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332 The APA Publishing Textbook of Mood Disorders, Second Edition
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CHAPTER 20
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Vagus Nerve Stimulation
and Deep Brain
Stimulation
Dora M. Meyer, M.Sc.
Hannah M. Kilian, M.Sc.
Thomas E. Schlaepfer, M.D.
One might ask why electrical stimulation of the brain should be beneficial
for patients with psychiatric disorders. Well, the answer is simple: Because neurons
in our brains communicate through electrochemical processes (e.g. action potentials)
(Galluccio et al. 2011; Hodgkin and Huxley 1952). So why not use “the language of
the body’s nervous system” (Famm et al. 2013, p. 159) for its treatment? Major depressive disorder (MDD) is still not completely understood; however, the following features have been consistently reported and have led to the understanding of MDD as
a brain-based disorder: dysfunctional neural circuits, decrements in neurotrophic fac
tors, dysfunctions in the hypothalamic-pituitary-adrenal axis, and alterations in gene
function (Krishnan and Nestler 2008). New insights into the pathophysiology of
depression, especially the hypothesis of a neural circuit of mood, have promoted the
field of brain stimulation therapies (noninvasive as well as invasive) in psychiatric
disorders (Berton and Nestler 2006). In this chapter, we focus on two invasive brain
stimulation techniques, each of which uses a system consisting of a pulse-generator
implanted subcutaneously and electrodes stimulating specific targets: 1) the vagus
nerve, for vagus nerve stimulation (VNS) and 2) selected brain targets, for deep brain
stimulation (DBS).
Both of these treatment methods are reserved for patients with treatment-resistant
depression (TRD)—that is, patients who have not responded, or have not sufficiently
responded, to conventional antidepressant treatments such as psychotherapy and
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psychopharmaceuticals. Clinical and biological risk factors for TRD have been reviewed (Bennabi et al. 2015), and differences in the etiology and biology of TRD in
comparison with treatment-responsive MDD have been investigated (Dunlop et al.
2017; McGrath et al. 2014). The heterogeneity of the biology of treatment resistance
prompts the question of whether there might be predictors of response and personalized approaches to treatment (Bewernick et al. 2017a). Estimates of the proportion of
patients with TRD have varied from 12% to 33% (Cepeda et al. 2018; Fife et al. 2017;
Mahlich et al. 2018; Rush et al. 2006), depending on the study and the definition of
TRD applied. This range indicates an urgent need for the development and clinical
testing of additional treatment methods such as VNS and DBS.
Vagus Nerve Stimulation
VNS is an invasive treatment alternative approved in the United States by the FDA
for the treatment of pharmacoresistant epilepsy since 1997. VNS has been approved
since 2005 for patients whose TRD has not responded to four or more adequate antidepressant treatment trials (Daban et al. 2008). VNS for TRD can only be applied as
an adjunctive treatment option to treatment as usual (TAU). The scientific use of TAU
describes any concomitant treatment strategy, including antidepressant medication
and nonpharmacological treatments (Berry et al. 2013). To date, more than 80,000 patients with pharmacoresistant epilepsy and more than 4,100 patients with TRD have
received VNS (personal communication, LivaNova, August 22, 2019).
The VNS system consists of a small pulse generator implanted subcutaneously in
the chest, a bipolar electrode that is partially wrapped around the left vagus nerve,
and a lead that connects the electrode and the generator (Figure 20–1). The electrode
delivers low-frequency, long-term intermittent electrical signals to the vagus nerve.
Stimulation parameters can be adapted noninvasively by the clinician using a tele
metric wand (Nemeroff et al. 2006). The therapeutic range of stimulation intensity is
defined as between 1 mA and 2 mA, as tolerated by the patient, with a frequency of
20 Hz, a pulse width of 250 μs, and a duty cycle (on and off time of intermittent signals) that can be adapted every 3 to 6 months (LivaNova 2020).
