International Journal of Neuropsychopharmacology (2010), 13, 45–59. Copyright f 2009 CINP
doi:10.1017/S146114570900008X
ARTICLE
Influence of prefrontal target region on the
efficacy of repetitive transcranial magnetic
stimulation in patients with medicationresistant depression: a [18F]-fluorodeoxyglucose
PET and MRI study
THEMATIC SECTION
New Aspects in the
Treatment of
Affective Disorders
Marie-Laure Paillère Martinot1,2, André Galinowski3, Damien Ringuenet1,4, Thierry Gallarda3,
Jean-Pascal Lefaucheur5, Frank Bellivier6, Christine Picq7, Pascale Bruguière7,
Jean-François Mangin1,8, Denis Rivière1,8, Jean-Claude Willer9, Bruno Falissard10,
Marion Leboyer5, Jean-Pierre Olié3, Eric Artiges1,11 and Jean-Luc Martinot1
1
Inserm U797, CEA – INSERM U797 ‘ Neuroimaging & Psychiatry ’, I2BM, IFR49 ; Université Paris-Sud & Université Paris Descartes,
Service Hospitalier Frédéric Joliot, F-91400 Orsay, France ; 2 AP-HP, Service de médecine de l’adolescent, Maison de Solenn, Hôpital
Cochin, Université Paris Descartes, Faculté de médecine, F-75014 Paris, France ; 3 INSERM, Physiopathologie des Maladies
Psychiatriques, U894-7, Paris, France ; Université Paris Descartes, Faculté de Médecine Paris Descartes, SHU, Hôpital Sainte-Anne,
Paris, France ; 4 AP-HP, Service de psychiatrie et addictologie, Hôpital Paul Brousse ; Université Paris-Sud, F-94800 Villejuif, France ;
5
AP-HP, Service de Physiologie, Henri Mondor-Albert Chenevier, Université Paris 12, Faculté de Médecine, IFR10, F-94000 Créteil,
France ; 6 INSERM, U995, IMRB, Department of Genetics, Psychiatry Genetics, Créteil, F-94000, France ; University Paris 12, Faculty of
Medicine, IFR10, Créteil, F-94000, France ; AP-HP, Henri Mondor-Albert Chenevier Hospitals, Department of Psychiatry, Créteil,
F-94000, France ; 7 AP-HP, Service de Médecine Physique et Réhabilitation, Groupe hospitalier Pitié-Salpêtrière, Inserm U 731,
Université Pierre & Marie Curie-Paris 6, UMR S 731, F-75013 Paris, France ; 8 CEA Neurospin, NMR Lab, I2BM, IFR49, F-91191
Gif-sur-Yvette, France ; 9 AP-HP ; Service de Neurophysiologie Clinique et Inserm U751, Groupe hospitalier Pitié-Salpêtrière, Université
Pierre & Marie Curie-Paris 6, F-75013 Paris, France ; 10 Inserm U669, Université Paris-Sud & Université Paris Descartes, AP-HP,
F-75014 Paris, France ; 11 Centre hospitalier d’Orsay, Service de Psychiatrie (91G16), F-91400 Orsay, France
Abstract
It is currently unknown whether the antidepressant effect of repetitive transcranial magnetic stimulation (rTMS)
depends on specific characteristics of the stimulated frontal area, such as metabolic changes. We investigated
the effect of high-frequency rTMS, administered over the most hypometabolic prefrontal area in depressed
patients in a two-site, double-blind, randomized placebo-controlled add-on study. Forty-eight patients with
medication-resistant major depression underwent magnetic resonance imaging and [18F]-fluorodeoxyglucose
positron emission tomography (PET) in order to determine a target area for rTMS. After randomization to
PET-guided (n=16), standard (n=18), or sham rTMS (n=14) conditions, the patients received 10 sessions of
10-Hz rTMS (1600 pulses/session) at 90 % motor threshold. Change from baseline in Montgomery–Åsberg
Depression Rating Scale (MADRS) scores did not differ between PET-guided, standard and sham groups at
2-wk end-point. Exploratory comparison of left PET-guided (n=9), right PET-guided, standard, and sham
rTMS revealed significant effects. The highest improvement in MADRS scores was observed with left
PET-guided (60¡31 %), significantly superior to sham (30¡37 %, p=0.01) and right-guided (31¡33 %, p=0.02)
stimulation. Comparison between left PET-guided and standard rTMS (49¡28 %) was not significant (p=0.12).
Comparison between stimulation over dorsolateral prefrontal cortex (BA 9-46), stimulation of other areas, and
sham rTMS was statistically significant. Stimulation over BA 9-46 region (n=15) was superior to sham rTMS
(p=0.02). The results do not support the general hypothesis of increased antidepressant effects of highfrequency rTMS with prefrontal hypometabolism-related PET guidance. Nonetheless, whether metabolism and
anatomy characteristics of left frontal area underneath the coil might account for an increase or speeding up of
rTMS effects needs further investigation.
Received 30 July 2008 ; Reviewed 16 September 2008 ; Revised 19 January 2009 ; Accepted 21 January 2009 ;
First published online 9 March 2009
Key words : Magnetic resonance imaging, positron emission tomography, randomized placebo-controlled
trial, resistant depression, transcranial magnetic stimulation.
Address for correspondence : Dr M.-L. Paillère Martinot, Maison de Solenn, Hôpital Cochin, 97 Boulevard de Port-Royal, 75014 Paris, France.
Tel. : +33 1 58 41 24 26 Fax : +33 1 58 41 28 08 Email : [email protected]
46
M.-L. Paillère Martinot et al.
Introduction
Over the past decade, repetitive transcranial magnetic
stimulation (rTMS) has emerged as a potential new
therapy for medication-resistant depression (George
et al. 1995 ; Lam et al. 2008 ; Pascual-Leone et al. 1996).
However, despite an increasing number of studies, the
optimal stimulation site has not been unequivocally
determined (Daskalakis et al. 2008 ; Fitzgerald et al.
