Serial Vagus Nerve Stimulation Functional MRI in
Ziad Nahas*,1,2, Charlotte Teneback1, Jeong-Ho Chae1,3, Qiwen Mu1, Chris Molnar1, Frank A Kozel1,
John Walker2, Berry Anderson1, Jejo Koola1, Samet Kose1, Mikhail Lomarev1,2,4, Daryl E Bohning2and
Mark S George1,2,5
1Department of Psychiatry, Brain Stimulation Laboratory, Mood Disorders Program, Institute of Psychiatry, Charleston, SC, USA;2Department of
Radiology, Radiology and Center for Advanced Imaging Research, Medical University of South Carolina, Charleston, SC, USA;3Department of
Psychiatry, Catholic University, Seoul, South Korea;4National Institute of Neurological Disorders (NINDS), Bethesda, MD, USA;5Department of
Psychiatry, Ralph H. Johnson VA Medical Center, Charleston, SC, USA
Vagus nerve stimulation (VNS) therapy has shown antidepressant effects in open acute and long-term studies of treatment-resistant
major depression. Mechanisms of action are not fully understood, although clinical data suggest slower onset therapeutic benefit than
conventional psychotropic interventions. We set out to map brain systems activated by VNS and to identify serial brain functional
correlates of antidepressant treatment and symptomatic response. Nine adults, satisfying DSM-IV criteria for unipolar or bipolar disorder,
severe depressed type, were implanted with adjunctive VNS therapy (MRI-compatible technique) and enrolled in a 3-month, double-
blind, placebo-controlled, serial-interleaved VNS/functional MRI (fMRI) study and open 20-month follow-up. A multiple regression mixed
model with blood oxygenation level dependent (BOLD) signal as the dependent variable revealed that over time, VNS therapy was
associated with ventro-medial prefrontal cortex deactivation. Controlling for other variables, acute VNS produced greater right insula
activation among the participants with a greater degree of depression. These results suggest that similar to other antidepressant
treatments, BOLD deactivation in the ventro-medial prefrontal cortex correlates with the antidepressant response to VNS therapy. The
increased acute VNS insula effects among actively depressed participants may also account for the lower dosing observed in VNS clinical
trials of depression compared with epilepsy. Future interleaved VNS/fMRI studies to confirm these findings and further clarify the regional
neurobiological effects of VNS.
Neuropsychopharmacology advance online publication, 3 January 2007; doi:10.1038/sj.npp.1301288
Keywords: vagus nerve stimulation; fMRI; depression; antidepressant
Depression is a major public health problem. Approxi-
mately, 60% of patients treated with antidepressants do not
achieve remission (O’Reardon and Amsterdam, 1998;
Fagiolini and Kupfer, 2003). Neuroimaging studies have
described the correlates of therapeutic interventions in an
effort to better understand the neurobiological character-
istics associated with clinical response. Although this area is
relatively new and findings differ, many studies suggest that
limbic and frontal brain regions change over time during
successful treatment of depression regardless of the therapy.
Such changes have been found with sleep deprivation (Wu
and Bunney, 1990; Ebert et al, 1991, 1994; Wu et al, 1992),
medications (Buchsbaum et al, 1997; Mayberg et al, 2000;
Nobler et al, 2000; Drevets et al, 2002), placebo (Kleinsch-
midt et al, 1999), electroconvulsive therapy (ECT) (Nobler
et al, 2001), transcranial magnetic stimulation (TMS)
(Teneback et al, 1999; Nahas et al, 2001b), deep brain
stimulation (DBS) (Mayberg et al, 2005), cognitive beha-
vioral therapy (Goldapple et al, 2004), or interpersonal
therapy (Brody et al, 2001).
Vagus nerve stimulation (VNS) is approved by the US
Food and Drug Administration (FDA) to treat refractory
partial-onset seizures and, more recently, treatment-resis-
tant depression. Antidepressant VNS effects were initially
found in an open acute study (Rush et al, 2000; Sackeim
et al, 2001) and long-term follow-up (Marangell et al, 2002;
Nahas et al, 2005). Despite lack of a significant effect greater
than placebo in a double-blind acute study (Rush et al,
2005a), of which this study was a part, the naturalistic 1- or
2-year follow-up study of adjunctive VNS therapy in two
independent cohorts (D01 (Nahas et al, 2005) and D02
Received 2 January 2006; revised 19 October 2006; accepted 24
Portions of this work were presented at the annual meeting of the
American College of Neuropsychopharmacology, San Juan, Puerto
Rico, December 2004.
