The potential role of vagus-nerve stimulation in the treatment of HIV-associated depression: A review of literature

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DOI: 10.2147/NDT.S136065
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Abstract
Depression is the most common comorbidity and neuropsychiatric complication in HIV. Estimates suggest that the prevalence rate for depression among HIV-infected individuals is three times that of the general population. The association between HIV and clinical depression is complex; however, chronic activation of inflammatory mechanisms, which disrupt central nervous system (CNS) function, may contribute to this association. Disruptions in CNS function can result in cognitive disorders, social withdrawal, fatigue, apathy, psychomotor impairment, and sleep disturbances, which are common manifestations in depression and HIV alike. Interestingly, the parasympathetic system-associated vagus nerve (VN) has primary homeostatic properties that restore CNS function following a stress or inflammatory response. Unfortunately, about 30% of adults with HIV are resistant to standard psychotherapeutic and psychopharmacological treatments for depression, thus suggesting the need for alternative treatment approaches. VN stimulation (VNS) and its benefits as a treatment for depression have been well documented, but remain unexplored in the HIV population. Historically, VNS has been delivered using a surgically implanted device; however, transcutanous VNS (tVNS) with nonsurgical auricular technology is now available. Although it currently lacks Food and Drug Administration approval in the US, evidence suggests several advantages of tVNS, including a reduced side-effect profile when compared to standard treatments and comparable results to implantable VNS in treating depression. Therefore, tVNS could offer an alternative for managing depression in HIV via regulating CNS function; moreover, tVNS may be useful for treatment of other symptoms common in HIV. From this, implications for nursing research and practice are provided.
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http://dx.doi.org/10.2147/NDT.S136065
The potential role of vagus-nerve stimulation
in the treatment of HIV-associated depression:
a review of literature
William C Nicholson
Mirjam-Colette Kempf
Linda Moneyham
David E Vance
School of Nursing, University of
Alabama at Birmingham, Birmingham,
AL, USA
Abstract: Depression is the most common comorbidity and neuropsychiatric complication in
HIV. Estimates suggest that the prevalence rate for depression among HIV-infected individuals
is three times that of the general population. The association between HIV and clinical depres-
sion is complex; however, chronic activation of inflammatory mechanisms, which disrupt
central nervous system (CNS) function, may contribute to this association. Disruptions in CNS
function can result in cognitive disorders, social withdrawal, fatigue, apathy, psychomotor
impairment, and sleep disturbances, which are common manifestations in depression and HIV
alike. Interestingly, the parasympathetic system-associated vagus nerve (VN) has primary
homeostatic properties that restore CNS function following a stress or inflammatory response.
Unfortunately, about 30% of adults with HIV are resistant to standard psychotherapeutic and
psychopharmacological treatments for depression, thus suggesting the need for alternative
treatment approaches. VN stimulation (VNS) and its benefits as a treatment for depression
have been well documented, but remain unexplored in the HIV population. Historically, VNS
has been delivered using a surgically implanted device; however, transcutanous VNS (tVNS)
with nonsurgical auricular technology is now available. Although it currently lacks Food and
Drug Administration approval in the US, evidence suggests several advantages of tVNS,
including a reduced side-effect profile when compared to standard treatments and comparable
results to implantable VNS in treating depression. Therefore, tVNS could offer an alternative
for managing depression in HIV via regulating CNS function; moreover, tVNS may be useful
for treatment of other symptoms common in HIV. From this, implications for nursing research
and practice are provided.
Keywords: tVNS, depression, HIV, vagus nerve
Introduction
Depression is the most common comorbidity and neuropsychiatric complication
in HIV-positive adults, with an occurrence rate of approximately 40%–60% over a
lifetime. Moreover, estimates suggest that the prevalence rate for depression among
HIV-infected individuals is three to four times that of the general population.1–3
Approximately 55%–65% of adults with HIV treated for depression experience a
reduction in depressive symptoms.4 However, as many as 30% of adults with HIV-
associated depression are resistant to standard treatments (eg, psychopharmacology
and psychotherapy), suggesting the need for alternative treatment approaches. As such,
novel technologies should be explored for use in this population.
The association between HIV and clinical depression is complex. Chronic activation
of stress mechanisms that disrupt central nervous system (CNS) function likely drives
Correspondence: William C Nicholson
School of Nursing, University of Alabama
at Birmingham, Room 328B, 1701
University Boulevard, Birmingham, AL
35249-1210, USA
Tel +1 205 996 9821
Email chancen@uab.edu
Journal name: Neuropsychiatric Disease and Treatment
Article Designation: Review
Year: 2017
Volume: 13
Running head verso: Nicholson et al
Running head recto: Vagus-nerve stimulation, HIV, and depression
DOI: http://dx.doi.org/10.2147/NDT.S136065
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this association, as both conditions present with pathological
proinflammatory states. According to Kim et al,5 a signifi-
cant relationship exists between depression and increases in
proinflammatory cytokines (such as IL6, IL1β, TNFα, and
CRP); moreover, severity of depression is correlated with
reductions in BDNF. Likewise, proinflammatory cytokines
and reduced BDNF have been associated with the progression
of HIV and its associated neurocognitive disorders.6,7
Comorbid depression in HIV reduces antiretroviral
medication adherence, which independently leads to poor
disease outcomes related to inflammation; however, depres-
sion is also independently and adversely associated with HIV
progression via decreased CD4+ and CD8+ T lymphocytes,
along with increased viral loads.1,8
In both disorders, the dysregulation of neuroendocrine
and neuroimmunological systems (via proinflammatory
cytokines) produces a cascade of events resulting in attenua-
tion of parasympathetic tone, pain, psychomotor disturbance,
depression, alterations in mood and cognition, anhedonia,
fatigue, apathy, cognitive disorders, dysregulated sleep,
appetite disruptions, and social withdrawal. These symp-
toms are collectively referred to as “sickness behavior”,
and are mediated by the vagus nerve (VN), along with being
among the most prevalent symptoms in HIV with comorbid
depression.9–12 Chronic disruption of the VN in response to
stress leads to alterations in homeostasis via constant activa-
tion of the hypothalamic–pituitary–adrenal (HPA) axis and
the sympathomedullary system.13 This activation increases
cytokine production, and in turn induces a chronic “sickness
state”. Contrarily, stimulation of the VN (particularly its α7
nicotinic pathway) can reverse the effects of sickness behav-
ior by producing an anti-inflammatory effect via regulation
of cytokine expression.14 In this context, HIV and depression
could be pathologically related via their effect on the VN, and
interventions targeting it could provide clinical benefit.
Implantable VN stimulation (iVNS) and its ben-
efits in treatment-resistant depression have been well
documented.15–18 iVNS is achieved via a surgically implanted
device; however, transcutaneous VNS (tVNS) with nonsurgi-
cal auricular technology is now available and offers potential
advantages, due to its comparable benefits to VNS, ease of
use, higher accessibility, and reduced side-effect profile,19 yet
the effectiveness of these technologies remains unexplored
in HIV.
The main purpose of this review is to explore tVNS’s
potential use for depression in the HIV-infected population.
First, we provide a basic overview of the VN’s association
to HIV and depression. Second, we briefly describe tVNS.
Third, the clinical efficacy of iVNS in depression is
discussed. Fourth, studies evaluating tVNS’s effectiveness
in the treatment of depression since its introduction in 2010
are reviewed. Finally, implications for research and clinical
practice are provided.
