Faculty Bibliography

Introduction: Antiseizure medications are the mainstay of epilepsy treatment. Currently therapies are not specific to epilepsy etiology, and control seizures in two thirds of cases. Drugs in clinical development aim to bridge that gap by targeting novel receptors and epileptogenesis. While currently approved antiseizure medications target focal or generalized epilepsies regardless of etiology, newly approved and investigational epilepsy drugs also target rare or orphan epilepsy syndrome indications, such as Lennox-Gastaut or Dravet syndrome. We identified investigational drugs through the Epilepsy Foundation pipeline tracker and conference proceedings of recent novel epilepsy drug conferences (XV AEDD, XIV EILAT).Areas Covered: We review antiseizure medications in clinical development and their targets (GABA, T-type calcium channels, 5-HT, potassium channels). We also discuss drugs with unknown or multiple mechanisms of action (cannabinoids, carisbamate, cenobamate). Therapies with potential disease-modifying effects in preclinical and clinical development are then outlined, ranging from gene-targeted treatments (antisense oligonucleotide, gene therapy, antisense transcript regulators) targeting specific genetic epilepsies, mTOR inhibitors, to inflammation-targeted treatments.Expert Opinion: Drugs to treat novel targets to control seizures as well as prevent epileptogenesis offer great promise. To assess disease modifying agents, we may need new clinical trial designs. Precision medicine therapies for genetic epilepsies may control seizures and restore brain health.

Sudden unexplained death in childhood (SUDC) affects children >1-year-old whose cause of death remains unexplained following comprehensive case investigation and is often associated with hippocampal abnormalities. We prospectively performed systematic neuropathologic investigation in 20 SUDC cases, including (i) autopsy data and comprehensive ancillary testing, including molecular studies, (ii) ex vivo 3T MRI and extensive histologic brain samples, and (iii) blinded neuropathology review by 2 board-certified neuropathologists. There were 12 girls and 8 boys; median age at death was 33.3 months. Twelve had a history of febrile seizures, 85% died during apparent sleep and 80% in prone position. Molecular testing possibly explained 3 deaths and identified genetic mutations in TNNI3, RYR2, and multiple chromosomal aberrations. Hippocampal abnormalities most often affected the dentate gyrus (altered thickness, irregular configuration, and focal lack of granule cells), and had highest concordance between reviewers. Findings were identified with similar frequencies in cases with and without molecular findings. Number of seizures did not correlate with hippocampal findings. Hippocampal alterations were the most common finding on histological review but were also found in possibly explained deaths. The significance and specificity of hippocampal findings is unclear as they may result from seizures, contribute to seizure pathogenesis, or be an unrelated phenomenon.

Excess mortality due to epilepsy is greatest among young adults. However, the relative proportions of sudden unexpected death in epilepsy (SUDEP) and other epilepsy-related causes of death are not well defined. We prospectively adjudicated cause of death in all 18- to 45-year-olds with a history of seizure/epilepsy who underwent medicolegal investigation in San Diego County between 2014 and 2017. We identified 108 decedents with definite or probable epilepsy; 62% died from an epilepsy-related cause. SUDEP accounted for 42.6% (N = 46) of deaths, which were usually unwitnessed deaths, at home in bed. Other frequent causes of death were drug overdose (N = 23), suicide (N = 8), trauma (N = 8), and drowning (N = 6). SUDEP autopsies were similar to those of decedents from other causes. Most deaths in young adults with epilepsy that undergo medico-legal investigation are epilepsy-related, and SUDEP is the leading cause. Improved seizure control can potentially save many lives.

Memory consolidation is hypothesized to involve the distribution and restructuring of memory representations across hippocampal and cortical regions. Theories suggest that, through extended hippocampal-cortical interactions, cortical ensembles come to represent more integrated, or overlapping, memory traces that prioritize commonalities across related memories. Sleep processes, particularly fast sleep spindles, are thought to support consolidation, but evidence for this relationship has been mostly limited to memory retention benefits. Whether fast spindles provide a mechanism for neural changes hypothesized to support consolidation, including the strengthening of hippocampal-cortical networks and integration across memory representations, remains unclear, as does the specificity of regions involved. Using functional connectivity analyses of human fMRI data (both sexes), we show that fast spindle density during overnight sleep is related to enhanced hippocampal-cortical functional connectivity the next day, when re-studying information learned before sleep. Spindle density modulated connectivity in distinct hippocampal-cortical networks depending on the category of the consolidated stimuli. Specifically, spindle density correlated with functional connectivity between anterior hippocampus and ventromedial prefrontal cortex (vmPFC) for object-word pairs, and posterior hippocampus and posteromedial cortex (PMC) for scene-word pairs. Using multivariate pattern analyses, we also show fast spindle density during post-learning sleep is associated with greater pattern similarity, or representational overlap, across individual object-word memories in vmPFC the next day. Further, the relationship between fast spindle density and representational overlap in vmPFC was mediated by the degree of anterior hippocampal-vmPFC functional connectivity. Together, these results suggest fast spindles support the network distribution of memory traces, potentially restructuring memory representations in vmPFC.SIGNIFICANCE STATEMENTHow new experiences are transformed into long-term memories remains a fundamental question for neuroscience research. Theories suggest that memories are stabilized as they are reorganized in the brain, a process thought to be supported by sleep oscillations, particularly sleep spindles. Although sleep spindles have been associated with benefits in memory retention, it is not well understood how spindles modify neural memory traces. This study found that spindles during overnight sleep correlate with changes in neural memory traces, including enhanced functional connectivity in distinct hippocampal-cortical networks and increased pattern similarity amongst memories in the cortex. The results provide critical evidence that spindles during overnight sleep may act as a physiological mechanism for the restructuring of neural memory traces.