*Correspondence: Dr Z Nahas, Brain Stimulation Laboratory, Mood
Disorders Program, Institute of Psychiatry, 67 President Street, Room
502 North, Charleston, SC 29403, USA, Tel: +1 843 792 5710,
Fax: +1 843 792 5702, E-mail: email@example.com
Neuropsychopharmacology (2007), 1–12
& 2007 Nature Publishing Group All rights reserved 0893-133X/07 $30.00
(George et al, 2005; Rush et al, 2005b)) showed the
antidepressant response increasing over time with initial
improvements largely sustained. Long-term results showed
delayed and consistent improvement with substantially
lesser relapse rates than other studies of similarly treat-
ment-resistant subjects (Prudic et al, 2004). The mechan-
isms of action underlying these intriguing VNS response
patterns remain unexplained.
Chae et al (2003) reviewed single photon emission
computed tomography (SPECT) (Ring et al, 2000; Vonck
et al, 2000; Van Laere et al, 2002; Barnes et al, 2003) and
positron emission tomography (Garnett et al, 1992; Ko et al,
1996; Henry et al, 1998, 1999) investigating the acute and/or
chronic effects of VNS for epilepsy and depression. A recent
SPECT study suggested that 4 weeks of active VNS therapy
in depression is associated with decreased activity in
hippocampus and amygdala and increased activity in left
prefrontal cortex (Zobel et al, 2005). Researchers have also
used functional MRI (fMRI) to investigate VNS in epilepsy
(Narayanan et al, 2002; Sucholeiki et al, 2002; Liu et al,
2003) and depression (Maniker et al, 2000; Bohning et al,
2001; Lomarev et al, 2002; Mu et al, 2004). Initial studies of
depressed participants showed the feasibility of performing
VNS-synchronized fMRI studies and compared the location
and amount of blood oxygenation level dependent (BOLD)
signal change caused by acute VNS for 7s with the period
when the device was not firing (Bohning et al, 2001). At
least five adjustable parameters likely contribute to the
immediate- and longer-term effects of VNS: intensity,
frequency, pulse width, ‘on’ time, and ‘off’ time. Recent
fMRI studies have demonstrated that the frequency
(Lomarev et al, 2002) and pulse width(Mu et al, 2004) of
VNS delivered to depressed adults produces dose-depen-
dent modulatory effects on acute brain activity (eg, less than
a minute). Little is known, however, about neurobiological
effects of VNS over time beyond a period of 3 months
(Henry et al, 2004) and dynamic regional brain activity
changes that may correlate with depressive symptoms’
severity. We used interleaved VNS/fMRI to serially scan
depressed participants in a VNS clinical trial investigating
how VNS parameters affect global and regional brain
activity as a function of disease severity and time (Harrison
et al, 2003).
This study investigated the effects of adjunctive VNS on
BOLD response over time among participants at the
Medical University of South Carolina (MUSC) in a
double-blind acute and open long-term follow-up clinical
trial (D-02) for treatment-resistant depression (Rush et al,
2005a). Participants had not responded adequately to at
least 2, but not more than 6, research-qualified medication
trials of different antidepressant classes. All VNS-implanted
outpatients enrolled at MUSC (n¼18) were approached
for this serial VNS/fMRI study; one declined because of
claustrophobia. All 17 others with either non-psychotic
major depressive disorder (n¼14) or non-psychotic,
depressed-phase bipolar disorder (n¼3) gave written
informed consent approved by the Institutional Review
Board for Human Research.
All scanning sessions coincided with scheduled D-02
clinical trial protocol visits. Before the MRI scans on the
same day, raters blinded to VNS active/placebo assignment
conducted assessments, including the Number of Failed
Antidepressants in current depressive episode (NFAD) at
baseline according to the Antidepressant Treatment History
Form (Sackeim, 2001) and the 24-item Hamilton Depression
Rating Scale (HRSD24) (Hamilton, 1967), the primary
clinical efficacy outcome for acute (Rush et al, 2005a) and
long-term follow-up (Rush et al, 2005b). The reliability of
the placebo condition was high as described by Rush et al
(2005a,b) despite a lack of physical sensation (Table 1).
Experimental Design and Procedure
The VNS/fMRI study was initiated simultaneously with
clinical randomization of the D-02 trial. To allow for
recovery from surgery, VNS was initiated 2 weeks after
implantation of the MRI-compatible device (Cyberonics,
Houston, TX) (Bohning et al, 2001). The VNS study
involved two phases, the 10-week, randomized, controlled,
masked trial during which concomitant medications were
stable and participants were scanned three times: rando-
mization and initial exposure to VNS (baseline); 2 weeks
after VNS intensity adjustment (Bweek 2); and 8 weeks
later (Bweek 10). The second phase was an open-label
follow-up study with scans at week 13, Bweek 20), then
quarterly (see study design in Figure 1).
