- Department of Neurobiology, University of Pittsburgh, School of Medicine, Pittsburgh, PA
Correspondence Address:
Erika E. Fanselow
Department of Neurobiology, University of Pittsburgh, School of Medicine, Pittsburgh, PA
DOI:10.4103/2152-7806.103014
Copyright: © 2012 Fanselow E. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.How to cite this article: Fanselow EE. Central mechanisms of cranial nerve stimulation for epilepsy. Surg Neurol Int 31-Oct-2012;3:
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Abstract
Stimulation of peripheral cranial nerves has been shown to exert anticonvulsant effects in animal models as well as in human patients. Specifically, stimulation of both the trigeminal and vagus nerves has been shown in multiple clinical trials to be anticonvulsant, and stimulation of these nerves at therapeutic levels does not cause pain or negatively affect brain function. However, the neuronal mechanisms by which such stimulation exerts therapeutic effects are not well understood. In this review, the possible locations of action for trigeminal nerve stimulation (TNS) and vagus nerve stimulation (VNS) are explored. Additionally, the multiple time scales on which TNS and VNS function are discussed.
Keywords: Anticonvulsant mechanisms, epilepsy, trigeminal nerve stimulation, vagus nerve stimulation
INTRODUCTION
There exist multiple types of direct or indirect neuro-stimulation methods for therapeutically altering brain activity. Such techniques include stimulating the brain indirectly, as with transcranial magnetic stimulation, stimulating the brain directly, as with deep brain stimulation, or affecting the brain indirectly via stimulation of peripheral nerves. These techniques have been used to treat a range of disorders, including epilepsy. However, little is understood about the neurobiological mechanisms by which any of these stimulation techniques affect brain function, and why or how they can act in a therapeutic manner.
One technique utilizing therapeutic neurostimulation for epilepsy is activation of peripheral cranial nerves. A relatively new therapeutic technique involves stimulating the trigeminal nerve. The trigeminal is the fifth cranial nerve, whose branches can be accessed for stimulation both surgically and transcutaneously. Trigeminal nerve stimulation (TNS) has been shown to reduce seizures in both animal models [
A similar treatment, vagus nerve stimulation (VNS), was approved by the Food and Drug Administration (FDA) for the treatment of epilepsy in 1997, and has been utilized in tens of thousands of patients. [
The studies of and clinical experience with TNS and VNS demonstrate that these neurostimulation paradigms can exert robust therapeutic effects without deleterious effects on normal brain function. Furthermore, TNS and VNS have been demonstrated to control multiple seizure types across multiple species (e.g., rat, dog, non-human primates, humans), suggesting that these anticonvulsant effects involve widespread neuromodulatory mechanisms that are well-conserved phylogenetically.
However, the mechanism by which stimulation of peripheral cranial nerves can exert central therapeutic effects, including affecting the propensity for seizures, is essentially an open question. This is due in part to a lack of knowledge about the feedforward and feedback effects of such stimulation throughout the central nervous system, and in part to a lack of understanding of the pathological mechanisms that underlie disorders such as epilepsy. This is complicated by the fact that epilepsy is not a disorder with homogenous etiology or symptoms.
This review will discuss what is known about mechanisms that might underlie the anticonvulsant effects of cranial nerve stimulation. First, the anatomy of the trigeminal and vagus nerves will be described briefly, and then hypotheses of mechanisms of action will be addressed by moving systematically up the anatomical axis. In addition to discussing potential anatomical locations of action, this article will address the multiple timeframes on which therapeutic cranial nerve stimulation can affect the central nervous system.
It should be noted that the putative mechanisms discussed here are not mutually exclusive; they may, in fact, interact with and complement one another during treatment. Furthermore, different mechanisms might be optimally evoked by specific stimulus parameters and may be uniquely suited for treating specific types of seizures or other disorders.
Overview of trigeminal and vagus nerve anatomy
The trigeminal nerve is responsible for sending afferent sensory information from the face to the central nervous system [
The vagus nerve innervates multiple structures and organs throughout the neck and torso. Its functions include parasympathetic influence of the heart, lungs, and digestive tract, along with visceral and somatic sensory input from multiple areas and motor control of the pharynx and larynx. Afferent sensory fibers from this complex nerve project to the nodose ganglion, where their cell bodies are located, and subsequently terminate in the NTS. The NTS, in turn, projects mono- or polysynaptically to a range of areas [
Efferent projections are not required for the anticonvulsant effects of vagus nerve stimulation
Whereas the branches of the trigeminal nerve used thus far for therapeutic TNS (V1 and V2) consist entirely of afferent fibers, the vagus nerve carries both afferent and efferent information. However, the number of afferent fibers in the vagus nerve outweighs the number of efferent fibers by a ratio of 4:1 (Ruffoli et al. [
Activation of peripheral C-fibers: Necessary or not?
