REVIEW
Can Repetitive Transcranial Magnetic Stimulation
Be Considered Effective Treatment Option for Negative
Symptoms of Schizophrenia?
Radovan Prikryl, MD, PhD and Hana Prikrylova Kucerova, PhD
Objective: Despite the development of second-generation antipsychotic
drugs, treatment-resistant symptoms still represent a serious problem in
schizophrenia. The aim of the present article was to review studies with
repetitive transcranial magnetic stimulation for negative symptoms
of schizophrenia and draw conclusions for clinical decision making.
Method: Literature for this review was identified by searching MED-
LINE and ISI Web of Science up to the year 2011.
Results: Five open studies, 13 sham-controlled studies, and 2 meta-
analysis and 2 review articles were included in the present paper. The
effect size of the high frequency repetitive transcranial magnetic stimu-
lation (rTMS) over the left prefrontal cortex in the treatment of negative
symptoms of schizophrenia is thought to be mild to moderate (Cohen
d = 0.43Y0.68).
Conclusion: Despite the promising results of some rTMS studies, the
potential of rTMS for the treatment of negative symptoms is currently
relatively unclear. Large clinical studies are therefore needed, especially
large multicentric studies such as depression rTMS studies.
Clinical Recommendations:
& There is an evidence showing that rTMS can be considered
the effective treatment option for negative symptoms of
schizophrenia.
& Based on the results of current meta-analyses, the effect size
of high-frequency rTMS in the treatment of negative symp-
toms of schizophrenia seems to be mild to moderate (Cohen
d = 0.43Y0.63).
& Despite limited evidence base, the associations between efficacy
and stimulation approaches (higher stimulation intensity,
higher number of sessions or 10 Hz stimulus frequency) appear.
Additional Comments:
& Neither the European Medicines Agency nor the Food and
Drug Administration has approved rTMS for the treatment of
negative symptoms of schizophrenia.
& Furthermore, large clinical studies are necessary to verify the
natural benefit of rTMS for general clinical practice.
Key Words: negative symptoms, schizophrenia, treatment, repetitive
transcranial magnetic stimulation, review
(J ECT 2013;29: 67Y74)
From the Central European Institute of Technology (CEITEC), Masaryk
University, and Department of Psychiatry Medical Faculty, Masaryk Uni-
versity Hospital, Brno, Czech Republic.
Received for publication December 21, 2011; accepted August 14, 2012.
Reprints: Radovan Prikryl, MD, PhD, Department of Psychiatry, University
Hospital Brno, Jihlavska 20, 625 00 Brno, Czech Republic
(e-mail: radovan.prikryl@post.cz).
This work was supported by the project CEITEC (Central European Institute
of Technology) (CZ.1.05/1.1.00/02.0068) from European Regional
Development Fund and by the project (Ministry of Health, Czech
Republic) for conceptual development of research organization
65269705 (University Hospital Brno, Brno, Czech Republic).
The authors have no conflicts of interest or financial disclosures to report.
Copyright * 2013 by Lippincott Williams & Wilkins
DOI: 10.1097/YCT.0b013e318270295f
Journal of ECT & Volume 29, Number 1, March 2013
Copyright 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
D espite the development of second-generation antipsychotic
drugs, treatment of negative symptoms of schizophrenia
still represents a serious problem in schizophrenia. Meta-analyses
assess the effect size of the second-generation antipsychotics in
the treatment of negative symptoms of schizophrenia as mild to
moderate at most.1,2 The failure to reach a satisfactory reduction
of negative symptoms by antipsychotics only has led to searching
for other therapeutic approaches such as combinations of anti-
psychotics and antidepressants,3 attempts to influence the glu-
tamatergic system by lamotrigine,4 specific psychotherapeutic
supportive programs,5 or augmentation by repetitive tran-
scranial magnetic stimulation (rTMS).6 Repetitive transcranial
magnetic stimulation is a brain neuromodulation method, which
has gradually found application in various severe neuropsychi-
atric disorders such as major depression, schizophrenia, tinnitus,
and others.7
LITERATURE SEARCH AND STUDY SELECTION
Literature for this review was identified by searching
MEDLINE and ISI Web of Science. The search for pertinent
publications was carried out using the terms repetitive tran-
scranial magnetic stimulation, negative symptoms, schizophrenia,
and treatment for the years 1985 through May 2011. Searches
were performed for original papers, reviews, and meta-analyses.
In addition, a hand search for relevant publications was con-
ducted by using references of articles retrieved. Five open studies,
13 sham-controlled studies, and 2 meta-analysis and 2 review
articles were included in the present paper.
