Beyond the Usual Suspects: Cerebellar Involvement in Epilepsy

Abstract

Early and Widespread Cerebellar Engagement During Hippocampal Seizures and Interictal Discharges

Streng ML, Kottke BW, Wasserman EM, Zecker L, Luong L, Kodandaramaiah S, Ebner TJ, Krook-Magnuson E. Neurobiol Dis. 2025 Sep;213:106991. doi: 10.1016/j.nbd.2025.106991. Epub 2025 Jun 9. PMID: 40499797; PMCID: PMC12315938.

Despite research illustrating the cerebellum may be a critical circuit element in processes beyond motor control, and growing evidence for a role of the cerebellum in a range of neurological disorders, including the epilepsies, remarkably little is known about cerebellar changes during seizures. We therefore implemented a novel method for repeated widefield calcium imaging of the cerebellum in awake, chronically epileptic mice. We found widespread changes in cerebellar Purkinje cell activity during temporal lobe seizures. Changes were noted in the anterior and posterior cerebellum (lobules IV-VII), along the midline (vermis), and both ipsilaterally and contralaterally (in the simplex and Crus I) to the seizure focus. This was true for both overtly behavioral seizures and for hippocampal seizures that remained electrographic only—arguing against cerebellar modulation simply reflecting motor components. Moreover, even brief interictal spikes produced widespread alterations in cerebellar activity. Perhaps most remarkably, changes in the cerebellum also occurred prior to any noticeable change in the hippocampal electrographic recordings. Together, these results underscore the relevance of the cerebellum with respect to seizure networks, warranting a more consistent consideration of the cerebellum in epilepsy.

Commentary

Even in models of focal epilepsy, mounting evidence suggests that the seizure-involved network extends far beyond the region of localized injury. In the study by Streng et al, ¹ the authors describe marked changes in the activity of the cerebellum associated with seizures in the intrahippocampal kainate (IHK) mouse model of temporal lobe epilepsy. This model uses focal injection of kainic acid to provoke hippocampal injury and the development of an epileptic focus. ² IHK animals exhibit rare, convulsive seizures of the low-voltage fast or hypersynchronous onset types, ³ similar to those observed in patients with temporal lobe epilepsy. They also display electrographic seizures and frequent interictal epileptiform discharges (IEDs). Interestingly, Streng et al observed cerebellar involvement not only in large behavioral seizures, but also in electrographic seizures and IEDs, suggesting that cerebellar activity was not merely a reflection of the motor component of convulsive seizures. Of note, electrographic seizures and IEDs were associated with early decreases in cerebellar activity, while conversely, overt behavioral seizures were associated with an early increase in cerebellar activity. These results offer a peek into the cerebellum's complex role as a modulator of seizure networks and suggest that the cerebellum is not uniformly pro- or anti-seizure. Increased cerebellar activity during behavioral seizures may reflect large-scale network synchrony and the recruitment of motor circuits, whereas decreased cerebellar activity during electrographic seizures is consistent with a disengagement from cortical activity. Determining the mechanisms driving these state-dependent differences will be an important future direction.

These changes in cerebellar activity are unlikely to reflect seizure propagation but rather underscore the functional connectivity that exists between these distant brain regions. This raises important questions about how to best define the boundaries of a seizure network. All brain regions have a mixture of local and long-range connections, so it is perhaps not surprising that seizure activity would influence remote brain regions via these long-range connections. We must then ask if these changes are consequential or merely incidental to the seizure activity. Previous work by Krook-Magnuson et al ⁴ suggests that cerebellar involvement in seizures is indeed consequential, and in fact, showed that targeted modulation of the cerebellum can suppress temporal lobe seizures. That work points to the therapeutic potential of targeting regions that are functionally connected to the ictogenic zone to effectively modulate ongoing seizure activity. Therefore, fully mapping the seizure-involved network and understanding the bidirectional influence across regions could help guide the development of new strategies to modulate and suppress seizures, particularly when direct intervention at the seizure onset zone is not feasible or carries undesirable clinical risks.

The authors also highlight the striking finding from this study that changes in the cerebellum can occur prior to the detections of ictal changes in the hippocampus, during both seizures and interictal epileptiform discharges. One interpretation of this result is that the cerebellar changes precede those of the hippocampus, perhaps reflecting a pro-ictal state from which seizures are more likely to occur. However, the use of different recording modalities should be considered when interpreting the sequence of events. For example, recordings of population and single-unit activity using multi-electrode arrays (MEAs) in patients with epilepsy have demonstrated a disconnect between high-amplitude ictal EEG with simultaneous low unit firing in the penumbra surrounding the actively recruited seizure core. ⁵ Here, seizure activity of the hippocampus was measured with local field potential (LFP) recordings, while the cerebellar activity was detected by widefield calcium imaging using the genetically encoded calcium indicator (GECI) GCaMP expressed in Purkinje neurons. As noted by the authors, LFP recordings have faster sampling than optical measures of calcium signal, and thus limitations in temporal resolution would not contribute to a relatively earlier detection of the cerebellar changes measured with calcium imaging. However, the sampled activity between the two recording techniques has key differences. LFP recordings primarily capture summated population-level synaptic activity. Conversely, GECI-based calcium imaging primarily captures the spiking activity of individual neurons (however, sustained elevations in subthreshold calcium are also detectable via GCaMP-based imaging ⁶ ). GCaMP indicators also integrate changes in intracellular calcium over tens to hundreds of milliseconds, ⁷ making them less reliant on synchronous activity to detect changes. Thus, neuronal calcium imaging may be sensitive to early activity changes that would be less readily captured with population-level measures such as LFP. However, even if the precise sequence of seizure-related changes between the regions is uncertain, the rapid involvement of the cerebellum is still notable. Further investigation is warranted to determine the directionality and causality of the hippocampal-cerebellar interactions during seizures. Collectively, this body of work emphasizes the relevance of including the cerebellum as a region of interest when evaluating seizure networks.

In addition to the widespread and bidirectional influence of ictal and epileptiform activity on the cerebellum, the authors found that the responsiveness of the cerebellum to IEDs was a significant predictor of disease severity. In the acute time scale, the cerebellar response to an IED event was attenuated in the time approaching the next convulsive seizure. This highlights the dynamic state of the extended seizure-involved network and the complexity of this system. An important next step would be to determine if restoring the responsiveness of the cerebellum could help to prolong or prevent the next seizure occurrence. Additionally, the authors provide preliminary evidence from one mouse that IED responsiveness of the cerebellum decreased in the days preceding a putative SUDEP event. Although SUDEP is rare, ⁸ it remains a significant concern for patients living with epilepsy and the clinicians who care for them. Future work aimed at understanding this relationship and testing if a similar phenomenon exists in patient populations would be of great interest. Having a predictor of SUDEP risk could help clinicians identify patients living with epilepsy who may benefit from closer monitoring or a modified treatment plan. Even more compelling would be the possibility that rescuing the diminished IED responsiveness of the cerebellum could reduce the risk of SUDEP. Taken together, this study challenges a narrow view of seizure networks and invites greater consideration of the cerebellum in the broader landscape of epilepsy pathophysiology.