2006a). Several reviews and meta-analyses of rTMS
studies in patients with resistant depression have demonstrated, at best, a moderate clinical effect of rTMS
(Burt et al. 2002 ; Gershon et al. 2003 ; Loo & Mitchell,
2005 ; Martin et al. 2002), and other studies have reported no difference between active and sham rTMS
(Couturier, 2005 ; Mogg et al. 2008). The high variability in response across studies has been related to
differences in parameters such as the patients’ clinical
characteristics and the intensity, frequency, and location of the stimulation (Daskalakis et al. 2008 ;
George et al. 2008 ; Herrmann & Ebmeier, 2006).
To increase the effects, some authors have proposed
bilateral stimulation with high-left and low-right frequencies (Fitzgerald et al. 2006b), or suggested that
longer durations of treatment (at least 6 wk) and/or
higher stimulation intensity might result in better effectiveness (Anderson et al. 2007 ; Avery et al. 2008 ;
O’Reardon et al. 2007) ; however, these strategies
increase the treatment complexity and cost (Knapp
et al. 2008).
The neurophysiology behind the potential antidepressant effect of rTMS is not clearly understood. The
effects of rTMS on mood have been related to its ability
to modulate brain functions such as cortical excitability (Pascual-Leone et al. 1994) or blood flow. Highfrequency rTMS (o5 Hz) has been shown to increase
brain activity both locally and in distant regions while
low-frequency TMS (f1 Hz) may decrease brain activity in depressed patients (Speer et al. 2000).
Based on empirical observations of mood-related
effects of prefrontal stimulation and reports of left
prefrontal hypometabolism in depressed patients in
previous neuroimaging studies (Baxter et al. 1989 ;
Bench et al. 1992 ; Martinot et al. 1990), George and
co-workers (1995) suggested that the most effective
antidepressant effect might be obtained by applying
rTMS to the left prefrontal cortex. Thereafter, PascualLeone et al. (1996) specified that the targeted area
should be Brodmann area (BA) 46 and, more recently,
functional studies have suggested that BA 9 would be
the optimal site (Fitzgerald et al. 2006 a). In addition,
high-frequency rTMS was found to be more effective
over the left dorsolateral prefrontal cortex (DLPFC)
than over the right DLPFC (Pascual-Leone et al. 1996).
Thus, most high-frequency rTMS studies have aimed
at stimulating the left DLPFC (particularly BA 46 or an
area encompassing left BA 9 and BA 46) either by
using a ‘standard ’ procedure that targets an area 5 cm
anterior to the hand motor cortical representation
(George et al. 1997 ; Paus & Barrett, 2004) or by using
neuronavigation devices (Herwig et al. 2003). However, the choice of this target region remains speculative (Fitzgerald et al. 2006a), and the clinical effects
have been only moderate, even when using neuronavigation (Herwig et al. 2003). Indeed, functional patterns most often result from group analyses and do not
take into account individual variability. Imaging
studies conducted in depressed patients have actually
revealed various metabolic patterns, with considerable inter-subject variability regarding the hypometabolic frontal subregions (Fitzgerald et al. 2006a ;
Videbech et al. 2002). Moreover, although BA 9 and BA
46 are connected to regions implicated in the regulation of mood, such as the anterior cingulate and the
caudate (Barrett et al. 2004), it is not clear whether the
prefrontal hypometabolic clusters that should be targeted are within those areas or within other subregions in the DLPFC. One study has suggested that
the application of high-frequency rTMS over hypometabolic prefrontal areas would yield better clinical
effects in patients (Kimbrell et al. 1999), which is in
line with earlier reported increased left prefrontal
metabolism in patients recovering from depression
(Baxter et al. 1989 ; Kennedy et al. 2001 ; Martinot
et al. 1990). Furthermore, the stimulation of the
DLPFC according to the underlying cortical dysfunction has been proposed to be superior to stimulation
that does not take the metabolic state into account
(Herwig et al. 2003 ; Garcia-Toro et al. 2006 ; Mottaghy
et al. 2002).
In the present study, we investigated whether focusing high-frequency rTMS on the most hypofunctional prefrontal cluster determined at the individual
level would be more effective than stimulation of
the ‘standard ’ location in the treatment of depressive
symptoms. Additionally, we sought to determine
whether stimulation side or stimulation over the BA 9
and/or BA 46 regions in the DLPFC would influence
the therapeutic effects of rTMS.
We designed a two-site, randomized controlled
study in which we compared the effects of positron
emission tomography (PET)-guided rTMS, left prefrontal standard rTMS, and sham rTMS in patients
with pharmaco-resistant depression. The PET-guided
rTMS target was the prefrontal cluster with the maximal hypometabolic voxel (i.e. peak voxel), which
Brain-imaging-guided TMS in resistant depression
was determined individually using [18F]-fluorodeoxyglucose PET (FDG PET).
Method
The investigation was performed in accordance with
the Declaration of Helsinki. The study was approved
by the ethics committee Ile de France 6, Paris. Written
informed consent was obtained from all subjects after
full description of the study.
Participants
Fifty-eight patients with a DSM-IV-R diagnosis of
major depressive disorder were recruited by senior
psychiatrists from consecutive admissions at five university psychiatry departments. Diagnoses were established on the basis of clinical interviews and
administration of the Mini-International Neuropsychiatric Interview (MINI ; Sheehan et al. 1998). The
patients were screened for resistance to at least two
trials of antidepressants of different classes given at
adequate doses (>150 mg/d in an equivalent dose of
imipramine) and duration (at least 4 wk for each
drug). No incentives were offered.
Exclusion criteria included age >65 yr, alcohol or
substance dependence in the past 6 months, electroconvulsive therapy (ECT) treatment in the past 6
months, any present medical condition, history of
epileptic seizures, history of neurological disorders or
substantial brain damage, and contraindication to
magnetic fields, according to established safety criteria
(Wassermann, 1998).
After initial screening, the patients underwent brain
imaging. Four patients were then excluded due to
silent neuropathological abnormalities. Of the remaining 54 patients, two patients dramatically improved in the 3-d gap between brain imaging and
the start of the TMS protocol. One patient who scored
18 on the Montgomery–Åsberg Depression Rating
Scale (MADRS ; Montgomery & Åsberg, 1979) and 16
on the Hamilton 21-item Depression Scale (HAMD21 ;
Hamilton, 1960) at baseline was excluded from the
study as she did not fulfil the scoring requirements for
inclusion in clinical trials (Mottram et al. 2000). Finally,
one patient was excluded from the TMS protocol as his
motor threshold was higher than the maximal capacity
of the rTMS device used. Thus, 50 patients (32 females)
entered the TMS study.