THEORETICAL MECHANISMS UNDERLYING
TREATMENT EFFECTS OF rTMS IN NEGATIVE
SYMPTOMS OF SCHIZOPHRENIA
Functional neuroimaging studies have linked increased
severity of negative symptoms of schizophrenia to reduced frontal
activation.8Y10 Disturbed dopaminergic neurotransmission has
been repeatedly described in schizophrenia.11 The activity of
dopamine neurons is among others modulated by the prefrontal
cortex (PFC) via activation and inhibitory pathways.11Y13 Whereas
the function of the activation pathway is mediated through both
direct and indirect glutamatergic projections onto dopamine
neurons, the inhibitory pathway is modulated through the pre-
frontal glutamatergic efferent terminals on gamma-aminobutyric
acid interneurons and striatomesencephalic gamma-aminobutyric
acid neurons. The model of dual modulation of the mesolimbic
dopaminergic network through PFC was also supported by the
conclusion of studies, which showed that the extracellular
concentration of dopamine in the nucleus accumbens is in-
creased after high-frequency stimulation of the PFC.14 Animal
studies also showed the necessity for the intact function of do-
pamine D1 receptors for optimal performance of the PFC.15,16
These facts lead to the hypothesis that a deficit in prefrontal
dopaminergic neurotransmission, mediated by the dopamine
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Prikryl and Kucerova
D1 receptors, may be the key etiopathogenetic basis of the
negative symptoms in schizophrenia.10,17,18
The mechanism of rTMS action, related to etiopathogen-
esis of the negative symptoms, has not been unambiguously ex-
plained. However, it was repeatedly shown that high-frequency
rTMS (10Y20 Hz) increases cerebral excitability, whereas low
frequency (G1 Hz) decreases it.19 Animal models also show that
rTMS increases the density of N-methyl D-aspartate (NMDA)
receptors, even after a single stimulation.20 A study using 5-Hz
stimulation of the left primary somatosensory cortex showed
an increase in cortical excitability through activation of NMDA
receptors.21 It can therefore be expected that rTMS may serve
as an agonist of NMDA receptors in the PFC if high-frequency
stimulation is applied over this area.22,23 After high-frequency
stimulation, there is also up-regulation of A-adrenergic and
serotonin 5HT1A and 5HT2 receptors.24 Both animal and hu-
man studies have also shown that high-frequency rTMS, applied
over the left PFC, modulates dopamine release in the meso-
limbic and mesostriatal systems of the brain. Selective increases
in extracellular dopamine, in the dorsal striatum, and nucleus
accumbens, have been repeatedly found in animal studies.25,26
Significant increases in the dopamine extracellular concen-
tration also appeared in the caudate nucleus and left putamen
in humans in positron emission tomography studies.27Y29 The
positive influence of rTMS on negative schizophrenia symp-
toms is therefore expected to mainly consist of its ability to
normalize prefrontal hypometabolism via modulation of perfu-
sion, cerebral metabolism, and neuronal excitability.30Y32
EFFICACY OF rTMS STUDIES IN THE TREATMENT
OF NEGATIVE SYMPTOMS
Open Clinical Trials
The first 2 pioneer works, which tried to treat schizo-
phrenic symptoms by stimulation of the PFC, were relatively
small open studies. They were based on low-frequency stimu-
lation of PFC, which led to transient improvement of mood or
alleviation of anxiety but failed in its effort to extensively in-
fluence other schizophrenic symptoms.33,34
Subsequent studies used high-frequency stimulation di-
rected to the area of the left PFC. Cohen showed a statistically
significant decrease in the intensity of negative symptoms in
6 subjects; however, the real clinical effect was assessed as
relatively small.35 A study by Jandl36 has shown that stimulation
leads to changes in the brain electric activity according to elec-
troencephalogram (EEG). Despite mild, although statistically
significant improvement of negative (9%) and affective (16%)
schizophrenia symptoms, they observed that right frontotem-
porally, delta and beta activities were reduced; whereas alpha
activity increased and left temporally and parieto-occipitally,
beta activity was reduced. The authors believe that despite the
small clinical improvement of negative symptoms, the estab-
lished changes in the EEG may be considered as neurophysi-
ologic signs of improvement of negative schizophrenia symptoms
after rTMS.36 Stimulation treatment of 4 patients with deficit
syndrome of schizophrenia led to a statistically significant de-
crease in the severity of negative symptoms and improvement
in the general functioning of the patients, which persisted for
a 1-month period of subsequent monitoring after the end of
stimulation.37,38
Sham-Controlled Studies
Summary of the most relevant sham-controlled studies of
rTMS in the treatment of negative symptoms of schizophrenia
is displayed in Table 1 (modified according to Jockers et al3).
