Faculty Bibliography

Introduction: About one-third of people with major depressive disorder (MDD) fail at least two antidepressant drug trials within the first year of treatment. Together with clinical and experimental evidence indicating that the pathophysiology of MDD is multifactorial, this observation underscores the importance of elucidating mechanisms beyond monoaminergic dysregulation that can contribute to the genesis and persistence of MDD. Methods: In contrast to other major psychiatric disorders, MDD is frequently comorbid with such neurological disorders and constitutes an independent risk factor for morbidity and mortality in disorders characterized by vascular endothelial dysfunction (cardiovascular disease and diabetes mellitus). Oxidative stress and neuroinflammation are mechanistically linked to the presence of neurovascular dysfunction with blood-brain barrier (BBB) hyperpermeability in selected neurological disorders, such as stroke, epilepsy, multiple sclerosis, traumatic brain injury, and Alzheimer's disease. We review accumulating evidence linking neurovascular dysfunction with BBB hyperpermeability to primary MDD without neurological comorbidity, and present a theoretical integration between these abnormalities to those involving oxidative stress and neuroinflammation in MDD. Results: Evidence of an association between MDD and neurovascular dysfunction is indirect, deriving primarily from studies assessing peripheral vascular endothelial dysfunction in MDD and from epidemiological data associating MDD with vascular disorders. The relative uptake ratio (RUR) of blood flow after hyperemic challenge has been validated as an index of endothelial function in clinical settings. A prospective cohort showed that the unadjusted mean RUR was significantly lower among 23 participants with MDD and 23 with minor depressive disorder compared with 277 nondepressed controls (P = .001); this effect remained significant after adjusting for age, sex, socioeconomic factors, medical comorbidity, andmedications (P!

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.

Object Subependymal giant cell astrocytomas (SEGAs) are benign tumors, most commonly associated with tuberous sclerosis complex (TSC). The vast majority of these tumors arise from the lateral ependymal surface adjacent to the foramen of Monro, therefore potentially encroaching on one or both foramina, and resulting in obstructive hydrocephalus that necessitates surgical decompression. The indications for surgery, intraoperative considerations, and evolution of the authors' management paradigm are presented. Methods Patients with TSC who underwent craniotomy for SEGA resection at New York University Langone Medical Center between January 1997 and March 2011 were identified. Preoperative imaging, clinical characteristics, management decisions, operative procedures, and outcomes were reviewed. Results Eighteen patients with TSC underwent 22 primary tumor resections for SEGAs. The indication for surgery was meaningful radiographic tumor progression in 16 of 21 cases. The average age at the time of operation was 10.3 years. Average follow-up duration was 52 months (range 12-124 months). The operative approach was intrahemispheric-transcallosal in 16 cases, transcortical-transventricular in 5, and neuroendoscopic in 1. Nine tumors were on the right, 9 on the left, and 3 were bilateral. Gross-total resection was documented in 16 of 22 cases in our series, with radical subtotal resection achieved in 4 cases, and subtotal resection (STR) in 2 cases. Two patients had undergone ventriculoperitoneal shunt placement preoperatively and 7 patients required shunt placement after surgery for moderate to severe ventriculomegaly. Two patients experienced tumor progression requiring reoperation; both of these patients had initially undergone STR. Conclusions The authors present their management strategy for TSC patients with SEGAs. Select patients underwent microsurgical resection of SEGAs with acceptable morbidity. Gross-total resection or radical STR was achieved in 90.9% of our series (20 of 22 primary tumor resections), with no recurrences in this group. Approximately half of our patient series required CSF diversionary procedures. There were no instances of permanent neurological morbidity associated with surgery.

Rationale: SUDEP is the most common epilepsy-related cause of death in persons with epilepsy. Evidence supports that increased SUDEP awareness and education can be translated into significantly reduced rates of epilepsy-related deaths. However, there is a lack of consensus regarding how health care practitioners should address SUDEP with patients, and a lack of evidence regarding patient educational interventions. The purpose of this study was to describe various health care providers' practices regarding discussion of SUDEP with their patients. Methods: Separate focus groups were conducted, each involving epileptologists (n=19), neurologists (n=16), or advanced practice nurses (n=8). The focus group moderator asked participants questions pertaining to reasons for and for not discussing SUDEP, and how they discuss SUDEP. Focus group data were analyzed via content analysis per each practitioner group, and comparisons were then made across groups. Data were organized via themes in order to answer the research questions. Results: Table 1 depicts final themes and definitions. Across all disciplines, reasons for discussing SUDEP included Practical Accountability, Moral Accountability, Proactivity, and Reactivity. For nurses only, an additional reason was Patient Advocacy. In terms of when not to discuss SUDEP, for all disciplines involved, and especially the physicians, the theme Not at First emerged. Additional themes that emerged for this question included, in the case of neurologists and epileptologists, Moral Accountability and Out of Options. Ways in which SUDEP is discussed included, in all groups, Discussion and Written Materials. In addition, prevalent in all groups was the finding that procedures for discussing SUDEP with patients and families need to be somewhat standardized, though the discussion should always be tailored to fit the patient's context. As well, more informative written materials should be developed. Conclusions: These results provide an initial view of the way in which var!

