Clinical Neuroscience Research 4 (2004) 71–79

www.elsevier.com/locate/clires

Mechanisms of action of vagus nerve stimulation (VNS)

Mark S. Georgea,b,c,*, Ziad Nahasa,b, Daryl E. Bohninga, Qiwen Mua,b,
F. Andrew Kozela,b,c, Jeffrey Borckhardtb, Stewart Denslowa
a
Center for Advanced Imaging Research, Medical University of South Carolina, Charleston, SC, USA
b
Brain Stimulation Laboratory, Department of Psychiatry, Medical University of South Carolina, 67 President Street, Room 502 North, Charleston, SC, USA
c
Ralph H. Johnson Veterans Hospital, Charleston, SC, USA

Abstract
In 1992, Dr Jake Zabara discovered in a canine model that repeated stimulation of the vagus nerve in the neck could stop seizures. Since
that time, repeated stimulation of the vagus nerve has been FDA approved as an anticonvulsant. Zabara’s work is built on a 50-year-old theme
in the literature where scientists had sought to exploit the fact that the vagus nerve is composed of 80% afferent fibers. Thus vagus stimulation
might potentially provide a ‘window’ into the brain. This manuscript reviews the basic science and brain imaging work done to date with
VNS, attempting to understand how VNS affects the brain. This research is crucial to perfecting VNS as an anticonvulsant, and for
determining other neuropsychiatric conditions that might be helped by VNS.
q 2004 Elsevier B.V. All rights reserved.
Keywords: Vagus nerve; VNS; Locus ceruleus; Anticonvulsant; Antidepressant; Brain stimulation; fMRI

1. Introduction the nucleus tractus solitarius (NTS) to diverse brain regions

1.1. Background
Of all the cranial nerves (CN), with the exception of CN I
for olfaction, the vagus nerve (CN X), has been the most
intriguing, and arguably the most misunderstood. The vagus
nerve helps to regulate the body’s autonomic functions, which
are important in a variety of emotional tasks. For reasons that
are unclear, most people are more familiar with the vagus
nerve’s efferent functions, where it serves as the messenger
for signals from the brain to the viscera. Traditionally, the
vagus nerve has been considered a parasympathetic efferent
nerve (controlling and regulating autonomic functions such as
heart rate and gastric tone). The afferent role of the vagus has
been underemphasized in the traditional literature. The vagus
is actually a mixed nerve composed of about 80% afferent
sensory fibers carrying information to the brain from the head,
neck, thorax and abdomen [1].
Over the past 100 years several different researchers have
convincingly demonstrated the extensive projections of
the vagus nerve via its sensory afferent connections in
* Corresponding author. Address: Brain Stimulation Laboratory,
Department of Psychiatry, Medical University of South Carolina, 67
President Street, Room 502 North, Charleston, SC, USA. Tel.: þ 1-843-
876-5142; fax: þ 1-843-792-5702.
E-mail address: georgem@musc.edu (M.S. George).
1566-2772/$ - see front matter q 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.cnr.2004.06.006
[2 –4] (see Table 1). As early as 1938, Bailey and Bremer
found that VNS in the cat elicited synchronized EEG
activity in orbital cortex [2]. Later in 1949, MacLean and
Pribram stimulated the vagus nerve and recorded EEG from
the cortical surface of anesthetized monkeys. They found
that vagus nerve stimulation caused inconsistent slow waves
generated from the lateral frontal cortex [4, p. 468]. Shortly
after that, Dell and Olson studied the effects of VNS in
awake cats with high cervical spinal lesions [3]. They found
that VNS evoked a slow wave response in the anterior rhinal
sulcus, as well as in the amygdala. More recently, MacLean
continued his 1949 work 30 years later using more
sophisticated techniques. Single unit recordings showed
that vagus stimulation produced specific activity in the
cingulate and other limbic regions. Activation of these cells
was specific to VNS, as rubbing the face and other
stimulatory controls had no effect on these regions. He
thus demonstrated that the brain effect was through a direct
vagus signal [5].
Reasoning from this body of literature, Zabara [6,7]
demonstrated an anticonvulsant action of VNS on exper-
imental seizures in dogs. Zabara hypothesized that VNS
could prevent or control the motor and autonomic
components of epilepsy [8]. Penry and others ushered in
the modern clinical application of VNS in 1988 using an
implanted device to treat epilepsy [9,10].
