The goal of this article is to discuss the possible contribution to antiepileptic
effects of the vagus nerve stimulation (VNS) from the functional connectivity between
the cortex and internal organs. According to our previous work, this connectivity
is particularly prominent during sleep, the brain state when epileptic activity is
prominent, as well. As such, the relationship between the brain and the viscera needs
to be put into the equation when considering VNS as a treatment for epilepsy.
Vagus nerve stimulation is widely used as a seizure-preventive action in many types
of otherwise incurable epilepsy and is extensively studied for treating other conditions
ranging from rheumatoid arthritis to depression (Vonck et al., 2001; Groves and Brown,
2005; Yuan and Silberstein, 2016; Dibue-Adjei et al., 2019; Noller et al., 2019).
It is well-known that vagus nerve is engaged in the bidirectional information transfer
between the internal organs and the brain, but how changes in activity going along
visceral pathways may be related to paroxysmal events occurring in various brain areas
remained unclear. The available literature describe several ideas proposed to explain
possible seizure preventing action of VNS, which mainly based on molecular mechanisms
of synaptic transmission in the central nervous system. Although neuronal desynchronization,
hippocampal plasticity, anti-inflammatory immune changes, and changes in neurotransmitter
concentrations are all currently considered as possibly involved in its antiepileptic
effects (Yuan and Silberstein, 2016), none of the existing theories explains the impressive
variety of demonstrated effects of VNS. We are offering for discussion another suggestion,
based on the role of the vagus nerve in autonomic regulation and on the recent results
of sleep studies.
In this opinion article we do not present any new experimental results, but only aim
to provide a possible link between four seemingly unrelated clusters of well-established
physiological observations, which, being considered together, might offer new directions
for thinking and investigation of VNS mechanisms.
First, there is a well-established connection between epileptic seizures and the state
of sleep (e.g., Shouse et al., 1996; Herman et al., 2001; Dinner, 2002; Combi et al.,
2004; Pavlova et al., 2004; Durazzo et al., 2008; Hofstra and de Weerd, 2009; Kothare
and Kaleyias, 2010; Mirzoev et al., 2012). Ictal activity is generally most frequent
in slow-wave sleep and during transition from wakefulness to sleep, but is very rarely
present in REM-sleep. Approximately half of all recorded seizures are happening during
slow wave sleep while this state occupies less than one third of circadian cycle in
humans. In addition, it is highly likely that some seizures happening during sleep
may stay undetected. We group these observations in the first cluster of the data.
A second cluster of observations to consider involves another generally recognized
feature of many types of epilepsy—the epileptogenic effects of rhythmic stimulations
delivered to various sensory systems (see e.g., Kaplan, 2003; Guerrini and Genton,
2004; Hirsch et al., 2004; Michelucci et al., 2004; Wilkins et al., 2004; Parra et
al., 2005). Ictal activity provoked by rhythmic exteroceptive stimulation may have
similar mechanism to physical resonance systems. Theoretically, any circuit with positive
feedback has its own internal resonance frequency. Rhythmic external stimulation,
even relatively weak, would initiate strong oscillations if the frequency of this
stimulation approaches this resonance frequency. In the nervous system, it would manifest
as paroxysmal activity. Neuronal circuits with feedback are common features at all
levels of the nervous system, and resonance effects in the nervous system were indeed
demonstrated (see e.g., Hutcheon and Yarom, 2000; Herrmann, 2001). In addition, widely
accepted mechanism of pathologically elevated excitability in epileptic focus can
be a part of this mechanism as it would be able to increase probability of the weak
rhythmic afferent signal to reach thresholds for such resonant oscillations.
Resonant model of epileptogenesis implies the presence of two components. The first
component is the local neuronal network with positive feedback, which has the fundamental
frequency of oscillation and is susceptible to paroxysmal activity. The second component
is the rhythmic afferent flow directed to that network that may cause the resonant
activation. Neither of these two components can provoke an ictal activity alone.
Anticonvulsant drugs can elevate the activation thresholds of the resonant network,
diminishing responses to the afferent signals, but are not able to eliminate the incoming
signals driving the network into ictal activity.
It might seem that resonance evoked by afferent inputs cannot be a mechanism of the
previously mentioned epileptic activity during sleep. In classical neuroscience paradigm,
sleep is considered as the state when brain is sensory deprived and any external rhythmic
stimulation is excluded. However, recent sleep studies offer an alternative source
of rhythmic sensory afferent signals directed to cerebral cortex, that are not attenuated,
but likely to be enhanced during sleep. We previously demonstrated that during sleep
cortical sensory areas begin receiving information coming from various visceral organs
(Pigarev, 1994, 2013; Pigarev et al., 2013; Pigarev and Pigareva, 2014, 2018). Experiments
that demonstrated propagation of the visceral afferent signals to the cerebral cortex
during sleep, were performed on gastrointestinal and cardio-respiratory systems, and
their work is inherently rhythmical (Pigarev, 1994; Pigarev et al., 2013; Lavrova,
2019; Lavrova et al., 2019). Thus, nervous signals in the involved sensory pathways
would be rhythmically organized during sleep. These results of sleep studies comprise
the third block of the relevant observations.