68 www.ectjournal.com
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Journal of ECT & Volume 29, Number 1, March 2013
The first published double-blind study tested the hypoth-
esis whether low-frequency rTMS, applied over the area of
the right PFC influences not only mood but also schizophrenic
symptoms. Both in the placebo and in the rTMS-treated group,
a slight improvement of psychopathology occurred; however,
no significant difference between the real and placebo stimu-
lation was found.39 Other works used only high-frequency
stimulation over the left PFC. In a small study, real rTMS, in
contrast to placebo, decreased the severity of negative symp-
toms of schizophrenia.48
In other studies, high-frequency rTMS over the left PFC
led to a statistically significant decrease in the severity of
schizophrenic symptoms without any influence on the depres-
sion or anxiety symptoms, which might be interpreted as evi-
dence of the specific antipsychotic effect of rTMS.40,49 Whereas
stimulation treatment seemed to be less effective in chronic
schizophrenic patients, the idea emerged that high-frequency
rTMS over the left prefrontal cortex had unspecific treatment
effects rather than direct antipsychotic effects.41
In common rTMS and EEG study, the correlation between
the individual alpha (8Y13 Hz) stimulation frequency and the
reduction of negative schizophrenia symptoms was studied. It
was based on the knowledge that patients with schizophrenia
show decreased alpha activity (both spectral performance
and coherence) not only under rest conditions but also during
sensory or cognitive stimulations.50Y52 The study came to the
conclusion that rTMS using the alpha frequency led to a more
marked reduction of negative symptoms compared to the com-
pared stimulation frequencies. In addition, the changes in EEG
during stimulation predicted clinical improvement.29 Even if
the results seem to be indeed interesting, the authors had no
comparison group at 10 Hz so it does not permit a clear con-
clusion about the definite benefit of alpha stimulation applica-
tion. However, the stimulation with frequency ranged between 8
and 13 Hz seems to be more effective in treatment of negative
symptoms than the other stimulation frequencies. For example,
20-Hz frequency stimulation reached no clinically relevant ef-
fect in treatment of the negative symptoms,44 but 10-Hz rTMS
in combination with a sufficient number of stimulation sessions15
led to a marked decrease in the intensity of negative symptoms.45
The study by Goyal et al42 came to the conclusion that
rTMS had been only effective in the treatment of negative symp-
toms but had failed in the treatment of positive symptoms of
schizophrenia. Another study failed in demonstrating rTMS
efficacy not only on negative symptoms but also on quality of
life, depression, anxiety, and cognitive functions.43 Both studies
were limited, however, by their small sample of patients and
related risks of false-negative results.
So far, published works have been based on the principal
theoretical hypothesis that it is only the left PFC that is involved
in the pathophysiology of negative schizophrenia symptoms.53
Despite this, the disrupted activation of the PFC, related with
negative schizophrenia results, also occurs in the right brain
hemisphere54 or bilaterally.55 Therefore, Fitzgerald et al46
designed a study in which they tried to verify the efficacy of bi-
lateral stimulation of the PFC in treatment of negative symptoms.
The results indicated, however, that there was no statistically
significant difference between real and placebo stimulations.
In randomized sham-controlled study with chronic schizo-
phrenia patients, only a subgroup of patients with pronounced
negative symptoms developed some clinical improvement as
indicated by significant changes in the Global Assessment of
Functioning Scale.56 Furthermore, no statistically significant
deterioration of cognitive performance was observed as a result
of rTMS treatment. Moreover, it was shown that a less favorable
* 2013 Lippincott Williams & Wilkins
 Journal of ECT
&

TABLE 1. Summary of the Most Relevant Sham-Controlled Studies of rTMS in the Treatment of Negative Symptoms of Schizophrenia

Study Randomly Duration

Study N Design Assigned Treatment Settings Location Total No. Pulses (Days) Rating Scale Outcome
Klein et al39 (1999) 35 Parallel Yes 2 trains/d, 60 s of 1 Hz Right PFC 1200 10 PANSS Real = sham
at 110% MT, 180-s

* 2013 Lippincott Williams & Wilkins

intertrain interval
Hajak et al40 (2004) 20 Parallel Yes 20 trains/d, 5 s of 10 Hz Left DLPFC 10,000 10 PANSS Real 9 sham
at 110% MT
Holi et al41 (2004) 22 Parallel Yes 20 trains/d, 5 s of 10 Hz Left DLPFC 10,000 10 PANSS Real = sham
at 110% MT, 30-s
intertrain interval
Goyal et al42 (2007) 10 Parallel Yes 20 trains/d, 4.9 s of Left DLPFC 9800 10 PANSS
Volume 29, Number 1, March 2013

Real 9 sham
10 Hz at 110% MT,
30-s intertrain interval
Mogg et al43 (2007) 17 Parallel Yes 20 trains/d, 10 s of Left DLPFC 20,000 10 PANSS Real = sham
10 Hz at 110% MT,
50-s intertrain interval
Novak et al44 (2006) 16 Parallel Yes 40 trains/d, 2.5 s of Left DLPFC 20,000 10 PANSS Real = sham
20 Hz at 90% MT,
30-s intertrain interval
Prikryl et al45 (2007) 22 Parallel Yes 15 trains/d, 10 s of Left DLPFC 22,500 15 PANSS, SANS Real 9 sham
10 Hz at 110% MT,
30-s intertrain interval
Fitzgerald et al46 (2008) 20 Parallel Yes 20 trains/d, 5 s of 10 Hz Bilateral DLPFC 30,000 (15,000 per side) 15 PANSS, SANS Real = sham
at 110% MT, 25-s
intertrain interval
Schneider et al47 (2008) 51 Parallel Yes 20 trains/d, 5 s of 10 Hz Left DLPFC 2000 20 SANS Real 10 Hz 9 sham
or 1
Hz at 110% MT, 15-s
intertrain interval
Real 1 Hz = sham
DLPFC indicates dorsolateral prefrontal cortex; MT, motor threshold; PANSS, Positive and Negative Syndrome Scale; SANS, Scale for the Assessment of Negative Symptoms.

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69www.ectjournal.com
Can rTMS Be Effective Treatment Option?
