Worrell, Gregory A.

Microglial calcium signaling underlies a number of key physiological and pathological processes in situ, but has not been studied in vivo in awake mice. Using multiple GCaMP6 variants targeted to microglia, we assessed how microglial calcium signaling responds to alterations in neuronal activity across a wide range. We find that only a small subset of microglial somata and processes exhibited spontaneous calcium transients in a chronic window preparation. However, hyperactive shifts in neuronal activity (kainate status epilepticus and CaMKIIa Gq DREADD activation) triggered increased microglial process calcium signaling, often concomitant with process extension. Additionally, hypoactive shifts in neuronal activity (isoflurane anesthesia and CaMKIIa Gi DREADD activation) also increased microglial process calcium signaling. Under hypoactive neuronal conditions, microglia also exhibited process extension and outgrowth with greater calcium signaling. Our work reveals that microglia have highly distinct microdomain signaling, and that processes specifically respond to bi-directional shifts in neuronal activity through increased calcium signaling.

Intracranial electroencephalography (iEEG) has been the mainstay of identifying the seizure onset zone (SOZ), a key diagnostic procedure in addition to neuroimaging when considering epilepsy surgery. In many patients, iEEG has been the basis for resective epilepsy surgery, to date still the most successful treatment for drug-resistant epilepsy. Intracranial EEG determines the location and resectability of the SOZ. Advances in recording and implantation of iEEG provide multiple options in the 21st century. This not only includes the choice between subdural electrodes (SDE) and stereoelectroencephalography (SEEG) but also includes the implantation and recordings from microelectrodes. Before iEEG implantation, especially in magnetic resonance imaging -negative epilepsy, a clear hypothesis for seizure generation and propagation should be based on noninvasive methods. Intracranial EEG implantation should be planned by a multidisciplinary team considering epileptic networks. Recordings from SDE and SEEG have both their advantages and disadvantages. Stereo-EEG seems to have a lower rate of complications that are clinically significant, but has limitations in spatial sampling of the cortical surface. Stereo-EEG can sample deeper areas of the brain including deep sulci and hard to reach areas such as the insula. To determine the epileptogenic zone, interictal and ictal information should be taken into consideration. Interictal spiking, low frequency slowing, as well as high frequency oscillations may inform about the epileptogenic zone. Ictally, high frequency onsets in the beta/gamma range are usually associated with the SOZ, but specialized recordings with combined macro and microelectrodes may in the future educate us about onset in higher frequency bands. Stimulation of intracranial electrodes triggering habitual seizures can assist in identifying the SOZ. Advanced computational methods such as determining the epileptogenicity index and similar measures may enhance standard clinical interpretation. Improved techniques to record and interpret iEEG may in the future lead to a greater proportion of patients being seizure free after epilepsy surgery.

Abstract Noninvasive wearable devices have great potential to aid the management of epilepsy, but these devices must have robust signal quality, and patients must be willing to wear them for long periods of time. Automated machine learning classification of wearable biosensor signals requires quantitative measures of signal quality to automatically reject poor‐quality or corrupt data segments. In this study, commercially available wearable sensors were placed on patients with epilepsy undergoing in‐hospital or in‐home electroencephalographic (EEG) monitoring, and healthy volunteers. Empatica E4 and Biovotion Everion were used to record accelerometry (ACC), photoplethysmography (PPG), and electrodermal activity (EDA). Byteflies Sensor Dots were used to record ACC and PPG, the Activinsights GENEActiv watch to record ACC, and Epitel Epilog to record EEG data. PPG and EDA signals were recorded for multiple days, then epochs of high‐quality, marginal‐quality, or poor‐quality data were visually identified by reviewers, and reviewer annotations were compared to automated signal quality measures. For ACC, the ratio of spectral power from 0.8 to 5 Hz to broadband power was used to separate good‐quality signals from noise. For EDA, the rate of amplitude change and prevalence of sharp peaks significantly differentiated between good‐quality data and noise. Spectral entropy was used to assess PPG and showed significant differences between good‐, marginal‐, and poor‐quality signals. EEG data were evaluated using methods to identify a spectral noise cutoff frequency. Patients were asked to rate the usability and comfort of each device in several categories. Patients showed a significant preference for the wrist‐worn devices, and the Empatica E4 device was preferred most often. Current wearable devices can provide high‐quality data and are acceptable for routine use, but continued development is needed to improve data quality, consistency, and management, as well as acceptability to patients.