In the MRI suite, and before participants entered the
scanner, the unblinded VNS programmer for the clinical
study (see Rush et al (2005a)) changed each subjects’ VNS
parameters from their ongoing settings to adapt to the
imaging block design paradigm (pulse width 500ms, pulse
frequency 20Hz, and duty cycle of 13.6s ‘on’ (including
3.3s ramp-up and 3.3s ramp-down and 41s ‘off’). These
settings were held constant throughout the imaging, about
1h. The output current was maintained at the same level as
the participant had been receiving except for the scan at
baseline when the output current was set to a ‘tolerable’
level or 0mA for those randomized to placebo.
Before and after each functional scan, the VNS generator
signal was checked, which allowed synchronization of the
fMRI scanning cycle with the VNS generator cycle (for a
detailed method refer to Bohning et al (2001)).
All MRI scanning was performed using a 1.5T clinical
MRI scanner with a send-receive head coil (Intera, Philips
Medical Systems, Bothell, WA, USA). A survey scan
ascertained head location for subsequent anatomical and
functional scans. A set of T1-weighted sagittal structural
images encompassing the whole brain were acquired using
the following parameters, TR¼625ms, TE¼20ms, slice
thickness¼5mm, gap¼1mm, field of view¼256mm,
number of slices¼27, matrix¼256?256. Using the same
slice coverage as the structural scans, a whole brain gradient
echoplanar imaging (EPI) sequence was obtained for each
participant, and employed the same scanning and recon-
struction parameters as the structural scan except for a TR
of 2837ms, a TE of 45ms, and a 128?128 matrix, resulting
in a voxel size of 2?2?6mm3. The functional scanning
session consisted of 400 images and lasted 18min and 54s.
VNS/fMRI in depression
Z Nahas et al
The VNS epoch was synchronized at the beginning of
each of the 10 cycles (scans 1–5). After scanning, VNS
parameters were reset to those programmed when the
participant reported for the scan.
Data Processing Methods
The fMRI image data were transferred to a Dell workstation,
converted into Analyze format using MRICro, and analyzed
with Statistical Parametric Mapping software, version 2
(Welcome Department of Imaging Neuroscience, London,
UK). Data were reoriented to correspond with standard
SPM format. Scans from each data set were co-registered to
an image created from their mean, and corrected for motion
using the standard SPM algorithm. Corrected images were
reviewed for remaining motion, which was less than 0.5mm
along all three major axes (x, y, z) for all participants.
Images were timing corrected using the center slice (seven
of 15) as the reference slice in an ascending sequence, with
an interscan interval of 2.837s. Using the SPM2 algorithm,
each data set was spatially normalized into Talairach space
(Talairach and Tournoux, 1988) by adjusting images to
conform to the SPM2 epi template through trilinear
interpolation. Input and output voxel dimensions were
2?2?6 and 4?4?4mm, respectively. Normalized data
were spatially smoothed using a Gaussian filter width of
Scans acquired during the placebo phase were also
Identification of voxels with statistically significant
activation during VNS in individual participants (f-maps
using SPM2 General Linear Model; fixed effect). A pixel-
by-pixel bidirectional t-test identified areas of significantly
decreased or increased response to VNS vs rest (or placebo
vs rest), using a delayed boxcar model (10 cycles of 40
scans). In each cycle, images 1–5 were considered the VNS
activation period. Images 21–23, corresponding to a period
of tone stimulation, are the subject of another analysis. The
remaining images, considered rest periods provided com-
parison with VNS. Potentially confounding motion over
time was regressed out, and a high-pass filter with a cutoff
period of 232s was applied to remove slow signal drift.
Using all participants’ f-maps, a one-sample t-test
determined areas of significant activation or deactivation
in response to VNS compared with rest periods for all
participants as a group. Only clusters of activation with Z-
values corresponding to po0.1 and meeting an extended
threshold of at least 15 voxels (960mm3) were considered in
the group analyses.