Prikryl and Kucerova
cognitive performance at baseline tends to improve after real
rTMS treatment with regard to psychopathology.57
The results are in line with those of earlier investigators,
suggesting a moderate, potentially clinically relevant treatment
effect of PFC high-frequency rTMS stimulation in the treatment
of negative symptoms of schizophrenia. Only high-frequency
stimulation over the left PFC is thought to be efficient in the
reduction of negative symptoms, whereas the other parameters
such as cognitive functions or quality of life are not influenced.47
META-ANALYSES OF rTMS STUDIES IN THE
TREATMENT OF NEGATIVE SYMPTOMS
The efficacy of rTMS in the treatment of negative schizo-
phrenia symptoms has also been proved in 2 meta-analyses.
The first published meta-analysis analyzed 19 studies, but
high-frequency stimulation over the left PFC was used only
in 13 studies. However, the statistical analysis finally included
8 studies because only in those studies were mean values and
standard deviations available. The analysis indicated that the
effect size corresponds to the value of Cohen d = 0.58, which
equates to a mild to moderate effect of rTMS on the alleviation
of negative symptoms.58 A possible explanation of the low ef-
fect of rTMS may consist of the fact that the number of studies
analyzed was relatively low and, in addition, 2 studies with
positive results29,40 were excluded owing to insufficiently sta-
tistically supported data. In particular, the study by Jin et al29
showed very promising results on a large patient population.
The second meta-analysis, published in 2010,59 primarily
analyzed 16 studies; however, owing to methodological draw-
backs or repeated publications of identical results, only 9 of
them were included in the final statistical analysis. When eval-
uating the studies using high-frequency stimulation of the left
PFC, the effect of treatment was low (Cohen d = 0.43); when
only studies with 10-Hz frequency are included in the analysis,
the effect of the treatment seems to be moderate (Cohen d = 0.63).
When studies, in which antipsychotic medication was not stable
during the stimulation course, were removed from the analysis,
the effect of the treatment sank to Cohen d = 0.34. The reason for
such a decrease in the treatment effect was the exclusion of the
study by Goyal et al42 in which patients without medication had
been included and during the course of stimulation therapy an-
tipsychotic drugs were applied. Another important conclusion
of the meta-analysis represents the finding that longer stimula-
tion therapy (3 and more weeks) turned out to be more efficient
than shorter stimulation times (Cohen d = 0.58 vs d = 0.32).
CRITICAL ASSESSMENT OF THE STUDIES WITH
RESPECT TO METHODS AND LIMITATIONS
Present studies using rTMS for treatment of negative
symptoms of schizophrenia indicate that there are many meth-
odological problems whose elimination or reduction could lead
to improved efficacy of rTMS and allow better application in
clinical practice. The principal problems include a varied clinical
picture, different phases of schizophrenia including age of the
included patients, distinction of primary and secondary symptoms
or parameters stimulation such as the intensity and stimulation
dose, direction of the stimulation coil, targeting coil localization,
or the problem of blinding in double-blind studies.60,61
CHARACTER OF THE NEGATIVE SYMPTOMS,
THEIR SYMPTOMATOLOGICAL PROFILE,
SCHIZOPHRENIA STAGE, AND PATIENTS AGE
Most of the studies did not sufficiently reckon with the
clinical heterogeneity of the patients included in the studies.
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Journal of ECT & Volume 29, Number 1, March 2013
However, the basic demographic characteristics of the patients
including their profile of cognitive functions may form im-
portant predictors of their response to rTMS. For example, in
the study by Mogg et al,43 a group of patients treated by real
rTMS was significantly older, and the duration period of the
disease was longer. The degree of pharmacoresistance was not
adequately assessed either.
As for the negative symptoms, it is also necessary to dis-
tinguish primary negative symptoms from secondary ones in-
cluding depression, influence of medication, psychosocial results
of schizophrenia, and others. The primary negative symptoms
are considered an important part of the deficit syndrome of
schizophrenia. It turns out, however, that patients with deficit
syndrome show, in contrast to patients without deficit syn-
drome, different neuroanatomic correlates,62,63 which may ex-
plain their different responses to rTMS.
Besides that, the symptoms of negative syndrome and
depressive syndrome mutually overlap. It turns out that the
total score of the Positive and Negative Syndrome Scale,64Y66
in contrast to the total score of the Scale for the Assessment of
Negative Symptoms65,67Y70 positively correlates with depressive
symptoms measured by means of the Hamilton and Montgomery
Depression scale.71 Because depression is often seen in schizo-
phrenia, it is therefore necessary to distinguish between neg-
ative and depressive symptoms, especially if the target area of
stimulation is the left PFC and its stimulation also positively
influences mood. A solution can be found with the Calgary De-
pression Scale for Schizophrenia, which specifically distinguishes
between negative and depressive symptoms of schizophrenia.
Another question, which remains to be answered, is the
character of the rTMS effect on negative symptoms.60 Actually,
it is not fully clear whether the stimulation effect nonspecifically
reduces all symptomatological domains of negative symptoms
or if the general alleviation of negative symptoms intensity is
primarily based on the influence on certain symptoms only.