Comparison group
Each patient was compared for FDG PET with 25
healthy volunteers (values given are mean¡S.D.) (age
47
37.04¡10.1 yr, 13 males) who were recruited from the
community by word of mouth and had no personal or
family history of psychiatric disorder, as assessed by a
medical examination. Due to the necessity to constitute the comparison group before starting the study,
there was a significant age difference between the
patients (age 47.14¡8.20 yr) and the comparison subjects (t test=x4.65, d.f.=73, p<0.0001). The comparison subjects did not significantly differ from patients
with respect to gender (five males, Fisher’s exact test,
two-tailed=0.57) and education level (years of education after primary school, patients 7.5¡4.14 yr ;
comparison subjects 9.24¡4.38, t test=x1.69, d.f.=
72, p=0.10).
Clinical assessment
Baseline assessment was performed on the day before
brain imaging, and the last clinical assessment was
performed after 10 sessions, on the last treatment day.
Clinical evaluations were performed by senior psychiatrists or psychologists trained together on ratings,
using the MADRS, HAMD21, and the Clinical Global
Impression of Illness – Severity (CGI-S).
Treatment allocation
Stratified randomization was performed in blocks including 11 subjects (4+4+3), with each treatment at
least once in the first four, the second four, and the last
three patients. Randomization was stratified on the
stimulation site and two allocation lists were generated by the Biostatistics Department. Allocation concealment was performed using closed envelopes that
indicated the treatment modality for each patient and
were kept in each stimulation site and opened by the
investigator performing the treatment immediately
before the first treatment session.
Hence, the patients were randomly assigned either
to PET-guided TMS (n=17), standard TMS (n=19), or
sham standard TMS (n=14). Patients and symptom
raters were blind to the treatment modality.
Comorbidities
Twelve patients reported symptoms of a comorbid
diagnosis of anxiety disorder (panic disorder with or
without agoraphobia, or generalized anxiety disorder) ;
four were in the PET-guided, three in the standard,
and five in the sham-treated groups (x2=1.52, p=
0.47). None of them had anxiety symptoms during the
scanning protocol. Sixteen patients had resistant bipolar depression (seven in the PET-guided group, four
in the standard group, and five in the sham group,
x2=1.86, p=0.39).
48
M.-L. Paillère Martinot et al.
Table 1. Comparison of demographic and clinical characteristics at baseline, and treatment effects after 10-d treatment with
repetitive transcranial magnetic stimulation (rTMS) in 48 patients with resistant depression across standard, PET-guided, and
sham treatment subgroups
Gender, females (n)
Age (yr)
Years of education
Duration of illness (yr)
Duration of episode (yr)
Baseline clinical scores
MADRS
HAMD21
CGI-S
Change from baseline
MADRS
HAMD21
CGI-S
Standard rTMS
(n=18)
PET-guided rTMS
(n=16)
Sham rTMS
(n=14)
11
Mean (S.D.)
48.19 (7.77)
7.94 (4.07)
16.82 (9.81)
3.09 (2.83)
10
Mean (S.D.)
46.9 (7.26)
6.75 (4.88)
20 (8.50)
2.75 (2.01)
10
Mean (S.D.)
46.57 (10.27)
8 (3.64)
19.14 (9.97)
1.65 (1)
32 (7.78)
26 (6.4)
5.28 (0.75)
34.31 (7.28)
26.31 (3.89)
5.44 (1.21)
x14.72 (8.94)
x10.83 (6.93)
x0.88 (1.23)
x16.44 (13.33)
x11.31 (8.36)
x1.07 (1.44)
Patients
(n)
KW test
d.f.
p
0.20
2
0.90
2
2
2
2
0.81
0.81
0.71
0.31
34.57 (6.07)
25.93 (6.65)
5 (0.78)
0.42
0.42
0.65
2.31
F(2, 42)
1.02
0.34
2.94
2
2
2
0.60
0.84
0.23
x10.5 (12.34)
x7.14 (10.62)
x0.29 (1.14)
F(2, 42)
1.26
1.39
1.20
0.29
0.26
0.31
Patients
(n)
Patients
(n)
x2 test
d.f.
p
Ongoing treatments
Tricyclic antidepressants
SSRIs
Mood stabilizers
Antipsychotics
Benzodiazepines
1
7
4
4
7
0
5
2
0
10
2
2
2
1
11
2.62
2.35
0.66
4.71
5.27
2
2
2
2
2
0.26
0.31
0.72
0.09
0.07
Past treatments
Tricyclic antidepressants
SSRIs
Mood stabilizers
Antipsychotics
Benzodiazepines
ECT
12
17
12
9
15
7
14
15
11
10
14
5
13
12
9
8
13
2
4.16
2.51
0.07
0.54
0.65
2.36
2
2
2
2
2
2
0.12
0.29
0.97
0.76
0.72
0.31
CGI-S, Clinical Global Impression – Severity ; ECT, electroconvulsive therapy ; HAMD21, Hamilton Depression Rating Scale
(21 items) ; KW, Kruskal–Wallis test ; MADRS, Montgomery & Åsberg Depression Rating Scale ; SSRIs, selective serotonin
reuptake inhibitors.
Medication
Brain imaging
rTMS was administered as add-on therapy (Table 1).
During the study, the patients were treated with
minimal and stable doses of their previous treatment
for at least 2 wk. Low-dose hypnotics prescribed in a
naturalistic manner were allowed in case of severe
insomnia only.
Current and past treatments, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs),
mood stabilizers, or ECT prescriptions, did not differ
between groups (Table 1).
All participants were investigated at rest. Magnetic
resonance imaging (MRI) high-resolution T1-weighted
images were acquired with a 3D MRI sequence (124
T1-weighted images ; field of view 24 cm ; 256r
256r128 matrix ; voxel size 0.94r0.94r1.3 mm3) on a
1.5 T GE Signa scanner (General Electrics Medical
Systems, USA).