Rationale: To review the efficacy and tolerability of stiripentol in the treatment of US children with Dravet syndrome. Methods: US clinicians who had prescribed stiripentol for two or more children with Dravet syndrome between 03/2005 and 03/2012 were contacted to request participation in this retrospective study. 111 Data collected included overall seizure frequency, frequency of prolonged seizures, use of rescue medications and ER/hospital visits in the year preceding stiripentol initiation, and with stiripentol therapy. We separately assessed efficacy in the following treatment groups: Group A: stiripentol without clobazam or valproate, Group B: stiripentol with clobazam but without valproate, Group C: stiripentol with valproate but without clobazam, and Group D: stiripentol with clobazam and valproate. Additionally, adverse effects were recorded. Results: Thirteen of 16 clinicians contacted for study participated and provided data on 82 children. Stiripentol was initiated a median of 6.0 years after seizure onset and 1.2 years after diagnosis of Dravet syndrome. Compared to baseline, overall seizure frequency was reduced in 2/6 in Group A, 28/35 in Group B, 8/14 in Group C and 30/48 in Group D. All children with prolonged seizure frequency greater than quarterly during the baseline period experienced a reduction in this frequency on the various treatment arms with stiripentol. Similarly, 2/4 patients in Group A, 25/25 in Group B, 5/10 in Group C and 26/33 in Group D experienced reduction in frequency of rescue medication usage and 1/1 in Group A, 12/12 in Group B, 3/5 in Group C and 18/19 in Group D had reduction in frequency of ER/hospital visits. Adverse effects were reported in 38, most commonly sedation and reduced appetite. Four patients (5%) discontinued stiripentol for adverse effects and two (2%) for lack of efficacy. Conclusions: Stiripentol is an effective and well-tolerated therapy which markedly reduced frequency of prolonged seizures in Dravet syndrome

Rationale: While the ionotropic glutamate receptors (iGluRs) have been extensively studied, little is known about the role of metabotropic glutamate receptors (mGluRs) in seizure generation and epileptogenesis associated with altered brain development, including Tuberous Sclerosis Complex (TSC) and focal cortical dysplasia (FCD). Animal model studies show that Group I mGluRs, including mGluR1 and mGluR5, are pro-convulsive, while specific mGluR antagonists are effective in suppressing seizure activity. Furthermore, experimental deletion of Tsc1 impairs mGluR-dependent long-term depression. We hypothesized that Group I mGluRs are expressed at higher levels in TSC and FCD compared to controls, which may significantly contribute to altered synaptic function, network excitability and information processing in these patients. Methods: Cortical samples from TSC (n= 5; ages 0.9-5 years) and non-TSC epilepsy patients (n=5; ages 21.5-37 years) were obtained during brain surgery for treatment of pharmaco-resistant epilepsy at NYU Langone Medical Center. The cases were further diagnosed as either TSC or FCD Type Ia by standard neuropathological examination. Age-matched and region-matched control specimens from cases with normal neurological history (n=6; ages 2-24 years) were obtained from University of Maryland Brain and Tissue Bank. The study was approved by the local Institutional Review Board. Frozen cortical samples were used to separate the membrane fraction and blots were probed for mGluR1 (1:1000) and mGluR5 (1:1000). Mean expression levels were compared among groups and statistical significance (p<0.05) was established using two-tailed t-tests. Results: mGluR1 expression was significantly upregulated relative to controls in both TSC (270+40% of control; p<0.05) and FCD cortex (136+10% of control; p<0.05), with higher levels in TSC relative to FCD (p<0.05). mGluR5 was also significantly elevated in TSC (370+34% of control; p<0.01) and FCD (321+25% of control; p<0.001), with no significant differen!