Multiple regression analysis. To investigate effects of
several clinical parameters on VNS response, a multiple
linear regression mixed model was designed using multiple
scans from each subject and the following covariates: (1)
each participant’s HDRS24at scanning (HDRS24); (2) weeks
since activation of VNS (TIME); (3) output current of VNS
at each session, adjusted independently for clinical para-
meters (OUTPUT); and (4) severity of illness, based on
the interaction between each participant’s baseline NFAD
Table 1 Scanning Schedule and Timeline for all Active VNS Scans
SubjectTIME HDRSNFADHDRS?NFAD Intensity
11 282 56 0.25
3 322 64 0.25
11 192 380.25
13 122 24 0.25
37 102 20 0.5
55212 42 0.5
21 245 120 0.25
3 195 95 0.25
11 225 110 0.25
14 225 1100.25
54 315 155 0.75
88 105 50 0.75
33197 133 0.5
55 227 1541
41 273 810.25
11 28384 0.5
51 262 520.25
47203 60 0.5
65113 33 0.5
7 1126252 0.25
67312 62 0.25
77 252 50 0.25
11306 180 0.5
41 306 1800.25
56 296 174 0.75
81 246 1441
9 11 263 78 0.5
VNS/fMRI in depression
Z Nahas et al
(HDRS24?NFAD). Despite us not being able to find any
references for the combined (HDRS24?NFAD) variable, it
was specifically chosen to differentiate among participants
presenting with identical depression ratings but differing
depressive histories and treatment resistance. Both of these
variables have shown influence on clinical outcomes and
thus likely to affect the brain activity and merit being
considered and explored in our regression model (Sackeim,
2001; Nahas et al, 2005). Other variables likely playing an
important role in the clinical outcomes to VNS therapy (ie
depression sub-type, comorbid psychiatric conditions, age,
specific concomitant medications, etc.) were considered but
not included in this model owing to small sample sizes and
unequal representation of the groups. These included
gender, bipolar or unipolar depression, type of concomitant
psychotropic medications. Individual participants’ f-maps
were entered into this analysis. Given that such an analysis
would require a larger sample size than simple t-test to
achieve the same power, only areas of activation meeting an
extended threshold of a minimum of 10 voxels (640mm3)
and Z-scores equivalent X2.5 were considered significant
(Harrison et al, 2003).
In all, 107 serial scans were acquired on 17 participants.
Each participant underwent a minimum of three and a
maximum of seven scans. In this analysis, we report 45
active VNS scans and nine placebo scans from nine
participants. Seven of these nine participants were originally
randomized to placebo then switched to active VNS
therapy. Fifty-three scans were not used in this analysis
and included technical difficulties (eg, participant move-
ment 42mm during scanning or poor quality, n¼26),
generator not restarting within scanner (n¼11), generator
not keeping pre-set on–off duty cycle within scanner
(n¼16), and one participant experiencing a panic attack
at baseline scan and exiting this study. No patient
experienced unintentional re-setting of VNS parameters
into a higher range of nerve stimulation during fMRI
sessions. The nine participants (six women) had a mean
age, 46.8 (76.2) years and mean duration of current
episode 71.2 (757.3) months (range, 9–194). The NFAD
and VNS output current ranged from 2 to 7 (median 3) and
0.25 to 1.0mA (median 0.5mA), respectively. Median
concomitant psychotropic drugs at each scheduled timeline
ranged between 3 and 5.5. All corresponding structural
high resolution T1 images revealed no overt regional
VNS Active Scans Group Results, Acute VNS
When all 45 active VNS scans were grouped together
(ignoring all other covariates such as time and depression
state), we found significant BOLD increases during VNS in
the bilateral superior temporal gyrus and left somatosen-
sory cortex. We found significant BOLD decreases in the left
middle frontal gyrus, left fusiform gyrus, left ventromedial
frontal lobe, right cerebellum, and midbrain (Figure 2 and
Placebo Scans Group Results
When nine placebo VNS scans were grouped together, we
found significant BOLD increases during the no stimulation
epoch compared with the rest in right orbitofrontal cortex
Control Placebo Group
Active VNS Treatment Group
Hold Fixed Stimulation
Active VNS with Adjustable Stimulation Parameters and Treatment as usual
Week 10 Week 12Week 20
for up to
40 SCANS PER CYCLE
1 VNSfMRI session with 400 scans and 10 cycles
Study design and time points for serial VNS fMRI. Note the detailed a VNS fMRI scanning paradigm with 10 cycles and a total of 400 scans per
VNS/fMRI in depression
Z Nahas et al
and right parietal cortex. Interestingly, no significant
deactivations were found.
Multiple Linear Regression Model
We report a statistically significant relationship between the
dependent variable, regional BOLD activation, and at least
one of the independent variables in this model.
TIME. No statistically significant BOLD increases were
associated with TIME.
TIME from VNS activation or exposure to VNS was
associated with significant BOLD immediate VNS-induced
decreases in right insula (BA 13), right medial frontal gyrus,
left frontal lobe (pre- and postcentral gyrus), right temporal
lobe, right parietal lobe (supramarginal gyrus), left occipital
lobe (BA 17), left parietal lobe (BA 2), and left cerebellum.