FDG PET 3D-images were obtained following a
transmission scan for attenuation correction from a
Siemens ECAT-EXACT-HR+ tomograph (Siemens
Brain-imaging-guided TMS in resistant depression
Medical Solutions, USA), which collects 63 simultaneous slices (intrinsic in-plane resolution 4.3 mm ;
voxel size 2.42r2.42r2.43 mm3). Two 3D time-frames
(10 min each) were collected 30 min after injection.
Attenuation- and decay-corrected PET images were
summed. All participants were injected with 111–222
MBq of FDG. The mean (¡S.D.) injected radioactivity
was 156.43¡10.55 MBq in the patients and 157.92¡
24.47 MBq in healthy subjects (unpaired t test=0.36,
d.f.=72, p=0.72).
Image processing
Image transformation and voxel-based analysis
were performed using Statistical Parametric Mapping software (SPM99, Wellcome Department of Cognitive Neurology, University College, London, UK ;
http://www.fil.ion.ucl.ac.uk/spm), implemented on
Matlab1.
Each FDG PET image was co-registered with the
corresponding T1 MRI image. As SPM provides no
FDG template, we first created a FDG template to improve spatial normalization. The healthy subjects’ MRI
images were spatially normalized using the FIL T1
template provided within the SPM99 software package ; then, the obtained transformation matrix was
used to normalize the FDG PET realigned images.
The mean sum of the comparison subjects’ FDG PET
images was computed, providing a mean image that
was then smoothed with an 8 mm full-width halfmaximum isotropic Gaussian kernel and was used as
the FDG template to normalize all subjects’ images.
Following spatial normalization, all images were
smoothed by 8 mm.
rTMS prefrontal target determination
In order to determine a TMS target based on prefrontal
hypometabolism in each patient, the individual FDG
PET baseline images were compared with the healthy
comparison group using the single-subject conditions
and covariates procedure in SPM99, with age and
gender as confounding covariates [a method similar to
that previously validated with SPM96 (Signorini et al.
1999)]. These ‘healthy comparison group minus singlepatient ’ contrasts were examined using an exploratory
height threshold at p<0.05, uncorrected, and an extent
threshold at k=10 voxels (80 mm3), in a whole-brain
analysis, which allowed determination of hypofunctional prefrontal clusters at the individual level. Then,
as the usual target for treating depression with rTMS
is the prefrontal cortex (including superior, middle
and inferior frontal gyri), the most significant peak
49
voxel (i.e. voxel with the highest t value) was chosen
in the prefrontal clusters within TMS coil-cortex accessible distance range. The coordinates in MNI space
(Montreal Neurological Institute) for the peak voxel
within the chosen cluster were obtained using SPM99.
This peak voxel chosen as a target was then projected
onto the head surface (MRI head mesh) using a procedure analogous to that described elsewhere for fMRI
(Andoh et al. 2006, 2008 ; Andoh et al. in press). Briefly,
MRI T1-weighted native images were segmented
using Brainvisa (http://brainvisa.info) image processing pipeline to obtain 3D individual head meshes
(Mangin et al. 1998). Then, the FDG PET ‘healthy
comparison group minus patient ’ SPM map was automatically projected onto the patient’s head mesh using
Anatomist (http://brainvisa.info) and the projection
of the previously chosen peak voxel on the SPM map
was selected as a target on the head mesh. This procedure allowed checking of the depth of the projected
FDG PET peak voxel. A depth <25 mm was required
to ensure that the magnetic field peak delivered by
rTMS could reach the cortex. Along with the peak
voxel projection, anatomical landmarks including the
nasion, vertex, and left and right auricular tragi were
selected. Coordinates of the landmarks computed with
Anatomist were then entered into an algorithm embedded in Brainvisa that allowed computation of
geodesic distances (i.e. tangents to the head surface)
between the target and the landmarks. The three
distances between target and nasion, target and
left auricular tragus, and target and right auricular
tragus were provided in millimetres by Anatomist
software and were then used to position the TMS coil
manually over the subject’s head (Andoh et al. in
press) (Fig. 1).
In addition, hand motor cortex targets were computed on each patient’s head mesh using the projection of the hand knob that was previously determined
on the subject’s MRI. In order to estimate the cortexunder-the-coil coordinates in each patient that had
been allocated to standard rTMS, standard location
was virtually re-constructed after treatment completion, 5 cm ahead of the motor target represented
on the head mesh, using the Anatomist distance scale
centred by the motor target. Then, a sphere centred
by the target was defined using the Anatomist distance scale ; variation in the distance scale radius
allowed selection of the cortical region closest to the
scalp on the brain mesh. MNI coordinates of those
standard locations at the brain surface were then
computed in Anatomist using each subject MRI
image normalized in SPM2. Those coordinates were
then translated into Talairach coordinates (Talairach
50
M.-L. Paillère Martinot et al.
(a)
(b)
t value
3
2
1
0
(c)
(d )
Fig. 1. Steps for determination of the PET-guided target. (a) Statistical parametric map (SPM) of FDG PET showing cortical
clusters of decreased metabolism in the prefrontal cortex. Crosshairs indicate peak voxel at MNI coordinates [x36, 40, 36] for
target (PET-guided subject no. 15). (b) Projection of the hypometabolic peak voxel to a 3D reconstruction of the original
anatomical MRI of the subject (brain mesh). (c) Correspondence between hypometabolism and cutaneous landmarks (red dots)
on the head mesh. (d) Target (distance map) for the positioning of the rTMS coil. The exact localization of the target is
automatically calculated as a distance in millimetres from anatomical landmarks such as the tragus of both ears, vertex, nasion,
and inion.
& Tournoux, 1988) using Pick Atlas toolbox (Maldjian
et al. 2003) in SPM2 and further translated into
Brodmann areas. Finally, in order to estimate coil–
cortex distance, scalp–cortex distance was measured
a posteriori in each patient using the head mesh
and brain mask (i.e. voxel value is 1 in the brain and
0 elsewhere) fusion procedure in Anatomist at the
target or at reconstructed standard locations. All of
these assessments were performed blind to clinical
ratings.
Stimulation procedure
rTMS treatment was administered in two stimulation
sites that were equipped with the same TMS devices
and by investigators who were not involved in clinical
ratings or PET target processing.