The vagus nerve’s inammatory
association with HIV and depression
A comprehensive description of the inflammatory response is
beyond the scope of this review (see Del Guerra et al20 for a
more thorough review). However, in order to understand the
association between depression and HIV, a brief and basic
overview of their relationship to inflammation in the context
of the VN is described. Psychological stress (eg, stigmatism
related to HIV diagnosis, discrimination), recurrent stressors,
resilience, and the inflammatory properties of HIV are likely
synergistic with the chronic activation of immune cells and
resultant depression. As such, HIV and depression will be
referred to as HIV-associated depression for simplicity and to
indicate their relationship via immunodisruption. This section
focuses on HIV as being the primary stressor that contributes
to depression. Specifically, discussion is focused on sickness
behavior in the context of HIV-associated depression, fol-
lowed by associations with the VN.
Sickness behavior in HIV-associated
depression
HIV activates T cells and monocytes (eg, CD4+), which enter
the CNS. Upon entry, these activated cells infect microglia
and astrocytes, while also inducing the production of proin-
flammatory cytokines. This cell activation (together with
perivascular macrophages) causes the release of neuroexcit-
atory amino acids (eg, glutamate), thereby disrupting calcium
channels and propagating an inflammatory state. Addition-
ally, cell activation promotes the formation and release of
nonstructural proteins such as HIV-Tat and gp120. As a result,
the blood–brain barrier is weakened and becomes vulnerable
to peripheral cytokines, which further perpetuates the inflam-
matory cycle and disrupts neuronal integrity.21,22
As a result, locus coeruleus-norepinephrine projections to
the hypothalamus and brain stem are activated. In response,
the amygdala and HPA axis stimulate the release of gluco-
corticoids (cortisol) and activate the sympathomedullary
system, which releases catecholamines (noradrenaline and
adrenaline) into the peripheral blood. This activation coor-
dinates glucocorticoid and catecholamine interaction with
immune cells, thereby promoting cytokine expression and
their transcription factors. Importantly, while antiretrovirals
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Vagus-nerve stimulation, HIV, and depression
buffer this cytokine expression, they do not completely
reverse this response.20,23
Consequently, unsuppressed cytokine release activates
an inflammatory state that manifests as “sickness or depres-
sive behavior”. Under normal conditions, this behavior is
protective, and regresses as cytokines normalize along with
the inflammatory response. The rebalancing of cytokines
allows them to resume their trophic responsibilities in
promoting neurogenesis, neuroplasticity, and maintenance
of cognitive function.24 However, in the case of HIV, this
sickness behavior persists into a pathological inflammatory
state. Importantly, the VN is grossly responsible for initiating
sickness behavior via its interaction with cytokines, and is a
critical response to immunoactivation.
Vagus nerve and sickness behavior
Herz and Kipnis25 suggested the VN mediates sickness
behavior. The VN is a major component of the autonomic
nervous system, which influences neuronal, endocrine, and
immune functions (neuroendocrine–immune axis) via its
efferent (motor) and afferent (sensory) pathways. The vagal
cholinergic anti-inflammatory pathway (CAP) interacts with
the CNS, and is primarily responsible for sickness behavior.
During acute-stress states, the CAP is activated in the
presence of a stressor and is responsive to proinflammatory
signals that initiate an immune response. Vagal afferents
detect central or peripheral pathogens (eg, via Toll-like
receptors) and carry proinflammatory cytokine signals to
the brain-stem nuclei. These signals are converted to the
nucleus tractus solitarius and project to autonomic output
centers (eg, limbic system, hippocampus, frontal cortex).
The medulla coordinates this response and stimulates vagal
efferent fibers, which project to the celiac ganglion.26 Vagal
fibers develop synapses on cell bodies within the celiac
ganglion, thus activating innate immune responses in the
spleen. Splenic nerves then release norepinephrine, which
communicates with β2-adrenergic receptor-expressing
T cells. Consequently, T cells release acetylcholine to inter-
act with α7 nicotinic receptors, which are present on the
cell surfaces of macrophages and other inflammatory cells
(eg, monocytes).27 Complex, vagal-associated brain activity
and signaling inhibits inflammation due to suppression of
cytokines, thereby regulating their release and stabilizing
the stress response.
Contrarily, chronic inflammation (such as is the case
with HIV-associated depression) interferes with the VN’s
ability to regulate the immune response successfully by
disrupting signaling in the CAP.28 As a result, glutamate and
γ-aminobutyric acid, along with central cytokine systems, are
chronically disrupted (creating a persistent proinflammatory
state), which interferes with their trophic and homeostatic
function. CD4+ and CD8+ T lymphocytes are dysregulated
at the splenic level, which disrupts catecholamine function,
thereby perpetuating stress signaling to the CNS.1,23
This chronic increase in cytokine and stress signaling
via a disrupted CAP persistently activates the amygdala,
HPA axis, and sympathomedullary system, which interferes
with appetite and sleep;11 moreover, this allows excessive
cortisol to bind to glucocorticoids and increases insulin
resistance. The resulting hypercortisolism and the actions
of HIV’s gp120 protein interferes with BDNF’s energy
metabolism, which supports brain health by lowering blood
glucose, reducing insulin resistance, and regulating food
intake.29 Consequently, BDNF is reduced and metabolic
disruptions occur, which interfere with neuroplasticity and
neurogenesis.30 Additionally, during this dysfunctional
immune response, nucleus accumbens activity is significantly
downregulated, which interferes with the reward pathway
(motivation, pleasure, and reinforcement learning), thus
promoting anhedonia and apathy.31 Moreover, increased
cytokine signaling to the basal ganglia results in psychomotor
disturbances and fatigue.32,33 The cytokine-induced CAP dis-
ruption compromises the prefrontal cortex and its functional
capacity to maintain executive function, attention, memory,
and adaptive social behaviors. Ultimately, this disruption per-
petuates pathological social withdrawal, anhedonia, fatigue,
psychomotor disturbances, and alterations to both mood and
cognition or sickness behavior.24
The chronic-stress mechanisms in HIV-associated depres-
sion are complex and have not yet been fully elucidated;
however, the overlapping symptomatology in HIV-associated
depression symptoms and their relationship to VN func-
tion should be considered a potential target for treatment
interventions.
Vagus-nerve stimulation
The US Food and Drug Administration approved iVNS for
use in treatment-resistant depression in 2005, while tVNS was
approved in Europe for depression in 2010. One such tVNS
device called Nemos (developed by Cerbomed in Erlangen,
Germany) has received authorization for use in epilepsy,
depression, and pain conditions. Likewise, another tVNS
device called GammaCore (developed by ElectroCore LLD
in Basking Ridge, NJ, US) has European approval for use in
prophylactic and acute treatment of migraines and headaches;
however, it is not approved for depression. Currently, tVNS
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is not approved in the US, but is being used for research trials
across multiple populations (eg, eating disorders, rheumatoid
arthritis, and irritable bowel syndrome).34
Transauricular vagus-nerve stimulation
The tVNS unit attaches to a battery-powered control unit
that connects to a headset with bilateral electrodes, which
are placed on the outer ear (see Figure 1). Alternatively,
adhesive anodes and cathodes can be placed over the mas-
toid process juxtaposed to the outer ears. Electrodes can be
applied either unilaterally or bilaterally, depending on the
device specifications.35
Three sensory nerves supply the outer ear (ie, auricu-
lotemporal and great auricular), but the tVNS unit specifically
targets the auricular branch of the VN (ABVN) and to a lesser
degree the greater auricular nerve. The ABVN predominantly
innervates the external auditory meatus and concha (cymba
and cavum), which provides the cutaneous access field of
the ABVN targeted by tVNS.34,36 The concha’s nerve fibers
provide the electrical stimulation point that allows changes
in intensity, pulse duration, and frequency from the tVNS
unit to induce signals via the myelinated Aβ fibers of the
ABVN.36 These ABVN fibers terminate in the nucleus of
the solitary tract of the brain stem. Neuronal projections
from this nucleus relay excitatory and inhibitory signals.
