Cerebral blood flow differences between high- vs low-frequency VNS therapy in the epileptic baboon

Abstract

Purpose: Cerebral blood flow (CBF) tracks physiological effects of ictal or interictal epileptic discharges (IEDs) and neurostimulation. This study compared CBF changes between high-frequency (HF; 300 Hz) microburst, and standard, low-frequency (LF; 30 Hz) vagal nerve stimulation (VNS) Therapy in 2 baboons with genetic generalized epilepsy (GGE), including one with photosensitivity.

Methods: The baboons were selected based on video recordings and scalp EEG studies. They were both implanted with Sentiva™ 1000 devices capable of stimulating at standard and microburst frequencies. Nine H₂¹⁵O (10-20 mCi) positron emission tomographic (PET) scans were performed each session (two PET sessions acquired for each animal). The baboons were sedated with ketamine, paralyzed, and monitored with scalp EEG. CBF changes were compared between the two modes of stimulation and resting scans in the first study, while in the second, VNS Therapy trials were combined with intermittent light stimulation (ILS) at 25 Hz and compared to CBF changes induced by ILS alone.

Results: ILS-associated IED rates were slightly reduced by HF- and LF-VNS Therapies in B1, while spontaneous IEDs were completely suppressed by HF-VNS Therapy in B2. Regional CBF changes were consistent between the two modes of therapy in each baboon, in particular with respect to the activation of the superior colliculus and cerebellum. Neither VNS mode suppressed the photoepileptic response in B1. In B2, IED suppression was associated with bilateral deactivations of the frontal and temporal cortices, cingulate and anterior striatum, as well as bilateral cerebellar activations.

Conclusions: This pilot study reveals similar activation/deactivation patterns between LF- and HF-VNS Therapies, but the most pronounced CBF differences between the two baboons and the two modes of stimulation may have been driven by the suppression of the epileptic network by HF-VNS Therapy in B2. Some therapeutic targets appear to be subcortical, including the putamen, superior colliculus, brainstem nuclei, as well as the cerebellum, all of which modulate corticothalamic networks, which is particularly reflected by CBF changes associated with HF-VNS Therapy. These findings need to be replicated in larger samples and correlated with long-term clinical outcomes.

Keywords: Baboon; Cerebral Blood Flow; Genetic Generalized Epilepsy; Microburst; Photosensitivity; VNS Therapy.