72 M.S. George et al. / Clinical Neuroscience Research 4 (2004) 71–79
Table 1
Early work involving VNS
VNS behavioral research
1938—Bailey and Bremer, VNS in cat elicited synchronous orbital cortex
activity
1949—MacLean and Pribram, VNS in monkeys, lateral frontal changes
1951—Dell and Olson, VNS evoked a slow wave response in the anterior
rhinal sulcus, as well as in the amygdala in awake cats with high cervical
spinal section
1980—MacLean, VNS in monkey—marked single unit effects on
cingulate, thalamus, basal limbic structures
1985—Zabara—dogs, VNS caused cortical EEG changes, stopped seizures
1988—Kiffin Penry (Bowman–Gray), human, resistant epilepsy patient
1998—MUSC, UTSW, NYSPI, Baylor—resistant depression
1.2. Relevant neuroanatomy (Fig. 1)
Although the route of entry into the brain is constrained,
VNS offers the potential for modulating and modifying
function in many brain regions, through trans-synaptic
connections. For a detailed discussion of vagus circuitry
see Refs. [11,12]. As an overview, it is important to
understand that the sensory afferent cell bodies of the
vagus reside in the nodose ganglion and relay information to
the nucleus of the solitary tract (NTS). The NTS relays
incoming sensory information to higher brain regions
through at least three pathways: (1) an autonomic feedback
loop; (2) direct projections to the reticular formation in the
medulla and; (3) ascending projections to the forebrain
largely through the parabrachial nucleus (PB) and the locus
ceruleus (LC) [13,14]. In addition to these routes, the NTS
sends direct projections to the amygdala [15 – 17] and
hypothalamus [18]. The PB sits adjacent to the LC [19]
Fig. 1. Vagus neuroanatomy. This simplified cross-sectional sagittal slice of
the brain highlights the vagus nerve afferents, which terminate in the
Nucleus Solitary Tract (NTS). From there they project to several important
brainstem and cerebellar regulatory nuclei, including the locus ceruleus. It is
thought that the vagus afferents, acting through these nuclei, then influence
higher order limbic and cortical regions. VNS is thus a ‘bottom-up’
approach to brain stimulation.
(one of the primary norepinephrine containing areas of the
brain) (see Fig. 1).
The PB/LC directly connect with various forebrain
structures, including the hypothalamus, amygdala and bed
nucleus of the stria terminalis, as well as several thalamic
regions that control the insula, orbitofrontal and prefrontal
cortex [20,21]. These brainstem and limbic anatomic
connections can be demonstrated in non-human animals
and in man (using functional neuroimaging). The oncogen
C-fos is a general marker for cellular activity. C-fos studies
in rats, while the vagus is being stimulated, revealed
increased activity in the amygdala, cingulate, LC, and
hypothalamus [22]. Further, the signal into the brain from
VNS can be amplified or reduced by modifying the activity
in several of these key relay nuclei. In a very important
study that demonstrates the potential for combining VNS
with general or local pharmacology, Walker and colleagues
outlined a possible role of the NTS in how VNS reduces
seizures [23]. By microinjecting the NTS with either GABA
agonists or glutamate antagonists, they found that increased
GABA or decreased glutamate in the NTS blocked seizures.
Indirectly, these findings suggest that VNS may change
NTS GABA and glutamate concentrations, with secondary
changes in the function of specific limbic structures noted
above (e.g. amygdala, cingulate, insula, and hippocampus).
In sum, incoming sensory (afferent) connections of the
vagus nerve provide direct projections to many of the brain
regions implicated in neuropsychiatric disorders. These
connections provide a basis for understanding how VNS
might be a portal to the brainstem and connected limbic and
cortical regions. These pathways likely account for the
neuropsychiatric effects of VNS, and they invite additional
theoretical considerations for potential research and clinical
applications.
1.3. VNS Methods
The broad term, ‘vagus nerve stimulation’ generally
refers to several different techniques used to stimulate the
vagus nerve, including studies in animals where the vagus
was accessed through the abdomen and diaphragm.
