Faculty Bibliography

Objective: To characterize efficacy and risks of diagnostic bilateral intracranial electroencephalography (bICEEG) in treatment-resistant epilepsy (TRE) patients with poorly lateralized epileptogenic zone (EZ) on non-invasive studies. Background: Patients with TRE are candidates for epilepsy surgery if the EZ is localized and deemed resectable. For cases with discordant non-invasive studies, bICEEG may definitively lateralize the EZ to identify surgical candidates. Methods: We retrospectively reviewed all 208 bICEEG cases at New York University (NYU) between 1994 and 2013. Endpoints included: progress to resection, Engel outcome, and peri-operative complications. Results: Of 208 patients, 19 were lost to follow-up. For 60[percnt], bICEEG lateralized the EZ and they progressed to therapeutic resection or further regional ICEEG. Subdural and depth electrodes were routinely used together but only the number of depth electrodes positively correlated with progress to resection and depth electrode use was not greater in temporal lobe cases. Forty-eight percent who progressed to resection were seizure free at last follow-up (mean 5.4yrs) compared with 13[percnt] of patients who did not have resection (mean 5.6yrs). Pre-operative seizure frequency greater than 1/day was associated with worse post-operative seizure control. The most common complication was infection requiring surgical intervention; occurrence was 3.1[percnt]. Rates of superficial infection, DVT, pulmonary embolism, stroke, and hemorrhage were each below 1[percnt]. Conclusions: At NYU, 60[percnt] of patients with TRE who underwent bICEEG progressed to EZ resection and 48[percnt] of these cases were seizure free. The risks of bICEEG monitoring are similar to our unilateral invasive monitoring. We conclude that bICEEG extends the benefit of epilepsy surgery to poorly lateralized TRE patients. Future analysis will determine the relative predictive value of seizure semiology, vEEG monitoring, MRI, MEG, and PET to progress to resection and Engel outcome in this series; as well as determine how depth electrodes augment subdural monitoring

A major impeding factor in designing effective therapies against glioblastoma (GBM) is its extensive molecular heterogeneity and the diversity of microenvironmental conditions within any given tumor. To test whether heterogeneity with the GBM stem cell (GSC) population is required to ensure tumor growth in such diverse microenvironments, we used human GBM biospecimens to examine the identity of cells marked by two established GSC markers: CD133 and activation of the Notch pathway. Using primary GBM cultures engineered to express GFP upon activation of Notch signaling, we observed only partial overlap between cells expressing cell surface CD133 and cells with Notch activation (n = 3 specimens), contrary to expectations based on prior literature. To further investigate this finding, we FACS-isolated these cell populations and characterized them. While both CD133+ (CD133 + /Notch-) and Notch+(CD133-/Notch+) cells fulfill GSC criteria, they differ vastly in their transcriptome, metabolic preferences and differentiation capacity, thus giving rise to histologically distinct tumors. CD133+ GSCs have increased expression of hypoxia-regulated and glycolytic genes, and are able to expand under hypoxia by activating anaerobic glycolysis. In contrast, Notch+ GSCs are unable to utilize anaerobic glycolysis under hypoxia, leading to decreased tumorsphere formation ability. While CD133+ GSCs give rise to histologically homogeneous tumors devoid of large tumor vessels, tumors initiated by Notch+ GSCs are marked by large perfusing vessels enveloped by pericytes. Using a lineage tracing system, we showed that pericytes are derived from Notch+ GSCs. In addition, Notch+ cells are able to give rise to all tumor lineages in vitro and in vivo, including CD133 + /Notch- cells, as opposed to Notch- populations, which have restricted differentiation capacity and do not generate Notch+ lineages. Our findings demonstrate that GSC heterogeneity is a mechanism used by tumors to sustain growth in diverse microenvironmental conditions