Rationale: For patients with medically intractable focal epilepsy, the best option for achieving seizure control is often surgical resection. In surgical planning, the potential for seizure reduction must be weighed against the risk of cognitive loss. The role that clinical and demographic factors play in predicting cognitive outcome is well established; however, little is known about the role of crosshemispheric white matter in promoting functional reorganization after surgery. In this study we measured the midsagittal crosssectional area of the corpus callosum (CC) on pre-surgical MRI to investigate whether this property is related to changes in working memory following surgery. Methods: A pre- and post-surgical neuropsychological test battery was obtained in 15 patients (9 males/6 females) who underwent temporal (n = 9), frontal (n = 4), temporal and frontal (n = 1) or parietal lobe (n = 1) resective surgery at NYU Langone Medical Center. Pre-surgical whole-brain T1-weighted 3D MRIs were acquired on all participants from the same dedicated research scanner. The midsaggital CC cross-sectional area was delineated and measured automatically on the MRI using 'yuki' (www.nitrc.org/projects/art), an automatic CC segmentation algorithm, described by Ardekani et al. 2012 (Figure 1A). The Working Memory Index (WMI) from the Wechsler Adult Intelligence Scale was used to probe change in concentration/working memory abilities (postsurgical W

Integrated PET/MR with simultaneous acquisition may improve the identification of pathologic findings in patients. This pilot study evaluated metabolic activity differences between epilepsy patients and healthy controls and directly correlated FDG uptake with MR regional abnormality. Epilepsy patients (n=11) and controls (n=6) were imaged on a whole-body simultaneous PET/MR scanner. After FDG injection, simultaneous images were acquired for 60 minutes. Statistical analyses on SUV values (over 117 brain regions, including left and right, for 96 cortical and 21 subcortical regions) derived from three normalization methods, by individual subject's mean cortical, white matter or global brain, were compared between groups. The asymmetry was compared. T2, T1 and PET co-registered images were also used for lesion detection and correlation of PET and MR regional abnormality. Left and right postcentral gyri were found to be consistently hypermetabolic regions, while right temporal pole and planum polare were consistently hypometabolic regions by all three normalization methods. Using the asymmetry index (AI > 10% or SUV ratios > 1.2), more metabolic asymmetry regions were detected in patients than in controls, with 96.2% agreement. The presence of hippocampal abnormalities or cortical tubers detected via T2 FLAIR in patients correlated well with the hypometabolism detected via FDG-PET. Our results showed specific patterns of metabolic abnormality and asymmetry over 117 brain regions in epilepsy patients, as compared to controls, suggest that simultaneous PET/MR imaging provides a useful tool to help understand etiopathogenesis and localize seizure foci.

Postictal psychosis is characterized by a fluctuating combination of thought disorder, auditory and visual hallucinations, delusions, paranoia, affective change, and aggression including violent behavior. We present a case of homicide following a cluster of seizures. The patient's history and postictal behavior were his consistent with postictal psychosis. Contributing factors resulting in homicide may have included increased seizure frequency associated with a change in his AED regimen seizure frequency. The AED change to levetiracetam may also have increased impulsiveness with diminished mood regulation following discontinuation of carbamazepine. There is evidence that he had a cluster of seizures immediately prior to the murder which may have resulted in the postictal disinhibition of frontal lobe inhibitory systems. This homicide and other violent behaviors associated with postictal psychosis may be avoided with earlier recognition and treatment.

Magnetic resonance imaging (MRI) techniques have been used to quantitatively assess focal and network abnormalities. Idiopathic generalized epilepsy (IGE) is characterized by bilateral synchronous spike-wave discharges on electroencephalography (EEG) but normal clinical MRI. Dysfunctions involving the neocortex, particularly the prefrontal cortex, and thalamus likely contribute to seizure activity. To identify possible morphometric and functional differences in the brains of IGE patients and normal controls, we employed measures of thalamic volumes, cortical thickness, gray-white blurring, fractional anisotropy (FA) measures from diffusion tensor imaging (DTI) and fractional amplitude of low frequency fluctuations (fALFF) in thalamic subregions from resting state functional MRI. Data from 27 patients with IGE and 27 age- and sex-matched controls showed similar thalamic volumes, cortical thickness and gray-white contrast. There were no differences in FA values on DTI in tracts connecting the thalamus and prefrontal cortex. Functional analysis revealed decreased fALFF in the prefrontal cortex (PFC) subregion of the thalamus in patients with IGE. We provide minimum detectable effect sizes for each measure used in the study. Our analysis indicates that fMRI-based methods are more sensitive than quantitative structural techniques for characterizing brain abnormalities in IGE.