Figures 3 and 4 represent the linear relationship of the
parameter estimates of VNS-induced activations over time.
These responses were extracted from the right medial
frontal gyrus (df¼44, F¼58.85, po0.0001, r2¼0.577) and
right insula (df¼44, F¼17.252, po0.0001, r2¼0.286).
Depressive symptoms were
significant BOLD increases in right temporal lobe, right
insula (Brodmann area (BA) 13), and left middle frontal
gyrus. Figure 5 represents the linear relationship of the
parameter estimates of VNS-induced activation function of
HDRS24(df¼44, F¼139.372, po0.0001, r2¼0.76). Note:
We subsequently ran the multiple regression analysis as
described above with only three covariates: (1) HDRS24; (2)
TIME; and (3) OUTPUT (data not presented). At similar
statistical thresholds, the results obtained from three
covariates were very similar to the one summarized here
with the exception of loss of right insula activation.
Depressive symptoms were associated with significant
BOLD decreases in right occipital lobe (Cuneus) and right
HDRS24?NFAD. Severity of depressive illness was asso-
ciated with significant BOLD increases in right cerebrum,
occipital, right and left cerebellum.
Severity of depressive illness was associated with sig-
nificant BOLD decreases in right inferior frontal gyrus, right
cingulate gyrus (BA 32), left cingulate gyrus, right insula
(BA 13), left middle frontal gyrus, left superior temporal
gyrus, right parietal lobe (BA 7), left putamen, and left
Output current. VNS output current was associated with
significant BOLD increases in left cerebellum, right parietal
lobe (somatosensory BA 2), right superior frontal gyrus,
and right middle frontal gyrus.
VNS output current was associated with significant BOLD
decreases in left parietal lobe (precuneus), right posterior
cingulate gyrus, and caudate.
This study used interleaved VNS/fMRI scanning to model
dynamic regional brain responses to VNS as a function of
time, the participant’s depressive state, the underlying
illness severity, and the stimulation output current. We
found that 7s trains of VNS at 20Hz and 500ms pulse
width decreased BOLD–fMRI response in the right medial
prefrontal cortex, anterior cingulate, and left anterior
temporal pole and right somatosensory cortex. It also led
to increased BOLD–fMRI response in the right superior
temporal gyrus. These results are consistent with known
vagus afferent projections (Henry, 2002; Craig, 2004) and
previous VNS imaging studies(Maniker et al, 2000; Bohning
et al, 2001; Lomarev et al, 2002; Mu et al, 2004). We only
found BOLD increases in right orbitofrontal cortex and no
significant decreases in the placebo group.
In addition to this overall analysis, which replicates and
extends previous work, we performed a multiple regression
model, controlling for other parameters known to influence
the VNS BOLD response. To our knowledge, this type of
analysis has not been previously used for VNS imaging
studies. Controlling for the important covariates, we found
that VNS-induced brain changes differed as a function of
duration of exposure to VNS, level of depression on the
study day, and VNS output current used in the scanner.
TIME since VNS device activation: our data suggest that
duration of exposure to VNS accounted for most of the
medial prefrontal/limbic deactivations. Even the right insula
became more deactivated over time, perhaps as a function
of improved clinical outcome. When participants initially
received VNS, the VNS induced limbic activation. However,
over time and with adjustment for other important
covariates, these areas became deactivated. In Figures 4
and 5, the linear relationship between VNS-induced
VNS-induced BOLD deactivations within all active 45 scans.