De novo mutations arising on the paternal chromosome make the largest known contribution to autism risk, and correlate with paternal age at the time of conception. The recurrence risk for autism spectrum disorders is substantial, leading many families to decline future pregnancies, but the potential impact of assessing parental gonadal mosaicism has not been considered. We measured sperm mosaicism using deep-whole-genome sequencing, for variants both present in an offspring and evident only in father's sperm, and identified single-nucleotide, structural and short tandem-repeat variants. We found that mosaicism quantification can stratify autism spectrum disorders recurrence risk due to de novo mutations into a vast majority with near 0% recurrence and a small fraction with a substantially higher and quantifiable risk, and we identify novel mosaic variants at risk for transmission to a future offspring. This suggests, therefore, that genetic counseling would benefit from the addition of sperm mosaicism assessment.

Objectives: Anhedonia, or the inability or the loss of the capacity to experience pleasure, is a core feature of several psychiatric disorders. Different types of anhedonia have been described including social and physical anhedonia, appetitive or motivational anhedonia, consummatory and anticipatory anhedonia. Musical anhedonia is a rare condition where individuals derive no reward responses from musical experience. Methods: We searched the PubMed electronic database for all articles with the search term "musical anhedonia". Results: A final set of 12 articles (six original research articles and six clinical case reports) comprised the set we reviewed. Conclusions: Individuals with specific musical anhedonia show normal responses to other types of reward, suggesting a specific deficit in musical reward pathways. Those individuals are not necessarily affected by psychiatric conditions, have normal musical perception capacities, and normal recognition of emotions depicted in music. Individual differences in the tendency to derive pleasure from music are associated with structural connections from auditory association areas in the superior temporal gyrus to the anterior insula. White matter connectivity may reflect individual differences in the normal variations of reward experiences in music. The moderate amount of heterogeneity between the reviewed studies is a limitation to the generalizability of our conclusions. (PsycInfo Database Record (c) 2021 APA, all rights reserved)

Sudden Unexplained Death in Childhood (SUDC) is the unexpected death of a child over age 12 months that remains unexplained after a thorough case investigation, including review of the child's medical history, circumstances of death, a complete autopsy and ancillary testing (1). First defined in 2005, SUDC cases are more often male, with death occurring during a sleep period, being found prone, peak winter incidence, associated with febrile seizure history in ~28% of cases and mild pathologic changes insufficient to explain the death (1, 2). There has been little progress in understanding the causes of SUDC and no progress in prevention. Despite reductions in sudden unexpected infant death (SUID) and other causes of mortality in childhood, the rate of SUDC has increased during the past two decades (3-5). In Ireland, SUID deaths were cut in half from 1994 to 2008 while SUDC deaths more than doubled (4). Surveillance issues, including lack of standardized certification practices, affect our understanding of the true magnitude of unexplained child deaths. Mechanisms underlying SUDC, like SUID, remain largely speculative. Limited and inconsistent evidence implicates abnormalities in brainstem autonomic and serotonergic nuclei, critical for arousal, cardiorespiratory control, and reflex responses to life-threatening hypoxia or hypercarbia in sleep (6). Abnormalities in medullary serotonergic neurons and receptors, as well as cardiorespiratory brainstem nuclei occur in some SUID cases, but have never been studied in SUDC. Retrospective, small SUDC studies with non-standardized methodologies most often demonstrate minor hippocampal abnormalities, as well as focal cortical dysplasia and dysgenesis of the brainstem and cerebellum. The significance of these findings to SUDC pathogenesis remains unclear with some investigators and forensic pathologists labeling these findings as normal variants, or potential causes of SUDC. The development of preventive strategies will require a greater understanding of underlying mechanisms.

Objectives/UNASSIGNED:Clinically relevant neuroanatomy is challenging to teach, learn and remember since many functionally important structures are visualized best using histology stains from serial 2D planar sections of the brain. In clinical patients, the locations of specific structures then must be inferred from spatial position and surface anatomy. A 3D MRI dataset of neuroanatomy has several advantages including simultaneous multi-planar visualization in the same brain, direct end-user manipulation of the data and image contrast identical to clinical MRI. We created 3D MRI datasets of the postmortem brain with high spatial and contrast resolution for simultaneous multi-planar visualization of complex neuroanatomy. Materials and Methods/UNASSIGNED:; time = 7 h). Besides resolution, this sequence has multiple adjustments to improve contrast compared to a clinical protocol, including 93% reduced turbo factor and 77% reduced effective echo time. Results/UNASSIGNED:This MRI microscopy protocol provided excellent contrast resolution of small nuclei and internal myelinated pathways within the basal ganglia, thalamus, brainstem, and cerebellum. Contrast was sufficient to visualize the presence and variation of horizontal layers in the cerebral cortex. 3D isotropic resolution datasets facilitated simultaneous multi-planar visualization and efficient production of specific tailored oblique image orientations to improve understanding of complex neuroanatomy. Conclusion/UNASSIGNED:structure visualization.