STIMULATION PARAMETERS: DOSE, INTENSITY,
AND PERIOD OF STIMULATION
The selected stimulation parameters represent the princi-
pal factor for the efficacy of rTMS. It turns out that a higher
number of pulses applied72 with longer duration of stimulation
treatment59 are associated with a greater therapeutic effect on
negative symptoms. In addition, higher intensity of stimulation,
defined as 110% or 120% of the individual motor threshold, is
a necessary condition for higher efficacy of rTMS.45 From the
view of stimulation frequency, the individualized alpha-band
frequency or 10-Hz frequency seem to be optimal for influencing
negative symptoms of schizophrenia.29,36
TARGETING COIL LOCALIZATION
Whereas rTMS studies aimed at the treatment of auditory
hallucinations or tinnitus have mostly used frameless stereo-
tactic navigation to accurately focus on the target stimulation
area, treatment of negative symptoms has used the classic
method for positioning of the stimulation coil. However,
Herwig et al73 has shown that this method is inaccurate for PFC
localization. Actually, as he found when comparing the classic
positioning and positioning controlled by magnetic resonance,
in only 7 of 22 patients was the target area of the PFC correctly
focused. Inaccuracies in focusing on the target stimulation area
may be solved by the use of frameless stereotactic neuronavi-
gation. Studies using neuronavigation, especially when auditory
hallucinations were treated, reached better results than those
using classic positioning of the stimulation coil.74 In his case
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Journal of ECT & Volume 29, Number 1, March 2013
reports, Langguth et al75 showed that when the area of increased
cerebral metabolism had been identified by means of fluor-
odeoxyglucose positron emission tomography and the stimula-
tion coil had been aimed at this area, he achieved not only a
reduction of intensity of auditory hallucinations but also a de-
crease in pathologically increased cerebral metabolism in that
area. Furthermore, it turns out that neuronal activity of the
temporoparietal cortex may predict the effect of rTMS in the
treatment of auditory hallucinations.72,76 However, such find-
ings have not been investigated in rTMS studies dealing with
treatment of negative symptoms.
TARGET POINTS OF STIMULATION
Although the most studies have chosen high-frequency
stimulation over the left PFC for the treatment of negative
symptoms, there are other potential stimulation targets. Struc-
tural and functional deficits for negative symptoms have been
found in the medial frontal areas,77 anterior cingulate,78 and in
the posterior cortical parietal cortex79 comprising the interior
parietal lobule.80 The cerebellum is also included in the patho-
physiology of schizophrenia, its role being in the modulation
of higher cognitive processes.81 There is a persistent problem
with stimulation of the cerebellum, namely, the accuracy of
targeting and relative soreness of stimulation. It is also known
that the frontal deficits in schizophrenia are bilateral; however,
only a few authors have tried to influence negative symptoms
using bilateral stimulation of the PFC.46 The application of se-
quential stimulation, aimed at the areas of the PFC and tem-
poroparietal cortex, seems to be an interesting experiment, which
brought marked reduction in not only negative but also posi-
tive schizophrenia symptoms.82 Hence, some other areas of
the brain or their simultaneous stimulation might therefore be
more appropriate for treatment of negative symptoms.
COIL-TO-CORTEX DISTANCE
The distance between the stimulation coil and surface of
the cerebral cortex plays an important role in rTMS efficacy.
Actually, in a study of patients older than 55 years in which the
stimulation dose was adjusted by the distance between the coil
and the cortex, better therapeutic effect was reached.83 This is
especially important for studies involving patients with negative
symptoms because, particularly, lower volumes of the frontal lobes
are repeatedly found in them in contrast to healthy volunteers.84
For that reason, the routine targeting of the stimulation coil on
the scalp may not be sufficient; and therefore, in all future
studies, the distance between the scalp and cortex should be
measured by means of magnetic resonance imaging to com-
pensate for individual distances between the motor and the
prefrontal area of the brain.85,86 Such an approach, however,
has not been used in any of the rTMS studies dealing with the
treatment of negative symptoms.
BLINDING CONDITIONS
It is clear that the double-blind studies are more beneficial
from both a clinical and statistical point of view. However,
there is a problem consisting in the method of blinding. Most
rTMS studies used a real stimulation coil for the conditions of
blinding; such a coil, however, was placed to make a 45-degree,
or possibly 90-degree, angle with the head surface. Such a
method of blinding cannot be considered ideal.61,87,88 Only a
small number of studies used a special sham coil.43 Nevertheless,
the sham coil does not represent an optimal method of blinding
because some of the tactile perceptions, perceived by patients
treated with active stimulation, are missing. The problem of
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Can rTMS Be Effective Treatment Option?
blinding in rTMS studies is admittedly more complicated even
if a sham coil is used.
