Faculty Bibliography

The two most common types of temporal lobe epilepsy are medial temporal sclerosis epilepsy (TLE-MTS) and MRI-normal temporal lobe epilepsy (TLE-no). TLE-MTS is specified by its stereotyped focus and spread pattern of neuronal damage, with pronounced neuronal loss in the hippocampus. TLE-no exhibits normal-appearing hippocampus and more widepsread neuronal loss. In both cases neuronal loss spread appears to be constrained by the white matter connections. Both varieties of epilepsy reveal pathological abnormalities in increased mean diffusivity (MD). We model MD distribution as a simple consequence of the propagation of neuronal damage. By applying this model on the structural brain connectivity network of healthy subjects we can predict at group level the mean diffusivity gray matter change in the epilepsy cohorts relative to a control group. DTI images were acquired from 10 patients with TLE-MTS, 11 patients with TLE-no, and 35 healthy subjects. Statistical validation at the group level suggests high correlation with measured neuronal loss (R = 0.56 for the TLE-MTS group and R = 0.364 for the TLE-no group). The results of this exploratory work pave the way for potential future clinical application of the proposed model on individual patients, including predicting neuronal loss spread, identification of seizure onset zones, and helping in surgical planning.

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: We assessed whether presurgical resting state functional magnetic resonance imaging (fMRI) provides information for distinguishing temporal lobe epilepsy (TLE) with mesial temporal sclerosis (TLE-MTS) from TLE without MTS (TLE-noMTS). METHODS: Thirty-four patients with TLE and 34 sex-/age-matched controls consented to a research imaging protocol. MTS status was confirmed by histologic evaluation of surgical tissue (TLE-MTS = 16; TLE-noMTS = 18). The fractional amplitude of low-frequency fluctuations (fALFFs) in the blood oxygen level-dependent (BOLD) resting-state fMRI signal, a marker of local metabolic demand at rest, was averaged at five regions of interest (ROIs; hippocampus, amygdala, frontal, occipital, and temporal lobe), along with corresponding volume and cortical thickness estimates. ROIs were labeled ipsilateral or contralateral according to seizure lateralization and compared across TLE-MTS, TLE-noMTS, and healthy controls (HCs). MTS status was regressed on ipsilateral hippocampal volume and fALFF to test for independent contributions. RESULTS: The TLE-MTS group had reduced fALFF in the ipsilateral amygdala and hippocampus; whereas, the TLE-noMTS group had marginally reduced fALFF in the ipsilateral amygdala but not hippocampus. These results were consistently obtained with and without application of global signal regression (GSR). Ipsilateral hippocampal volume contributed to 37% of the variance in MTS status (p < 0.001) and fALFF contributed an additional 10% (p = 0.021). Two MTS cases were accurately classified with fALFF but not volume, and three were accurately classified with volume but not fALFF. At the lobar level, fALFF (with GSR) was reduced in the ipsilateral temporal and bilateral frontal lobes of patients with TLE-MTS and bilateral frontal lobes of patients with TLE-noMTS in the context of normal cortical thickness. SIGNIFICANCE: This study indicates that resting-state fMRI provides complementary functional information for MTS classification. Findings validate fALFF as a measure of regional brain integrity in TLE and highlight the value of using multi-modal imaging to provide independent diagnostic information in presurgical epilepsy evaluations.

Sudden unexpected death in epilepsy (SUDEP) can affect individuals of any age, but is most common in younger adults (aged 20-45 years). Generalised tonic-clonic seizures are the greatest risk factor for SUDEP; most often, SUDEP occurs after this type of seizure in bed during sleep hours and the person is found in a prone position. SUDEP excludes other forms of seizure-related sudden death that might be mechanistically related (eg, death after single febrile, unprovoked seizures, or status epilepticus). Typically, postictal apnoea and bradycardia progress to asystole and death. A crucial element of SUDEP is brainstem dysfunction, for which postictal generalised EEG suppression might be a biomarker. Dysfunction in serotonin and adenosine signalling systems, as well as genetic disorders affecting cardiac conduction and neuronal excitability, might also contribute. Because generalised tonic-clonic seizures precede most cases of SUDEP, patients must be better educated about prevention. The value of nocturnal monitoring to detect seizures and postictal stimulation is unproven but warrants further study.

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.

