Faculty Bibliography

BACKGROUND: Despite the increasing interest in sex differences in disease manifestations and responses to treatment, very few data are available on sex differences in seizure types and semiology. The Epilepsy Phenome/Genome Project (EPGP) is a large-scale, multi-institutional, collaborative study that aims to create a comprehensive repository of detailed clinical information and DNA samples from a large cohort of people with epilepsy. We used this well-characterized cohort to explore differences in seizure types as well as focal seizure symptoms between males and females. METHODS: We reviewed the EPGP database and identified individuals with generalized epilepsy of unknown etiology (GE) (n = 760; female: 446, male: 314), nonacquired focal epilepsy (NAFE) (n = 476; female: 245, male: 231), or both (n = 64; female: 33, male: 31). Demographic data along with characterization of seizure type and focal seizure semiologies were examined. RESULTS: In GE, males reported atonic seizures more frequently than females (6.5% vs. 1.7%; p < 0.001). No differences were observed in other generalized seizure types. In NAFE, no sex differences were seen for seizure types with or without alteration of consciousness or progression to secondary generalization. Autonomic (16.4% vs. 26.6%; p = 0.005), psychic (26.7% vs. 40.3%; p = 0.001), and visual (10.3% vs. 19.9%; p = 0.002) symptoms were more frequently reported in females than males. Specifically, of psychic symptoms, more females than males endorsed deja vu (p = 0.001) but not forced thoughts, derealization/depersonalization, jamais vu, or fear. With corrections for multiple comparisons, there were no significant differences in aphasic, motor, somatosensory, gustatory, olfactory, auditory, vertiginous, or ictal headache symptoms between sexes. CONCLUSIONS: Significant differences between the sexes were observed in the reporting of atonic seizures, which were more common in males with GE, and for autonomic, visual, and psychic symptoms associated with NAFE, which were more common in females.

OBJECTIVE: We studied the frequency of auras in generalized epilepsy (GE) using a detailed semistructured diagnostic interview. METHODS: In this cross-sectional study, participants with GE were drawn from the Epilepsy Phenome/Genome Project (EPGP). Responses to the standardized diagnostic interview regarding tonic-clonic (grand mal) seizures were then examined. This questionnaire initially required participants to provide their own description of any subjective phenomena before their "grand mal seizures." Participants who provided answers to these questions were considered to have an aura. All participants were then systematically queried regarding a list of specific symptoms occurring before grand mal seizures, using structured (closed-ended) questions. RESULTS: Seven hundred ninety-eight participants with GE were identified, of whom 530 reported grand mal seizures. Of these, 112 (21.3%) reported auras in response to the open-ended question. Analysis of responses to the closed-ended questions suggested that 341 participants (64.3%) experienced at least one form of aura. CONCLUSIONS: Auras typically associated with focal epilepsy were reported by a substantial proportion of EPGP subjects with GE. This finding may support existing theories of cortical and subcortical generators of GE with variable spread patterns. Differences between responses to the open-ended question and closed-ended questions may also reflect clinically relevant variation in patient responses to history-taking and surveys. Open-ended questions may underestimate the prevalence of specific types of auras and may be in part responsible for the underrecognition of auras in GE. In addition, structured questions may influence participants, possibly leading to a greater representation of symptoms.

People with pharmacoresistant epilepsy are often candidates for resective epilepsy surgery. The presurgical evaluation for epilepsy aims to localize the epileptic network that initiates seizures (which should be disrupted or removed) and determine its spatial relationship to eloquent cortex (which should be preserved). Noninvasive functional imaging techniques play an increasingly important role in planning epilepsy surgery and assessing the feasibility, risks, and benefits of surgery. Magnetoencephalography (MEG) can be a very useful part of a comprehensive presurgical evaluation as it can model the sources of epileptiform activity and localize eloquent cortices within the same study. This review is designed to assist anyone in the field of neurology or related disciplines understand some methods and terminology relevant to clinical MEG. Every effort is made to present the information in nontechnical, approachable ways so that readers will come away with a basic understanding of how to interpret MEG findings when the reported data on one of their patients are presented to them.

OBJECTIVE: Genetic loss of Tsc1/Tsc2 function in tuberous sclerosis complex (TSC) results in altered mammalian target of rapamycin (mTOR) signaling and abnormal brain development. Although earlier studies have focused on characterization of cortical tubers, in this study we sought to examine the unique cellular and molecular features of the perituberal cortex in order to better understand its contribution to epileptogenesis, cognitive dysfunction, and autism. METHODS: Standard histologic and immunohistochemical labeling was used to assess structural abnormalities and cell-specific pattern of mTORC1 activation in surgically resected cortical tubers and perituberal cortex. Western blotting was performed to quantify the expression of the mTORC1 and mTORC2 biomarkers phospho-S6 (Ser235/236), phospho-S6 (Ser240/244), and phospho-Akt (Ser473), in addition to evaluating the differential expression levels of several neuronal and glial-specific proteins in tubers and peritubers, as compared to non-TSC epilepsy specimens. RESULTS: Tubers demonstrated mild to severe disruption of cortical lamination, the presence of pS6-positive dysplastic neurons and giant cells, an overall increase in mTORC1 and a decrease in mTORC2 activity, increased axonal connectivity and growth, and hypomyelination. Perituberal cortex presented similar histologic, immunohistochemical, and molecular features; however, they were overall milder. Axonal growth was specific for TSC and was negatively correlated with deficient myelination. SIGNIFICANCE: Our results show an extension of cellular dysplasia and dysregulated mTOR signaling in the perituberal tissue, and demonstrate for the first time aberrant connectivity in human TSC brain. This study provides new insights into the pathophysiology of neurologic dysfunction associated with TSC and supports the intrinsic epileptogenicity of normal-appearing perituberal cortex.

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.