State-Dependent Entrainment of Prefrontal Cortex Local Field Potential Activity Following Patterned Stimulation of the Cerebellar Vermis

Abstract

The cerebellum is involved in sensorimotor, cognitive, and emotional functions through cerebello-cerebral connectivity. Cerebellar neurostimulation thus likely affects cortical circuits, as has been shown in studies using cerebellar stimulation to treat neurological disorders through modulation of frontal EEG oscillations. Here we studied the effects of different frequencies of cerebellar stimulation on oscillations and coherence in the cerebellum and prefrontal cortex in the urethane-anesthetized rat. Local field potentials were recorded in the right lateral cerebellum (Crus I/II) and bilaterally in the prefrontal cortex (frontal association area, FrA) in adult male Sprague-Dawley rats. Stimulation was delivered to the cerebellar vermis (lobule VII) using single pulses (0.2 Hz for 60 s), or repeated pulses at 1 Hz (30 s), 5 Hz (10 s), 25 Hz (2 s), and 50 Hz (1 s). Effects of stimulation were influenced by the initial state of EEG activity which varies over time during urethane-anesthesia; 1 Hz stimulation was more effective when delivered during the slow-wave state (Stage 1), while stimulation with single-pulse, 25, and 50 Hz showed stronger effects during the activated state (Stage 2). Single-pulses resulted in increases in oscillatory power in the delta and theta bands for the cerebellum, and in frequencies up to 80 Hz in cortical sites. 1 Hz stimulation induced a decrease in 0–30 Hz activity and increased activity in the 30–200 Hz range, in the right FrA. 5 Hz stimulation reduced power in high frequencies in Stage 1 and induced mixed effects during Stage 2.25 Hz stimulation increased cortical power at low frequencies during Stage 2, and increased power in higher frequency bands during Stage 1. Stimulation at 50 Hz increased delta-band power in all recording sites, with the strongest and most rapid effects in the cerebellum. 25 and 50 Hz stimulation also induced state-dependent effects on cerebello-cortical and cortico-cortical coherence at high frequencies. Cerebellar stimulation can therefore entrain field potential activity in the FrA and drive synchronization of cerebello-cortical and cortico-cortical networks in a frequency-dependent manner. These effects highlight the role of the cerebellar vermis in modulating large-scale synchronization of neural networks in non-motor frontal cortex.

Non-invasive Brain Stimulation of the Cerebellum in Emotion

“…Since animal and human research relates theta activity with the septo-hippocampal complex and anterior cingulate cortex, which are important limbic brain structures involved in cognition and emotion, it was speculated that, in addition to the cerebellocortical connections found by previous studies, the cerebellum is part of the core neural limbic circuitry involved in emotions. The findings of both studies are in line with more recent research that has found evidence that cerebellar stimulation can entrain local field potentials in the frontal cortex and drive synchronization of cerebellocortical and cortico-cortical networks (Tremblay et al 2019). Results reported in this study do not only further substantiate the contributions of the medial cerebellum to large-scale synchronization in non-motor-related brain areas, but also provide indirect and incremental support for cerebellar involvement in the experience and regulation of emotions.…”

Neocortical and cerebellar malformations affect flurothyl-induced seizures in female C57BL/6J mice

“…Attention to the role of the cerebellum in seizures and epilepsy is growing in the clinical setting as well as in experimental studies with animal models. For example, there is a greater appreciation that the cerebellum can influence the physiology of neocortical (Popa et al, 2013;Watson et al, 2014;Tremblay et al, 2019) as well as subcortical structures such as the hippocampus via polysynaptic pathways (Yu and Krook-Magnuson, 2015;Bohne et al, 2019;Watson et al, 2019;Zeidler et al, 2020). Neocortical modulation of cerebellar physiology has also been demonstrated (Ros et al, 2009).…”

Evidence of state-dependence in the effectiveness of responsive neurostimulation for seizure modulation

“…In particular, we show that stimulation parameters which are effective in one brain state may not be effective, or even have opposite effects, in another brain state. In vitro and in vivo animal models have revealed that the modulatory impact of electrical stimulation is frequency-dependent and timing-dependent [ 21 , 30 , 31 ], but, to our knowledge, this is the first demonstration in human neuromodulation protocols in epilepsy. A state-based view of electrical stimulation paradigms implies that the impact of neurostimulation extends beyond direct seizure termination, consistent with an emerging concept of RNS having long-term neuromodulatory effects [ 32 ] that facilitate transitions from high and low seizure risk states, which may bear an indirect relation to cortical “up” and “down” states.…”