These vagal projections are stated to be responsible for its
neuroplastic, neurogenic, neuroprotective, and antidepres-
sant properties.37
Stimulation can be self-administered, yet stimulation
parameters have not been established; therefore, clinical
models for this device do not include a standardized duration,
frequency, or administration paradigm. The manufacturers
recommend daily use (one to four times) for at least 1 hour
(maximum of 4 hours); however, research regarding the
efficacy of these specific parameters is limited. Various
approaches have been researched, but are contingent on
which specific tVNS unit is being utilized.38,39 In all studies,
intensity is adjusted based on perceptual tolerance and kept
below each individual’s pain threshold. Pain thresholds are
defined as the minimal amount of stimulation that evokes a
tingling or unpleasant sensation.
The side-effect profile for tVNS is appealing, due to it
being the least innocuous of standard biological treatments
for depression. Adverse effects tend to be stimulation-related
and tend to occur during those time intervals. The most com-
mon symptoms reported are itching, outer-ear discomfort,
local pain on stimulation side, and neck pain that corresponds
anatomically to the location of the electrodes. Additionally,
VNS can be safely used in pregnancy along with concomitant
psychotropic medications (eg, antidepressants) and electro-
convulsive therapy.18
Depression and iVNS
Approximately 21 research studies have been conducted
to examine the relationship between iVNS and treatment-
resistant depression. Meta-analytic and systematic reviews
have found a beneficial effect for iVNS in this population.40–42
These beneficial results support the inclusion of iVNS as a
treatment option in national guidelines for depression (eg,
Canadian Network for Mood and Anxiety Treatments, British
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Vagus-nerve stimulation, HIV, and depression
Association for Psychopharmacology, and National Institute
for Health and Care Excellence).41,43–45
However, due to the methodological limitations of iVNS
(cost, surgical requirements, and the higher risk posed
to participants by implanting a sham device), a majority
of the iVNS studies did not utilize a control group. This
thus limits the inferences that can be made about the find-
ings. Instead, most utilized a before–after design, which
increases the potential for a placebo effect and could explain
a portion of beneficial results, thereby minimizing the
overall effect.42
Of note, in the studies where randomized controlled
trials were utilized, results were mixed. Rush et al46 did not
demonstrate any significant benefits for VNS in a 10-week
(n=235), acute, blind, randomized controlled trial. Contrarily,
in a 12-month naturalistic follow-up to this study, Rush
et al47 found a significant reduction in depressive scores and
global improvement. Likewise, Sackheim et al48 conducted
both a pilot and randomized controlled study. In the latter
study, participants were randomized into active or sham
groups (n=205), with 15% of the early responders showing
a 50% reduction in depressive symptoms at 30 months and
77% maintaining this response at 24 months. Of the late
responders, 20% showed a reduction at 12 months and 65%
maintained this response at 24 months.
Due to the lack of adequate control trials and mixed
results of the randomized studies available, more research
is needed to determine the utility of iVNS as an effective
intervention for treatment-resistant depression. Fortunately,
the novel tVNS devices allow researchers to bypass the
limitations of traditional iVNS and enable more rigorous
clinical trials. As such, it is important to review the avail-
able tVNS research to determine its efficacy for depressive
symptomatology and whether the advantageous nonsurgical,
transauricular design improves on the previous methodologi-
cal limitations of traditional iVNS. If effective, these devices
could offer those experiencing HIV and comorbid depression
an alternative for treatment.
Materials and methods
A systematic PubMed search of the literature was conducted
on December 1, 2016 for 2010–2016. The PRISMA (Pre-
ferred Reporting Items for Systematic Reviews and Meta-
Analyses) approach (see Figure 2) was used as the method
for conducting the literature review.49 The year 2010 was
chosen due to the tVNS unit being made available to the
general research market at that time. One study was con-
ducted in 2007 that utilized this device.50 However, it did
not directly measure the effects of tVNS on depression, and
thus was not included. The search was restricted to peer-
reviewed research articles published in English. Keywords
operated in the search were “tVNS and depression” yielding
35 articles and “tVNS and HIV” yielding 0 articles. The
tVNS and depression results were narrowed by removing
the words, “epilepsy”, “tinnitus”, and “implantable”, which
resulted in ten articles. Inclusion criteria further limited
the review to quantitative clinical trials and human stud-
ies, which netted five articles. Due to the small number of
results, case studies were added back, resulting in a total
of six articles. A more detailed review of these studies can
be found in Table 1.
Results
Hein et al38 conducted the first pilot study to explore the
effects of tVNS in major depression (n=37). Two random-
ized sham-controlled (add-on) studies were conducted,
with participants being stimulated for 5 days each week for
14 days. The first study (n=22) used an active-control group
(n=11) and a sham-control group. The sham control received
stimulation to the center of the left earlobe, which is without
vagal innervation. Stimulation intensity was 0–600 mA with
a frequency of 1.5 Hz for 15 minutes daily. Ranges were
adjusted just below the participant’s perception threshold. In
the second study (n=15), seven participants were given active
stimulation while the remaining received sham stimulation.
However, the stimulation occurred for 15 minutes twice daily
(morning and evening) with fixed parameters of 130 mA and
1.5 Hz. The Hamilton Depression Rating Scale (HAM-D)
and Beck Depression Inventory (BDI) were administered at
baseline (day 0) and at the conclusion of the study (day 14).
Using pooled analysis, both studies showed a significant
mean difference between the active and sham groups on
the BDI. Contrarily, neither showed significant differences
on the HAM-D. No significant side effects were noted due
to tVNS use.
Trevizol et al35 reported the first case-study utilizing tVNS
in a 38-year-old man with major depression. This patient
received stimulation for 5 days each week for 14 days at
120 Hz with a pulse duration of 250 µs for 30 minutes daily.
The HAM-D was administered at baseline along with the
Montreal Cognitive Assessment. After 14 days, this patient’s
symptoms went into complete remission and remained stable
at a 2-month follow-up. No significant side effects were
noted due to tVNS use.
Trevizol et al51 conducted a proof-of-concept trial (n=12)
exploring the effects of tVNS in major depressive disorder.
The HAM-D was the primary instrument used to evalu-
ate depression, with end-point response defined as a 50%
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reduction in baseline scores. Patients received stimulation for
5 days each week for 14 days at 120 Hz with pulse duration
of 250 µs, and intensity was set at 12 mA for 30 minutes
daily. After 14 days, all participants demonstrated a clinical
response with a 50% reduction in depressive symptoms.
Five patients exhibited remission of depressive symptoms
(score of ,8 on the HAM-D). Response was maintained at
1-month follow-up. Cognition remained stable, as measured
by the Montreal Cognitive Assessment. No adverse effects
were reported. Ten participants reported diurnal sleepiness
after stimulation, with six patients experiencing nausea, but
no medication or treatment was required. There were no
dropouts reported.