VNS/fMRI in depression
Z Nahas et al
Table 2 SPM Output/Tailarach Coordinates
ConditionRegionTailarach coordinates (x, y, z)Cluster size (n)z-score
Active VNS group (n¼45)
Increases with VNS compared to rest
Left superior temporal gyrus
?56, 0, 0
?36, ?28, 60
52, ?16, 4
Left somatosensory cortex (BA1)243.40
Right superior temporal gyrus313.19
Decreases with VNS compared to rest
Right frontal oculomotor eye field (BA8)36, 16, 52444.07
Right posterior cingulate gyrus (BA31)8, ?36, ?32
56, 4, ?28
0, 8, ?16
48, ?72, 0
56, ?44, ?16
44, ?60, ?32
28, ?4, ?16
?20, ?52, ?32
Right middle temporal gyrus (BA21)423.90
Right subgenual cingulate (BA25)323.59
Right inferior temporal gyrus (BA37)413.42
Right inferior temporal gyrus (BA37)413.32
Right cerebellum18 3.30
Right uncinate fasciculus173.13
Left cerebellum23 3.03
Placebo group (n¼9)
Increases with placebo compared to rest
Right middle temporal gyrus (BA39) 52, ?68, 16
44, 40, ?20
Right inferior frontal gyrus (BA47) 324.20
Decreases with placebo compared to rest
Multiple linear regression model
Right temporal Lobe 20, ?60, 20
44, ?4, 12
?36, 4, 40
Right insula (BA13)133.15
Left middle frontal gyrus12 2.86
Right cerebellum24, ?68, ?32
12, ?96, 4
8, ?72, ?20
Right occipital lobe 393.14
Right insula (BA13)36, 12, ?4
24, ?8, 56
40, 40, 8
Right frontal lobe 68 3.76
Right frontal lobe 673.58
Right supramarginal gyrus40, ?48, 32
?36, ?28, 64
40, 4, ?24
8, 8, 52
Left postcentral gyrus383.29
Right temporal lobe 19 3.20
Right medial frontal gyrus26 3.19
Left occipital lobe (BA 17)
?16, ?96, ?12
?56, 8, 8
?12, ?64, ?32
?56, ?20, 44
Left precentral gyrus 142.86
Left postcentral gyrus (BA 2)10 2.68
VNS/fMRI in depression
Z Nahas et al
parameters estimates became predominantly negative after
week 30. This is also the time when pronounced clinical
improvements in symptoms take place.
Depression level on scan day: the treatment resistance of
each participant’s depression helps explain the larger but
complementary deactivation of medial and lateral prefrontal
cortex and left superior temporal gyrus, whereas depressive
symptoms alone contribute to activation of the right insula.
This is important given the insula’s role in vicero-
autonomic and limbic function, and in somatic pain (Craig,
2003). Also of interest is the dynamic switch in the right
insula’s response to VNS. Acute VNS appears to primarily
deactivate the right insula in mild-to-moderate depression
but correlate with higher activation in relationship to
increased severity of depressive symptoms (see Figure 6).
This reversal in response may be in keeping with known
anatomy of the vagus nerve and afferent parasympathetic
pathways that provide sensory inputs to a hierarchically
integrative network that extends to the insula via the
thalamus and ultimately provides a means of ‘introceptive’
representations (Craig, 2004). It also provides a hypothesis
explaining why VNS output current has been substantially
lower in depression than epilepsy studies, despite an
attempt in all studies to increase the VNS output inten-
sity to the highest tolerated dose. Among participants
with greater depression, VNS produces more activation
in the right insula, an integrative center for pain percep-
tion. Depressed patients may perceive greater pain than
epilepsy patients receiving VNS at the same parameter
VNS output current: the patient’s subjective perception of
VNS greatly depends on the stimulation parameters,
particularly the intensity of the stimulation (Sackeim et al,
2001). The increased activity in the right somatosensory
area (likely neck and throat) associated with higher VNS
output current provides an internal quality control. In
addition, greater output current is associated with increased
activity in the right middle frontal gyrus and decreased
activity in the posterior cingulate.
Access to Mood-Regulating Networks
The vagus nerve, classically described as the ‘wandering
nerve’, sends signals from the central nervous system to
control the peripheral cardiovascular, respiratory, and
Table 2 Continued
ConditionRegion Tailarach coordinates (x, y, z) Cluster size (n)z-score
Right cerebellum 24, ?68, ?32
?48, ?72, ?24
12, ?96, 4
Left cerebellum 103.07
Right occipital lobe 102.88
Right parietal lobe (BA 7)12, ?76, 44
44, ?4, 12
?36, 4, 40
?20, ?56, 16
?52, ?4, 0
?8, 0, 36
?28, ?20, 24
?8, 24, 20
?24, 0, 8
12, 16, 32
Right insula (BA 13)198 3.77
Left middle frontal gyrus64 3.49
Left temporal lobe128 3.26
Left superior temporal gyrus102.98
Left cingulate16 2.93
Left, sub-lobar, extra-nuclear, white 172.90
Right inferior frontal gyrus112.72
Left putamen 142.70
Right cingulate gyrus (BA 32) 202.59
Left brainstem, pons
?8, ?16, ?20 102.52
Current output increases
?12, ?64, ?36
28, ?36, 64
0, 28, 48
Right parietal lobe (BA 2)18 3.11
Right superior frontal gyrus11 2.90
Right middle frontal gyrus 20, ?12, 6012 2.83
Current output decreases
Left parietal lobe, precuneus
?20, ?64, 32
8, ?20, 32
0, 12, 12
Right cingulate gyrus 24 3.01
Inter-hemispheric extending to right caudate 172.80
VNS/fMRI in depression
Z Nahas et al
gastrointestinal systems. However, 80% of its fibers are
afferent, carrying information from the viscera to the brain
(Foley and DuBois, 1937). The fibers enter the midbrain at
the nucleus tractus solitaris (NTS) level. From the midbrain,
they either loop back to the periphery in a reflex arc,
connect to the reticular activating system, or reach the
parabrachial nucleus and its connections to the NTS, raphe
nucleus, locus ceruleus (LC), the thalamus, paralimbic,
associated with HDRS24(top right), decreases in medial prefrontal and limbic structures associated with TIME of Exposure to VNS therapy (bottom left) and
increases in right somatosensory cortex associated with intensity of stimulation (bottom right).
