Faculty Bibliography

The neural mechanisms that support working memory (WM) depend on persistent neural activity. Within topographically organized maps of space in dorsal parietal cortex, spatially selective neural activity persists during WM for location. However, to date the necessity of these topographic subregions of human parietal cortex for WM remain unknown. To test the causal relationship of these areas to WM, we compared the performance of patients with lesions to topographically organized parietal cortex to controls on a memory-guided saccade (MGS) task as well as a visually-guided saccade (VGS) task. The MGS task allowed us to measure WM precision continuously with great sensitivity, while the VGS task allowed us to control for any deficits in general spatial or visuomotor processing. Compared to controls, patients generated memory-guided saccades that were significantly slower and less accurate, while visually-guided saccades were unaffected. These results provide key missing evidence for the causal role of topographic areas in human parietal cortex for WM, as well as the neural mechanisms supporting WM.

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 dominant theory, based on electrophysiological and lesion evidence from nonhuman primate studies, posits that the dorsolateral prefrontal cortex (dlPFC) stores and maintains working memory (WM) representations. Yet, neuroimaging studies have consistently failed to translate these results to humans; these studies normally find that neural activity persists in the human precentral sulcus (PCS) during WM delays. Here, we attempt to resolve this discrepancy. To test the degree to which dlPFC is necessary for WM, we compared the performance of patients with dlPFC lesions and neurologically healthy controls on a memory-guided saccade task that was used in the monkey studies to measure spatial WM. We found that dlPFC damage only impairs the accuracy of memory-guided saccades if the damage impacts the PCS; lesions to dorsolateral dlPFC that spare the PCS have no effect on WM. These results identify the necessary subregion of the frontal cortex for WM and specify how this influential animal model of human cognition must be revised. SIGNIFICANCE STATEMENT: High-level cognition depends on working memory (WM) as a critical building block, and many symptoms of psychiatric disorders may be the direct result of impaired WM. Canonical theory posits a critical role for the dorsolateral prefrontal cortex (dlPFC) in WM based on studies of nonhuman primates. However, we find that spatial WM in humans is intact after dlPFC damage unless it impacts the more caudal PCS. Therefore, the human dlPFC is not necessary for spatial WM and highlights the need for careful translation of animal models of human cognition.

BACKGROUND: Vagus nerve stimulation (VNS) is an established surgical treatment for medically intractable epilepsy with more than 75 000 devices implanted worldwide. While there are many reports documenting efficacy, complications, and clinical use, there are very few reports concerning VNS battery replacement and revision surgeries. OBJECTIVE: To review our experience with VNS battery replacement and revision surgery. METHODS: We retrospectively reviewed 1144 consecutive VNS procedures performed by a single surgeon between 1998 and 2012. Six hundred forty-four of those procedures were the initial placement of the VNS device. These patients were then followed to determine when a battery change occurred and what type of revision or removal was necessary. RESULTS: In the study, 46% of patients required at least 1 or more type of battery replacement or revision surgery. The most common types of surgery were for generator battery depletion (27%), poor efficacy (9%), and lead malfunction (8%). Only 2% of patients were noted to have an infection. CONCLUSION: VNS battery replacement, revisions, and removals account for almost one-half of all VNS procedures. Our findings suggest important long-term expectations for VNS including expected complications, battery life, and other surgical issues. Review of the literature suggests that this is the first large review of VNS revisions by a single center. Our findings are important to better characterize long-term surgical expectations of VNS therapy. A significant portion of patients undergoing VNS therapy will eventually require revision. ABBREVIATION: VNS, vagus nerve stimulation.

Surface-based cortical thickness (CT) analyses are increasingly being used to investigate variations in brain morphology across the spectrum of brain health, from neurotypical to neuropathological. An outstanding question is whether individual differences in cortical morphology, such as regionally increased or decreased CT, are associated with domain-specific performance deficits in healthy adults. Since CT studies are correlational, they cannot establish causality between brain morphology and cognitive performance. A direct comparison with classic lesion methods is needed to determine whether the regional specificity of CT-cognition correlations is similar to that observed in patients with brain lesions. We address this question by comparing the neuroanatomical overlap of effects when 1) whole brain vertex-wise CT is tested as a correlate of performance variability on a commonly used neuropsychological test of executive function, Trailmaking Test Part B (TMT-B), in healthy adults and 2) voxel-based lesion-symptom mapping (VBLSM) is used to map lesion location to performance decrements on the same task in patients with frontal lobe lesions. We found that reduced performance on the TMT-B was associated with increased CT in bilateral prefrontal regions in healthy adults and that results spatially overlapped in the left dorsomedial prefrontal cortex with findings from the VBLSM analysis in patients with frontal brain lesions. Findings indicate that variations in the structural integrity of the left dorsomedial prefrontal lobe, ranging from individual CT differences in healthy adults to structural lesions in patients with neurological disorders, are associated with poor performance on the TMT-B. These converging results suggest that the left dorsomedial prefrontal region houses a critical region for the complex processing demands of TMT-B, which include visuomotor tracking, sequencing, and cognitive flexibility.

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 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.