To solve the methodological problems of blinding, an
rTMS study supported by the National Institute of Mental
Health was designed in 2009. Its title is Optimization of rTMS
for Treatment of Depression and is quite exceptional owing to
its new method of blinding because the person acquainted with
the method of stimulation does not come into contact with the
patient or his/her dates or the evaluator of the clinical condi-
tion.89,90 However, in the area of rTMS use for treatment of
schizophrenia, no such study, solving the blinding in this way,
has ever been designed. Future works should therefore try to
assure mutual blinding of the patient, rTMS operator, and the
person assessing the clinical change.61
PATIENTS COMPLIANCE WITH rTMS
TREATMENT OF NEGATIVE SYMPTOMS
Although the treatment with rTMS is generally well tol-
erated, it is quite difficult to recruit patients with prominent
negative symptoms of schizophrenia to rTMS studies. Patients
with negative symptoms are not motivated to undergo rTMS
treatment probably owing to the core negative symptoms such
as anhedonia or loss of interest. Even if a number of dropouts,
especially owing to rTMS inefficacy or adverse events, are
reported in studies, information concerning how many patients
have been screened for study inclusion is completely missing.
CONCLUSIONS AND PERSPECTIVES
FOR FUTURE RESEARCH
Future studies investigating rTMS efficacy on negative
symptoms of schizophrenia should not only aim at the refine-
ment of stimulation parameters with an effort to maximize the
use of their potential; they should not only assess rTMS in-
fluence on the level of symptom reduction but should include
functional potential changes or parameters in quality of life in
the assessment. In the area of stimulation parameters, there is
the possibility of application of a higher number of stimulation
pulses during a single stimulation session, possibly 2 stimula-
tion sessions in a single day. As known from rTMS studies
in depression, 20 to 30 stimulation sessions show higher effi-
ciency than half of that number.91 Also, the possibilities of
bifrontal stimulation have been only marginally investigated so
far, not to mention the possibility of sequential stimulation of
2 brain areas.82 To date, with the exception of the alpha activi-
ties change on the EEG, no changes in brain metabolism, in case
of remission of the negative symptoms induced by rTMS stim-
ulation, have been demonstrated. It is a question whether a
statistical method, based on an analysis of the region of interest
(eg, frontal cortex), should be used for functional imaging in-
stead of the commonly used voxel-based analysis. The para-
meters, such as quality of life, general functioning, or change
in cognitive functions, have also been only minimally investi-
gated. It is possible that any change in those parameters would
be much more beneficial for patients than a mere reduction
of the defined target symptoms. Future studies should also be
aimed at the persistent effects of acute stimulation treatment
with possible transfer of the patients to maintenance therapy,
as in cases of ECT.
Despite the promising results of some rTMS studies, the
potential of rTMS for the treatment of negative symptoms is
currently relatively unclear. Large clinical studies are therefore
needed, especially large multicentric studies such as depression
rTMS studies.56
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Prikryl and Kucerova
CONCLUSION
Schizophrenia is a serious disease, which can only be par-
tially influenced by contemporary pharmacological treatment.92
Owing to low adherence, a high degree of pharmacoresistance
associated with the progress of the disease, and deterioration of
the socioeconomic status of patients, there is a logical pressure
on augmenting treatments of negative symptoms even if fur-
ther large clinical studies are necessary to verify the natural
benefit of this method for general clinical practice.
REFERENCES
1. Leucht S, Pitschel-Walz G, Abraham D, et al. Efficacy and
extrapyramidal side-effects of the new antipsychotics olanzapine,
quetiapine, risperidone and sertindole compared to conventional
antipsychotics and placebo. A meta-analysis of randomized controlled
trials. Schizophr Res. 1999;4:51Y68.
2. Leucht S, Corves C, Arbter D, et al. Second-generation versus
first-generation antipsychotic drugs for schizophrenia: a meta-analysis.
Lancet. 2009;3:31Y41.
3. Jockers-Scherubl MC, Bauer A, Godemann F, et al. Negative symptoms
of schizophrenia are improved by the addition of paroxetine to
neuroleptics: a double-blind placebo-controlled study.
Int Clin Psychopharmacol. 2005;20:27Y31.
4. Premkumar TS, Pick J. Lamotrigine for schizophrenia. Cochrane
Database Syst Rev. 2006;4: CD005962. DOI: 10.1002/14651858.
5. Buckley PF, Stahl SM. Pharmacological treatment of negative
symptoms of schizophrenia: therapeutic opportunity or cul-de-sac?
Acta Psychiatr Scand. 2007;115:93Y100.
6. Matheson SL, Green MJ, Loo C, et al. Quality assessment and
comparison of evidence for electroconvulsive therapy and repetitive
transcranial magnetic stimulation for schizophrenia: a systematic
meta-review. Schizophr Res. 2010;11:201Y210.
7. Schlaepfer T, Mark G, Mayberg H, on behalf of the WFSBP Task Force
on Brain Stimulation. The World Federation of Societies of Biological
Psychiatry (WFSBP) guidelines on brain stimulation treatments in
psychiatry. World J Biol Psychiatry. 2010;11:2Y18.
8. Weinberger DR, Egan MF, Bertolino A, et al. Prefrontal neurons and the
genetics of schizophrenia. Biol Psychiatry. 2001;50:825Y844.
9. Hill K, Mann L, Laws KR, et al. Hypofrontality in schizophrenia:
a meta-analysis of functional imaging studies. Acta Psychiatr
Scand. 2004;4:243Y256.