Observable rhythmic motility of the visceral organs generally has relatively low frequencies
in comparison to frequencies of exteroceptive sensory stimulation reported as epileptogenic
(10–50 Hz). However, nervous signals from these organs transferring along the nerves
might have another organization in time, and more complicated frequency spectrums.
Namely, these nervous signals can interfere with resonant frequencies of different
brain regions leading to ictal events. In addition to that, one should remember that
not only the exact correspondence of frequencies leads to a resonance, as resonance
is possible for both the fundamental frequency and for its harmonics and sub harmonics.
Afferent information flow from some internal organs may have frequency pattern close
to the resonant frequency of a particular brain circuit susceptible to paroxysmal
events. In our opinion, during sleep epileptic activity could be initiated in such
area by the rhythmical visceral afferentation, similarly to generation of such events
by rhythmical exterosensory stimulation in wakefulness. Indeed, registration of vagal
electrical activity during natural sleep in cat demonstrated synchronized appearance
of spindle-like activity in vagus itself and in a range of cortical and subcortical
regions receiving vagal input (Leichnetz, 1972).
Assuming that in some cases epileptic events are generated in response to resonant
frequencies of visceral afferentation, antiepileptic effect of VNS may have a simple
explanation. For therapeutic purpose, stimulation usually is applied to the left cervical
vagal trunk that contains fibers from the recurrent laryngeal, cardiopulmonary, and
subdiaphragmatic vagal branches. At this level, roughly 80% of the vagal fibers are
afferent, and 20% are efferent (Krahl, 2012). With such fiber composition, VNS would
change the pattern of visceral activity transmitted to the brain by the vagus nerve,
and is likely to cause prominent reorganization of activities within the crucial structures
receiving vagal afferentation and altering further visceral input, such as nucleus
tractus solitarius, parabrachial nucleus, and hypothalamus.
The role of VNS as disrupting the afferent flow to the regions susceptible for convulsive
activity is in good accordance with the ability of a surprisingly wide range of frequencies
of VNS to reduce epileptic activity. Frequencies from 1 to 143 Hz were used for this
purpose, although frequencies above 50 Hz are not recommended in clinical practice
as potentially damaging to the vagus nerve itself (for details see Terry, 2014). It
was also proposed that stimulation of the afferent vagus nerve fibers can change the
fundamental resonant frequencies of the brain circuits itself (Fanselow, 2012).
Furthermore, stimulation of the efferent vagal fibers also alters the frequencies
of rhythmically working visceral organs, such as heart, stomach and intestine (e.g.,
Martinson, 1965; Chang et al., 2003; Osharina et al., 2006; Tong et al., 2010; Bonaz
et al., 2016; Frøkjaer et al., 2016). Changes of rhythmicity of the various visceral
organs elicited by stimulation of the vagus efferent fibers and altering activity
of the visceral organs should modify the frequency composition of the visceral afferent
signals coming to the brain areas not only by vagal, but also by spinal cord pathways.
All of the changes described above are expected to move visceral afferent frequencies
out of the resonance range, thereby blocking paroxysmal activity. These visceral effects
of VNS we present as the fourth cluster of the relevant observations.
Taking all the above mentioned into account it seems important to study background
spike firing in the vagus nerve during wakefulness and sleep, and the effect of VNS
on this firing. The former subject was actually investigated in one study in cat.
It was shown that during natural sleep activity in vagus nerve itself and in a range
of cortical and subcortical regions receiving vagal input demonstrated spindle-like
synchronized pattern, and prominent amplitude and frequency differences were noted
between wakefulness, slow wave and REM sleep states (Leichnetz, 1972). However, the
technique used at that time (ink electroencephalography) did not allow observing single
spikes and only the integrated power of spike activity was recorded. Nevertheless,
the results obtained by Leichnetz revealed that circadian dynamic is indeed present
in vagal activity. Ramet et al. (1992) also indirectly observed increased vagal activity
during sleep in humans. However, to the best of our knowledge, this topic has not
been studied in detail using contemporary techniques. Such studies would be instrumental
in finding the optimal parameters of VNS.
This opinion may meet disagreement based on a doubt concerning the increased involvement
of the cerebral cortex in the processing of visceral information during sleep. Our
view is based on electrophysiological experiments performed in rabbits, cats, and
monkeys (see for review, e.g., Pigarev, 2014; Pigarev and Pigareva, 2014). However,
results of these studies are not widely known yet, most likely because their subject,
being located between three very different disciplines—classical sensory physiology,
physiology of the visceral systems and sleep research, usually slips attention of
the corresponding three groups of researchers. Recently several independent laboratories
started demonstrating similar results. Lecci et al. (2017) found the relationship
between slow periodicity in the cortical EEG during sleep and heart rate variability.