One hypothesis put forth several decades ago for the central effects of VNS was that therapeutic levels of nerve stimulation required recruitment of small diameter, unmyelinated C-fibers, which have a higher stimulus threshold (e.g., require higher current or longer pulses) than A or B-fibers. C-fibers constitute a majority of the cervical vagus nerve fibers and ~40% of the trigeminal nerve fibers. [
Tests of C-fiber recruitment by therapeutic levels of TNS have not been published. However, animals do not show signs of distress during such stimulation, [
Brainstem participation in the therapeutic effects of cranial nerve stimulation
The brainstem is a complex network of diverse neurons that has profound effects on neuronal activity throughout the neuroaxis. One set of brainstem components that is particularly relevant to the discussion of therapeutic nerve stimulation is the group of nuclei that disseminate neuromodulatory compounds. These include areas such as the locus coeruleus, the main source of noradrenergic input to the brain, and the raphe nuclei, the primary source of serotonin in the brain. In addition, as described above, the NTS is a key brainstem region for the sake of our discussion here.
Nucleus of the solitary tract
The NTS is innervated by both the trigeminal and vagus nerves, [
Locus coeruleus/noradrenergic influence
The locus coeruleus is a nucleus in the brainstem that sends noradrenergic input to many levels of the central nervous system, including the raphe nuclei, the thalamus, the hippocampus, and the neocortex. [
There is ample evidence showing that both norepinephrine and activity of the locus coeruleus can exert anticonvulsant effects. First, lesioning the locus coeruleus can lead to increased kindling in rats. [
Because the locus coeruleus projects widely throughout the neocortex, [
Raphe nuclei/serotonergic input
The raphe nuclei consist of multiple groups of cells, many of which contain serotonin. Neurons in these nuclei, project to a number of downstream targets relevant here, including the midline and intralaminar nuclei of the thalamus, the hippocampus, and the neocortex. [
Dorr and Debonnel [
Additionally, there are reciprocal connections between the locus coeruleus and the raphe nuclei, [
Collectively, these three brainstem regions are poised anatomically to directly or indirectly influence the neurochemistry of wide regions of the central nervous system. Their influence on seizure activity is generally inhibitory, though this depends in part on the receptor subtype that is activated in a given brain region by a given neuromodulator. It is thus likely that specific brainstem nuclei participate in the anticonvulsant effects of TNS and VNS.
Anticonvulsant effects of thalamic activity
The thalamus is made up of relatively discrete nuclei that subserve several functions. One of these functions is to transfer sensory information from the brainstem to the cortex. For example, tactile information from the face is relayed via the trigeminal nerve and the trigeminal ganglion to a group of brainstem nuclei, which project to the ventral posterior medial (VPM) thalamus. From VPM, the tactile information is sent to the primary somatosensory cortex (SI). In this capacity, the thalamus acts as a ‘relay’ [
Neurons in the relay nuclei can function in two modes. [
Another function of the thalamus involves the midline and intralaminar nuclei, which appear to be related to ‘arousal’ or behavioural state. [
With these two general functions, the thalamus is able to affect neuronal activity in large parts of the thalamocortical system. This is relevant to seizure activity in at least three ways. First, if thalamic nuclei are in the ‘burst’ mode described above, their neurons can participate readily in spike-and-wave discharges (SWD), which have been associated with absence epilepsy. Activation of neurons in thalamic nuclei by brainstem regions such as the NTS, trigeminal nuclei, locus coeruleus, and raphe nuclei, could push neurons into the ‘tonic’ mode, which would presumably prevent SWDs. Thus, stimulation of the trigeminal or vagus nerves might, by way of brainstem, influence on the thalamus, lead to a reduction in seizures that involve these thalamocortical rhythms.
A second method by which changes in thalamic activity might reduce seizures is by affecting overall levels of neuronal firing in the neocortex and limbic system. The midline and intralaminar thalamic nuclei have widespread, diffuse projections to the neocortex that are thought to be ‘activating′, causing heightened attention and behavioral arousal. They also send similar projections to the limbic system. Neurons in the midline and intralaminar thalamic regions can fire in burst and tonic modes, as with the relay nuclei. When in burst mode, they appear to participate in SWDs and in this manner could contribute to specific types of seizure activity. However, these thalamic nuclei receive noradrenergic and serotonergic input from the brainstem, [
Finally, if the thalamus is involved in coordinating the oscillatory activity of multiple cortical regions, any manipulation that interrupts the thalamic activity would, theoretically, also interrupt the spread of the seizure activity as it travels across the neocortex. Thus, even if a cortically-based seizure were initiated, its spread could be limited by an interruption in thalamic activity.