10. Stoeber G, Ben-shachar D, Cardon M, et al. Schizophrenia: from the
brain to peripheral markers. A consensus paper of the WFSBP task
force on biological markers. World J Biol Psychiatry. 2009;10:127Y155.
11. Laruelle M, Kegeles LS, Abi-Dargham A. Glutamate, dopamine, and
schizophrenia: from pathophysiology to treatment. Ann NY
Acad Sci. 2003;1003:138Y158.
12. Bertolino A, Breier A, Callicott JH, et al. The relationship between
dorsolateral prefrontal neuronal N-acetylaspartate and evoked release of
striatal dopamine in schizophrenia. Neuropsychopharmacology.
2000;22:125Y132.
13. Meyer-Lindenberg A, Miletich RS, Kohn PD, et al. Reduced prefrontal
activity predicts exaggerated striatal dopaminergic function in
schizophrenia. Nat Neurosci. 2002;5:267Y271.
14. Jackson ME, Frost AS, Moghaddam B. Stimulation of prefrontal cortex
at physiologically relevant frequencies inhibits dopamine release in
the nucleus accumbens. J Neurochem. 2001;78:920Y923.
15. Goldman-Rakic PS, Muly EC, Williams GV. D1 receptors in prefrontal
cells and circuits. Brain Res Rev. 2001;31:295Y301.
16. Winterer G, Weinberger DR. Genes, dopamine and cortical signal-to-
noise ratio in schizophrenia. Trends Neurosci. 2004;27:683Y690.
72 www.ectjournal.com
Copyright 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of ECT & Volume 29, Number 1, March 2013
17. Weinberger DR, Berman KF, Chase TN. Mesocortical dopaminergic
function and human cognition. Ann NY Acad Sci. 1988;537:330Y338.
18. Knable MB, Weinberger DR. Dopamine, the prefrontal cortex and
schizophrenia. J Psychopharmacol. 1997;11:123Y131.
19. Post RM, Kimbrell TA, Frye M. Implications of kindling and quenching
for the possible frequency dependence of rTMS. CNS Spectr.
1997;2:54Y60.
20. Ragert P, Dinse HR, Pleger B, et al. Combination of 5 Hz repetitive
transcranial magnetic stimulation (rTMS) and tactile coactivation
boosts tactile discrimination in humans. Neurosci Lett.
2003;348:105Y108.
21. Knecht S, Ellger T, Breitenstein C, et al. Changing cortical excitability
with low-frequency transcranial magnetic stimulation can induce
sustained disruption of tactile perception. Biol Psychiatry.
2003;53:175Y179.
22. DSouza DC, Charney DS, Krystal JH. Glycine site agonists of the
NMDA receptor: a review. CNS Drug Rev. 1995;1:227Y260.
23. Kole MH, Fuchs E, Ziemann U, et al. Changes in 5-HT1A and NMDA
binding sites by a single rapid transcranial magnetic stimulation
procedure in rats. Brain Res. 1999;826:309Y312.
24. Ben-Shachar D, Gazawi H, Riboyad-Levin J, et al. Chronic repetitive
transcranial magnetic stimulation alters A-adrenergic and 5-HT2
receptor characteristics in rat brain. Brain Res. 1999;816:78Y83.
25. Taber MT, Fibiger HC. Electrical stimulation of the prefrontal cortex
increases dopamine release in the nucleus accumbens of the rat:
modulation by metabotropic glutamate receptors.
J Neurosci. 1995;15:3896Y3904.
26. Keck M, Welt T, Muller M, et al. Repetitive transcranial magnetic
stimulation increases the release of dopamine in the mesolimbic and
mesostriatal system. Neuropharmacology. 2002;43:101.
27. Strafella AP, Paus T, Barrett J, et al. Repetitive transcranial magnetic
stimulation of the human prefrontal cortex induces dopamine release in
the caudate nucleus. J Neurosci. 2001;21:RC157.
28. Strafella AP, Paus T, Fraraccio M, et al. Striatal dopamine release
induced by repetitive transcranial magnetic stimulation of the human
motor cortex. Brain. 2003;126:2609Y2615.
29. Jin Y, Potkin SG, Kemp AS, et al. Therapeutic effects of individualized
frequency transcranial magnetic stimulation (rTMS) on the negative
symptoms of schizophrenia. Schizophr Bull. 2006;32:556Y561.
30. Fox P, Ingham R, George MS, et al. Imaging human intra-cerebral
connectivity by PET during TMS. Neuroreport. 1997;8:2787Y2791.
31. Conca A, Peschina W, Konig P, et al. Effect of chronic repetitive
transcranial magnetic stimulation on regional cerebral blood flow and
regional cerebral glucose uptake in drug treatment resistant depressives:
a brief report. Neuropsychobiology. 2002;45:27Y31.
32. Mottaghy FM, Keller CE, Gangitano M, et al. Correlation of cerebral
blood flow and treatment effects of repetitive transcranial magnetic
stimulation in depressed patients. Psychiatry Res. 2002;115:1Y14.
33. Geller V, Grisaru N, Abarbanel JM, et al. Slow magnetic stimulation
of prefrontal cortex in depression and schizophrenia.
Prog Neuropsychopharmacol Biol Psychiatry. 1997;21:105Y110.