TMS protocol
We used Magstim super-rapid1 devices with active
and sham air-cooled figure-of-eight coils (Magstim
Co., UK). Both coils had the same appearance and
made a similar noise. The patients were blind to the
treatment modality and had never previously been
treated with TMS. They had all been told that the
treatment side could be related to their brain-imaging
data. The investigators administering the treatment
were blind to the clinical ratings but not to the status of
the coil.
Motor threshold (MT) was determined according to
a standardized procedure (Rothwell et al. 1999) either
on the left thumb, if the stimulation target was on
the right hemisphere, or the right thumb, for the left
hemisphere.
Brain-imaging-guided TMS in resistant depression
Twenty trains of 8 s with 60-s inter-train intervals
were administered with stimulus frequency at 10 Hz
and intensity at 90 % of MT, resulting in a total of 1600
pulses over 20 min. rTMS was administered on 10
consecutive working days, providing a total of 16 000
impulses. Sham rTMS was performed using the same
procedure. All patients wore earplugs.
Coil positioning
The patients wore a stretchable swimming cap on
which the target position was drawn according to the
computed geodesic distances of the target in the
guided group, or according to the motor cortex location
in the other groups. PET-guided rTMS was applied on
the target determined for each patient, either on the
left or on the right hemisphere.
Standard stimulation was left prefrontal, 5 cm
anterior to the motor hot-spot of the hand (abductor
pollicis brevis muscle).
51
right PET-guided, standard, sham) and stimulation
site (1, 2) as independent variables.
In addition, an exploratory analysis of the effects of
the active treatment over BA 9-46 compared with
active rTMS over other areas and with sham rTMS
was performed. Responders were defined as having a
MADRS score change from baseline o50 %.
The Kruskal–Wallis test was used to compare age,
years of education, duration of illness, duration of episode, and scalp–cortex distance in the three treatment
groups. Age and years of education between patients
and controls of the brain-imaging protocol were compared using unpaired t tests. Gender differences were
compared using x2 test.
Significance was set at p<0.05, two-tailed. Moreover, due to the small sample sizes of the subgroups in
the secondary analysis, indices of effect size (Cohen’s
d ; Cohen, 1988) and Number needed to treat (NNT ;
Cook & Sackett, 1995) were computed.
Statistical analysis
Sample size determination was based on an estimation
of the effects variability size, as reported in the literature at the beginning of the study (7-point decrease
in HAMD21 score, with a similar standard deviation)
(George et al. 1995). At least 15 patients in the placebotreated group and 16 patients in each actively treated
group were required to control for an a-level error
of 5 % and a b-level error of 20 %, based on unilateral
assumptions.
The clinical data were analysed using JMP 6 software from SAS (USA). Intent-to-treat efficacy analysis
was performed on all patients who had a baseline
measure and at least one post-baseline observation
available for analysis, as previously done in other
studies (O’Reardon et al. 2007). The main efficacy criterion was change from baseline in MADRS score.
Secondary criteria included change from baseline in
HAMD21 and CGI-S scores.
The primary analysis compared baseline scores and
change from baseline across treatment subgroups
using factorial ANOVA with treatment subgroup
(guided, standard, sham) and stimulation site (1, 2) as
independent variables. Post-hoc analyses were performed using least square (LS) means differences
Student’s t tests.
Second, as the FDG PET targets were located in
both brain hemispheres and the effects of rTMS depend on the stimulated hemisphere (Pascual-Leone
et al. 1996), the PET-guided group was divided into
left-side and right-side treatment subgroups. A secondary analysis was performed using factorial
ANOVA with treatment subgroup (left PET-guided,
Results
Due to marked anxiety, two patients dropped out at
the beginning of the study (after one or two rTMS
sessions) (Fig. 2) ; one of them was in the left PETguided group (a 49-yr-old female, MADRS score : 38,
HAMD21 : 30) and the other in the standard group
(a 38-yr-old male, MADRS : 37, HAMD21 : 25). These
patients were excluded from further analyses. No
other serious adverse event was observed. Overall, the
stimulation was well tolerated.
Brain-imaging analysis allowed computation of
functional SPM map-driven targets in all of the
patients except for two who did not display any prefrontal hypometabolic cluster. Those two patients
were both randomly allocated to the standard group.
In all the patients randomly assigned to the PETguided treatment, a stimulation target could be determined from functional SPM maps (Table 2, Fig. 3).
Thirty out of 48 patients (10 sham, 11 standard, and 9
PET-guided treated, i.e. 62.5 % of the patients) displayed the most hypometabolic peak voxel in the left
hemisphere, and 16 patients in the right hemisphere (4
sham, 5 standard, and 7 PET-guided treated, i.e. 33.3 %
of the patients). Those hypometabolic peak voxels
corresponded to BA 9 or BA 46 MNI coordinates in
37.5 % of the patients (Tables 2, 3).
Scalp–cortex distance measured with Anatomist
was 19.6¡6.4 mm in the PET-guided group and 18.4¡
4.9 mm in the standard group (t test=0.63, d.f.=32,
p=0.53). No difference was found in scalp–cortex
distance between standard, left and right target subgroups (Kruskal–Wallis test=0.40, d.f.=2, p=0.82).
52
M.-L. Paillère Martinot et al.
Assessed for eligibility (n = 58)
Excluded (n = 8)
Not meeting MRI criteria (n = 4)
Not meeting clinical criteria
after MRI (n = 3)
Too high motor threshold (n = 1)
Randomized (n = 50)
Sham TMS (n = 14)
No dropout
Analysed (n = 14)
PET-guided active TMS (n = 17)
Standard active TMS (n = 19)
Dropout (n = 1)
Reason: anxiety
Dropout (n = 1)
Reason: anxiety
Analysed (n = 16)
Analysed (n = 18)
Fig. 2. Reasons for discontinuation after enrolment in a study of PET-guided, standard and sham rTMS in patients with
resistant depression.
Eight patients in the PET-guided group and seven
patients in the standard group were actually stimulated over BA 9-46 (Table 2, Fig. 3).
The response rate was 55 % in the standard group,
50 % for the whole PET-guided group, and 21 % in the
sham group (3/14 patients, x2=0.13). In the patients
treated over BA 9/46, 47 % were responders, while in
the patients treated over other areas, 58 % were responders (Fisher’exact test=0.73, two-tailed) (Table 2).
