Faculty Bibliography

High frequency oscillations (HFOs) are bursts of neural activity in the range of 80 Hz or higher, recorded from intracranial electrodes during epileptiform discharges. HFOs are a proposed biomarker of epileptic brain tissue and may also be useful for seizure forecasting. Despite such clinical utility of HFOs, the spatial context and neuronal activity underlying these local field potential (LFP) events remains unclear. We sought to further understand the neuronal correlates of ictal high frequency LFPs using multielectrode array recordings in the human neocortex and mesial temporal lobe during rhythmic onset seizures. These multiscale recordings capture single cell, multiunit, and LFP activity from the human brain. We compare features of multiunit firing and high frequency LFP from microelectrodes and macroelectrodes during ictal discharges in both the seizure core and penumbra (spatial seizure domains defined by multiunit activity patterns). We report differences in spectral features, unit-local field potential coupling, and information theoretic characteristics of high frequency LFP before and after local seizure invasion. Furthermore, we tie these time-domain differences to spatial domains of seizures, showing that penumbral discharges are more broadly distributed and less useful for seizure localization. These results describe the neuronal and synaptic correlates of two types of pathological HFOs in humans and have important implications for clinical interpretation of rhythmic onset seizures.

Identifying cerebral vulnerability in late life may help prevent or slow the progression of aging-related chronic diseases. However, non-invasive biomarkers aimed at detecting subclinical cerebral changes in the elderly are lacking. Here, we have examined the potential of plasma total tau (t-tau) for identifying cerebral and cognitive deficits in normal elderly subjects. Patterns of cortical thickness and cortical glucose metabolism were used as outcomes of cerebral vulnerability. We found that increased plasma t-tau levels were associated with widespread reductions of cortical glucose uptake, thinning of the temporal lobe, and memory deficits. Importantly, tau-related reductions of glucose consumption in the orbitofrontal cortex emerged as a determining factor of the relationship between cortical thinning and memory loss. Together, these results support the view that plasma t-tau may serve to identify subclinical cerebral and cognitive deficits in normal aging, allowing detection of individuals at risk for developing aging-related neurodegenerative conditions.

BACKGROUND:To evaluate efficacy, pharmacokinetics (PK) and pharmacodynamics of single-agent everolimus in pediatric patients with radiographically progressive low-grade glioma (LGG). METHODS:once daily as a tablet or liquid for a planned 48-week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded. PK and pharmacodynamic endpoints were assessed in consenting patients. RESULTS:Twenty-three eligible patients (median age 9.2 years) were enrolled. All patients received prior chemotherapy (median number of prior regimens two) and/or radiotherapy (two patients). By week 48, two patients had a partial response, 10 stable disease, and 11 clinical or radiographic progression; two discontinued study prior to 1 year (toxicity: 1, physician determination: 1). With a median follow up of 1.8 years (range 0.2-6.7 years), the 2-, 3-, and 5-year progression-free survivals (PFS) were 39 ± 11%, 26 ± 11%, and 26 ± 11%, respectively; two patients died of disease. The 2-, 3-, and 5-year overall survival (OS) were all 93 ± 6%. Grade 1 and 2 toxicities predominated; two definitively related grade 3 toxicities (mucositis and neutropenia) occurred. Grade 4 elevation of liver enzymes was possibly related in one patient. Predose blood levels showed substantial variability between patients with 45.5% below and 18.2% above the target range of 5-15 ng/mL. Pharmacodynamic analysis demonstrated significant inhibition in phospho-S6, 4E-BP1, and modulation of c-Myc expression. CONCLUSION/CONCLUSIONS:Daily oral everolimus provides a well-tolerated, alternative treatment for multiple recurrent, radiographically progressive pediatric LGG. Based on these results, everolimus is being investigated further for this patient population.

BACKGROUND:The terminology and classification of seizures and epilepsy has undergone multiple revisions in the last several decades, which can lead to confusion and miscommunication amongst physicians and researchers. In 2017, the International League Against Epilepsy (ILAE) revised the classification of both seizures and epilepsy types in an effort to use less ambiguous terminology. Over time, definitions for status epilepticus, febrile seizures, and neonatal seizures have also evolved, as has the delineation of various epilepsy syndromes by age. METHODS:Review of the literature for old and new terminology and various epilepsy syndromes was accomplished using the PubMed database system. RESULTS:In the following article, we review old terminology for classifying seizures and epilepsy as compared to the new (2017) ILAE guidelines. We discuss neonatal seizures, status epilepticus, febrile seizures, autoimmune epilepsy and various epilepsy syndromes by age of onset. CONCLUSION/CONCLUSIONS:Adopting a classification system that uses plain language allows for more effective and efficient communication between individuals and across specialties. Definitions of various syndromes and seizure types have evolved over time and are reviewed.

Deep brain stimulation (DBS) is a surgical treatment for advanced Parkinson's disease (PD) that has undergone technological evolution that parallels an expansion in clinical phenotyping, neurophysiology, and neuroimaging of the disease state. Machine learning (ML) has been successfully used in a wide range of healthcare problems, including DBS. As computational power increases and more data become available, the application of ML in DBS is expected to grow. We review the literature of ML in DBS and discuss future opportunities for such applications. Specifically, we perform a comprehensive review of the literature from PubMed, the Institute for Scientific Information's Web of Science, Cochrane Database of Systematic Reviews, and Institute of Electrical and Electronics Engineers' (IEEE) Xplore Digital Library for ML applications in DBS. These studies are broadly placed in the following categories: (1) DBS candidate selection; (2) programming optimization; (3) surgical targeting; and (4) insights into DBS mechanisms. For each category, we provide and contextualize the current body of research and discuss potential future directions for the application of ML in DBS.

Many human genetic diseases, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by single point mutations. HGPS is a rare disorder that causes premature aging and is usually caused by a de novo point mutation in the LMNA gene. Base editors (BEs) composed of a cytidine deaminase fused to CRISPR/Cas9 nickase are highly efficient at inducing C to T base conversions in a programmable manner and can be used to generate animal disease models with single amino-acid substitutions. Here, we generated the first HGPS monkey model by delivering a BE mRNA and guide RNA (gRNA) targeting the LMNA gene via microinjection into monkey zygotes. Five out of six newborn monkeys carried the mutation specifically at the target site. HGPS monkeys expressed the toxic form of lamin A, progerin, and recapitulated the typical HGPS phenotypes including growth retardation, bone alterations, and vascular abnormalities. Thus, this monkey model genetically and clinically mimics HGPS in humans, demonstrating that the BE system can efficiently and accurately generate patient-specific disease models in non-human primates.