Abstract Advances in ambulatory intracranial EEG devices have enabled objective analyses of circadian and multiday seizure periodicities, and seizure clusters in humans. This study characterizes circadian and multiday seizure periodicities, and seizure clusters in dogs with naturally occurring focal epilepsy, and considers the implications of an animal model for the study of seizure risk patterns, seizure forecasting and personalized treatment protocols. In this retrospective cohort study, 16 dogs were continuously monitored with ambulatory intracranial EEG devices designed for humans. Detailed medication records were kept for all dogs. Seizure periodicity was evaluated with circular statistics methods. Circular non-uniformity was assessed for circadian, 7-day and approximately monthly periods. The Rayleigh test was used to assess statistical significance, with correction for multiple comparisons. Seizure clusters were evaluated with Fano factor (index of dispersion) measurements, and compared to a Poisson distribution. Relationships between interseizure interval (ISI) and seizure duration were evaluated. Six dogs met the inclusion criteria of having at least 30 seizures and were monitored for an average of 65 weeks. Three dogs had seizures with circadian seizure periodicity, one dog had a 7-day periodicity, and two dogs had approximately monthly periodicity. Four dogs had seizure clusters and significantly elevated Fano factor values. There were subject-specific differences in the dynamics of ISI and seizure durations, both within and between lead and clustered seizure categories. Our findings show that seizure timing in dogs with naturally occurring epilepsy is not random, and that circadian and multiday seizure periodicities, and seizure clusters are common. Circadian, 7-day, and monthly seizure periodicities occur independent of antiseizure medication dosing, and these patterns likely reflect endogenous rhythms of seizure risk.

ObjectiveDrug‐resistant focal epilepsy is widely recognized as a network disease in which epileptic seizure propagation is likely coordinated by different neuronal oscillations such as low‐frequency activity (LFA), high‐frequency activity (HFA), or low‐to‐high cross‐frequency coupling. However, the mechanism by which different oscillatory networks constrain the propagation of focal seizures remains unclear.MethodsWe studied focal epilepsy patients with invasive electrocorticography (ECoG) recordings and compared multilayer directional network interactions between focal seizures either with or without secondary generalization. Within‐frequency and cross‐frequency directional connectivity were estimated by an adaptive directed transfer function and cross‐frequency directionality, respectively.ResultsIn the within‐frequency epileptic network, we found that the seizure onset zone (SOZ) always sent stronger information flow to the surrounding regions, and secondary generalization was accompanied by weaker information flow in the LFA from the surrounding regions to SOZ. In the cross‐frequency epileptic network, secondary generalization was associated with either decreased information flow from surrounding regions’ HFA to SOZ's LFA or increased information flow from SOZ's LFA to surrounding regions’ HFA.InterpretationOur results suggest that the secondary generalization of focal seizures is regulated by numerous within‐ and cross‐frequency push–pull dynamics, potentially reflecting impaired excitation–inhibition interactions of the epileptic network. ANN NEUROL 2019;86:683–694

Abstract Brain stimulation offers an alternative to focal resection for the treatment of focal drug-resistant epilepsy. Chronic subthreshold cortical stimulation is an individualized biomarker-informed open-loop continuous electrical stimulation approach targeting the seizure onset zone and surrounding areas. Before permanent implantation, trial stimulation is performed during invasive monitoring to assess stimulation efficacy as well as to optimize stimulation location and parameters by modifying interictal EEG biomarkers. We present clinical and neurophysiological results from a retrospective analysis of 21 patients, showing a median percent reduction in seizure frequency of 100% and responder rate of 89% with a median follow-up of 27 months. About 40% of patients were free of disabling seizures for a 12-month period or longer. We find that stimulation-induced decreases in delta (1–4 Hz) power and increases in alpha and beta (8–20 Hz) power during trial stimulation correlate with improved long-term clinical outcomes. These results suggest chronic subthreshold cortical stimulation may be an effective alternative approach to treating focal drug-resistant epilepsy and that short-term stimulation-related changes in spectral power may be a useful interictal biomarker and relate to long-term clinical outcome.

ABSTRACTSeizures and other electrophysiological disturbances are an under‐recognized cause of coma, focal deficits, and prolonged encephalopathy following subdural hematoma evacuation. In these patients, it is possible that seizures remain unrecognized on scalp EEG. It has been shown that a high burden of seizures and other electrophysiological disturbances exist following surgical evacuation and underlie the encephalopathy commonly seen in this patient population, predisposing them to medical complications and confounding estimates of prognosis. As part of a research protocol, we are performing intraoperative placement of cortical surface (non‐parenchyma penetrating) intracranial EEG on patients who present after trauma and require emergent decompressive hemicraniectomy.In this case report of a patient with high‐velocity traumatic epidural, subdural, and subarachnoid hemorrhages, we identified frequent non‐convulsive seizures or seizure‐like SIRPIDs with intracranial cortical surface monitoring that were not identified on simultaneous scalp EEG. Stimulation consistently triggered these electrographic seizures in addition to rhythmic lateralized periodic discharges. His mental status improved rapidly after resolution of these electrographic seizures shortly after increasing antiseizure medications, suggesting that they may have been contributing to his encephalopathy. More research is needed to determine the frequency of this phenomenon and determine whether treatment of such seizures improves patient outcomes.