However, for virtually all human studies, VNS refers
to stimulation of the left cervical vagus nerve using a
commercial device, the VNS Therapy System [24] (see
Fig. 2). (An important exception to this rule was the recent
work using a modified form of VNS to stimulate both
subdiaphragmatic vagus nerves for the treatment of
obesity.) [25]
VNS has been commercially available for the treatment
of resistant partial onset seizures in Europe since 1994, and
in the US since 1997. About 22,000 people with epilepsy
worldwide have been treated with the VNS therapy system
(September 2003). Typically, although not always, epi-
lepsy patients considering VNS have had unsatisfactory
seizure control despite treatment with multiple medi-
cations. In many ways, VNS resembles implanting
 M.S. George et al. / Clinical Neuroscience Research 4 (2004) 71–79
Fig. 2. The VNS therapy system. The current method of delivering VNS in
humans is depicted in this photograph of a model. She is holding a wand
over her chest which interacts with the VNS generator, which is connected
to the vagus nerve in the neck through a subcutaneous wire. The treating
physician can program the VNS generator, using a hand-held PDA, to
deliver stimulation with varying use parameters (frequency, intensity, time
on, time off, pulse width).
a cardiac pacemaker. In both VNS and cardiac pacemakers,
a subcutaneous generator sends an electrical signal to an
organ through an implanted electrode. In fact, the surgery
for implanting the NCP generator in the chest is much like
inserting a cardiac pacemaker [26]. The two techniques
differ in the site of stimulation. With VNS, the electrical
stimulation is delivered through the NCP Pulse Generator,
an implantable, multi-programmable, bipolar pulse gen-
erator (about the size of a pocket watch) that is implanted
in the left chest wall to deliver electrical signals to the left
vagus nerve through a bipolar lead. Thus, VNS resembles
in some ways deep brain stimulation (DBS) [27], with the
main differences being the location of the end wire
(Vagus—VNS, Deep Brain, DBS), the need for breaching
the skull with consequent risks in DBS but not VNS, and
the nature of the electrical pulse—(intermittent and
relatively low frequency with VNS, constant and high
frequency (. 100 Hz) with DBS). In VNS the electrode
is wrapped around the vagus nerve in the neck and
is connected to the generator subcutaneously.
The VNS implantation surgery is typically an outpatient
procedure, most commonly but not exclusively done by
neurosurgeons. The VNS generator can be controlled by a
laptop computer (or even a personal digital assistant (PDA))
and an infrared wand. As a safety feature, the VNS therapy
system is designed to shut off in the presence of a constant
magnetic field. Each patient is thus given a magnet that,
when held over the pulse generator, turns off stimulation.
73
When the magnet is removed, normal programmed
stimulation resumes. This allows patients to control and
temporarily eliminate stimulation-related side effects during
key behaviors like public speaking (voice tremor) or heavy
exercising (mild shortness of breath). This safety feature
was an impediment to using functional MRI scanning in
conjunction with VNS, but this technical problem has been
partially solved [28,29].
How VNS compares to other brain stimulation methods
(ECT, TMS, DBS). While both VNS and electroconvulsive
therapy (ECT) have anticonvulsant effects, unlike ECT,
VNS does not cause a seizure and seems to be free of
harmful cognitive side effects [30]. VNS differs from
another new brain stimulation technique, transcranial
magnetic stimulation (TMS), in that VNS initially stimulates
deep brain regions (the vagus through the NTS and locus),
with secondary stimulation of limbic cortex. This might be
labeled a ‘bottom-up’ approach to brain stimulation. In
contrast, TMS is limited to direct superficial cortical
stimulation, with secondary effects on subcortical structures
(a ‘top-down’ approach) [31,32]. The other key differences
between TMS and VNS involve regional specificity and
chronicity. TMS can be focused anywhere over the skull,
while VNS is neuroanatomically limited in its entry pathway
into the brain (NTS and other brainstem nuclei). However,
VNS delivers constant treatment (i.e. intermittent stimu-
lation) for many years, while TMS requires patients to return
to the clinic to receive subsequent courses of TMS.
This difference with TMS brings up the important
question of whether VNS effects might be regionally
‘focused’ with different parameters of stimulation. Animal
studies and two human studies suggest that various VNS
parameters can cause different behaviors (like emotional
memory), implying that the secondary circuits affected by
VNS might be altered with different intensities or
frequencies or other stimulation parameters such as pulse
width. Recent interleaved VNS/functional magnetic reson-
ance imaging (fMRI) data suggest that VNS may have
different regional effects as a function of various use
parameters, either frequency [33] or pulse width [34].
