Multisite thalamic recordings to characterize seizure propagation in the human brain.

Neuromodulation of the anterior nuclei of the thalamus (ANT) has shown to be efficacious in a subset of patients with refractory focal epilepsy. One important uncertainty is to what extent thalamic subregions other than the ANT could be recruited more prominently in the propagation of focal onset seizures. We designed the current study to simultaneously monitor the engagement of the ANT, mediodorsal (MD) and pulvinar (PUL) nuclei during seizures in patients who could be candidates for thalamic neuromodulation. We studied 11 patients with clinical manifestations of presumed temporal lobe epilepsy (TLE) undergoing invasive stereo-encephalography (sEEG) monitoring to confirm the source of their seizures. We extended cortical electrodes to reach the ANT, MD and PUL nuclei of the thalamus. More than one thalamic subdivision was simultaneously interrogated in nine patients. We recorded seizures with implanted electrodes across various regions of the brain and documented seizure onset zones (SOZ) in each recorded seizure. We visually identified the first thalamic subregion to be involved in seizure propagation. Additionally, in eight patients, we applied repeated single pulse electrical stimulation in each SOZ and recorded the time and prominence of evoked responses across the implanted thalamic regions. Our approach for multisite thalamic sampling was safe and caused no adverse events. Intracranial EEG recordings confirmed SOZ in medial temporal lobe, insula, orbitofrontal and temporal neocortical sites, highlighting the importance of invasive monitoring for accurate localization of SOZs. In all patients, seizures with the same propagation network and originating from the same SOZ involved the same thalamic subregion, with a stereotyped thalamic EEG signature. Qualitative visual reviews of ictal EEGs were largely consistent with the quantitative analysis of the corticothalamic evoked potentials, and both documented that thalamic nuclei other than ANT could have the earliest participation in seizure propagation. Specifically, pulvinar nuclei were involved earlier and more prominently than ANT in more than half of the patients. However, which specific thalamic subregion first demonstrated ictal activity could not be reliably predicted based on clinical semiology or lobar localization of SOZs. Our findings document the feasibility and safety of bilateral multisite sampling from the human thalamus. This may allow more personalized thalamic targets to be identified for neuromodulation. Future studies are needed to determine if a personalized thalamic neuromodulation leads to greater improvements in clinical outcome.

Rapid Response EEG: Current State and Future Directions.

PURPOSE OF REVIEW: To critically appraise the literature on the application, methods, and advances in emergency electroencephalography (EEG). RECENT FINDINGS: The development of rapid EEG (rEEG) technologies and other reduced montage approaches, along with advances in machine learning over the past decade, has increased the rate and access to EEG acquisition. These achievements have made EEG in the emergency setting a practical diagnostic technique for detecting seizures, suspected nonconvulsive status epilepticus (NCSE), altered mental status, stroke, and in the setting of sedation. Growing evidence supports using EEG to expedite medical decision-making in the setting of suspected acute neurological injury. This review covers approaches to acquiring EEG in the emergency setting in the adult and pediatric populations. We also cover the clinical impact of this data, the time associated with emergency EEG, and the costs of acquiring EEG in these settings. Finally, we discuss the advances in artificial intelligence for rapid electrophysiological interpretation.

Effect of rapid EEG on anti-seizure medication usage

Objective: To study how early diagnoses from rapid EEG (rEEG) during the initial evaluation of patients with suspected non-convulsive seizures correlates with changes in anti-seizure medication (ASM) use. Methods: We performed a retrospective chart review of 100 consecutive adult patients at an academic medical center who underwent rEEG monitoring for suspected non-convulsive seizures. We collected information on the timing of ASM administration and categorized EEG diagnoses as seizures (SZ), highly epileptiform patterns (HEP), or normal or slow activity (NL/SL). We used a χ² test to determine whether the use of ASMs was significantly different between SZ/HEP and NL/SL cases. Results: Of 100 patients, SZ were found in 5%, HEP in 14%, and no epileptiform/ictal activity in 81%. Forty-six percent of patients had received ASM(s) before rEEG. While 84% of HEP/SZ cases were started or continued on ASMs, only 51% of NL/SL cases were started or continued on ASMs after rEEG (χ² [1, n=100] = 7.09, p=0.008). Thirty-seven patients had received sedation (i.e., propofol or dexmedetomidine) prior to rEEG. In 15 patients (13/30 NL/SL, 2/7 HEP/SZ), sedation was discontinued following rEEG. Significance: Our study demonstrates that seizures were rapidly ruled out with rEEG in 81% of patients while 19% of patients were rapidly identified as having seizures or being at higher risk for seizures. The rapid evaluation of patients correlated with a significant reduction in ASM treatment in NL/SL cases compared to HEP/SZ cases. Thus, early access to EEG information may lead to more informed and targeted management of patients suspected to have nonconvulsive seizures.