Fang et al52 conducted a single-blinded clinical trial
(n=49) exploring the effects of tVNS in mild–moderate
major depression. A total of 34 patients were included in the
study analysis (after 14 dropped out and one was excluded
for excessive head movement), and were divided into active
(n=18) and sham (n=16) groups. The active group received
stimulation at 20 Hz with a wave width less than 1 ms with
intensity adjusted based on tolerance or perception threshold
(4–6 mA). Stimulation occurred twice a day for 30 minutes
at least 5 days a week for 1 month. After functional magnetic
resonance imaging (fMRI) and HAM-D to evaluate depres-
sion symptoms, the results supported the efficacy of tVNS, as
significant decreases in depressive symptoms (#50% reduc-
tion) were found. In support, the fMRI results corresponded
to increased functional connectivity in the default-mode
network of the brain (known to be decreased in depression).
No significant side effects were noted due to tVNS use.
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Figure 2 PRISMA ow diagram demonstrating screening method for articles.
Note: Adapted from Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med.
2009;6(7):e1000097.49
Abbreviations: PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; tVNS, transcutaneous vagus nerve-stimulation.
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Vagus-nerve stimulation, HIV, and depression
Table 1 Summary of transcutaneous vagus nerve stimulation treatment studies of major depression
Study Participants VNS parameters Procedure and measures Data analysis/ndings Strengths and
limitations
Hein et al38 Study 1
n=22 (mean age 44 years;
male/female 9/13)
Two randomized groups:
tVNS (n=11), sham (n=11)
Study 2
n=15 (mean age 48 years;
male/female 6/9)
Two randomized groups:
tVNS (n=8), sham (n=7)
Study 1
Intensity: 0–600 mA; not xed
Frequency (Hz): 0.5–100
15 minutes daily/14 days
Study 2
Intensity: 130 mA; xed
Frequency (Hz): 1.5
15 minutes/2× daily/14 days
Study 1
Bilateral NET-2000 TENS unit inserted, inner ear
Sham: same procedure; no stimulation
Study 2
Bilateral NET-1000 tVNS unit inserted, inner ear
Sham: same as above
Outcome measures
Reduced scores on BDI and HAM-D
Study 1
BDI scores reduced from
27 to 14 in active group
No reduction in sham
Study 2
BDI scores reduced from
31 to 25.8 in active group
No reduction in sham
Overall
No changes in HAM-D
in either study
Strengths
Naturalistic
Limitations
Short duration
Cotreatment with
antidepressants/
psychotherapy
No blinding
Small study
Trevizol et al35 n=1 (38-year-old man), case
study
Stimulation: 120 Hz, 250 µs
30 minutes daily/14 days
tVNS external device used
Autoadhesive rubber electrodes of 20 cm2 placed
over the mastoid process bilaterally
Outcome measures
Reduced scores on HAM-D
HAM-D scores improved
Remission achieved (,8)
Strengths
Novel study
Limitations
Case study
No sham or control
Trevizol et al51 n=12 (mean age 45.9 years;
male/female 2/10)
No randomized groups
Intensity: 12 mA
Stimulation: 120 Hz, 250 µs duration
30 minutes daily/14 days
Neurodyn II external device used
Autoadhesive rubber electrodes of 15 cm2 placed
over the mastoid process bilaterally
Outcome measures
50% or greater reduction of scores on HAM-D
HAM-D reduction from
27.9 to 8.2 (mean difference
19.75, SD 4.2)
All exhibited $50% reduction
in scores
Five participants exhibited
remission (,8)
Response maintained at
1 month follow-up
Strengths
Proof of concept
Follow-up
Limitations
No sham, blinding,
or randomization
Convenience sample
Fang et al52 n=34 (mean age not reported;
male/female not reported)
Two randomized groups:
tVNS (n=18), sham (n=16)
Intensity: 4–6 mA
Stimulation: 20 Hz of 1 ms duration
30 minutes 2× daily/4 weeks
40-minute device training
Seated position or laying on side with electrode
clips attached bilaterally
Self-administration at home; complete daily log;
log checked every 4 weeks
Sham treatment self-administered; electrodes
clipped to superior scapha with no vagal
connection; required to complete daily entries
in a diary log for 4 weeks
Outcome measures
Primarily reduced scores on HAM-D (.50%)
Secondarily reduced scores on HAM-A, SAS,
and SDS
Depression scores reduced on
HAM-D in tVNS group
Signicant interaction between
treatment and sham group
and treatment time on all
measures (except HAM-A)
Strengths
Randomized
Single-blind
Longer duration
Sham stimulation
Limitations
Self-administered
sham protocol
Self-record logs
Small study
(Continued)
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Table 1 (Continued)
Study Participants VNS parameters Procedure and measures Data analysis/ndings Strengths and
limitations
Rong et al39 n=160
Two randomized groups:
tVNS (n=91, mean age
40.1 years; male/female
23/68), sham (n=69, mean
age 43.88 years; male/female
20/49)
Intensity: 4–6 mA
Stimulation: 20 Hz of 0.2 ms
30 minutes 2× daily/12 weeks
Same protocol as Fang et al,52 with exception of
an active control
After 4 weeks, sham group received tVNS for
8 weeks
Outcome measures
Primarily reduced scores on HAM-D (.50%)
Secondarily reduced scores on HAM-A, SAS,
and SDS
Week 4 (0–4)
HAM-D scores reduced in
both groups; signicantly
greater in tVNS group
Signicant changes between
treatment and sham group on
HAM-D
No signicant response
between tVNS group (at
4 weeks or 4–8 weeks) and
sham (at 4–8 weeks or
8–12 weeks)
Week 12
Signicant response between
tVNS groups at 0–4, 4–8, and
8–12 weeks
Strengths
Randomized
Naturalistic
Active control
Large study
Longer duration
Sham stimulation
Limitations
Self-administered
sham protocol
Self-record logs
Liu et al53 n=49
Two randomized groups:
tVNS (n=18, mean age
37.83 years; male/female
6/12), sham (n=16, mean
age 42.56 years; male/female
5/11)
Intensity: 4–6 mA
Stimulation: 20 Hz of ,1 ms
30 minutes 2× daily/4 weeks
Same protocol as Fang et al52
Outcome measures
Primarily reduced scores on HAM-D (.50%)
Secondarily reduced scores on HAM-A, SAS,
and SDS
HAM-D scores reduced
Signicant interaction between
treatment and sham groups
and treatment time on all
measures
Signicant interaction on
HAM-D subscales between
tVNS and sham group
Strengths
Randomized
Single-blind
Large study
Longer duration
Sham stimulation
Limitations
Self-administered
Sham protocol
Self-record logs
Abbreviations: BDI, Beck Depression Inventory; HAM-A, Hamilton Anxiety Rating Scale; HAM-D, Hamilton Depression Rating Scale; NET, neuroelectric therapy; SAS, Self-Rating Anxiety Scale; SDS, Self-Rating Depression Scale;
TENS, transcutaneous electrical nerve stimulation; tVNS, transcutaneous (auricular) vagus nerve stimulation.
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Vagus-nerve stimulation, HIV, and depression
Rong et al39 conducted a nonrandomized study (n=160).