Effects of cranial nerve stimulation on the limbic system
Because the limbic system is heavily implicated in many epilepsies, it is important to consider the effects of TNS and VNS on this region. A main route by which stimulation of the trigeminal or vagus nerves could influence the limbic system is via the neuromodulatory effects of brainstem activation. Generally, noradrenergic input from the locus coeruleus to the limbic system appears to be anticonvulsant, [
Changes in neocortical activity as a result of cranial nerve stimulation
Morruzi and Magoun [
One method for investigating cortical excitability in response to an antiepileptic treatment is by measuring the current threshold at which motor seizures are evoked by electrical stimulation of the motor cortex. De Herdt and colleagues [
In contrast to the vagus nerve, the trigeminal nerve passes afferent tactile sensations to the brainstem, which transmits them to the ventral posterior medial (VPM) thalamus (a relay nucleus of the thalamus), and then on to the primary somatosensory cortex (SI). The signal is propagated through this pathway very rapidly (generally less than 10 ms from the periphery to SI) and evokes an excitatory-inhibitory sequence in both VPM and SI. It is possible that neocortical activity resulting from this afferent input has a disrupting effect on neuronal firing in the neocortex, which could be involved in preventing the spread of neocortical seizures. Additionally, this effect could occur quickly and might be responsible for the rapid anticonvulsant effects of TNS. [
Imaging studies of cranial nerve stimulation
Schrader and colleagues investigated which brain regions were activated or deactivated by TNS, using positron emission tomography (PET) scanning. [
Positron emission tomography scanning has also been employed in studies designed to determine which areas of the brain are involved in the therapeutic effects of VNS. Henry and colleagues [
Note, however, that other imaging studies have contradicted these results. Generally, single-photon emission computed tomography (SPECT) studies tend to show decreases in blood flow in areas that show increases with PET scans. [
Multiple studies have shown that there are increases in cerebral blood flow in the SI cortex during VNS. [
Time scales of trigeminal nerve stimulation and vagus nerve stimulation efficacy
An interesting finding about TNS and VNS is that there is evidence for both short- and long-term effects for each type of stimulation. On the short-term end of the spectrum, both TNS [
Another observed phenomenon is that the effects of VNS have been shown to outlast the duration of the stimulus-ON periods. This may be one reason that the common ~30 seconds ON, ~5 minutes OFF stimulus paradigm used in VNS has therapeutic value. Most of the studies demonstrating this have shown that the anticonvulsant effects last on the order of tens of seconds to tens of minutes. For example, Zabara [
On a longer time scale, Van Bockstaele and colleagues [
Finally, there are reports of very long-term increases in the anticonvulsant effects of VNS. [
Advantages to understanding the mechanisms of therapeutic peripheral nerve stimulation
Why is it important to understand the mechanisms by which TNS or VNS cause anticonvulsant effects in the central nervous system? First, the current methods for setting stimulus parameters for these treatments are somewhat empirical, starting with recommended standards and modifying these on a patient-by-patient basis. [
CONCLUSIONS
In summary, it is not yet clear how or where TNS or VNS exert their anticonvulsant effects. Given the above-mentioned findings, there are several possible loci for influence, which are not mutually exclusive. First, for neocortex and hippocampus, it is possible that neuromodulatory activity (e.g., noradrenergic input) leads to desynchronization in these regions, which prevents the correlated activity of neurons that may otherwise develop into seizures or pre-seizure conditions. Second, the thalamus is known to be involved in the oscillatory components of certain types of seizures (e.g., absence seizures) and may be responsible, in part, for the spread of seizures, due to its widespread connections with diverse regions of the neocortex. Thus, changing thalamic activity, even if it involves a putative increase in activity, as suggested by multiple imaging studies, may interrupt this process, limiting the spread of seizures. Third, on a longer time scale, the excitability of epileptogenic tissue may decrease due to neuroplastic changes in relevant structures, potentially changing the epileptogenic tissue in such a way as to make it less prone to seizures. As studies of TNS and VNS mechanisms progress, these techniques can potentially be improved, so they are efficacious in a larger number of patients and can yield even higher rates of seizure reduction.
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