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Physiology and Neuroanatomy of the Vagus Nerve
The vagus nerve is one of the 12 cranial nerves (cranial nerve X) regulating the body’s
automatic functions with efferent and afferent fibers projecting from the periphery to
the nucleus spinalis nervi trigemini. Approximately 80% of the fibers are afferent fibers
carrying sensory information to the brain. The left vagus nerve terminates in the medulla and innervates the nucleus tractus solitarius bilaterally. The nucleus tractus solitarius has projections to several other brain regions, such as the parabrachial nucleus,
the cerebellum, the dorsal raphe nucleus, the periaqueductal gray, and the locus coeruleus. Secondary projections lead to limbic, paralimbic, and cortical regions (e.g.,
thalamus, hypothalamus, amygdala, insula, infralimbic cortex, bed nucleus of stria
terminalis). These brain regions are partially associated with the regulation of mood
and emotion, seizure activity, and pain perception (Henry 2002; Nemeroff et al. 2006).
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FIGURE 20–1. Vagus nerve stimulation therapy system consisting of a generator, a lead,
and the electrode.
To view this figure in color, see Plate 6 in Color Gallery in middle of book.
Source. Image courtesy of LivaNova USA, Inc. (“LivaNova”), August 22, 2019. Copyright © 2018, LivaNova. Used with permission.
State of the Art
Vagus Nerve Stimulation in Epilepsy
Anticonvulsant effects of VNS have been shown in patients with pharmacoresistant
epilepsy (i.e., at least six partial-onset seizures despite antiepileptic treatment). The
first pilot trials were conducted in 1990, followed by double-blind, placebo-controlled
trials, paving the way for approval of VNS in epilepsy (Ben-Menachem 2002). Two
randomized controlled trials (RCTs) comparing active/high (30 seconds of VNS every
5 minutes) with sham or low stimulation (30 seconds of VNS every 180 minutes) re
ported a higher reduction in seizure frequency for the active group (24.5%–28% decrease) compared with the sham stimulation group (6.1%–15% decrease) 3 months after
VNS commencement (Ben-Menachem et al. 1994; Handforth et al. 1998). Response
rates with a seizure reduction of greater than 50% increased with the duration of longterm VNS, resulting in a response rate of 43% after 2 years (Ben-Menachem 2002). Altogether, VNS is associated with a sustained level of seizure reduction lasting up to
5 years and is well tolerated by patients (Englot et al. 2011; Nemeroff et al. 2006).
Independent of the anticonvulsant effects of VNS, mood improvements also have
been reported (Elger et al. 2000; Harden et al. 2000). These observations supported the
idea of an antidepressant-like effect of VNS. Imaging studies followed, demonstrat-
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ing that VNS alters activity in brain regions associated with mood regulation. Together with the apparent biological plausibility, the evidence of antidepressant-like
effects of VNS in animal models, and the fact that anticonvulsants and electroconvul
sive therapy (ECT) are effective in depression, a rationale for studying VNS in TRD
was established (Nemeroff et al. 2006). Since then, comprehensive studies have inves
tigated the antidepressant efficacy of VNS in TRD.
Vagus Nerve Stimulation in Depression
Mode of action. Studies using single photon emission computed tomography
(SPECT) to analyze regional cerebral blood flow (CBF) reported an increase in the left
dorsolateral prefrontal cortex (DLPFC) 4 weeks (Zobel et al. 2005) and 10 weeks (Ko
sel et al. 2011) after VNS onset. Both studies also demonstrated decreases in the right
posterior cingulate area. Another study investigating CBF through PET imaging
demonstrated increased metabolic activity in the orbitofrontal cortex (OFC), bilateral
anterior cingulate cortex, and right superior and medial frontal cortex 3 months after
VNS onset, as well as decreases in the bilateral temporal cortex and right parietal area
(Conway et al. 2006). Immediate effects (20 hours after VNS onset) of CBF changes in
patients with epilepsy showed similarly increased activity in the OFC and frontal gy
rus (Henry et al. 2004). Nonetheless, other studies could not replicate these findings
and reported contradictory results demonstrating significant decreases in activity in
the OFC (Conway et al. 2012) and the left DLPFC (Conway et al. 2013).
Longer-term studies investigating CBF changes 1 year after VNS onset also reported inconsistent results. DLPFC activity returned to near-baseline levels (Conway
et al. 2013), whereas activity in the ventromedial prefrontal cortex continued to decline
gradually over time (Pardo et al. 2008). Another methodological approach to addressing those questions is represented in functional MRI studies. Those studies reported
findings that reveal changes in the medial temporal, prefrontal, and limbic structures
(Nahas et al. 2007; Nemeroff et al. 2006). Furthermore, two functional MRI studies investigated the influence of different parameter settings on brain activity and demonstrated frequency- and dose-dependent modulatory effects (Lomarev et al. 2002; Mu
et al. 2004).