OBJECTIVE: Epilepsy surgery is the most effective treatment for select patients with drug-resistant epilepsy. In this article, we aim to provide an accurate understanding of the current epidemiologic characteristics of this intervention, as this knowledge is critical for guiding educational, academic, and resource priorities. METHODS: We profile the practice of epilepsy surgery between 1991 and 2011 in nine major epilepsy surgery centers in the United States, Germany, and Australia. Clinical, imaging, surgical, and histopathologic data were derived from the surgical databases at various centers. RESULTS: Although five of the centers performed their highest number of surgeries for mesial temporal sclerosis (MTS) in 1991, and three had their highest number of MTS surgeries in 2001, only one center achieved its peak number of MTS surgeries in 2011. The most productive year for MTS surgeries varied then by center; overall, the nine centers surveyed performed 48% (95% confidence interval [CI] -27.3% to -67.4%) fewer such surgeries in 2011 compared to either 1991 or 2001, whichever was higher. There was a parallel increase in the performance of surgery for nonlesional epilepsy. Further analysis of 5/9 centers showed a yearly increase of 0.6 +/- 0.07% in the performance of invasive electroencephalography (EEG) without subsequent resections. Overall, although MTS was the main surgical substrate in 1991 and 2001 (proportion of total surgeries in study centers ranging from 33.3% to 70.2%); it occupied only 33.6% of all resections in 2011 in the context of an overall stable total surgical volume. SIGNIFICANCE: These findings highlight the major aspects of the evolution of epilepsy surgery across the past two decades in a sample of well-established epilepsy surgery centers, and the critical current challenges of this treatment option in addressing complex epilepsy cases requiring detailed evaluations. Possible causes and implications of these findings are discussed.

Focal cortical dysplasia (FCD) is a malformation of cortical development that is associated with high rates of cognitive morbidity. However, the degree to which specific irregularities of dysplastic tissue directly impact cognition remains unknown. This study investigates the relationship between blurring of the cortical gray and white matter boundary on magnetic resonance imaging (MRI) and global cognitive abilities in FCD. Gray-white blurring (GWB) is quantified by sampling the non-normalized T1 image intensity contrast above and below the gray and white matter interface along the cortical mantle. Spherical averaging is used to compare resulting GWB for patients with histopathologically verified FCD with matched controls. Whole-brain correlational analyses are used to investigate the relationship between blurring and general cognitive abilities, controlling for epilepsy duration. Results show that cognitive performance is reduced in patients with FCD relative to controls. Patients show increased GWB in bilateral temporal, parietal, and frontal regions. Furthermore, increased GWB in these regions is linearly related to decreased cognition and mediates group differences in cognitive performance. These findings demonstrate that GWB is a marker of reduced cognitive efficiency in FCD that can potentially be used to probe general and domain-specific cognitive functions in other neurological disorders.

Focal cortical dysplasia (FCD) is the most common cause of pediatric epilepsy and the third most common lesion in adults with treatment-resistant epilepsy. Advances in MRI have revolutionized the diagnosis of FCD, resulting in higher success rates for resective epilepsy surgery. However, many patients with histologically confirmed FCD have normal presurgical MRI studies ('MRI-negative'), making presurgical diagnosis difficult. The purpose of this study was to test whether a novel MRI postprocessing method successfully detects histopathologically verified FCD in a sample of patients without visually appreciable lesions. We applied an automated quantitative morphometry approach which computed five surface-based MRI features and combined them in a machine learning model to classify lesional and nonlesional vertices. Accuracy was defined by classifying contiguous vertices as "lesional" when they fell within the surgical resection region. Our multivariate method correctly detected the lesion in 6 of 7 MRI-positive patients, which is comparable with the detection rates that have been reported in univariate vertex-based morphometry studies. More significantly, in patients that were MRI-negative, machine learning correctly identified 14 out of 24 FCD lesions (58%). This was achieved after separating abnormal thickness and thinness into distinct classifiers, as well as separating sulcal and gyral regions. Results demonstrate that MRI-negative images contain sufficient information to aid in the in vivo detection of visually elusive FCD lesions.

OBJECTIVE: For patients with medically intractable focal epilepsy, the benefit of epilepsy surgery must be weighed against the risk of cognitive decline. Clinical factors such as age and presurgical cognitive level partially predict cognitive outcome; yet, little is known about the role of cross-hemispheric white matter pathways in supporting postsurgical recovery of cognitive function. The purpose of this study is to determine whether the presurgical corpus callosum (CC) midsagittal area is associated with pre- to postsurgical change following epilepsy surgery. METHODS: In this observational study, we retrospectively identified 24 adult patients from an epilepsy resection series who completed preoperative high-resolution T1 -weighted magnetic resonance imaging (MRI) scans, as well as pre- and postsurgical neuropsychological testing. The total area and seven subregional areas of the CC were measured on the midsagittal MRI slice using an automated method. Standardized indices of auditory-verbal working memory and delayed memory were used to probe cognitive change from pre- to postsurgery. CC total and subregional areas were regressed on memory-change scores, after controlling for overall brain volume, age, presurgical memory scores, and duration of epilepsy. RESULTS: Patients had significantly reduced CC area relative to healthy controls. We found a positive relationship between CC area and change in working memory, but not delayed memory; specifically, the larger the CC, the greater the postsurgical improvement in working memory (beta = 0.523; p = 0.009). Effects were strongest in posterior CC subregions. There was no relationship between CC area and presurgical memory scores. SIGNIFICANCE: Findings indicate that larger CC area, measured presurgically, is related to improvement in working memory abilities following epilepsy surgery. This suggests that transcallosal pathways may play an important, yet little understood, role in postsurgical recovery of cognitive functions.