The diarylheptanoid (+)-aR,11S-myricanol and two flavones from bayberry (Myrica cerifera) destabilize the microtubule-associated protein tau.

Target-based drug discovery for Alzheimer's disease (AD) centered on modulation of the amyloid ß peptide has met with limited success. Therefore, recent efforts have focused on targeting the microtubule-associated protein tau. Tau pathologically accumulates in more than 15 neurodegenerative diseases and is most closely linked with postsymptomatic progression in AD. We endeavored to identify compounds that decrease tau stability rather than prevent its aggregation. An extract from Myrica cerifera (bayberry/southern wax myrtle) potently reduced both endogenous and overexpressed tau protein levels in cells and murine brain slices. The bayberry flavonoids myricetin and myricitrin were confirmed to contribute to this potency, but a diarylheptanoid, myricanol, was the most effective anti-tau component in the extract, with potency approaching the best targeted lead therapies. (+)-aR,11S-Myricanol, isolated from M. cerifera and reported here for the first time as the naturally occurring aglycone, was significantly more potent than commercially available (±)-myricanol. Myricanol may represent a novel scaffold for drug development efforts targeting tau turnover in AD.

Bending tau into shape: the emerging role of peptidyl-prolyl isomerases in tauopathies.

The Hsp90-associated cis-trans peptidyl-prolyl isomerase--FK506 binding protein 51 (FKBP51)--was recently found to co-localize with the microtubule (MT)-associated protein tau in neurons and physically interact with tau in brain tissues from humans who died from Alzheimer's disease (AD). Tau pathologically aggregates in neurons, a process that is closely linked with cognitive deficits in AD. Tau typically functions to stabilize and bundle MTs. Cellular events like calcium influx destabilize MTs, disengaging tau. This excess tau should be degraded, but sometimes it is stabilized and forms higher-order aggregates, a pathogenic hallmark of tauopathies. FKBP51 was also found to increase in forebrain neurons with age, further supporting a novel role for FKBP51 in tau processing. This, combined with compelling evidence that the prolyl isomerase Pin1 regulates tau stability and phosphorylation dynamics, suggests an emerging role for isomerization in tau pathogenesis.

Rationally designed dehydroalanine (DeltaAla)-containing peptides inhibit amyloid-beta (Abeta) peptide aggregation.

Among the pathological hallmarks of Alzheimer's disease (AD) is the deposition of amyloid-beta (Abeta) peptides, primarily Abeta (1-40) and Abeta (1-42), in the brain as senile plaques. A large body of evidence suggests that cognitive decline and dementia in AD patients arise from the formation of various aggregated forms of Abeta, including oligomers, protofibrils and fibrils. Hence, there is increasing interest in designing molecular agents that can impede the aggregation process and that can lead to the development of therapeutically viable compounds. Here, we demonstrate the ability of the specifically designed alpha,beta-dehydroalanine (DeltaAla)-containing peptides P1 (K-L-V-F-DeltaA-I-DeltaA) and P2 (K-F-DeltaA-DeltaA-DeltaA-F) to inhibit Abeta (1-42) aggregation. The mechanism of interaction of the two peptides with Abeta (1-42) seemed to be different and distinct. Overall, the data reveal a novel application of DeltaAla-containing peptides as tools to disrupt Abeta aggregation that may lead to the development of anti-amyloid therapies not only for AD but also for many other protein misfolding diseases. (c) 2009 Wiley Periodicals, Inc. Biopolymers 91: 456-465, 2009.