Recent psychophysiological studies further support the
notion that VNS use parameters have biological importance.
For example, Borckhardt and colleagues at MUSC have
studied acute pain sensitivity in VNS-implanted depression
patients. Fig. 3 shows preliminary data from eight subjects,
showing that different levels of VNS intensity, frequency, or
pulse width all have significant effects on immediately
perceived pain. A vitally important area for the further
development of VNS will be determining whether VNS can
be regionally focused with different use parameters, and
produce different behaviors based on the affected anatomy.
VNS differs from DBS in that with VNS the surgery is
simpler and there is no device directly implanted into the
brain. DBS is used to treat Parkinson’s Disease, and has
shown promising open results in obsessive compulsive
disorder (OCD) [35].
74 M.S. George et al. / Clinical Neuroscience Research 4 (2004) 71–79

Fig. 3. Pain thresholds in VNS implanted patients as a function of VNS use parameters. These are pooled data from eight VNS patients who have been
systematically tested for their acute pain response while the VNS is delivered with different frequencies (left), intensities (middle) or pulse width (right). Note
that the left most setting is with no VNS, providing an internal sham control. Acutely, real VNS causes subjects to remove their finger sooner from the hotplate.
Different responses are seen with the different use parameters. Although acutely VNS makes subjects more sensitive to pain, chronic treatment has been shown
to cause a reduction in pain sensitivity. Any understanding of the mechanisms of action of VNS must incorporate the differences between acute effects (minutes
to hours), and the longer term effects (weeks to months to years).

2. VNS as a treatment
2.1. Epilepsy
See the article by Labar in this issue for a full discussion
of the clinical use of VNS in controlling epilepsy. An
important point from this literature that directly speaks to
potential mechanisms of action is that in patients with
epilepsy, the long-term efficacy of VNS is either
maintained or improved [36], while the frequency of
adverse events generally decreases as patients accommo-
date to stimulation [37]. Data from uncontrolled obser-
vations suggest that, contrary to a tolerance effect,
improvement in seizure control is maintained or may
improve over time [37,38]. It appears that there is little or
no tolerance over time to the anticonvulsant actions of
VNS. The patient with the longest exposure to VNS has
had the system operating for 14 years.
There are several different programmable variables in
determining how to deliver VNS. These ‘use parameters’
include the pulse width of the electrical signal (130, 250,
500, 750, 1000 ms), the intensity (0.25 – 4 mA is clinically
tolerated), the frequency of stimulation (1 –145 Hz), the
length of stimulation (7 –270 s) and the length of time
between trains of stimuli (0.2 s –180 min). In general, the
initial epilepsy use parameter settings were derived from
the animal studies where anticonvulsant effects were found.
The initial epilepsy studies compared efficacy in two
groups, based on different use parameters. There was a
high-stimulation group (30 Hz, 30 s on, 5 min off, 500 ms
pulse width) and a low stimulation group (1 Hz, 30 s on,
90– 180 min off, 130 ms pulse width). The majority of the
VNS epilepsy efficacy and safety data come from trials with
use parameters similar to those used in the high-stimulation
group. Similarly, most of the data from other neuropsychia-
tric disorders (depression, anxiety) involve VNS at use
parameters similar to those used in the initial epilepsy
studies. It is difficult to imagine that these use parameters
are the maximally effective choices, or that the same
parameters work equally well in all conditions. Epilepsy
physicians frequently switch non-responding patients to use
parameters different from their current settings. However,
there has been no clear demonstration that changing settings
improves efficacy. Further work understanding the transla-
tional neurobiology of these use parameter choices, and how
they relate to clinical symptoms, is a key area for future
growth of the field.
2.2. Depression
For a full discussion of the initial reasoning behind
using VNS in depression in June, 1998, see Ref. [39].
Dr Marangell in this volume reviews the clinical anti-
depressant work with VNS. In the initial decision to perform
a clinical trial in depression, the knowledge of vagus
connections in the brainstem, in particular the role of the LC
was crucial. Additional supporting information came from
(1) mood effects of VNS observed in patients with epilepsy
[40,41], (2) evidence from positron emission tomography
(PET) imaging that VNS affects the function of important
 M.S. George et al. / Clinical Neuroscience Research 4 (2004) 71–79 75

Fig. 4. Long term results in Acute VNS depression responders. These are individual plots of each person who was classified as a responder in the original VNS
depression trial, with their acute, 1 year and 2 year change from baseline depicted on the y-axis. In general, those who responded acutely continue to do well
clinically at 2 years of therapy, although some patients suffered relapse.

