The mechanism by which vagus nerve stimulation reduces seizure frequency apparently relies on at least some of the widespread neural connections between the vagus nerve and regions of the brainstem, midbrain, diencephalon, and forebrain (Vonck et al 2001). Approximately 80% of the vagus nerve fibers are afferent and primarily project to the nucleus of the solitary tract. Stimulation of the vagus nerve or the nucleus of the solitary tract may either directly synchronize or desynchronize EEG (Koo 2001b). The specific effect depends on the frequency of stimulation whether stimulation of the nerve is sufficiently intense to activate both myelinated A and B fibers and unmyelinated C fibers. The issue of fiber type activation is bypassed by direct stimulation of the nucleus of the solitary tract, which produces desynchronization at frequencies over 30 Hz and synchronization at frequencies between 1 to 17 Hz. However, the relevance of this effect to understanding the mechanism of vagus nerve stimulation is limited because few studies of the antiepileptic effect of nucleus of the solitary tract stimulation have been performed. One reported result is that the nucleus of the solitary tract stimulation interferes with feline amygdaloid kindling in cats (Magdaleno-Madrigal et al 2002).
The effect of vagus nerve stimulation on the EEG is complicated because of the different fiber types within the nerve. Early animal experiments indicated that C fiber activation produced desynchronization and vagus nerve stimulation effectiveness was proportional to the degree of C fiber recruitment. This was contradicted by rat experiments that demonstrated that the vagus nerve stimulation effect is independent of C fiber function (Woodbury and Woodbury 1990; Krahl et al 2001), and vagus nerve stimulation-induced slow hyperpolarization of cortical pyramidal cells diminishes with activation of C fibers (Zagon and Kemeny 2000). Electrophysiologic recordings of the human vagus nerve during vagus nerve stimulation implantation have provided complimentary evidence that the human vagus nerve stimulation effect is through A and B fibers only (Koo et al 2001a). Overall, the data based on fiber type recruitment are discordant and do not readily lend itself to an explanation of the efficacy of vagus nerve stimulation.
The nucleus of the solitary tract and the locus coeruleus are brainstem structures that each may have a role in the antiepileptic effect of vagus nerve stimulation. Increases in GABA transmission or decreases in glutamate transmission in the mediocaudal nucleus of the solitary tract reduce the severity of limbic motor seizures in rats (Walker et al 1999). Thus, the balance of excitation and inhibition within the nucleus of the solitary tract may affect seizure susceptibility. The locus coeruleus is indirectly connected to the nucleus of the solitary tract and has been found to have an increased discharge rate in rats during vagus nerve stimulation (Groves et al 2005). Although the changes within the locus coeruleus during vagus nerve stimulation are not known, chemical ablation of the locus coeruleus attenuates the seizure suppressing effect of vagus nerve stimulation (Krahl et al 1998). This is consistent with the recognized antiepileptic effect of norepinephrine and may be a more downstream neurochemical mechanism (Fornai et al 2011). The hippocampus is one potential downstream location, and vagus nerve stimulation efficacy in a rodent model of limbic epilepsy has been found to be dependent on vagus nerve stimulation’s increase to hippocampal norepinephrine concentration (Raedt et al 2011). This furthers the support for this anti-seizure mechanism for vagus nerve stimulation.
Evoked potential recordings have shown a major pathway from the nucleus of the solitary tract to the intralaminar and ventroposterior thalamus via the parabrachial nucleus (Dell and Olson 1951). As measured by [O-15]water PET, vagus nerve stimulation produces regional cerebral blood flow changes within the thalamus bilaterally that correlate to changes in seizure frequency (Henry et al 1999). This increase in thalamic activity is the most consistent finding among the other rCBF and functional MRI studies of chronic vagus nerve stimulation. (Narayanan et al 2002; Henry et al 2004). A perfusion SPECT study found significant correlations between right amygdalar and hippocampal perfusion changes and seizure control (Van Laere et al 2002).
Intracranial and scalp EEG recordings have demonstrated vagus nerve stimulation associated changes that may provide some mechanistic insights. In one patient, the frequency of epileptiform spikes and sharps were recorded from the hippocampus with depth electrodes with vagus nerve stimulation at 5 Hz and 30 Hz (Olejniczak 2001). The change in vagus nerve stimulation frequency did not alter the frequency of spikes but did affect the frequency of sharps. Sharp discharge frequency decreased from baseline with 30 Hz stimulation and increased from baseline with 5 Hz stimulation. This is consistent with the observation that the antiepileptic vagus nerve stimulation effect occurs with stimulation above approximately 20 Hz. If the physiological difference between epileptiform spikes and sharps is their degree of synchronization, then perhaps vagus nerve stimulation is limited to affect activity only up to a certain degree of synchronization.
A transcranial magnetic stimulation study also has demonstrated vagus nerve stimulation associated changes with possible mechanistic implications. In a series of 5 patients, stimulation produced a significant increase in intracortical inhibition without a change in resting motor threshold (Di Lazzaro et al 2004). This suggests a GABAa mechanism. Within this series, the patient without a change in intracortical inhibition was the only one without an improvement in seizure control.
Other investigations have identified vagus nerve stimulation-induced synchronization or a combination of synchronization and desynchronization. Intracranial EEG recordings from 3 patients demonstrated increased EEG power and decreased complexity, indicating greater synchronization (Widman 2000). Serial EEGs performed on 21 patients during vagus nerve stimulation therapy showed an early increase in clustering of the interictal epileptiform discharges for the 5 patients with highly frequent interictal epileptiform discharges prior to vagus nerve stimulation and a later reduction in interictal epileptiform discharge frequency and duration for all 21 patients (Koo 2001b). The investigator interprets the initial clustering of interictal epileptiform discharges as evidence for initially increased synchronization with progressively greater desynchronization over months. This novel observation of a combination response may lead to new insights into the physiologic basis of vagus nerve stimulation. In a study that did not follow patients over time, the stimulation period was correlated with a decrease in interictal epileptiform discharge frequency (Kuba et al 2002).
In part because the antiepileptic effect of vagus nerve stimulation increases slowly over months to years, vagus nerve stimulation has been investigated for a possible antiepileptogenic effect that is distinct from its acute effects. Kindling experiments during vagus nerve stimulation support an antiepileptogenic effect with a marked delay in the kindling process (Fernandez-Guardiola 1999; Magdaleno-Madrigal et al 2002). Indeed, none of the animals subjected to vagus nerve stimulation reached a stage 6 seizure within the framework of the study. At present, there is no evidence for an antiepileptogenic effect in humans. Based on a statistical analysis of “seizure loads” in patients who were involved in the clinical trials leading to FDA approval of the device, Dasheiff and colleagues concluded that vagus nerve stimulation does not “unkindle” seizures (Dasheiff et al 2001). However, the demonstration of kindling in humans has been tenuous, and “unkindling” has not been defined in animals (such as by demonstration of progressively increasing afterdischarge thresholds and decreasing afterdischarge durations). Moreover, it is generally understood that the changes produced by kindling are permanent. Although the analysis by Dasheiff and colleagues is interesting, it is not evidence to suggest that some plastic changes are not involved in contributing to the efficacy of vagus nerve stimulation.