Recording from neural networks at the resolution of action potentials is critical for understanding how information is processed in the brain. Here, we address this challenge by developing an organic material-based, ultraconformable, biocompatible and scalable neural interface array (the 'NeuroGrid') that can record both local field potentials(LFPs) and action potentials from superficial cortical neurons without penetrating the brain surface. Spikes with features of interneurons and pyramidal cells were simultaneously acquired by multiple neighboring electrodes of the NeuroGrid, allowing for the isolation of putative single neurons in rats. Spiking activity demonstrated consistent phase modulation by ongoing brain oscillations and was stable in recordings exceeding 1 week's duration. We also recorded LFP-modulated spiking activity intraoperatively in patients undergoing epilepsy surgery. The NeuroGrid constitutes an effective method for large-scale, stable recording of neuronal spikes in concert with local population synaptic activity, enhancing comprehension of neural processes across spatiotemporal scales and potentially facilitating diagnosis and therapy for brain disorders.

Historically, the study of speech processing has emphasized a strong link between auditory perceptual input and motor production output. A kind of 'parity' is essential, as both perception- and production-based representations must form a unified interface to facilitate access to higher-order language processes such as syntax and semantics, believed to be computed in the dominant, typically left hemisphere. Although various theories have been proposed to unite perception and production, the underlying neural mechanisms are unclear. Early models of speech and language processing proposed that perceptual processing occurred in the left posterior superior temporal gyrus (Wernicke's area) and motor production processes occurred in the left inferior frontal gyrus (Broca's area). Sensory activity was proposed to link to production activity through connecting fibre tracts, forming the left lateralized speech sensory-motor system. Although recent evidence indicates that speech perception occurs bilaterally, prevailing models maintain that the speech sensory-motor system is left lateralized and facilitates the transformation from sensory-based auditory representations to motor-based production representations. However, evidence for the lateralized computation of sensory-motor speech transformations is indirect and primarily comes from stroke patients that have speech repetition deficits (conduction aphasia) and studies using covert speech and haemodynamic functional imaging. Whether the speech sensory-motor system is lateralized, like higher-order language processes, or bilateral, like speech perception, is controversial. Here we use direct neural recordings in subjects performing sensory-motor tasks involving overt speech production to show that sensory-motor transformations occur bilaterally. We demonstrate that electrodes over bilateral inferior frontal, inferior parietal, superior temporal, premotor and somatosensory cortices exhibit robust sensory-motor neural responses during both perception and production in an overt word-repetition task. Using a non-word transformation task, we show that bilateral sensory-motor responses can perform transformations between speech-perception- and speech-production-based representations. These results establish a bilateral sublexical speech sensory-motor system.

Sensory integration of touch and sight is crucial to perceiving and navigating the environment. While recent evidence from other sensory modality combinations suggests that low-level sensory areas integrate multisensory information at early processing stages, little is known about how the brain combines visual and tactile information. We investigated the dynamics of multisensory integration between vision and touch using the high spatial and temporal resolution of intracranial electrocorticography in humans. We present a novel, two-step metric for defining multisensory integration. The first step compares the sum of the unisensory responses to the bimodal response as multisensory responses. The second step eliminates the possibility that double addition of sensory responses could be misinterpreted as interactions. Using these criteria, averaged local field potentials and high-gamma-band power demonstrate a functional processing cascade whereby sensory integration occurs late, both anatomically and temporally, in the temporo-parieto-occipital junction (TPOJ) and dorsolateral prefrontal cortex. Results further suggest two neurophysiologically distinct and temporally separated integration mechanisms in TPOJ, while providing direct evidence for local suppression as a dominant mechanism for synthesizing visual and tactile input. These results tend to support earlier concepts of multisensory integration as relatively late and centered in tertiary multimodal association cortices.