Design Matrix (top left) of the multiple regression model used and selected independent variables BOLD contrasts including: increases in insula
weeks (df¼44, F¼58.85, po0.0001, r2¼0.577). Note that the linear response becomes predominantly negative after week 30.
Relationship between VNS-induced parameters estimates response in the right medial prefrontal gyrus and exposure to active VNS therapy in
VNS/fMRI in depression
Z Nahas et al
limbic, and cortical regions, including anterior insula and
cingulate cortex (Hallowitz and MacLean, 1977). VNS
modulates brain function through this route (Henry,
2002). The interplay between VNS and central nervous
system monoamines has been demonstrated (Ben-Mena-
chem et al, 1995; Naritoku et al, 1995; Krahl et al, 1998;
Carpenter et al, 2004). The brainstem evidences specific
acute markers of neuronal activity in vagus nerve nuclei, LC
noradrenergic nuclei, and cochlear nucleus (Naritoku et al,
1995). Lesioning the LC interferes with the antiepileptic
effect in rodents (Krahl et al, 1998). VNS induces specific
nuclear fos immunolabeling in several forebrain structures,
including the posterior cortical amygdaloid nucleus and
cingulate retrosplenial cortex (Naritoku et al, 1995).
Conversely, cerebral spinal fluid (CSF) studies involving
epilepsy patients reveal increased g-aminobutyric acid
(GABA) as well as homovanillic acid (HVA), and 5-
hydroxyindoleacetic acid (5-HIAA), the major metabolites
of dopamine and serotonin, respectively, and decreased
glutamate after 3 months of treatment (Ben-Menachem
et al, 1995). After 24 weeks in depressed subjects, VNS
caused increases in CSF HVA but not in mean concentra-
tion of NE, 5-HIAA, 3-methoxy-4-hydroxyphenylglycol, or
GABA (Carpenter et al, 2004).
F¼17.252, po0.0001, r2¼0.286). Note that here again, the linear response becomes predominantly negative after week 30.
Relationship between VNS-induced parameters estimates response in the right insula and exposure to active VNS therapy in weeks (df¼44,
time of scanning as measured by HDRS (df¼44, F¼139.372, po0.0001, r2¼0.76). Note that the linear response becomes predominantly positive after a
HDRS score of 22.
Relationship between VNS-induced parameters estimates response in the right insula and the depressive symptoms of each individual at the
VNS/fMRI in depression
Z Nahas et al
Comparison with Other Imaging Studies of
The prefrontal/limbic pattern of activations observed in our
study supports this general neuroanatomic framework.
Moreover, VNS-induced effects are largely consistent with
other published investigations of antidepressant mechan-
isms of action. Much of this literature has focused primarily
on exploring pharmacologic interventions and their postu-
lated effects on mood-regulating brain networks. Chronic
antidepressant drug treatment, such as a serotonin reuptake
inhibitors (SSRI) like sertraline (Buchsbaum et al, 1997;
Nobler et al, 2000; Drevets et al, 2002), fluoxetine (Mayberg
et al, 2000), or paroxetine (Brody et al, 2001), seems to
reduce metabolism in the limbic areas and/or ventral
ACC of subjects showing a persistent, positive treatment
response. Clinical remission was also associated with
decreased ACC activity in a study of subjects receiving
either an SSRI or a norepinephrine-serotonin reuptake
inhibitor (NSRI) (Holthoff et al, 2004), although these two
classes of antidepressants may not share identical effects on
Other brain stimulation modalities for treating depression
have also shown dynamic modulation of prefrontal/limbic
regions. ECT’s antidepressant effect focuses on the dynamic
interplay between the ictal and post-ictal phases (Rosenberg
et al, 1988). During the ictal period, cerebral blood flow
increases up to 300% of baseline and cerebral metabolic rate
up to 200%; these measures decrease post-ictally. The
degree of prefrontal and medial frontal deactivation
immediately after ECT correlates with later clinical im-
provement. This inverse relationship holds true 2 months
after ECT (Nobler et al, 2001). TMS, when applied
repetitively over the prefrontal cortex, has also shown
antidepressant effects (Kozel and George, 2002; Gershon
et al, 2003) and is associated with local and transynaptic
distal modulation of subcortical regions, including ACC and
amygdala (Teneback et al, 1999; Speer et al, 2000; Nahas
et al, 2001b; Strafella et al, 2001). Its antidepressive
properties may also depend on the severity of underlying
depression (Teneback et al, 1999) and the stimulation
parameters (Kimbrell et al, 1999; Nahas et al, 2001b). A real-
time assessment of brain activity with prefrontal interleaved
TMS fMRI (Bohning et al, 1998) in a depressed cohort with
concomitant medications, very similar to our cohort, has
shown medial prefrontal deactivation (Li et al, 2003) not
seen in healthy volunteers (Nahas et al, 2001a). Finally, an
open study has reported antidepressant benefits of DBS
posterior to the subgenual cingulate with concurrent
deactivation of that region (Mayberg et al, 2005).