PURPOSE: To ascertain the cause of mortality and incidence of sudden unexpected death in epilepsy (SUDEP) in patients with supernumerary isodicentric chromosome 15 (idic15). METHODS: Cases were obtained from those reported to the Dup15q Alliance (www.dup15q.org) between April 2006 and June 2012; ~709 families were registered in their database. We performed a case-control study comparing reported SUDEP cases to living patients with epilepsy from the Dup15q Alliance registry who volunteered to be interviewed to examine clinical risk factors. KEY FINDINGS: There were nineteen deaths with idic15; 17 had epilepsy, and nine deaths were due to probable or definite SUDEP (4 females, median age of death was 13.5years, range: 3-26years). Possible SUDEP occurred in 2 others. The remainder died from status epilepticus (3), pneumonia (3), aspiration (1), and drowning (1). Nonambulatory status and lack of seizure control were more common among SUDEP cases than living dup15q patients. SIGNIFICANCE: Our findings suggest that SUDEP is a common cause of death among children and young adults with isodicentric chromosome 15q11.2q13 duplications and patients with the most severe neurologic dysfunction may be at highest risk. Further studies are needed to examine if this specific genetic defect plays a role in the mechanism of SUDEP in these patients.

INTRODUCTION: Perampanel is an AMPA receptor antagonist recently approved for the treatment of partial and generalized epilepsies with tonic-clonic seizures as an add-on therapy. METHODS: This single-center postmarketing study retrospectively evaluated the efficacy of perampanel in patients with partial onset and other seizure types, with a special emphasis on its efficacy, safety, and tolerability. RESULTS: Review of medical records revealed that adequate data were available on 101 patients taking perampanel. Fifty-seven patients were female. Sixteen patients were of pediatric age range. The average dose of perampanel was 6.5mg, and average treatment duration was 8.2months. After treatment, median seizure frequency reduction was 50% overall, 50% in children, and 33% in adults; 44% in primary generalized, 38% in secondarily generalized, and 33% in partial seizures. Responder rate (50% seizure frequency reduction) was 51% overall, 63% in children, and 49% in adults; 60% in partial seizures, 43% in secondarily generalized tonic-clonic seizures, 53% in primary generalized tonic-clonic seizures, and 56% in other seizure types. Seizure freedom was attained in 6% of cases. Most common adverse events were sleepiness/fatigue (35%), behavioral problems (30%), and dizziness (22%). Adverse events were correlated with dosage. Average dose was 7.3mg in patients with adverse events vs. 5.5mg in those without adverse events. Patients who developed fatigue, cognitive decline, headaches, and weight gain were more likely to discontinue perampanel than those patients who experienced coordination issues and behavioral problems. CONCLUSIONS: These findings suggest that perampanel is safe, well-tolerated, and effective in treatment of various types of adult and pediatric epilepsy syndromes. Fatigue, cognitive decline, headache and weight gain were the main causes of perampanel discontinuation.

We present a new approach to extracting low-dimensional neural trajectories that summarize the electrocorticographic (ECoG) signals recorded with high-channel-count electrode arrays implanted subdurally. In our approach, Hidden-Markov Factor Analysis (HMFA), a finite set of factor analyzers are used to model the relationship between the high-dimensional ECoG neural space and a low-dimensional latent neural space; the factor analyzers at different time points are in turn linked together with a hidden Markov model. The recorded ECoG signals were band-pass filtered such that our analysis was focused on a sub-band (76-100Hz) of high gamma. HMFA affords the quantization of the ECoG neural space and dimensionality reduction in a common probabilistic space. We applied this method to the ECoG recordings of 2 subjects who responded with button presses to audiovisual stimuli in an experimental task. Using a goodness-of-fit metric that measures how well the ECoG activity of each electrode can be predicted by all the other electrodes, we found that HMFA performed best when compared with Gaussian-Process Factor Analysis (GPFA) and other related spatiotemporal modeling techniques. In contradistinction to HMFA, GPFA and the other techniques integrate temporal smoothing with dimensionality reduction. We believe that this method will provide a powerful tool for relating high-channel-count ECoG signals to the perception and behavior of subjects.

To augment neural monitoring, a minimally intrusive multi-modal capture system was designed and implemented in the epilepsy clinic. This system provides RGB-D audio-video synchronized with patient electrocorticography (ECoG), which records neural activity across cortex. We propose an automated approach to studying the human brain in a naturalistic setting. We demonstrate coarse functional mapping of ECoG electrodes correlated to contralateral arm movements. Motor electrode mapping was generated by analyzing continuous movement data recorded over several hours from epilepsy patients in hospital rooms. From these recordings we estimate the kinematics of patient hand movement behaviors using computer vision algorithms. We compare movement behaviors to neural data collected from ECoG, specifically high-γ (70-110 Hz) spectral features. We present a functional map of electrode responses to natural arm movements, generated using a statistical test. We demonstrate that our approach has the potential to aid in the development of automated functional brain mapping using continuous video and neural recordings of patients in clinical settings.