Due to the inconsistencies of study results, the mechanisms of action of VNS remain unclear. Nonetheless, VNS seems to have effects on brain function and to resolve classic brain abnormalities associated with depression. Metabolic changes occur
early after VNS onset and might mediate or support the clinical improvement (Daban
et al. 2008). Gradual brain adaptations following long-term VNS might be necessary
for subsequent brain stem changes and are associated with the late, then sustained,
therapeutic effect (Conway et al. 2013). Thus, VNS can be regarded as the “bottomup” approach to brain stimulation.
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Clinical evidence. Despite the approval of VNS for TRD, only a small number of
RCTs have investigated its efficacy in a double-blind, sham-controlled design. Unfortunately, the first RCT (D-02) showed no significant difference in the response rates
between sham and active VNS in an acute trial of 10 weeks (Rush et al. 2005). Another
RCT (D-21) compared different stimulation intensities with a double-blind random
assignment of patients to a low-, medium-, or high-stimulation group over 22 weeks
and also did not report any significant group differences (Aaronson et al. 2013).
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In general, uncontrolled studies investigating the short-term efficacy (≤12 weeks)
of VNS in TRD show heterogeneous findings (Berry et al. 2013; Daban et al. 2008). In
the first uncontrolled pilot trial (D-01), the first data in 30 patients showed a 40% re
sponse rate (Rush et al. 2000), whereas the enlarged trial with 59 patients reported a
smaller response rate of 30.5% (Sackeim et al. 2001). These findings were replicated
by Schlaepfer et al. (2008b), demonstrating a response rate of 36% (D-03). Extended
studies with follow-up visits at 12 and 24 months showed increased response rates of
40%–55% and high compliance (Bajbouj et al. 2010; Nahas et al. 2005; Schlaepfer et al.
2008b). More recently, an observational study with a long-term follow-up ≤5 years af
ter VNS implantation (D-23) reported a response rate of 67.6% (Aaronson et al. 2017).
This result is promising due to the large sample size (N=795), although the reported
results represent the cumulative response, constituting the accumulation of patients
that responded at any postbaseline visit.
Despite heterogeneous results and the fact that RCT trials and postmarketing observational studies are lacking, the importance of additional treatments for patients
with TRD is supported by studies that compared patients who received VNS plus
TAU with patients who received TAU only. The D-04 study reported response rates of
5.8%, 11.6%, and 18.4% after 3, 12, and 24 months, respectively, for patients treated
with TAU only (Dunner et al. 2006). The cumulative response rate of this group over
60 months was 40.9%, compared with 67.7% for the VNS-plus-TAU group (P<0.001)
(Aaronson et al. 2017). Taken together, the VNS-plus-TAU group showed a greater
likelihood of first-time response (three times as likely as that for patients who received TAU) and higher sustained response rates, demonstrating the superiority of
adjunctive VNS (Berry et al. 2013; George et al. 2005).
Summarizing the published data to date, VNS is associated with a slowly growing
but then sustained antidepressant efficacy (Berry et al. 2013; Sackeim et al. 2007). It
has been noted critically that the positive long-term effects could be a result of the natural disease course and be mediated by placebo effects, regression toward the mean,
spontaneous remission, or the Hawthorne effect (Martin and Martín-Sánchez 2012).
However, this seems rather unlikely considering the maintenance of benefit seen in
the VNS-plus-TAU group compared with the generally high propensity for relapse
seen among TRD patients without additional VNS treatment (Rush et al. 2006;
Sackeim et al. 2007). Patients who received VNS plus TAU had undergone more unsuccessful trials of ECT and of multiple drug treatment classes prior to receiving VNS
and had experienced more lifetime depression-related hospitalizations compared
with patients who received TAU only (Berry et al. 2013). Therefore, the benefit of VNS
plus TAU for patients with chronic TRD is indisputable, and this treatment represents
a promising option for patients whose illness has been classified as treatment resistant. The term treatment resistant seems rather inappropriate, given the high response
rates in the VNS-plus-TAU group as well as in the TAU-only group; these findings
suggest that depression classified as resistant to previous treatments can respond to
further treatment options and is not totally resistant to every future trial.
