Faculty Bibliography

Transcranial electrical stimulation has widespread clinical and research applications, yet its effect on ongoing neural activity in humans is not well established. Previous reports argue that transcranial alternating current stimulation (tACS) can entrain and enhance neural rhythms related to memory, but the evidence from non-invasive recordings has remained inconclusive. Here, we measure endogenous spindle and theta activity intracranially in humans during low-frequency tACS and find no stable entrainment of spindle power during non-REM sleep, nor of theta power during resting wakefulness. As positive controls, we find robust entrainment of spindle activity to endogenous slow-wave activity in 66% of electrodes as well as entrainment to rhythmic noise-burst acoustic stimulation in 14% of electrodes. We conclude that low-frequency tACS at common stimulation intensities neither acutely modulates spindle activity during sleep nor theta activity during waking rest, likely because of the attenuated electrical fields reaching the cortical surface.

Musical hallucinations are uncommon phenomena characterized by intrusive and frequently distressful auditory musical percepts without an external source, often associated with hypoacusis, psychiatric illness, focal brain lesion, epilepsy, and intoxication/pharmacology. Their physiological basis is thought to involve diverse mechanisms, including "release" from normal sensory or inhibitory inputs as well as stimulation during seizures, or they can be produced by functional or structural disorders in diverse cortical and subcortical areas. The aim of this review is to further explore their pathophysiology, describing the functional neuroimaging findings regarding musical hallucinations. A literature search of the PubMed electronic database was conducted through to 29 December 2015. Search terms included "musical hallucinations" combined with the names of specific functional neuroimaging techniques. A total of 18 articles, all clinical case reports, providing data on 23 patients, comprised the set we reviewed. Diverse pathological processes and patient populations with musical hallucinations were included in the studies. Converging data from multiple studies suggest that the superior temporal sulcus is the most common site and that activation is the most common mechanism. Further neurobiological research is needed to clarify the pathophysiology of musical hallucinations.

Extensive pioneering studies performed in the hippocampus have greatly contributed to our knowledge of an endogenous cannabinoid system comprised of the molecular machinery necessary to process endocannabinoid lipid messengers and their associated cannabinoid receptors. Moreover, a foundation of knowledge regarding the function of hippocampal circuits, and its role in supporting synaptic plasticity has facilitated our understanding of the roles cannabinoids play in the diverse behaviors in which the hippocampus participates, in both normal and pathological states. In this review, we present an historical overview of research pertaining to the hippocampal cannabinoid system to provide context in which to understand the participation of the hippocampus in cognition, behavior, and epilepsy. We also examine potential roles for the hippocampal formation in mediating dysfunctional behavior, and assert that these phenomena reflect disordered physiological activity within the hippocampus and its interactions with other brain regions after exposure to synthetic cannabinoids, and the phytocannabinoids found in marijuana, such as Delta9-THC and cannabidiol. In this regard, we examine contemporary hypotheses concerning the hippocampal endocannabinoid system's participation in psychotic disorders, schizophrenia, and epilepsy, and examine cannabinoid-sensitive cellular mechanisms contributing to coherent network oscillations as potential contributors to these disorders.

OBJECTIVE: Sudden unexplained death in epilepsy is the leading cause of death in young adult epilepsy patients, typically occurring during the early postictal period, presumably resulting from brainstem and cardiorespiratory dysfunction. We hypothesized that ictal discharges in the brainstem disrupt the cardiorespiratory network, causing mortality. To study this hypothesis, we chose an animal model comprising focal unilateral hippocampal injection of 4-aminopyridine (4-AP), which produced focal recurrent hippocampal seizures with secondary generalization in awake, behaving rats. METHODS: We studied ictal and interictal intracranial electrographic activity (iEEG) in 23 rats implanted with a custom electrode array into the hippocampus, the contralateral cortex, and brainstem. The hippocampal electrodes contained a cannula to administer the potassium channel blocker and convulsant (4-AP). iEEG was recorded continuously before, during, and after seizures induced by 4-AP infusion into the hippocampus. RESULTS: The control group (n = 5) was monitored for 2-3 months, and the weekly baseline iEEG recordings showed long-term stability. The low-dose group (1 muL 4-AP, 40 mm, n = 5) exhibited local electrographic seizures without spread to the contralateral cerebral cortex or brainstem. The high-dose group (5 muL 4-AP, 40 mm, n = 3) had several hippocampal electrographic seizures, which spread contralaterally and triggered brainstem discharges within 40 min, and were associated with violent motor seizures followed by dyspnea and respiratory arrest, with cortical and hippocampal iEEG flattening. The group that received high-dose 4-AP without brainstem implantation (n = 5) had similar seizure-related respiratory difficulties. Finally, five rats that received high-dose 4-AP without EEG recording also developed violent motor seizures with postictal respiratory arrest. Following visualized respiratory arrest in groups III, IV, and V, manual respiratory resuscitation was successful in five of 13 animals. SIGNIFICANCE: These studies show that hippocampal seizure activity can spread or trigger brainstem epileptiform discharges that may cause mortality, possibly mediated by respiratory network dysfunction.