The study was divided into an active group (n=91) that
received tVNS for 12 weeks and a control group (n=69)
that received sham stimulation for 8 weeks followed by
4 weeks of tVNS. A total of 148 participants completed the
trial at 1 month and 138 participants at 2 months. Stimula-
tion parameters were set at 20 Hz (width of 0.2 ms), with
intensity increased gradually from 0 until tolerance threshold
was achieved (4–6 mA). As per the other studies’ protocols,
stimulation was administered twice daily for 30 minutes per
session. Depression was assessed using the HAM-D. After
1 month of treatment, there was a significant difference
between the active group and the sham group with a decrease
in scores (#50% reduction). Additionally, this improvement
was maintained at 12 weeks. Interestingly, this study explored
subgroups within the tVNS participants to determine if there
was a difference in response when comparing mild (HAM-D
score of ,20) to moderate depression. Although the effect
size was smaller, this study demonstrated a significant reduc-
tion in mild symptoms as well. No adverse side effects were
noted due to tVNS use.
Utilizing the same experimental and stimulation proce-
dures same as Rong et al39 and Lui et al,53 research from Fang
et al52 conducted a single-blind clinical trial (n=49) exploring
the neurological effects of tVNS in depression. Stimulation
occurred over a 1-month period. Resting fMRI scans were
conducted pre- and post-tVNS intervention, while depres-
sive symptomatology was assessed utilizing the HAM-D as
the primary end point. After 1 month of treatment, HAM-D
scores significantly reduced in the tVNS group when com-
pared to the sham. Moreover, the functional connectivity
between the amygdala–lateral prefrontal networks showed
a significant increase. Increases in this resting-state connec-
tivity corresponded to the HAM-D reduction in depressive
symptomatology. No significant side effects were noted due
to tVNS use.
Discussion
The purpose of this review was to examine tVNS’s potential
use in HIV-associated depression via a review of its use in the
depression population. Overall, the results of the review are
promising and support the findings of previous studies that
utilized traditional iVNS devices. Each found a significant
reduction in depressive symptoms. Furthermore, as expected,
no significant side effects occurred from utilizing the tVNS
units. In an effort to standardize stimulation parameters, each
study relied on a similar protocol developed by Hein et al38
for experimental reference and utilized similar procedures.
This effort and replication of positive results provides the
first step in developing a standardized clinical paradigm for
the use of tVNS in a clinical setting for depression. Con-
trarily, the limited stimulation parameters (see parameters in
Table 1) restrict interpretability or feasibility of use outside
those parameters. In reference to HIV-associated depression,
its utilization could require a different stimulation protocol
that has not yet been researched.
Interpretations of positive results should be approached
with caution, as there were few research studies available,
which restricts any conclusive statements about tVNS’s
efficacy. While some were adequately powered,39 other trials
were restricted to a case-study design35 or used participants
from the same cohort.52,53 Additionally, due to one instrument
being utilized as the outcome measure (HAM-D) in each of
these studies, it cannot be ruled out that this instrument is
not capturing a heterogeneous population.
Simply, contention surrounds the accuracy of HAM-D
cutoff scores for remission versus active depression. In addi-
tion, it does not include specific diagnostic information,
which is included in other depression-screening scales,
thereby providing a more general assessment of depression.
Therefore, the construct validity of the HAM-D is of concern,
due to it lacking the conceptual clarity of other available
measures. This limitation could restrict the HAM-D’s iden-
tification of depressive symptom subtypes.54 For example,
Hein et al38 found depressive symptoms remitted utilizing the
HAM-D in both the sham and control groups. A similar effect
was found in Fang et al.52 This finding could suggest that the
improvements in depression as it relates to tVNS are not as
specific in the HAM-D versus other scales; therefore, this
could affect interpretability in the context of various types
of depression (such as HIV-associated depression). Despite
these methodological limitations, the results of this review
suggest tVNS should be considered as a treatment option for
HIV-associated depression.
Limitations to this review were the restriction of review
articles to those in English. It is possible that other research
trials have been published in the non-English literature, which
could have added valuable results to this review. Consider-
ing the lack of research examining tVNS and depression in
humans, animal studies (which have to be considered with
caution) could have provided a deeper understanding of
tVNS’s potential use in HIV-associated depression.
Implications for HIV research
Based on this review, the most compelling evidence for
tVNS’s use in HIV-associated depression was found in the
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Nicholson et al
studies conducted by both Fang et al52 and Lui et al.53 Each
of these studies explored the neurological effects of tVNS
on depression via brain imaging and rating scales. The
results identified improved functional connectivity in the
default-mode network (eg, hippocampus, amygdala, medial
prefrontal cortex, and anterior cingulate), which is involved
in affect, cognition (particularly prospective memory), and
emotional regulation. This confirms previous studies in
depression that have implicated altered default-mode network
connectivity as playing a primary role in its expression. More-
over, studies have shown cytokines have a profound effect
on this network, and its sensitivity to inflammation has been
linked to depression and cognitive impairment.55
Evidence from the HIV CHARTER cohort study suggests
depressive episodes (over a lifetime) were present in approxi-
mately 50% of cases with neurocognitive impairment.56
Interestingly, in a cross-sectional study (n=111, 58 HIV+
and 53 HIV-), Thomas et al57 demonstrated diminished
functional connectivity in the default-mode network as
playing a critical role in the neurodegenerative process of
HIV or more specifically HIV-associated neurocognitive
disorder (HAND). Furthermore, they demonstrated HIV’s
disruption of connectivity in the salience and executive-
control networks that are responsible for working memory
and emotional conflict processing.
In a recent short-term study with 30 healthy adults
(15 women), Jacobs et al58 found tVNS improved associative-
memory performance when compared to a control group.
These researchers’ hypothesized that tVNS mediated stress-
related effects (eg, inflammation) on memory function via its
interaction with β-adrenergic receptors located on afferent
vagal fibers that project into the nucleus tractus solitarius.
This vagal activation stimulates the locus coeruleus to release
norepinephrine, thereby modulating cortical and subcorti-
cal network activity. The results suggest tVNS changes the
functional pathways for learning and consolidation that favor
neuroplasticity. Interestingly, functional decline in learning
efficiency and memory retrieval has increased in HIV during
the antiretroviral era.59
Bachis et al29 demonstrated BDNF’s ability to inhibit
HIV’s gp120 protein, showing an inverse relationship in
its expression. This suggests BDNF helps reduce micro-
glial and astrocyte infection in the CNS via independent
and anti-inflammatory properties. Therefore, they posited
that increased BDNF could counteract gp120’s interaction
with monocytes. Interestingly, Biggio et al60 demonstrated
long-term iVNS’s ability to increase BDNF expression in
the hippocampus and induce neuroplasticity. This effect
diminished after 3 weeks without iVNS. They concluded
that long-term BDNF promoted the survival and trophism
of new granule cells in the hippocampus, which persisted in
the presence of iVNS.
In support of this, Furmaga et al61 demonstrated iVNS
promoted increased BDNF activity via phosphorylation of
its primary receptor (TrkB). These researchers noted that
this activity provided an antidepressant effect that was
independent of those accomplished with antidepressant
medications. This mechanism suggests tVNS could aug-
ment current antidepressant medications (eg, paroxetine,
sertraline), thus providing an enhanced effect or offering
an alternative neurological pathway for treatment. Impor-
tantly, tVNS has been shown to modify proinflammatory
cytokines in murine models.62 More recently, in a healthy
sample of 20 men and women, Lerman et al63 demonstrated
tVNS’s ability to downregulate inflammatory cytokines in
the context of lipopolysaccharides (induce an inflamma-
tory response). While tVNS has not been explored in the
context of BDNF, research supports its comparability to
iVNS. This suggests that tVNS could help provide both anti-
inflammatory and antidepressant effects for HIV-associated
depression via increased BDNF activity and cytokine regula-
tion. Additionally, tVNS could possibly provide a treatment
option for HAND.