limbic structures [42], (3) the role of anticonvulsant
medications in mood disorders [43] and (4) neurochemical
studies in both animals and humans that revealed that VNS
alters concentrations of monoamines within the CNS
(transmission of serotonin [44], norepinephrine [19,45],
gamma aminobutyric acid (GABA), and glutamate [23].
Most interestingly, VNS as used in the initial open study
was more effective in depressed patients with lower degrees
of treatment resistance. For the group of 59 patients, a
history of treatment resistance and intensity of concurrent
antidepressant treatment during the acute VNS trial were
related to VNS outcome. For example, none of the 13
patents who had not responded adequately to more than
seven research defined adequate antidepressant trials in
the current episode responded, while 39% of the remaining
46 patients did respond ðP ¼ 0:0057Þ [46].
Results seen at the end of the 10-week acute phase appear
to largely continue and even improve over 9 months of long-
term maintenance VNS treatment following exit from the
acute study [47], and even persist as long as 2 years out.

Fig. 5. Long-term results in Acute VNS depression non-responders. These are individual plots of each person who was classified as a non-responder in the
original VNS depression trial, with their acute, 1 year and 2 year change from baseline depicted on the y-axis. Many of the subjects who failed to respond
acutely responded later. Understanding the long-term effects of VNS is an important area of clinical and basic science research.
76 M.S. George et al. / Clinical Neuroscience Research 4 (2004) 71–79
Changes in psychotropic medications and in VNS stimulus
parameters were allowed during this long-term follow-up.
In general, initial responders continue to do well, while
many initial non-responders later achieve a response
(see Figs. 4 and 5). Focusing on who responds to VNS,
and when, may provide valuable clues to its mechanisms of
action.
2.3. Other potential applications
Anxiety. As reviewed above, the sensory afferent nerve
fibers that VNS stimulates in the vagus travel to the brain
and terminate in the nucleus solitary tract (NTS). These
fibers are the primary means by which the brain receives
information from the organs within the gut [45]. From there,
information travels to the LC, the primary site of all
norepinephrine fibers in the brain. Norepinephrine has long
been considered to be a critical neurotransmitter
system involved in the pathogenesis and regulation of
anxiety [48,49]. A device that directly stimulates this
norepinephrine control site would likely have important
effects on anxiety.
The historical importance of this pathway is that VNS
modulates can be seen in the oldest theory about the brain
origins of fear—the James – Lange theory of emotions.
William James [50] radically argued that all emotion
actually resided in the body, and it was the brains’
interpretation of this signal through the vagus nerve, that
caused someone to be anxious. Interestingly, this theory has
been hard to disprove, and most modern anxiety researchers
think that the ultimate answer lies in central – peripheral
loops. However, all agree that the information flowing
through the vagus to the brain is an important part of anxiety
regulation. Obviously a device that directly affects this
information flow could be a powerful way to alter anxiety.
Animal c-fos studies, and PET, single photon emission
computed tomography (SPECT) and more recently fMRI
studies of VNS indicate that VNS causes brain activity
changes in regions long thought to regulate anxiety. Thus,
the function of areas of the brain implicated in anxiety
appears to be altered by VNS. Moreover, there were some
anti-anxiety effects in the initial open pilot depression study.
In these 30 patients, improvements in the HRSD items 9
(agitation), 10 (psychic anxiety) and 11 (somatic anxiety)
were significantly improved (P , 0:001 using signed rank
test). The improvement in agitation was from 0.6 to 0.2
(73% improvement), in psychic anxiety from 2.3 to 1.2
(50% improvement) and in somatic anxiety from 1.6 to
1.0 (36% improvement). For all these reasons, a multisite
open treatment trial in resistant anxiety disorder patients
was launched in May 2001. This study has enrolled 10
anxiety disorder patients across the several sites with a
primary diagnosis of either OCD, post-traumatic stress
disorder (PTSD), or panic disorder. Seven of these 10 had a
primary diagnosis of OCD. As a group, they were treatment-
resistant and had tried and failed 18 prior psychotropic
medications. For the full 10 subjects, there was a 35%
decrease in the Hamilton Anxiety Scale at 3 months, and a
26% drop at 6 months. Three of the seven OCD patients met
response criteria on the YBOC at 3 and 6 months. Further
work in this area is warranted.