Primary analyses
There was no between-group difference in patients’
baseline characteristics or in changes from baseline in
MADRS, HAMD21, or CGI scores (Table 1). No significant effect of stimulation site or significant interaction between treatment group and stimulation site was
observed.
Secondary analyses
The comparison between left PET-guided, right
PET-guided, standard rTMS, and sham rTMS groups
revealed a significant between-group difference in
MADRS score changes from baseline (Table 4). No
significant effect of stimulation site or significant interaction between treatment group and stimulation
site was observed. Post-hoc analysis showed that leftguided rTMS was significantly more effective than
sham and right-guided conditions, with large effect
sizes. No difference was found between left-guided
and standard, although the effect size was in the
medium range favouring the left-guided group.
Standard and sham, standard and right-guided, and
right-guided and sham conditions did not differ from
each other (Table 4).
The comparison of the 15 patients stimulated over
BA 9-46 with the 19 patients treated over other areas
(BA 6, BA 8, BA 10, BA 45, BA 47) and with the 14
sham-treated patients showed a significant difference
in treatment effects (F=3.34, d.f.=2, p=0.04) favouring the BA 9-46 stimulation (MADRS mean change
x20.4¡10.6) over sham stimulation [MADRS LS
mean difference 10.5, t=2.48, d.f.=42, 95 % CI 2–19,
p=0.02 ; Cohen’s d=0.86 ; NNT=3.96] and, at a trend
level, over stimulation of other BAs (MADRS mean
change x12.1¡10.3, LS mean difference 7.54, t=1.93,
d.f.=42, 95 % CI 0–15, p=0.06 ; Cohen’s d=0.79 ;
NNT=8.92). Sham stimulation was similar to ‘ other
BA ’ stimulation [MADRS LS mean difference 2.9, t=
0.74, d.f.=42, 95 % CI x5 to 11, p=0.46 ; Cohen’s d=
0.14 ; NNT=2.74].
Discussion
We investigated whether individual prefrontal metabolic rate underneath the stimulation site could influence the effects of rTMS. We used a PET-guided
method to treat pharmaco-resistant depressed patients
with high-frequency rTMS over the most hypometabolic prefrontal area accessible to the magnetic field.
After a 2-wk treatment, improvement in depression
scores did not differ between patients treated with
Brain-imaging-guided TMS in resistant depression
53
Table 2. Actively stimulated cerebral regions in 34 depressed patients, scalp–cortex distances, and MADRS scores
improvement with PET-guided or standard rTMS
PET-guided
rTMS
MNI coordinates of
hypometabolism peak voxel
Subject no.
x
y
z
Regionsa
(BA)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
x46
6
x18
8
10
18
58
x36
x4
x38
34
x14
x48
44
x36
x32
26
56
56
40
30
36
24
36
66
32
36
58
36
42
40
28
26
18
28
56
58
52
24
42
8
x6
50
34
16
6
36
54
LMFG (46)
RMFG (9)
LSFG (9)
RSFG (8)
RSFG (8)
RSFG (8)
RIFG (45)
LMFG (9)
LMFG (10)
LIFG (47)
RMFG (8)
LSFG (9)
LIFG (46)
RIFG (46)
LMFG (9)
LSFG (8)
Standard
rTMS
MADRS
% improvementb
46.34
36.59
78.38
83.72
22.86
x16.67
0
69.57
6.98
70
53.33
14.81
93.94
37.04
91.49
68
Scalp–cortex
distance (mm)
15.6
33.9
18.1
28
32.7
17.5
15.2
22.2
17.3
19.3
14.5
14.5
17.3
17.1
13.9
16.3
MNI coordinates of
standard location
Subject no.
x
y
z
Regionsa
(BA)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
x40
x37
x43
x45
x38
x42
x51
x44
x39
x45
x45
x49
x45
x52
x35
x37
x47
x49
13
17
22
23
23
18
4
22
14
2
30
33
33
25
14
14
28
20
56
57
49
50
48
53
42
43
58
50
41
29
41
35
63
58
39
46
LSFG (8)
LSFG (8)
LMFG (8)
LMFG (8)
LMFG (8)
LSFG (8)
LMFG (9)
LMFG (9)
LSFG (8)
LMFG (6)
LMFG (9)
LMFG (46)
LMFG (9)
LMFG (9)
LMFG (6)
LSFG (6)
LMFG (9)
LMFG (8)
MADRS
% improvementb
28
62.07
50
64.29
52.63
82.35
73.17
78.38
72.22
95
64
40
x12.50
42.42
25.81
6.98
27.27
29.73
Scalp–cortex
distance (mm)
19
32.4
20
12.1
16.8
19.8
16
18.6
13.5
18.5
14.5
16.8
20
27
16.5
14.1
21.1
14
BA, Brodmann area ; MADRS, Montgomery & Åsberg Depression Rating Scale ; MNI, Montreal Neurological Institute ; PET,
positron emission tomography.
a
Regions : LSFG, left superior frontal gyrus ; LMFG, left middle frontal gyrus ; LIFG, left inferior frontal gyrus ;
RSFG, right superior frontal gyrus ; RMFG, right middle frontal gyrus ; RIFG, right inferior frontal gyrus.
b
Responders have a MADRS change from baseline o50 %.
54
M.-L. Paillère Martinot et al.
Fig. 3. Cortical representation on a white-matter mesh of all of the stimulation sites in 34 actively treated depressed
patients. Red dots indicate PET-guided targets ; blue dots represent standard locations. Dots overlap Brodmann areas
(BA) 9 (n=11), 46 (n=4), 8 (n=13), and BA 6, 10, 45, and 47 (n=6).
standard rTMS, sham rTMS, or PET-guided TMS.
However, the improvement of patients with the
left-side PET-guided condition surpassed that of rightside PET-guided and that of sham-treated patients.
Moreover, the results showed an advantage in stimulating over BA 9-46.
These findings confirm the previously reported lack
of antidepressant effect of high-frequency rTMS over
right prefrontal cortex, even when taking into account
the regional hypometabolism to guide stimulation.
