Distinct fastigial output channels and their impact on temporal lobe seizures

Despite being canonically considered a motor control structure, the cerebellum is increasingly recognized for important roles in processes beyond this traditional framework, including seizure suppression. Excitatory fastigial neurons project to a large number of downstream targets, and it is unclear if this broad targeting underlies seizure suppression, or if a specific output may be sufficient. To address this question, we used the intrahippocampal kainic acid mouse model of temporal lobe epilepsy, male and female animals, and a dual-virus approach to selectively label and manipulate fastigial outputs. We examined fastigial neurons projecting to the superior colliculus, medullary reticular formation, and central lateral nucleus of the thalamus, and found that these comprise largely non-overlapping populations of neurons which send collaterals to unique sets of additional thalamic and brainstem regions, creating distinct, somewhat overlapping, output channels. We found that neither optogenetic stimulation of superior colliculus nor reticular formation output channels attenuated hippocampal seizures. In contrast, on-demand stimulation of fastigial neurons targeting the central lateral nucleus robustly inhibited seizures. Our results indicate that fastigial control of hippocampal seizures does not require simultaneous modulation of many fastigial output channels. Rather, selective modulation of the fastigial output channel to the central lateral thalamus, specifically, is sufficient for seizure control. This may provide a means for more selective therapeutic interventions, which provide seizure control while minimizing unwanted side effects. More broadly, our data highlight the concept of specific cerebellar output channels, whereby discrete cerebellar nucleus neurons project to specific aggregates of downstream targets, with distinct functional outcomes.

Estimating the Parameters of the Epileptor Model for Epileptic Seizure Suppression

Epilepsy is one of the most common brain disorders worldwide, affecting millions of people every year. Given the partially successful existing treatments for epileptiform activity suppression, dynamic mathematical models have been proposed with the purpose of better understanding the factors that might trigger an epileptic seizure and how to mitigate it, among which Epileptor stands out, due to its relative simplicity and high prediction ability. Recent studies using such a model have provided evidence that establishing a feedback-based control approach is possible. However, for this strategy to work properly, Epileptor's parameters, which describe the dynamic characteristics of a seizure, must be known beforehand. Therefore, this work proposes a methodology for estimating such parameters based on a successive optimization technique. The results show that it is feasible to approximate their values, and integrating this system identification approach with observers and controllers can be carried out, which might provide an interesting alternative for seizure suppression in practice in the future.

Therapeutic Targets for the Treatment of Comorbidities Associated with Epilepsy

One of the most common neurological disorders, which occurs among 1% of the population worldwide, is epilepsy. Therapeutic failure is common with epilepsy and nearly about 30% of patients fall in this category. Seizure suppression should not be the only goal while treating epilepsy but associated comorbidities, which can further worsen the condition, should also be considered. Treatment of such comorbidities such as depression, anxiety, cognition, attention deficit hyperactivity disorder and, various other disorders which co-exist with epilepsy or are caused due to epilepsy should also be treated. Novel targets or the existing targets are needed to be explored for the dual mechanism which can suppress both the disease and the comorbidity. New therapeutic targets such as IDO, nNOS, PAR1, NF-κb are being explored for their role in epilepsy and various comorbidities. This review explores recent therapeutic targets for the treatment of comorbidities associated with epilepsy.