The deactivations of medial prefrontal cortex with VNS are
similar to other antidepressant treatments, but they also
suggest adaptation over time. Unlike pharmacologic inter-
ventions evidencing antidepressant effects after a few weeks
of treatment (Mayberg et al, 2000), VNS clinical anti-
depressant effects occur later, after several months. The
turning point for right insula, a key region in explicit
subjective awareness (Critchley et al, 2004), and medial
prefrontal activations seems to occur around 30 weeks of
active VNS. If replicated in future studies, this particular
characteristic may reflect VNS’ relatively delayed time of
effect. Of interest is a recent SPECT study showing limbic
deactivations with only 4 weeks of VNS therapy (Zobel et al,
2005). Given the rapid response rate seen in this European
study, the treatment resistance level may play an important
role in how quickly VNS modulates these networks. In
addition, SPECT and fMRI modalities differ in time their
respective time resolutions and thus may explain some of
the divergent results. Effective and progressive modulation
of key brain regions may ultimately explain this distinctive
therapeutic feature. Another distinctive clinical feature
awaiting replication is the prolonged response and fewer
relapses of depressed participants receiving adjunctive VNS
(Nahas et al, 2005). Although our data do not fully explain
this phenomenon, the progressive adaptation of crucial
neuronal networks may complement animal epilepsy
models in which VNS confers chronic progressive prophy-
lactic effects, with seizure counts reduced more after
chronic stimulation than after acute stimulation over less
than a day. Similar research is needed in animal depression
The ‘magnetic switch’ designed to allow epilepsy patients to
self-administer an extra train of stimulation to help curb a
full-blown seizure has limited our ability to successfully
scan all participants. Despite a customized surgical
implantation rotating the device about 451 counterclockwise
to allow generator reactivation once the participant is
parallel to the main magnetic field of the scanner, the VNS
generator restarted in the scanner during only two-thirds of
the sessions. This difficulty affected the statistical power of
this study. Additionally, this fMRI paradigm had a relatively
brief active-VNS epoch. The small number of participants
with bipolar depression in the study precluded specific
analysis differentiating MDD from BPAD responses. Given
the adjunctive nature of this therapy, controlling for
concomitant psychotropic medications is a limitation to
this study. The median number was, however, relatively
stable across the length of the study. Finally, the correla-
tions presented here were derived from nine subjects but a
total of 45 scans. And although this the largest imaging
study reported in VNS literature, this does limit the
interpretation of these data.
In conclusion, VNS/fMRI seems useful in studying the
effects of VNS on brain activity both acutely and over time.
VNS/fMRI may even allow in the future tailoring of
stimulation parameters to optimally modulate specific
regions and study progressive therapeutic adaptations.
Although VNS and other antidepressant interventions share
several general similarities, much work remains to fully
elucidate the VNS mechanisms of actions.
Grant support was received from Cyberonics Inc. (DEB),
The Dana Foundation (DEB), The Stanley Foundation (CT)
and a grant in kind from the Center for Advanced Imaging
Research (CAIR) at MUSC. Other support includes NIMH
VNS/fMRI in depression
Z Nahas et al
K08 MH070615-01A1 (ZN), NIMH R21 MH065630-01 (CM,
ZN), NIMH R01 MH069896-01 A1 (MSG, SK, BA, CM, ZN),
NINDS R01 NS40956-01 (DEB, MSG, ZN, JW). ZN and MSG
are paid consultants to CYBX. MSG is a member of CYBX
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