This is in contrast with the study by Herwig and coworkers (2003), who found similar positive effects of
both right and left rTMS when stimulation occurred
over the DLPFC. Our findings also contradict the
hypothesis that stimulating hypometabolic areas with
high-frequency rTMS, irrespective of the stimulation
side, should improve depressive symptoms (Kimbrell
et al. 1999), as right PET-guided rTMS effects were
similar to sham stimulation effects. As in a recent study,
using higher intensity stimulation and a larger number of patients (O’Reardon et al. 2007), no difference
was seen between standard and sham modalities at
2-wk end-point. In that larger and longer trial, significant effects of rTMS appeared at the 4-wk end-point.
In contrast, in the present study, an early significant
effect of left PET-guided over sham rTMS could be
detected at 2 wk. However, no difference was found
between left PET-guided and standard stimulation.
Despite the small number of subjects, our results indicate a strong effect size of the left PET-guided over
the sham modality, with a NNT of y2 in order to
achieve treatment response. Thus, it could be suggested
that targeting left hypometabolic prefrontal areas
might increase – or speed up – the effect of the treatment compared with standard location alone.
Two previous studies with rather small numbers
of patients attempted to locate the stimulation coil over
hypofunctional areas using either SPECT imaging
(Garcia-Toro et al. 2006) or neuronavigation and
PET imaging (Herwig et al. 2003). Those trials were
not able to show any difference between the effects
of standard stimulation and stimulation of the hypofunctional side. However, in both studies the stimulation was applied over the neuronavigated DLPFC as
a whole region of interest (when hypofunctional)
(Herwig et al. 2003), or over hypofunctional prefrontal
or temporoparietal cortices (Garcia-Toro et al. 2006).
Furthermore, in those studies the stimulation was not
focused over the prefrontal hypometabolism peak
voxel as the functional data were not co-registered on
individual MRIs.
In line with previous hypotheses (Fitzgerald et al.
2006a ; Pascual-Leone et al. 1996), the present study
shows that stimulation of BA 9-46 appeared to be
more effective than sham rTMS. However, due to
the small sample size, it was difficult to disentangle
the effect related to BA 9-46 stimulation from the
effect of stimulating a specific hypofunctional cluster
or the effect of a combination of both, as 6/15 patients
were treated with the left-guided modality, while,
conversely, most of the left PET-guided patients
(6/9) were stimulated over BA 9-46. Moreover, the
number of responders in patients treated over BA 9-46
did not differ from that treated over other areas,
with 8/15 patients treated over BA 9-46 being nonresponders.
Brain-imaging-guided TMS in resistant depression
55
Table 3. Hypometabolic prefrontal regions in 14 sham-treated patients and in 18 patients treated with standard rTMS
MNI coordinates of hypometabolism peak voxel
Sham group
Subject no.
x
y
z
Regions (BA)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
x40
x40
46
x4
x32
x20
x40
x28
x48
42
x2
x26
12
28
46
32
24
62
30
58
14
32
10
40
54
46
32
30
28
34
42
16
50
28
34
52
42
34
4
34
58
50
Left middle frontal gyrus (10)
Left middle frontal gyrus (9)
Right middle frontal gyrus (9)
Left medial frontal gyrus (10)
Left middle frontal gyrus (8)
Left superior frontal gyrus (10)
Left middle frontal gyrus (9)
Left middle frontal gyrus (8)
Left middle frontal gyrus (8)
Right middle frontal gyrus (46)
Left medial frontal gyrus (10)
Left superior frontal gyrus (9)
Right superior frontal gyrus (8)
Right middle frontal gyrus (8)
6
x46
x40
x48
18
x2
6
34
14
42
40
62
62
38
34
46
32
4
20
11
46
x12
10
x6
52
40
66
36
52
12
x40
26
x6
x20
x44
x6
32
32
64
22
18
66
12
54
22
46
4
14
Standard group
Subject no.a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Right medial frontal gyrus (9)
Left middle frontal gyrus (9)
Left middle frontal gyrus (9)
Left inferior frontal gyrus (45)
Right superior frontal gyrus (10)
Left medial frontal gyrus (10)
Right medial frontal gyrus (9)
No hypofrontality
Left superior frontal gyrus (9)
Right superior frontal gyrus (8)
Left medial frontal gyrus (10)
No hypofrontality
Left inferior frontal gyrus (45)
Right superior frontal gyrus (8)
Left medial frontal gyrus (10)
Left middle frontal gyrus (8)
Left inferior frontal gyrus (45)
Left medial frontal gyrus (10)
BA, Brodmann area ; MNI, Montreal Neurological Institute.
a
Subject no. corresponds to the same subject no. as in Table 2.
In addition to the small size of the sample in
each subgroup of PET-guided treatment, other limitations and possible confounding factors need to
be addressed. First, the comparison group was recruited before the patients in order to compare the
first included patients’ FDG PET images to those
of healthy subjects and, thus, determine a target for
stimulation. Although we aimed to constitute a
healthy subject group with a wide age range, there
was a significant age difference between the patient
and comparison groups as the comparison group
had to be the same for all comparisons. We cannot
rule out the possibility that the hypofunctional
clusters detected in older patients would not have
been observed in a comparison with age-matched
control subjects. However, this is unlikely as the
age ranges were similar across patient subgroups,
and as age was included as a confounding covariate
in modelling the statistical comparisons to minimize
this effect.
56
M.-L. Paillère Martinot et al.