Not only are the results promising in these pilot studies
as relates to depression, but other tVNS studies have impli-
cations in conditions that comorbidly present in HIV and
depression alike. For example, Ay et al64 demonstrated in rat
models that cutaneous VNS inhibited cerebral ischemia-in-
duced immunoactivation. Furthermore, it reduced the degree
of tissue injury and functional deficiencies that resulted from
the cerebral event. The effectiveness in ischemia has implica-
tions for HIV and related cerebrovascular pathology. HIV
patients are admitted to hospitals 60% more often for stroke,
despite a reduction in overall hospitalizations in the general
population. Research suggests cerebrovascular inflammation
via chronic immunoactivation could play a critical role in
HAND.21 Likewise, Ayerbe et al65 reported a 29% prevalence
of depression up to 10 years poststroke, with a 40%–52%
cumulative incidence within 5 years. Importantly, predictors
of this depression were prestroke depression and cognitive
impairment.
Currently, no studies exist that explore tVNS as a treat-
ment option for HIV; furthermore, no infectious models exist
in nonhumans that can actually duplicate the physiological
effects HIV has on humans, which suggests the need to test
it directly in adults with HIV.66 The safety, effectiveness,
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Vagus-nerve stimulation, HIV, and depression
and tolerability of tVNS have been reviewed for sepsis, atrial
fibrillation, depression, epilepsy, migraines, and tinnitus,
which provides a strong foundation for its use in HIV. In
consideration of current knowledge and available technol-
ogy, research in HIV-associated depression is warranted
with tVNS. The potential benefits of this research are not
restricted to depression or cognitive disorders, but could also
be utilized as a buffer to comorbidities associated with HIV
(eg, stroke, metabolic disruptions, and neuropathy) or that
result as a consequence of HIV treatment.
Implications for clinicians
The safety, efficacy, and self-administration capabilities of
the tVNS units have clinical utility for clinicians. If research
determines their efficacy in the HIV population, these devices
could provide a cost-effective and safe alternative for HIV-
associated depression treatment. In an outpatient setting,
these devices can be calibrated, prescribed for use at home,
and utilized as augmenting agents to standard antidepressant
treatments or individual therapies for comorbid depression
and HIV symptomatology (eg, cognitive disorders). If effec-
tive, these devices could help reduce the polypharmacy often
faced in HIV by replacing select psychotropic medications
and select cardiovascular medications;67 moreover, they could
potentially alleviate or help control common side effects that
result from the use of these medications (eg, QRS elonga-
tion, tinnitus, headaches, metabolic disturbances, and motor
dysfunction).68–70
Disclosure
The authors report no conflicts of interest in this work.
References
1. Arseniou S, Arvaniti A, Samakouri M. HIV infection and depression.
Psychiatry Clin Neurosci. 2013;68(2):96–109.
2. Everall I, Vaida F, Khanlou N, et al. Cliniconeuropathologic correlates
of human immunodeficiency virus in the era of antiretroviral therapy.
J Neurovirol. 2009;15(5–6):360–370.
3. Nanni MG, Caruso R, Mitchell AJ, Meggiolaro E, Grassi L. Depression in
HIV infected patients: a review. Curr Psychiatry Rep. 2014;17(1):530.
4. Sherr L, Clucas C, Harding R, Sibley E, Catalan J. HIV and depres-
sion: a systematic review of interventions. Psychol Health Med. 2011;
16(5):493–527.
5. Kim YK, Na KS, Myint AM, Leonard BE. The role of pro-inflammatory
cytokines in neuroinflammation, neurogenesis and the neuroendocrine
system in major depression. Prog Neuropsychopharmacol Biol Psychia-
try. 2016;64:277–284.
6. Fields J, Dumaop W, Langford TD, Rockenstein E, Masliah E. Role
of neurotrophic factor alterations in the neurodegenerative process in
HIV associated neurocognitive disorders. J Neuroimmune Pharmacol.
2014;9(2):102–116.
7. Lotrich FE, Albusaysi S, Ferrell RE. Brain-derived neurotrophic
factor serum levels and genotype: association with depression during
interferon-α treatment. Neuropsychopharmacology. 2012;38(6):985–995.
8. Sin NL, Dimatteo MR. Depression treatment enhances adherence to
antiretroviral therapy: a meta-analysis. Ann Behav Med. 2013;47(3):
259–269.
9. Andréasson A, Arborelius L, Erlanson-Albertsson C, Lekander M. A
putative role for cytokines in the impaired appetite in depression. Brain
Behav Immun. 2007;21(2):147–152.
10. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From
inflammation to sickness and depression: when the immune system
subjugates the brain. Nat Rev Neurosci. 2008;9(1):46–56.
11. Imeri L, Opp MR. How (and why) the immune system makes us sleep.
Nat Rev Neurosci. 2009;10(3):199–210.
12. Wolff CL, Alvarado MR, Wolff RM. [Depression in HIV infection:
prevalence, risk factors and management]. Rev Chilena Infectol. 2010;
27(1):65–74. Spanish.
13. Thrivikraman K, Zejnelovic F, Bonsall RW, Owens MJ. Neuroendocrine
homeostasis after vagus nerve stimulation in rats. Psychoneuroendo-
crinology. 2013;38(7):1067–1077.
14. Bonaz B, Sinniger V, Pellissier S. Anti-inflammatory properties of the
vagus nerve: potential therapeutic implications of vagus nerve stimula-
tion. J Physiol. 2016;594(20):5781–5790.
15. Albert U, Maina G, Aguglia A, et al. Vagus nerve stimulation for
treatment-resistant mood disorders: a long-term naturalistic study. BMC
Psychiatry. 2015;15:64.
16. Bajbouj M, Merkl A, Schlaepfer TE, et al. Two-year outcome of vagus
nerve stimulation in treatment-resistant depression. J Clin Psychophar-
macol. 2010;30(3):273–281.
17. George MS, Rush AJ, Marangell LB, et al. A one-year comparison of
vagus nerve stimulation with treatment as usual for treatment-resistant
depression. Biol Psychiatry. 2005;58(5):364–373.
18. Sackheim HA, Keilp JG, Rush J, et al. The effects of vagus nerve stimula-
tion on cognitive performance in patients with treatment-resistant depres-
sion. Neuropsychiatry Neuropsychol Behav Neurol. 2001;14(1):53–62.
19. Ben-Menachem E, Revesz D, Simon BJ, Silberstein S. Surgically
implanted and non-invasive vagus nerve stimulation: a review of effi-
cacy, safety and tolerability. Eur J Neurol. 2015;22(9):1260–1268.
20. Del Guerra FB, Fonseca JL, Figueiredo VM, Ziff EB, Konkiewitz EC.
Human immunodeficiency virus-associated depression: contributions
of immuno-inflammatory, monoaminergic, neurodegenerative, and
neurotrophic pathways. J Neurovirol. 2013;19(4):314–327.
21. Hong S, Banks WA. Role of the immune system in HIV-associated neu-
roinflammation and neurocognitive implications. Brain Behav Immun.
2015;45:1–12.