Obesity. Information about hunger and satiety from the
stomach and small intestine travels through the vagus nerve
to the brain. It seems plausible to ask whether vagus
stimulation might change eating patterns and other forms of
craving. To investigate this, Roslin and colleagues in NY
implanted bilateral subdiagphragmatic vagus stimulators in
several normal weight mongrel dogs. Over several months,
chronic intermittent VNS in this manner resulted in
substantial weight loss. Interestingly, there was no
change in the dog’s metabolism. Rather, they took much
longer to consume their food, and they even left food on
their plate —something mongrel dogs rarely do, if ever [25].
Recently, six subjects with morbid obesity have been
implanted in this manner [25]. There was a recent abstract
from an obesity meeting where a group has implanted an
electrical stimulator within the gastric mucosa in morbidly
obese subjects, with positive results [51]. This procedure
may be simply a different method of vagus nerve
stimulation, with the vagus fibers in the stomach being
stimulated rather than the actual nerve in the diaphragm or
neck.
Pain. The classical pain pathway involves nerves that
enter the dorsal horn of the spinal cord and then travel
through the spine to the brainstem and later thalamus. Pain
is then perceived in the thalamus, and thalamocingulate
fibers then provide the affective weighting to the pain signal.
In addition to this circuit, some information about pain,
especially visceral pain, travels through the vagus nerve.
A recent study showing changes in pain perception as a
function of different VNS settings hints at the promise of
using VNS for some form of pain modulation. Acutely,
VNS increases pain perception [52], but used chronically,
VNS results in a decrease in pain perception [53]. It is
extremely important to eventually understand these mech-
anisms of action, both in terms of the functional and
translational neurobiology and the dynamic temporal
changes over time.
3. Brain effects of VNS and mechanisms of action
Because we still lack full and complete understanding
of the pathophysiology of either the depressions or the
epilepsies, we have only partial clues about how anti-
convulsant, antidepressant and mood stabilizing treatments
work. At a simplistic level, antidepressants and anti-
convulsants can inhibit an area of pathological hyper-
activity, excite an area of pathological hypoactivity, or
provide for restored regional balance or synchrony. In
animal models, there is good evidence that VNS restores
neuronal synchrony [7].
 M.S. George et al. / Clinical Neuroscience Research 4 (2004) 71–79
3.1. Limitations of animal models
One of the major limitations of VNS is the relatively small
body of knowledge about the brain effects of VNS as a
function of the various use parameters. A contributing factor
to this lack of information is the relative difficulty of
stimulating the vagus in animals in a manner that resembles
the way VNS is applied in humans. For example, the vagus is
a very small nerve in the rat or mouse. Even when someone is
skilled enough to be able to expose the vagus and attach a
wire, the coil must be smaller in animals than in humans,
requiring the production of a special small animal VNS
electrode. On top of this, the VNS generator is almost as large
as a small rat or mouse and the animal thus cannot wear the
generator. Thus, in most animal studies to date, VNS has
been performed intermittently with the rat restrained in a
harness or cage, and the VNS generator attached to the wire
through a cap-like connection on the head, running to the
vagus in the neck. This results in VNS application that is only
for several hours a day, unlike in humans where the device
cycles on and off 24 h each day. To achieve 24-h stimulation
in a rat, one must restrict the animal’s movements in a way
that greatly changes the animal’s behavior.
Despite these technical hurdles, Krahl and colleagues
have performed several elegant animal studies with VNS.
They have demonstrated that LC lesions suppress the
antiepileptic effects of VNS [19]. Most recently they have
found that intermittent VNS (30 min/day) in the rat in the
Porsolt Swim test produces ‘antidepressant’ effects that
equal ECS or desipramine. Finally, Walker and colleagues
have shown that changing pharmacology at the NTS can
enhance or reduce the anti-epilepsy effects of VNS [23].
More animal studies in epilepsy and depression exploring the
biological effects of the VNS use parameters (intensity, pulse
width, frequency, duty cycle, dosing strategy) are needed.
3.2. Functional imaging
Functional brain imaging is not hampered by the
technical issues surrounding VNS studies in small animals,
although there are other complexities and hurdles.
