Faculty Bibliography

Little is known about the neural mechanisms that allow humans and animals to plan actions using knowledge of task contingencies. Emerging theories hypothesize that it involves the same hippocampal mechanisms that support self-localization and memory for locations. Yet limited direct evidence supports the link between planning and the hippocampal place map. We addressed this by investigating model-based planning and place memory in healthy controls and epilepsy patients treated using unilateral anterior temporal lobectomy with hippocampal resection. Both functions were impaired in the patient group. Specifically, the planning impairment was related to right hippocampal lesion size, controlling for overall lesion size. Furthermore, although planning and boundary-driven place memory covaried in the control group, this relationship was attenuated in patients, consistent with both functions relying on the same structure in the healthy brain. These findings clarify both the neural mechanism of model-based planning and the scope of hippocampal contributions to behavior.

BACKGROUND AND PURPOSE/OBJECTIVE:-THC/CBD cannabis extracts on seizure activity and associated measures of endocannabinoid (eCB) system signalling. EXPERIMENTAL APPROACH/METHODS:Cannabis extract effects on in vivo neurological and behavioural responses, and on bioanalyte levels, were measured in rats and dogs. Extract effects on seizure activity were measured using electroencephalography-telemetry in rats. eCB signalling was also investigated using radioligand binding in cannabis extract-treated rats, and treatment-naïve rat, mouse, chicken, dog and human tissue. KEY RESULTS/RESULTS:-THC suggested interspecies differences in eCB signalling, being more pronounced in a species that exhibited cannabis extract-induced seizures (rat) than a species that did not (dog). CONCLUSION AND IMPLICATIONS/CONCLUSIONS:Sustained cannabis extract treatment caused differential seizure, behavioural and bioanalyte levels between rats and dogs. Supporting radioligand binding data suggest species differences in eCB signalling. Interspecies variations may have important implications for predicting cannabis-induced convulsions from animal models.

Importance/UNASSIGNED:Sudden unexplained death in childhood (SUDC) is the fifth leading category of death among toddlers but remains underrecognized and inadequately studied. Objective/UNASSIGNED:To assess the potential role of febrile seizures (FS) and other risk factors associated with SUDC and describe the epidemiology, mechanisms, and prevention of SUDC. Design, Setting, and Participants/UNASSIGNED:This case series study reviewed 622 consecutive sudden child death cases aged 1 to 17 years from 2001 to 2017 from 18 countries. Data were collected from family members of children who died suddenly; these families voluntarily registered with the SUDC Foundation. Data analysis was conducted from November 2017 to February 2019. Main Outcome Measures/UNASSIGNED:Certified manner of death characterized as accident, natural, or undetermined. Results/UNASSIGNED:A total of 391 families with decedents aged 1 to 6 years completed a comprehensive interview on medical and social histories, and circumstances of death with forensic evaluations revealing a cause of death (sudden explained death in childhood [SEDC]) or no cause of death (SUDC). Of these children, 231 (59.1%) were male, the mean (SD) age at death was 24.9 (12.8) months, and 104 (26.6%) had a history of FS. Compared with the general population FS prevalence (2%-5%), FS prevalence among SUDC (28.8%; 95% CI, 23.3%-34.2%) and SEDC (22.1%; 95% CI, 14.8%-29.3%) were elevated. The odds of death during sleep was 4.6-fold higher in SUDC than in SEDC cases (odds ratio, 4.61; 95% CI, 1.92-11.09; adjusted P = .008). The siblings of SUDC cases were followed up for 3144 life-years, and none died prematurely from SUDC. Conclusions and Relevance/UNASSIGNED:This analysis of the largest SUDC cohort confirmed an increased FS rate and found significantly increased rates of FS among SEDC. This study suggests that seizures may contribute to some SUDC and SEDC deaths. The risk of sudden death in a sibling was low. To develop and assess preventive strategies, population-based studies are needed to define the epidemiology and spectrum of risk factors and identify biomarkers of patients with FS at high risk of sudden death.