22. Saylor D, Dickens AM, Sacktor N, et al. HIV-associated neurocognitive
disorder: pathogenesis and prospects for treatment. Nat Rev Neurol.
2016;12(4):234–248.
23. Rivera-Rivera Y, Vázquez-Santiago FJ, Albino E, Sánchez MD, Rivera-
Amill V. Impact of depression and inflammation on the progression of
HIV disease. J Clin Cell Immunol. 2016;7(3):423.
24. Raedler TJ. Inflammatory mechanisms in major depressive disorder.
Curr Opin Psychiatry. 2011;24(6):519–525.
25. Herz J, Kipnis J. Bugs and brain: how infection makes you feel blue.
Immunity. 2016;44(4):718–720.
26. Cuoco JA, Fennie CN, Cheriyan GK. The cholinergic anti-inflammatory
pathway: a novel paradigm for translational research in neuroimmunol-
ogy. J Neurol Neurosci. 2016;7(2):86.
27. Ballester LY, Capó-Vélez CM, García-Beltrán WF, et al. Up-regulation
of the neuronal nicotinic receptor α7 by HIV glycoprotein 120: potential
implications for HIV-associated neurocognitive disorder. J Biol Chem.
2012;287(5):3079–3086.
28. Delgado-Vélez M, Báez-Pagán CA, Gerena Y, et al. The α7-nicotinic
receptor is upregulated in immune cells from HIV-seropositive women:
consequences to the cholinergic anti-inflammatory response. Clin Transl
Immunology. 2015;4(12):e53.
29. Bachis A, Major EO, Mocchetti I. Brain-derived neurotrophic factor
inhibits human immunodeficiency virus-1/gp120-mediated cerebellar
granule cell death by preventing gp120 internalization. J Neurosci.
2003;23(13):5715–5722.
Neuropsychiatric Disease and Treatment downloaded from https://www.dovepress.com/ by 168.151.252.26 on 30-Jun-2017
For personal use only.
Powered by TCPDF (www.tcpdf.org) 1 / 1
Neuropsychiatric Disease and Treatment 2017:13
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
1688
Nicholson et al
30. Calabrese F, Rossetti AC, Racagni G, Gass P, Riva MA, Molteni R.
Brain-derived neurotrophic factor: a bridge between inflammation and
neuroplasticity. Front Cell Neurosci. 2014;8:430.
31. Gold PW. The organization of the stress system and its dysregulation
in depressive illness. Mol Psychiatry. 2014;20(1):32–47.
32. Capuron L, Pagnoni G, Drake DF, et al. Dopaminergic mechanisms of
reduced basal ganglia responses to hedonic reward during interferon
alfa administration. Arch Gen Psychiatry. 2012;69(10):1044–1053.
33. Brydon L, Harrison NA, Walker C, Steptoe A, Critchley HD. Periph-
eral inflammation is associated with altered substantia nigra activity
and psychomotor slowing in humans. Biol Psychiatry. 2008;63(11):
1022–1029.
34. Howland RH. Vagus nerve stimulation. Curr Behav Neurosci Rep. 2014;
1(2):64–73.
35. Trevizol AP, Taiar I, Barros MD, Liquidatto B, Cordeiro Q, Shiozawa P.
Transcutaneous vagus nerve stimulation (tVNS) protocol for the treat-
ment of major depressive disorder: a case study assessing the auricular
branch of the vagus nerve. Epilepsy Behav. 2015;53:166–167.
36. Ellrich J. Transcutaneous vagus nerve stimulation. Eur Neurol Rev.
2011;6(4):262–264.
37. Grimonprez A, Raedt R, Baeken C, Boon P, Vonck K. The antidepres-
sant mechanism of action of vagus nerve stimulation: evidence from
preclinical studies. Neurosci Biobehav Rev. 2015;56:26–34.
38. Hein E, Nowak M, Kiess O, et al. Auricular transcutaneous electrical
nerve stimulation in depressed patients: a randomized controlled pilot
study. J Neur Transm (Vienna). 2013;120(5):821–827.
39. Rong PJ, Fang JL, Wang LP, et al. Transcutaneous vagus nerve stimu-
lation for the treatment of depression: a study protocol for a double
blinded randomized clinical trial. BMC Complement Altern Med.
2012;12:255.
40. Berry SM, Broglio K, Bunker M, Jayewardene A, Olin B, Rush AJ.
A patient-level meta-analysis of studies evaluating vagus nerve stimula-
tion therapy for treatment-resistant depression. Med Devices (Auckl).
2013;6:17–35.
41. Cimpianu CL, Strube W, Falkai P, Palm U, Hasan A. Vagus nerve
stimulation in psychiatry: a systematic review of the available evidence.
J Neural Transm (Vienna). 2016;124(1):145–158.
42. Martin J, Martín-Sánchez E. Systematic review and meta-analysis of
vagus nerve stimulation in the treatment of depression: variable results
based on study designs. Eur Psychiatry. 2012;27(3):147–155.
43. Cleare A, Pariante C, Young A, et al. Evidence-based guidelines for
treating depressive disorders with antidepressants: a revision of the
2008 British Association for Psychopharmacology guidelines. J Psy-
chopharmacol. 2015;29(5):459–525.
44. National Institute for Health and Care Excellence. Vagus Nerve Stimula-
tion for Treatment-Resistant Depression. London: NICE; 2009.
45. Milev RV, Giacobbe P, Kennedy SH, et al. Canadian network for
mood and anxiety treatments (CANMAT) 2016 clinical guidelines for
the management of adults with major depressive disorder – section 4:
neurostimulation treatments. Can J Psychiatry. 2016;61(9):561–575.
46. Rush AJ, Marangell LB, Sackeim HA, et al. Vagus nerve stimulation
for treatment-resistant depression: a randomized, controlled acute phase
trial. Biol Psychiatry. 2005;58(5):347–354.
47. Rush AJ, Sackeim HA, Marangell LB, et al. Effects of 12 months of
vagus nerve stimulation in treatment-resistant depression: a naturalistic
study. Biol Psychiatry. 2005;58(5):355–363.
48. Sackeim HA, Brannan SK, Rush AJ, George MS, Marangell LB, Allen J.
Durability of antidepressant response to vagus nerve stimulation (VNS).
Int J Neuropsychopharmacol. 2007;10(6):817–826.
49. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items
for systematic reviews and meta-analyses: the PRISMA statement.
PLoS Med. 2009;6(7):e1000097.
50. Kraus T, Hösl K, Kiess O, Schanze A, Kornhuber J, Forster C. BOLD
fMRI deactivation of limbic and temporal brain structures and mood
enhancing effect by transcutaneous vagus nerve stimulation. J Neural
Transm (Vienna). 2007;114(11):1485–1493.
51. Trevizol AP, Shiozawa P, Taiar I, et al. Transcutaneous vagus nerve
stimulation (taVNS) for major depressive disorder: an open label proof-
of-concept trial. Brain Stimul. 2016;9(3):453–454.
52. Fang J, Rong P, Hong Y, et al. Transcutaneous vagus nerve stimula-
tion modulates default mode network in major depressive disorder.
Biol Psychiatry. 2016;79(4):266–273.
53. Liu J, Fang J, Wang Z, et al. Transcutaneous vagus nerve stimulation
modulates amygdala functional connectivity in patients with depression.
J Affect Disord. 2016;205:319–326.
54. Möller HJ. Standardized rating scales in psychiatry: methodological
basis, their possibilities and limitations and descriptions of important
rating scales. World J Biol Psychiatry. 2009;10(1):6–26.