PET and SPECT. The initial brain imaging studies with
VNS were done in epilepsy patients, using the radiotracer-
based techniques of SPECT and PET. These techniques
have a spatial resolution of 5 –8 mm, and they image an
average of brain activity over relatively long periods of time
(SPECT 1 min, O15 PET 1 min, fluorodeoxyglucose (FDG)
PET 20 min). These differences in temporal and spatial
resolution make comparisons across these studies difficult,
as the different scanning techniques provide an average of
different lengths of brain activity. For a full discussion of
these studies and this complex literature, see Ref. [54].
Henry and colleagues at Emory have performed some of
the most important and elegant imaging studies to date.
They have shown that VNS in epilepsy patients causes acute
blood flow changes in the neuroanatomical regions known
77
to involve visceral afferents [42]. Interestingly, they
also showed that this VNS-induced activation varied as a
function of the intensity (electrical charge) of stimulation,
and that VNS epilepsy responders had more acute changes
in thalamus activity than did non-responders [55]. There
have been several other VNS SPECT and PET studies.
3.2.1. Functional magnetic resonance imaging (fMRI)
fMRI has higher spatial and temporal resolution than
PET or SPECT, without radiation exposure. However, it is
not easy to scan VNS patients with fMRI. For example, as
a safety measure, the VNS generator is programmed to
turn itself off in the presence of a high magnetic field.
Several groups have simultaneously mastered the technical
problems involved in performing fMRI in patients
implanted with VNS generators [28,29,33,56]. At MUSC,
Bohning and colleagues have now used fMRI to demon-
strate the functional regional anatomy of VNS in patients
with depression. VNS causes acute changes in hypothala-
mus, orbitofrontal cortex, the medial temporal lobe
subsuming the amygdala and hippocampus, insula, medial
prefrontal cortex, and cingulate gyrus. At a smaller degree
of significance, the thalamus was activated. These are the
regions that are consistently implicated in mood and anxiety
regulation, and are also regions to which norepinephrine
fibers from the LC project.
More recently, this group has begun to use fMRI to
determine whether different brain effects are associated with
different VNS use parameters, to study the brain changes
over time, and to relate these changes to clinical
antidepressant or antianxiety effects. In an initial study
examining the differences in the brain of VNS at two
different frequencies (5 and 20 Hz), they found that 20 Hz
VNS had markedly more significant activation than did
5 Hz VNS [33]. Studies like this which relate CNS effects
with stimulation parameters and clinical outcomes hold the
promise of helping to clarify the neurobiology of VNS and
that of the underlying neuropsychiatric condition.
3.3. Other neurobiological studies
Early epilepsy studies found that VNS changed CSF
5-HIAA, a serotonin metabolite [44]. It was thus surprising
that a recent study in depression of CSF changes over time
failed to confirm this finding, and instead found significant
increases in CSF HVA, a dopamine metabolite [57].
4. Future directions
In conclusion, current knowledge suggests that VNS
might well have a role in the treatment of several
neuropsychiatric disorders, in addition to its current role
in epilepsy. It is an interesting new method of influencing
brain activity, with almost 100% compliance and interesting
clinical effects that appear over the course of many months
78 M.S. George et al. / Clinical Neuroscience Research 4 (2004) 71–79
or even years of treatment. However, more knowledge about
the neurobiology of VNS would likely substantially aid its
applications in these new pioneering applications. Further
work is needed involving animal studies, functional brain
imaging and acute psychophysiological studies in VNS
implanted humans, and then hypothesis driven clinical
trials, in order to perfect and refine the technique. Particular
importance needs to be paid to both the acute effects, as well
as longer term effects that might suggest permanent
neuronal remodeling.
VNS is thus a most interesting new approach to therapy
and understanding of the brain with several theoretical but
still unproven mechanisms of action.
Acknowledgements
The authors and the Brain Stimulation Laboratory have
received grant support from the Defense Advanced
Research Projects Agency (DARPA), the Stanley Foun-
dation, the National Alliance for Research on Schizophrenia
and Depression (NARSAD), the Borderline Personality
Disorders Foundation (BPDRF), NINDS grant RO1-
AG40956, the Charles A. Dana Foundation, and Cybero-
nics. Drs George and Nahas have received speakers fees
from Cyberonics, and Dr George is a consultant to
Cyberonics.
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