The principles underlying functional asymmetries in cortex remain debated. For example, it is accepted that speech is processed bilaterally in auditory cortex, but a left hemisphere dominance emerges when the input is interpreted linguistically. The mechanisms, however, are contested, such as what sound features or processing principles underlie laterality. Recent findings across species (humans, canines and bats) provide converging evidence that spectrotemporal sound features drive asymmetrical responses. Typically, accounts invoke models wherein the hemispheres differ in time-frequency resolution or integration window size. We develop a framework that builds on and unifies prevailing models, using spectrotemporal modulation space. Using signal processing techniques motivated by neural responses, we test this approach, employing behavioural and neurophysiological measures. We show how psychophysical judgements align with spectrotemporal modulations and then characterize the neural sensitivities to temporal and spectral modulations. We demonstrate differential contributions from both hemispheres, with a left lateralization for temporal modulations and a weaker right lateralization for spectral modulations. We argue that representations in the modulation domain provide a more mechanistic basis to account for lateralization in auditory cortex.

PURPOSE OF REVIEW/OBJECTIVE:To review the history, pharmacology, and clinical science of cannabidiol (CBD) in the treatment of epilepsy. RECENT FINDINGS/RESULTS:Phase III randomized controlled trials and prospective open label trials have provided efficacy and safety data for the use of CBD in pediatric onset severe epilepsies. The product that was studied in the vast majority of these published trials, Epidiolex (>99% of CBD and <0.10% Δ9-tetrahydrocannabinol (THC); GW pharmaceuticals, Cambridge, UK), has now been FDA approved based on this published data. SUMMARY/CONCLUSIONS:Identification of CBD, Δ9-THC, and the endocannabinoid system in the mid-20th century has led to advancement of cannabis-based therapies for epilepsy. Based on clinical trial data, Epidiolex is the first CBD medication approved by a national regulatory agency (US Food and Drug Administration for Dravet and Lennox Gastaut syndrome; European Medicines Agency for Lennox Gastaut syndrome). Approval of CBD as a treatment for these rare and severe pediatric-onset epilepsy syndromes is an important milestone, but the complete spectrum of use of cannabis-derived products, and the use of CBD for other epilepsy syndromes remains to be determined.

BACKGROUND:Sleep spindles are involved in memory consolidation and other cognitive functions. Numerous automated methods for detection of spindles have been proposed; most of these rely on spectral analysis in some form. However, none of these approaches are ideal, and novel approaches to the problem could provide additional insights. NEW METHOD/UNASSIGNED:Here, we apply delay differential analysis (DDA), a time-domain technique based on nonlinear dynamics to detect sleep spindles in human intracranial sleep data, including laminar electrode, stereoelectroencephalogram (sEEG), and electrocorticogram (ECoG) recordings. RESULTS:We show that this approach is computationally fast, generalizable, requires minimal preprocessing, and provides excellent agreement with human scoring. COMPARISON WITH EXISTING METHODS/UNASSIGNED:score than all other tested methods except the automated detections published with the DREAMS data. Further, in addition to being a fast and reliable method for spindle detection, DDA also provides a novel characterization of spindle activity based on nonlinear dynamical content of the data. CONCLUSIONS:This additional, non-frequency-based perspective could prove particularly useful for certain atypical spindles, or identifying spindles of different types.

BACKGROUND:Although they form a unitary phenomenon, the relationship between extracranial M/EEG and transmembrane ion flows is understood only as a general principle rather than as a well-articulated and quantified causal chain. METHOD/METHODS:We present an integrated multiscale model, consisting of a neural simulation of thalamus and cortex during stage N2 sleep and a biophysical model projecting cortical current densities to M/EEG fields. Sleep spindles were generated through the interactions of local and distant network connections and intrinsic currents within thalamocortical circuits. 32,652 cortical neurons were mapped onto the cortical surface reconstructed from subjects' MRI, interconnected based on geodesic distances, and scaled-up to current dipole densities based on laminar recordings in humans. MRIs were used to generate a quasi-static electromagnetic model enabling simulated cortical activity to be projected to the M/EEG sensors. RESULTS:The simulated M/EEG spindles were similar in amplitude and topography to empirical examples in the same subjects. Simulated spindles with more core-dominant activity were more MEG weighted. COMPARISON WITH EXISTING METHODS/UNASSIGNED:Previous models lacked either spindle-generating thalamic neural dynamics or whole head biophysical modeling; the framework presented here is the first to simultaneously capture these disparate scales simultaneously. CONCLUSIONS:This multiscale model provides a platform for the principled quantitative integration of existing information relevant to the generation of sleep spindles, and allows the implications of future findings to be explored. It provides a proof of principle for a methodological framework allowing large-scale integrative brain oscillations to be understood in terms of their underlying channels and synapses.