Table 4. Depression scores comparison across treatment subgroups including left and right targets
Standard
(n=18)
MADRS baseline (mean¡S.D)
MADRS mean change from
baseline (mean¡S.D)
% Improvement (mean¡S.D)
32.0 (7.8)
x14.7 (8.9)
49.0 (28.0)
Left (n=9)
Right (n=7)
Sham (n=14)
F(3, 40)
p
34.0 (8.5)
x20.3 (12.8)
34.7 (6.0)
x11.4 (13.2)
34.6 (6.1)
x10.5 (12.3)
0.41
3.04
0.75
0.04
60.0 (31.2)
31.0 (33.3)
30.2 (36.9)
3.67
0.02
Statistics
Post-hoc analyses
MADRS change–from
baseline
Left-guided vs. standard
Left-guided vs. right-guided
Left-guided vs. sham
Standard vs. sham
Standard vs. right-guided
Right-guided vs. sham
t test
x1.58
x2.51
x2.61
x1.36
x1.45
0.39
d.f.
p
40
40
40
40
40
40
0.12
0.02
0.01
0.18
0.16
0.70
LS mean difference
(95 % CI)
x7 (x16 to 2)
x14.5 (x26 to x3)
x12 (x22 to x3)
x5 (x13 to 3)
x7 (x18 to 3)
2 (x9 to 13)
da
NNT
0.49
0.76
0.78
0.39
0.29
0.15
9
2.6
2.2
2.9
3.7
13.9
CI, Confidence interval ; LS, least square ; MADRS, Montgomery & Åsberg Depression Rating Scale ; NNT, number needed
to treat.
a
Cohen’s d effect sizes are as follows : small (d=0.20), medium (d=0.50), large (d=0.80).
Second, as in other studies of single-subjects vs. a
group (Ohta et al. 2008), the statistical threshold used
in the single-patient vs. healthy group analysis (p<
0.05, uncorrected) was low compared with the p<0.001
threshold often used in group analyses, as we aimed to
display enough hypometabolic clusters to choose a
peak voxel within the range of the magnetic field.
Nevertheless, two patients did not display hypofrontality, even at this threshold. We cannot preclude
that choosing a more stringent threshold would
have allowed selection of patients with more severe
hypofrontality, which perhaps would have yielded
stronger effects of PET-guided rTMS.
Third, the parameters used in this study (90 % MT,
10 sessions) might be viewed as being in the low
range. Indeed, some studies have underlined the better efficacy of higher stimulation intensities and prolonged treatment over several weeks (O’Reardon et al.
2007). However, although low parameters have been
found to yield inconsistent effects (Boutros et al. 2002),
the use of higher intensities or treatment durations has
not always provided better results (Garcia-Toro et al.
2001). Moreover, in the present study, the number of
pulses per session (1600) was high (Gershon et al. 2003)
and, although the treatment duration was short
(2 wk), the response rate in all the actively treated
patients (59 %) was higher than in many other studies
(Ebmeier & Herrmann, 2008).
Fourth, parallel with rTMS, the patients were receiving various medications such as benzodiazepines,
or antipsychotics, whose influence on cortical excitability might have blurred the effects of the rTMS
treatment. More patients were treated with benzodiazepines in the PET-guided group (10/16, 62 %) than
in the standard group (7/18, 38 %), which could have
diminished the effects in the PET-guided group, and
conversely, more antipsychotics were prescribed in
the standard group (22 % vs. 0 %), which could have
diminished the efficacy of stimulation in the standard
group. However, the randomization groups only differed from each other at the trend level with regard to
those medications, and given the high response rate in
this study (59 %), this medication effects seem unlikely. Conversely, it is also unlikely that the findings
might result from an ‘ add-on ’ effect of concomitant
medications, since such effects are controversial (Burt
et al. 2002 ; Bretlau et al. 2008 ; Herwig et al. 2007), and
should be the same in all groups. It is also unlikely that
a comorbid diagnosis of bipolar or anxiety disorders
interfered with response to rTMS as these disorders
were equally prevalent across subgroups.
Another limitation arises from the operator-dependent target determination method, in which the choice
of the hypometabolism peak voxel must take into
account the hypometabolism depth and the hemispheric level (Talairach z coordinate) in order to
Brain-imaging-guided TMS in resistant depression
stimulate areas that are accessible to the magnetic
field. However, this procedure was the same for the
right- and left-sided targets, and performed by the
same investigator blind to patient randomization. The
measure of coil–cortex distance or the reconstruction
of standard locations from previously determined
motor cortex targets are also operator-dependent, although easily reproducible with Anatomist. Of note,
the reconstructed standard locations corresponded to
BA 8 and BA 6 in 61 % of the patients, which is close to
the 68 % BA 8-6 in Herwig et al.’s study (2001), in
which they used neuronavigation to reconstruct standard locations.
It is also possible that the accuracy of the TMS
guidance and focality might have blurred the effects.
However, this guidance method has an accuracy of
10 mm comparable to that of frameless stereotactic
neuronavigating systems (Andoh et al. in press). The
focality of the TMS figure-of-eight coil is theoretically
2–3 cm2 at 110 % intensity of MT, and may depend on
stimulation intensity, coil–cortex distance, and hemisphere radius (Thielscher & Kammer, 2004). The size
of the cortical area stimulated at 90 % MT intensity, as
in the present study, should be very small, <2.5 cm2
according to Thielscher & Kammer (2004). Yet in a few
patients stimulation of contiguous areas other than
those targeted might have confounded the expected
effects.
Finally, it is unlikely that the absence of a rightsided sham-treated group might have biased the results because the right-sided stimulated patients
showed no significant improvement.
Conclusion
This study does not support the hypothesis of increased effectiveness of high-frequency rTMS when
applied over hypometabolic prefrontal regions, irrespective of the side of stimulation. Stimulation of the
DLPFC (BA 9 and/or 46) was more effective than
sham, but failed to be an effective target area for
stimulation in half of the patients. Finally, whether
brain-imaging guidance over the left prefrontal cortex
might speed up or increase the effects of rTMS in the
treatment of resistant depression warrants further investigation.
Acknowledgements
The study was supported by a grant to Dr M.-L.
Paillère-Martinot, from the ‘Programme Hospitalier
de Recherche Clinique, Délégation à la Recherche
Clinique de l’Assistance Publique-Hôpitaux de
57
Paris ’ (AP-HP) and the Health Ministry (PHRC/
AOM-98099), a grant from the French Institute for
Health and Medical Research (INSERM-PROGRES
A99013LS), and an AP-HP/INSERM interface grant.
Dr D. Ringuenet was supported by the ‘Fondation
pour la Recherche Médicale ’ (FRM) and the Atomic
Energy Commission (CEA). The authors are grateful
to Professor André Syrota, Frédéric Dollé, Dr Bernard
Guéguen, Dr Jani Penttilä, Dr François Pinabel, Xavier
Neveu and Edouard Duchesnay for their support.
Statement of Interest
None.
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