In experiments combining functional MRI and electrogastroscopy the reflection of slow
gastric rhythms in cortical sensory areas was observed in humans (Rebollo et al.,
2018). There is also a growing body of evidence pointing to the link between visceral
abnormalities and psychiatric disorders. For example, it was proposed that degeneration
of cells in the intestinal enteric nervous system might have causal link with the
following appearance of Parkinson disease (for a review see e.g., Smith and Parr-Brownlie,
2019). Fatal familiar insomnia syndrome, which leads to progressive inability to sleep,
also results in severe autonomic dysfunction finally finishing by death (Lugaresi
and Provini, 2007). It is generally believed that insular, orbitofrontal and medial
prefrontal areas are directly involved in autonomic regulation (Neafsey, 1990; Ongür
et al., 1998; Ongür and Price, 2000; Nieuwenhuys, 2012), but at the same time they
are known to take part in regulation of the sleep-wake cycle (Saper et al., 2010;
Chen et al., 2016). Significant increase in neuronal activity associated with slow
waves during sleep was found in the inferior frontal, medial prefrontal, posterior
cingulate areas and the precuneus (Dang-Vu et al., 2008). The overall, it was found
that reorganization of the interneuronal connections during wake to sleep transition
leads to formation of new cortical neuronal networks (Larson-Prior et al., 2011).
One may argue that VNS is also efficient in wakefulness. Influence of VNS in wakefulness
can be understood taking into account that seizures often start in the high order
associative cortical areas. It is known that local or partial sleep also starts developing
from these cortical areas (Pigarev et al., 1997). According to the visceral theory
of sleep (Pigarev and Pigareva, 2014) development of the local sleep in limited parts
of the cerebral cortex indicates the onset of visceral information transfer to those
cortical areas while behaviorally this state correspond to wakefulness or drowsiness.
In addition, it was reported that epileptic attacks often happen during developing
drowsiness (Mirzoev et al., 2012).
On the other hand, some cortical areas receiving vagal input, such as the insular
cortex, are involved in the processing of visceral information in wakefulness as well.
The role of the insular cortex in mediating bodily feelings—“interoceptive awareness”—has
been discussed by Craig (Craig, 2011; for a review of the insula functions see Nieuwenhuys,
2012). Thus, rhythmic visceral afferentation definitely reaches insular cortex in
wakefulness, and “visceral” mechanism of epileptogenesis may work through the insular
network not only during sleep. However, we have recently reported the prevalence of
insular neurons responding to non-noxious intestinal electrostimulation in slow wave
sleep in comparison to wakefulness (Levichkina and Pigarev, 2016), and it is therefore
expected that responses of the insular cortex to VNS can be more prominent in sleep
as well.
Finally, it was hypothesized (Morchiladze et al., 2018) that some mental disorders
can be associated with pathological chronic inactivation of the mechanisms blocking
the propagation of visceral information toward the central nervous system in wakefulness.
As a result, these visceral signals could be added to the normal exterosensory information
flows as noise, disrupting their normal analysis. If this “noise” has rhythmic structure,
it would be able to evoke seizers in a similar way to the exterosensory rhythmic signals.
In the context of the probable role of the visceral rhythmic afferentation in genesis
of paroxysmal events it might be important to analyze the noted comorbidity of epilepsy
to a number of visceral issues such as gastrointestinal bleed, chronic diseases of
cardio- and respiratory systems, pneumonia and diabetes (Gaitatzis et al., 2004).
It is not excluded that described positive effect of the ketogenic diet for treatment
of epilepsy (e.g., D'Andrea Meira et al., 2019) also can be related to probable change
of some rhythms in gastro-intestinal system and consequently of frequencies in the
visceral afferent messages in response to the changed food content.
We do not intend to present this “visceral” mechanism of seizure generation and proposed
mechanism of VNS antiepileptic effect as the only possibility. Obviously different
types of epilepsy are likely to have other mechanisms of seizure initiation. The goal
of our comment is to draw attention to the additional factor, which has not been considered
yet. Important and unexpected feature of the proposed mechanism is that theoretically
paroxysmal activity may start in a healthy brain. A deviation from normal activity
of, e.g., organs of the gastro-intestinal or cardio-respiratory systems would lead
to an emergence of signals with pathologic frequency composition directed to the central
nervous system during sleep, with a possibility to cause epileptic events if these
signals happen to be within the resonant ranges of the particular brain circuits.
In light of that, it seems reasonable, especially in the pharmacoresistent cases,
when no obvious morphological deviations in the brain tissue were found, to consider
paying special attention to the visceral state of a patient, and particularly to the
visceral systems with clearly rhythmic patterns of activity.
Author Contributions
All authors listed have made a substantial, direct and intellectual contribution to
the work, and approved it for publication.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.