Electrical stimulation in the anterior nucleus of the thalamus (ANT) has previously been found to be efficacious for reducing seizure frequency in patients with epilepsy. Bilateral deep brain stimulation (DBS) of the ANT is an open-loop system that can be used in the management of treatment-resistant epilepsy. In contrast, the responsive neurostimulation (RNS) system is a closed-loop device that delivers treatment in response to prespecified electrocorticographic triggers. The efficacy and safety of RNS targeting the ANT is unknown. We describe 3 patients with treatment-resistant multifocal epilepsy who were implanted with an RNS system, which included unilateral stimulation of the ANT. After >33 months of follow-up, there were no adverse effects on mood, memory or behavior. Two patients had ≥50% reduction in disabling seizures and one patient had a 50% reduction compared to pretreatment baseline. Although reduction in seizure frequency has been modest to date, these findings support responsive neurostimulation of the ANT as feasible, safe, and well-tolerated. Further studies are needed to determine optimal stimulation parameters.

OBJECTIVE:Patients with Lennox-Gastaut syndrome (LGS) who completed 1 of 2 randomized, double-blind, placebo-controlled trials of add-on cannabidiol (CBD) (GWPCARE3, NCT02224560 or GWPCARE4, NCT02224690) were invited to enroll in an open-label extension (OLE) study evaluating the long-term safety and efficacy of CBD (GWPCARE5, NCT02224573). Herein we present an interim analysis of the safety, efficacy, and patient-reported outcomes from this trial. METHODS:Patients received a pharmaceutical formulation of highly purified CBD oral solution (Epidiolex; 100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week titration period, in addition to their existing medications. Doses could be reduced if not tolerated or increased up to 30 mg/kg/d if thought to be of benefit. RESULTS:This interim analysis was based on a November 2016 data cut. Of 368 patients who completed treatment in GWPCARE3 and GWPCARE4, 366 (99.5%) enrolled in the OLE study (GWPCARE5). Median treatment duration was 38 weeks at a mean modal dose of 23 mg/kg/d. Most patients (92.1%) experienced adverse events (AEs), primarily of mild (32.5%) or moderate (43.4%) severity. The most common AEs were diarrhea (26.8%), somnolence (23.5%), and convulsion (21.3%). Thirty-five patients (9.6%) discontinued treatment due to AEs. Liver transaminase elevations were reported in 37 patients (10.1%), of whom 29 were receiving concomitant valproic acid; 34 cases resolved spontaneously or with dose modification of CBD or concomitant medication. Median reduction from baseline in drop seizure frequency (quantified monthly over 12-week periods) ranged from 48% to 60% through week 48. Median reduction in monthly total seizure frequency ranged from 48% to 57% across all 12-week periods through week 48. Eighty-eight percent of patients/caregivers reported an improvement in the patient's overall condition per the Subject/Caregiver Global Impression of Change scale. SIGNIFICANCE/CONCLUSIONS:In this study, long-term add-on CBD treatment had an acceptable safety profile in patients with LGS and led to sustained reductions in seizures.

BACKGROUND AND PURPOSE/OBJECTIVE:The brain stem is compactly organized with life-sustaining sensorimotor and autonomic structures that can be affected by numerous pathologies but can be difficult to resolve on conventional MR imaging. MATERIALS AND METHODS/METHODS:We applied an optimized TSE T2 sequence to washed postmortem brain samples to reveal exquisite and reproducible brain stem anatomic MR imaging contrast comparable with histologic atlases. This resource-efficient approach can be performed across multiple whole-brain samples with relatively short acquisition times (2 hours per imaging plane) using clinical 3T MR imaging systems. RESULTS:< .10). CONCLUSIONS:Compared with traditional atlases, multiplanar MR imaging contrast has advantages for learning and retaining brain stem anatomy for clinicians and trainees. Direct TSE MR imaging sequence discrimination of brain stem anatomy can help validate other MR imaging contrasts, such as diffusion tractography, or serve as a structural template for extracting quantitative MR imaging data in future postmortem investigations.