Diminished circadian and ultradian rhythms of human brain activity in pathological tissue in vivo.

Chronobiological rhythms, such as the circadian rhythm, have long been linked to neurological disorders, but it is currently unknown how pathological processes affect the expression of biological rhythms in the brain. Here, we use the unique opportunity of long-term, continuous intracranially recorded EEG from 38 patients (totalling 6338 hours) to delineate circadian (daily) and ultradian (minute to hourly) rhythms in different brain regions. We show that functional circadian and ultradian rhythms are diminished in pathological tissue, independent of regional variations. We further demonstrate that these diminished rhythms are persistent in time, regardless of load or occurrence of pathological events. These findings provide evidence that brain pathology is functionally associated with persistently diminished chronobiological rhythms in vivo in humans, independent of regional variations or pathological events. Future work interacting with, and restoring, these modulatory chronobiological rhythms may allow for novel therapies.

An interactive framework for the detection of ictal and interictal activities: Cross-species and stand-alone implementation.

BACKGROUND AND OBJECTIVE: Despite advances on signal analysis and artificial intelligence, visual inspection is the gold standard in event detection on electroencephalographic recordings. This process requires much time of clinical experts on both annotating and training new experts for this same task. In scenarios where epilepsy is considered, the need for automatic tools is more prominent, as both seizures and interictal events can occur on hours- or days-long recordings. Although other solutions have already been proposed, most of them are not integrated on clinical and basic science environments due to their complexity and required specialization. Here we present a pipeline that arises from coordinated efforts between life-science researchers, clinicians and data scientists to develop an interactive and iterative workflow to train machine-learning tools for the automatic detection of electroencephalographic events in a variety of scenarios. METHODS: The approach consists on a series of subsequent steps covering data loading and configuration, event annotation, model training/re-training and event detection. With slight modifications, the combination of these blocks can cope with a variety of scenarios. To illustrate the flexibility and robustness of the approach, three datasets from clinical (patients of Dravet Syndrome) and basic research environments (mice model of the same disease) were evaluated. From them, and in response to researchers' daily needs, four real world examples of interictal event detection and seizure classification tasks were selected and processed. RESULTS: Results show that the current approach was of great aid for event annotation and model development. It was capable of creating custom machine-learning solutions for each scenario with slight adjustments on the analysis protocol, easily accessible to users without programming skills. Final annotator similarity metrics reached values above 80% on all cases of use, reaching 92.3% on interictal event detection on human recordings. CONCLUSIONS: The presented framework is easily adaptable to multiple real world scenarios and the interactive and ease-to-use approach makes it manageable to clinical and basic researches without programming skills. Nevertheless, it is conceived so data scientists can optimize it for specific scenarios, improving the knowledge transfer between these fields.

Epilepsy and neuropsychiatric comorbidities in mice carrying a recurrent Dravet syndrome SCN1A missense mutation.

Dravet Syndrome (DS) is an encephalopathy with epilepsy associated with multiple neuropsychiatric comorbidities. In up to 90% of cases, it is caused by functional happloinsufficiency of the SCN1A gene, which encodes the alpha subunit of a voltage-dependent sodium channel (Nav1.1). Preclinical development of new targeted therapies requires accessible animal models which recapitulate the disease at the genetic and clinical levels. Here we describe that a C57BL/6 J knock-in mouse strain carrying a heterozygous, clinically relevant SCN1A mutation (A1783V) presents a full spectrum of DS manifestations. This includes 70% mortality rate during the first 8 weeks of age, reduced threshold for heat-induced seizures (4.7 °C lower compared with control littermates), cognitive impairment, motor disturbances, anxiety, hyperactive behavior and defects in the interaction with the environment. In contrast, sociability was relatively preserved. Electrophysiological studies showed spontaneous interictal epileptiform discharges, which increased in a temperature-dependent manner. Seizures were multifocal, with different origins within and across individuals. They showed intra/inter-hemispheric propagation and often resulted in generalized tonic-clonic seizures. 18F-labelled flourodeoxyglucose positron emission tomography (FDG-PET) revealed a global increase in glucose uptake in the brain of Scn1aWT/A1783V mice. We conclude that the Scn1aWT/A1783V model is a robust research platform for the evaluation of new therapies against DS.