OBJECTIVE: To determine the definite and potential frequency of seizures and epilepsy as a cause of death (COD) and how often this goes unrecognized. METHODS: Prospective determination of seizures or epilepsy and final COD for individuals aged 18-90 years with out-of-hospital sudden cardiac deaths (SCDs) from the population-based San Francisco POST SCD Study. We compared prospective seizure or epilepsy diagnosis and final COD as adjudicated by a multidisciplinary committee (pathologists, electrophysiologists, and a vascular neurologist) vs retrospective adjudication by 2 epileptologists with expertise in seizure-related mortality. RESULTS: Of 541 SCDs identified during the 37-month study period (mean age 62.8 years, 69% men), 525 (97%) were autopsied; 39/525 (7.4%) had seizures or epilepsy (mean age: 58 years, range: 27-92; 67% men), comprising 17% of 231 nonarrhythmic sudden deaths. The multidisciplinary team identified 15 cases of epilepsy, 6 sudden unexpected deaths in epilepsy (SUDEPs), and no deaths related to acute symptomatic seizures. The epileptologists identified 25 cases of epilepsy and 8 definite SUDEPs, 10 possible SUDEPs, and 5 potential cases of acute symptomatic seizures as a COD. CONCLUSIONS: Among the 25 patients identified with epilepsy by the epileptologists, they found definite or possible SUDEP in 72% (18/25) vs 24% (6/25) by the multidisciplinary group (6/15 cases they identified with epilepsy). The epileptologists identified acute symptomatic seizures as a potential COD in 5/14 patients with alcohol-related seizures. Epilepsy is underdiagnosed among decedents. Among patients with seizures and epilepsy who die suddenly, seizures and SUDEP often go unrecognized as a potential or definite COD.

Gene identification in epilepsy has mainly been limited to large families segregating genes of major effect and de novo mutations in epileptic encephalopathies. Many families that present with common non-acquired focal epilepsies and genetic generalized epilepsies remain unexplained. We assembled a cohort of 'genetically enriched' common epilepsies by collecting and phenotyping families containing multiple individuals with unprovoked seizures. We aimed to determine if specific clinical epilepsy features aggregate within families, and whether this segregation of phenotypes may constitute distinct 'familial syndromes' that could inform genomic analyses. Families with three or more individuals with unprovoked seizures were studied across multiple international centres. Affected individuals were phenotyped and classified according to specific electroclinical syndromes. Families were categorized based on syndromic groupings of affected family members, examined for pedigree structure and phenotypic patterns and, where possible, assigned specific familial epilepsy syndromes. A total of 303 families were assembled and analysed, comprising 1120 affected phenotyped individuals. Of the 303 families, 117 exclusively segregated generalized epilepsy, 62 focal epilepsy, and 22 were classified as genetic epilepsy with febrile seizures plus. Over one-third (102 families) were observed to have mixed epilepsy phenotypes: 78 had both generalized and focal epilepsy features within the same individual (n = 39), or within first or second degree relatives (n = 39). Among the genetic generalized epilepsy families, absence epilepsies were found to cluster within families independently of juvenile myoclonic epilepsy, and significantly more females were affected than males. Of the 62 familial focal epilepsy families, two previously undescribed familial focal syndrome patterns were evident: 15 families had posterior quadrant epilepsies, including seven with occipito-temporal localization and seven with temporo-parietal foci, and four families displayed familial focal epilepsy of childhood with multiple affected siblings that was suggestive of recessive inheritance. The findings suggest (i) specific patterns of syndromic familial aggregation occur, including newly recognized forms of familial focal epilepsy; (ii) although syndrome-specificity usually occurs in multiplex families, the one-third of families with features of both focal and generalized epilepsy is suggestive of shared genetic determinants; and (iii) patterns of features observed across families including pedigree structure, sex, and age of onset may hold clues for future gene identification. Such detailed phenotypic information will be invaluable in the conditioning and interpretation of forthcoming sequencing data to understand the genetic architecture and interrelationships of the common epilepsy syndromes.

Recent clinical trials indicate that cannabidiol (CBD) may reduce seizure frequency in pediatric patients with certain forms of treatment-resistant epilepsy. Many of these patients experience significant impairments in quality of life (QOL) in physical, mental, and social dimensions of health. In this study, we measured the caregiver-reported Quality of Life in Childhood Epilepsy (QOLCE) in a subset of patients enrolled in a prospective, open-label clinical study of CBD. Results from caregivers of 48 patients indicated an 8.2 +/- 9.9-point improvement in overall patient QOLCE (p < 0.001) following 12 weeks of CBD. Subscores with improvement included energy/fatigue, memory, control/helplessness, other cognitive functions, social interactions, behavior, and global QOL. These differences were not correlated to changes in seizure frequency or adverse events. The results suggest that CBD may have beneficial effects on patient QOL, distinct from its seizure-reducing effects; however, further studies in placebo-controlled, double-blind trials are necessary to confirm this finding.