Neuromodulation of the Pedunculopontine Nucleus to Treat Sleep Disorders in Epilepsy

Introduction: Sleep is critical for our well-being. Too little, fragmented, or poorly structured sleep negatively impacts daytime function. It has long been known that sleep quality and epilepsy are interconnected. Among the various nuclei involved in sleep regulation, the pedunculopontine nucleus (PPN) plays a key role in controlling arousal and regulating rapid eye movement (REM) sleep. We hypothesize that frontal seizures may disrupt the normal function of the PPN, leading to changes in sleep architecture, and that modulation of PPN activity might restore normal sleep patterns.

Methods: We used a non-human primate (NHP) model of frontal lobe seizures for this study. NHPs have a sleep pattern similar to that of humans, and the reciprocal interactions between sleep and seizures can be studied without confounds from medications or environmental factors. We recorded and acutely stimulated the PPN in two NHPs during focal motor seizures induced by local injection of penicillin (a GABAA_a antagonist). Each injection induced a series of focal seizures lasting 4–6 hours. Animals were implanted with a chronic electrode in the PPN and EEG screws. We measured the effect of PPN stimulation (sham, 20 Hz, 80 Hz, and 125 Hz) on seizure frequency and on nocturnal and diurnal sleep patterns.

Results: We induced 12 seizure sessions in NHP1 and 13 in NHP2. Seizures were focal and characterized by tonic contraction of the left arm. We found increased correlation between PPN and cortical activity during each ictal events, with residual oscillations in the PPN after the cortical seizure ended. Both NHPs experienced disruption of their nocturnal sleep pattern on the night of the seizures, even after the cortical seizure had stopped; however, no changes were observed in their diurnal sleep patterns on the following day. Acute stimulation of the PPN at 80 Hz and 125 Hz further increased nighttime activity and worsened sleep disturbance.

Conclusion: We found that high-frequency PPN stimulation worsened nocturnal sleep disturbances induced by seizures, whereas acute low-frequency PPN stimulation was insufficient to reduce them. We believe that chronic stimulation at low frequency may increase the likelihood of preventing seizure-induced sleep disorders.