE STATEMENTBursts of ∼14Hz oscillations, lasting about a second, have been recognized for over 80 years as cardinal features of mammalian sleep. Recent findings suggest that they play a key role in organizing cortical activity during memory consolidation. We used linear microelectrode arrays to study their intracortical organization in humans. We found that spindles could be divided into two types. One mainly engages upper layers of the cortex, which are considered to be specialized for associative activity. The other engages both upper and middle layers, including those devoted to sensory input. The interaction of these two spindle types may help organize the interaction of sensory and associative aspects of memory consolidation.

It has come to our attention that we did not specify whether the stimulation magnitudes we report in this Article are peak amplitudes or peak-to-peak. All references to intensity given in mA in the manuscript refer to peak-to-peak amplitudes, except in Fig. 2, where the model is calibrated to 1 mA peak amplitude, as stated. In the original version of the paper we incorrectly calibrated the computational models to 1 mA peak-to-peak, rather than 1 mA peak amplitude. This means that we divided by a value twice as large as we should have. The correct estimated fields are therefore twice as large as shown in the original Fig. 2 and Supplementary Figure 11. The corrected figures are now properly calibrated to 1 mA peak amplitude. Furthermore, the sentence in the first paragraph of the Results section 'Intensity ranged from 0.5 to 2.5 mA (current density 0.125-0.625 mA mA/cm²), which is stronger than in previous reports', should have read 'Intensity ranged from 0.5 to 2.5 mA peak to peak (peak current density 0.0625-0.3125 mA/cm²), which is stronger than in previous reports.' These errors do not affect any of the Article's conclusions.

The neocortex is composed of six anatomically and physiologically specialized layers. It has been proposed that integration of activity across cortical areas is mediated anatomically by associative connections terminating in superficial layers, and physiologically by slow cortical rhythms. However, the means through which neocortical anatomy and physiology interact to coordinate neural activity remains obscure. Using laminar microelectrode arrays in 19 human participants, we found that most EEG activity is below 10-Hz (delta/theta) and generated by superficial cortical layers during both wakefulness and sleep. Cortical surface grid, grid-laminar, and dual-laminar recordings demonstrate that these slow rhythms are synchronous within upper layers across broad cortical areas. The phase of this superficial slow activity is reset by infrequent stimuli and coupled to the amplitude of faster oscillations and neuronal firing across all layers. These findings support a primary role of superficial slow rhythms in generating the EEG and integrating cortical activity.

Reliable posture labels in hospital environments can augment research studies on neural correlates to natural behaviors and clinical applications that monitor patient activity. However, many existing pose estimation frameworks are not calibrated for these unpredictable settings. In this paper, we propose a semi-automated approach for improving upper-body pose estimation in noisy clinical environments, whereby we adapt and build around an existing joint tracking framework to improve its robustness to environmental uncertainties. The proposed framework uses subject-specific convolutional neural network models trained on a subset of a patient's RGB video recording chosen to maximize the feature variance of each joint. Furthermore, by compensating for scene lighting changes and by refining the predicted joint trajectories through a Kalman filter with fitted noise parameters, the extended system yields more consistent and accurate posture annotations when compared with the two state-of-the-art generalized pose tracking algorithms for three hospital patients recorded in two research clinics.

Transcranial electrical stimulation has widespread clinical and research applications, yet its effect on ongoing neural activity in humans is not well established. Previous reports argue that transcranial alternating current stimulation (tACS) can entrain and enhance neural rhythms related to memory, but the evidence from non-invasive recordings has remained inconclusive. Here, we measure endogenous spindle and theta activity intracranially in humans during low-frequency tACS and find no stable entrainment of spindle power during non-REM sleep, nor of theta power during resting wakefulness. As positive controls, we find robust entrainment of spindle activity to endogenous slow-wave activity in 66% of electrodes as well as entrainment to rhythmic noise-burst acoustic stimulation in 14% of electrodes. We conclude that low-frequency tACS at common stimulation intensities neither acutely modulates spindle activity during sleep nor theta activity during waking rest, likely because of the attenuated electrical fields reaching the cortical surface.

Although responsive neurostimulation (RNS) is approved for treatment of resistant focal epilepsy in adults, little is known about response to treatment of specific cortical targets. We describe the experience of RNS targeting the insular lobe. We identified patients who had RNS implantation with at least one electrode within the insula between April 2014 and October 2015. We performed a retrospective review of preoperative clinical features, imaging, electrocardiogram (EEG), intraoperative electrocorticography (ECoG), and postoperative seizure outcome. Eight patients with at least 6 months of postimplant follow-up were identified. Ictal localization was inconclusive with MRI or scalp EEG findings. Intracranial EEG monitoring or intraoperative ECoG demonstrated clear ictal onsets and/or frequent interictal discharges in the insula. Four patients demonstrated overall 50-75% reduction in seizure frequency. Two patients did not show appreciable seizure improvement. One patient has experienced a 75% reduction of seizure frequency, and another is nearly seizure free postoperatively. There were no reported direct complications of insular RNS electrode placement or stimulation, though two patients had postoperative complications thought to be related to craniotomy (hydrocephalus and late infection). Our study suggests that insular RNS electrode placement in selected patients is relatively safe and that RNS treatment may benefit selected patients with insular epilepsy.

OBJECTIVES: We assessed the efficacy and risks of diagnostic bilateral intracranial EEG (bICEEG) in treatment-resistant epilepsy (TRE) patients with poorly lateralized epileptogenic zone (EZ) on non-invasive studies as reflected by progress to resection, Engel outcome and complication rate. METHODS: This is a retrospective chart review of 199 patients with TRE who had diagnostic bICEEG at New York University Medical Center between 1994 and 2013. Study endpoints were progress to resection, surgical outcome and perioperative complications. Univariate analysis was performed with ANOVA, t-test or Fischer's Exact test; multivariable analysis was performed using discriminant function analysis. RESULTS: bICEEG lateralized the EZ and the patient had resection in 60.3% of cases. The number of depth electrodes used was positively correlated with resection, and surgical complications during bICEEG negatively correlated. Vagal nerve stimulators were implanted in 58.2% of patients who did not undergo resection and 20.7% of those who did. Among the 87 patients who progressed to resection and had more than 1-year follow-up, 47.1% were seizure free compared with 12.7% of the 55 who did not. Male sex correlated with good postoperative seizure control. The most common complication was infection requiring debridement, occurring in 3.1% of admissions (9 of 290). CONCLUSION: At our center, 60% of patients undergoing bICEEG progress to resection and 57% of these had more than 90% reduction in seizures. We conclude that bICEEG allows the benefits of epilepsy surgery to be extended to patients with poorly lateralized and localized TRE.