Given the data so far, VNS is very unlikely to replace ECT. Compared with VNS,
ECT serves as an effective acute episodic treatment option, albeit with high relapse
rates of 94% within 6 months (Berry et al. 2013). VNS can be implemented as an option for the maintenance of ECT treatment, because repetitive ECT sessions have been
associated with deleterious cognitive effects and nontolerance of anesthesia (Daban
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et al. 2008; Nemeroff et al. 2006). Additionally, patients who responded to ECT previously had a higher cumulative VNS response rate than those who did not respond to
ECT, supporting the idea of ECT response as predictor for VNS response (Aaronson
et al. 2017). However, VNS appears to be more efficient in patients with low to mod
erate but not extreme antidepressant resistance, and patients who had never received
ECT were 3.9 times more likely to respond to VNS (Daban et al. 2008).
Overall, predictors of response have not been well examined. Yet one of the first
symptoms to be ameliorated following onset of VNS concerns sleep disturbances. Im
provement of sleep architecture may be predictive of an antidepressant effect and
should be investigated in detail in future studies (Armitage et al. 2003).
In conclusion, the first studies may have been underdosed, considering the current
recommendations of stimulation intensities greater than 1 mA (Daban et al. 2008), and
RCTs with a double-blind, sham-controlled design are difficult to create due to com
mon adverse events associated with VNS—mainly voice alterations and increased
cough (Martin and Martín-Sánchez 2012; Schlaepfer et al. 2008b). Long-term natural
istic observational studies are urgently needed for a better evaluation of the antidepressant efficacy of VNS. Also, it is questionable that VNS has not found an uptake in
general treatment and that reimbursement for the psychiatric use of VNS is lacking.
The current RESTORE-LIFE study (ClinicalTrials.gov Identifier NCT03320304) may
help address those questions.
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Deep Brain Stimulation
DBS involves a permanent or intermittent electrical stimulation of a specific brain area.
In a stereotactic surgical procedure, electrodes are implanted permanently in previ
ously defined target areas. A transcutaneously programmable pulse generator, placed
subcutaneously in the clavicular region, sends electric impulses to these electrodes
(Figure 20–2). Typical parameter settings are frequencies between 90 Hz and 130 Hz,
pulse widths of about 90 μs, and voltages between 4 V and 8 V (Schlaepfer and Bewer
nick 2013). Compared with ablative neurosurgical interventions, DBS is less invasive
and mostly reversible, and its features are adjustable, allowing clinicians to maximize
treatment benefit and minimize adverse events individually, as well as allowing
sham-controlled hypothesis testing (Lozano et al. 2019; Schlaepfer et al. 2014).
History
Although the first attempts at electric brain stimulation and recording via intracerebral implantation of electrodes for psychiatric treatment purposes were made in the
1950s (Hariz et al. 2010), it was several decades later that a Grenoble group established
modern DBS by introducing permanent electrical stimulation as an addition to thalamotomy for the treatment of extrapyramidal movement disorders in 1987 (Benabid et
al. 1987). By 1994, the first patient with Parkinson’s disease had been treated with DBS
solely, resulting in an immense tremor reduction (Benabid et al. 1994). Since then, DBS
has become a standard treatment for movement disorders, especially Parkinson’s disease, and more than 150,000 patients have been treated with DBS (Medtronic 2017).
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FIGURE 20–2. Schematic structure of a deep brain stimulation system.
To view this figure in color, see Plate 7 in Color Gallery in middle of book.
Source. Dora Meyer, 2021.
In Germany alone, about 800 new implantations have been counted annually since
2014, with a peak of about 1,000 in 2019 (Gemeinsamer-Bundesausschus 2021).
In 1999, DBS was successfully used for treatment of a psychiatric disorder, obsessive-compulsive disorder (OCD), for the first time (Nuttin et al. 1999). In an attempt
to replace irreversible capsulotomy with DBS, the authors chose to stimulate the anterior limb of the internal capsule (ALIC), a target that had been used for capsulotomy
previously. Inspired by their promising results, several research groups followed and
demonstrated that electrical stimulation of different brain targets is associated with a
remarkable reduction of obsessive and compulsive symptoms (Borders et al. 2018).
Besides the subthalamic nucleus and nucleus accumbens, which have been proven effective in RCTs (Denys et al. 2010; Mallet et al. 2008), the superolateral branch of the
medial forebrain bundle seems to be a promising new target in DBS for OCD (Coenen
et al. 2017; Meyer et al. 2019), although RCTs are still pending. DBS for treatment-
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