55. Marsland AL, Kuan DC, Sheu LK, et al. Systemic inflammation and
resting state connectivity of the default mode network. Brain Behav
Immun. 2017;62:162–170.
56. Heaton RK, Clifford DB, Franklin DR, et al. HIV-associated neu-
rocognitive disorders persist in the era of potent antiretroviral therapy:
CHARTER study. Neurology. 2010;75(23):2087–2096.
57. Thomas JB, Brier MR, Snyder AZ, Vaida FF, Ances BM. Pathways to
neurodegeneration: effects of HIV and aging on resting-state functional
connectivity. Neurology. 2013;80(13):1186–1193.
58. Jacobs HI, Riphagen JM, Razat CM, Wiese S, Sack AT. Transcutaneous
vagus nerve stimulation boosts associative memory in older individuals.
Neurobiol Aging. 2015;36(5):1860–1867.
59. Cohen RA, Seider TR, Navia B. HIV effects on age-associated neu-
rocognitive dysfunction: premature cognitive aging or neurodegenera-
tive disease? Alzheimers Res Ther. 2015;7(1):37.
60. Biggio F, Gorini G, Utzeri C, et al. Chronic vagus nerve stimulation
induces neuronal plasticity in the rat hippocampus. Int J Neuropsychop-
harmacol. 2009;12(9):1209–1221.
61. Furmaga H, Carreno FR, Frazer A. Vagal nerve stimulation rapidly
activates brain-derived neurotrophic factor receptor TrkB in rat brain.
PLoS One. 2012;7(5):e34844.
62. Huston JM, Gallowitsch-Puerta M, Ochani M, et al. Transcutaneous
vagus nerve stimulation reduces serum high mobility group box 1
levels and improves survival in murine sepsis. Crit Care Med. 2007;
35(12):2762–2768.
63. Lerman I, Hauger R, Sorkin L, et al. Noninvasive transcutaneous vagus
nerve stimulation decreases whole blood culture-derived cytokines
and chemokines: a randomized, blinded, healthy control pilot trial.
Neuromodulation. 2016;19(3):283–290.
64. Ay I, Nasser R, Simon B, Ay H. Transcutaneous cervical vagus nerve
stimulation ameliorates acute ischemic injury in rats. Brain Stimul.
2016;9(2):166–173.
65. Ayerbe L, Ayis S, Wolfe CD, Rudd AG. Natural history, predictors
and outcomes of depression after stroke: systematic review and meta-
analysis. Br J Psychiatry. 2013;202(1):14–21.
66. Hatziioannou T, Evans DT. Animal models for HIV/AIDS research.
Nat Rev Microbiol. 2012;10(12):852–867.
67. Tseng A, Szadkowski L, Walmsley S, Salit I, Raboud J. Association
of age with polypharmacy and risk of drug interactions with anti-
retroviral medications in HIV-positive patients. Ann Pharmacother.
2013;47(11):1429–1439.
68. Bet PM, Hugtenburg JG, Penninx BW, Hoogendijk WJ. Side effects
of antidepressants during long-term use in a naturalistic setting. Eur
Neuropsychopharmacol. 2013;23(11):1443–1451.
69. Casaretti L, Paolillo S, Formisano R, et al. [Metabolic and cardiovascu-
lar effects of combined antiretroviral therapy in patients with HIV infec-
tion: systematic review of literature]. Monaldi Arch Chest Dis. 2015;
76(4):175–182. Italian.
70. Jernigan MG, Kipp GM, Rather A, Jenkins MT, Chung AM. Clinical
implications and management of drug-drug interactions between anti-
retroviral agents and psychotropic medications. Ment Health Clin. 2013;
2(9):274–285.
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    Brain and viscera interplay within the autonomic nervous system where the vagus nerve (VN), containing approximately 80% afferent and 20% efferent fibres, plays multiple key roles in the homeostatic regulations of visceral functions. Recent data has suggested the anti-inflammatory role of the VN. This vagal function is mediated through several pathways, some of them still debated. The first one is the anti-inflammatory hypothalamic-pituitary adrenal axis which is stimulated by vagal afferent fibres and leads to the release of cortisol by the adrenal glands. The second one, called the cholinergic anti-inflammatory pathway, is mediated through vagal efferent fibres that synapse onto enteric neurons which release acetylcholine (ACh) at the synaptic junction with macrophages. ACh binds to α-7-nicotinic ACh receptors of those macrophages to inhibit the release of tumour necrosis (TNF)α, a pro-inflammatory cytokine. The last pathway is the splenic sympathetic anti-inflammatory pathway, where the VN stimulates the splenic sympathetic nerve. Norepinephrine released at the distal end of the splenic nerve links to the β2 adrenergic receptor of splenic lymphocytes that release ACh. Finally Ach inhibits the release of TNFα by spleen macrophages through α-7-nicotinic ACh receptors. Understanding of these pathways is interesting from a therapeutic point of view, since they could be targeted in various ways to stimulate anti-inflammatory regulation in TNFα related diseases such as inflammatory bowel disease and rheumatoid arthritis. Among others, VN stimulation, either as an invasive or non-invasive procedure, is becoming increasingly frequent and several clinical trials are ongoing to evaluate the potential effectiveness of this therapy to alleviate chronic inflammation. This article is protected by copyright. All rights reserved.
  • Article
    Objectives: The purpose of this study was to test the transcutaneous noninvasive vagus nerve stimulator (nVNS) (gammaCore©) device to determine if it modulates the peripheral immune system, as has been previously published for implanted vagus nerve stimulators. Materials and methods: A total of 20 healthy males and females were randomized to receive either nVNS or sham stimulation (SST). All subjects underwent an initial blood draw at 8:00 am, followed by stimulation with nVNS or SST at 8:30 am. Stimulation was repeated at 12:00 pm and 6:00 pm. Additional blood samples were withdrawn 90 min and 24 hour after the first stimulation session. After samples were cultured using the Myriad RBM TruCulture (Austin, TX) system (WBCx), levels of cytokines and chemokines were measured by the Luminex assay and statistical analyses within and between groups were performed using the Wilcoxon Signed Ranks Test and Mann-Whitney U with the statistical program R. Results: A significant percent decrease in the levels of the cytokine interleukin [IL]-1β, tumor necrosis factor [TNF] levels, and chemokine, interleukin [IL]-8 IL-8, macrophage inflammatory protein [MIP]-1α, and monocyte chemoattractant protein [MCP]-1 levels was observed in the nVNS group non-lipopolysaccharide (LPS)-stimulated whole blood culture (n-WBCx) at the 24-hour time point (p < 0.05). In SST group, there was a significant percent increase in IL-8 at 90 min post-stimulation (p < 0.05). At 90 min, the nVNS group had a greater percent decrease in IL-8 concentration (p < 0.05) compared to SST group. The nVNS group had a greater percent decrease in cytokines (TNF, IL-1β) and chemokines (MCP-1 and IL-8) at 24 hour (p < 0.05) in comparison to SST. LPS-stimulated whole blood cultures (L-WBCx) did not show a significant decrease in cytokine levels in either the nVNS or SST group across any time points. The nVNS group showed a significant percent increase in LPS-stimulated IL-10 levels at the 24-hour time point in comparison to SST. Conclusions: nVNS downregulates inflammatory cytokine release suggesting that nVNS may be an effective anti-inflammatory treatment.