34. Feinsod M, Kreanin B, Chistyakov A, et al. Preliminary evidence for
beneficial effect of low-frequency repetitive transcranial magnetic
stimulation in patients with major depression and schizophrenia.
Depress Anxiety. 1998;7:65Y68.
35. Cohen E, Bernardo M, Misana J, et al. Repetitive transcranial magnetic
stimulation in the treatment of chronic negative schizophrenia: a pilot
study. J Neurol Neurosurg Psychiatry. 1999;67:129Y130.
36. Jandl M, Bettner R, Sack A, et al. Changes in negative symptoms and
EEG in schizophrenic patients after repetitive transcranial magnetic
stimulation (rTMS): an open-label pilot study. J Neural Transm.
2005;112:955.
* 2013 Lippincott Williams & Wilkins
Journal of ECT & Volume 29, Number 1, March 2013
37. Sachdev P, Loo C, Mitchell P, et al. Transcranial magnetic stimulation
for the deficit syndrome of schizophrenia: a pilot investigation.
Psychiatry Clin Neurosci. 2005;29:354Y357.
38. Sachdev PS. Transcranial magnetic stimulation for the deficit syndrome
of schizophrenia. Acta Neuropsychiatrica. 2007;19:56Y58.
39. Klein E, Kolsky Y, Puyerovsky M, et al. Right prefrontal slow repetitive
transcranial magnetic stimulation in schizophrenia: a double blind
sham-controlled pilot study. Biol Psychiatry. 1999;46:1451Y1454.
40. Hajak G, Marienhagen J, Langguth B, et al. High-frequency repetitive
transcranial magnetic stimulation in schizophrenia: a combined
treatment and neuroimaging study. Psychol Med. 2004;34:1157Y1163.
41. Holi MM, Eronen M, Toivonen K, et al. Left prefrontal repetitive
transcranial magnetic stimulation in schizophrenia.
Schizophr Bull. 2004;30:429Y434.
42. Goyal N, Nizamie SH, Desarkar P. Efficacy of adjuvant high frequency
repetitive transcranial magnetic stimulation on negative and positive
symptoms of schizophrenia: preliminary results of a double blind
sham-controlled study. J Neuropsychiatry Clin Neurosci.
2007;19:464Y467.
43. Mogg A, Purvis R, Eranti S, et al. Repetitive transcranial magnetic
stimulation for negative symptoms of schizophrenia: a
randomized controlled pilot study. Schizophr Res. 2007;93:221Y228.
44. Novak T, Horacek J, Mohr P, et al. The double-blind sham-controlled
study of high-frequency rTMS (20 Hz) for negative symptoms in
schizophrenia. Negative results. Neuro Endocrinol Lett.
2006;25:209Y213.
45. Prikryl R, Kasparek T, Skotakova S, et al. Treatment of negative
symptoms of schizophrenia using repetitive transcranial
magnetic stimulation in a double-blind, randomized controlled study.
Schizophr Res. 2007;95:151Y157.
46. Fitzgerald PB, Herciny S, Hoy K, et al. A study of the effectiveness of
bilateral transcranial magnetic stimulation in the treatment of the
negative symptoms of schizophrenia. Brain Stimulation. 2008;1:27Y32.
47. Schneider AL, Schneider TL, Stark H. Repetitive transcranial magnetic
stimulation (rTMS) as an augmentation treatment for the negative
symptoms of schizophrenia: a 4-week randomized placebo controlled
study. Brain Stimulation. 2008;1:106Y111.
48. Nahas Z, McConnell KCS, Molloy M, et al. Could left prefrontal rTMS
modify negative symptoms and attention in schizophrenia?
Biol Psychiatry. 1999;45:37.
49. Rollnik JD, Huber TJ, Mogg H, et al. High frequency repetitive
transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal
cortex in schizophrenic patients. Neuroreport. 2000;11:4013Y4015.
50. Stevens JR, Livermore A. Telemetered EEG in schizophrenia: spectral
analysis during abnormal behavior episodes. J Neurol Neurosurg
Psychiatry. 1982;45:385Y395.
51. Colombo C, Gambini O, Macciardi F, et al. Alpha reactivity in
schizophrenia and in schizophrenic spectrum disorders: demographic
clinical and hemispheric assessment. Int J Psychophysiol.
1989;7:47Y54.
52. Hoffman R, Buchsbaum M, Escobar M, et al. EEG coherence of
prefrontal areas in normal and schizophrenia males during perceptual
activation. J Neuropsychiatry Clin Neurosci. 1991;3:169Y175.
53. Klemm E, Danos P, Grunwald F, et al. Temporal lobe dysfunction and
correlation of regional cerebral blood flow abnormalities with
psychopathology in schizophrenia and major depressionVa study with
single proton emission computed tomography. Psychiatry Res.
1996;69:1Y10.
54. Wolkin A, Sanfilipo M, Wolf AP, et al. Negative symptoms and
hypofrontality in chronic schizophrenia. Arch Gen
Psychiatry. 1992;49:959Y965.
* 2013 Lippincott Williams & Wilkins
Copyright 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Can rTMS Be Effective Treatment Option?
55. Sabri O, Erkwoh R, Schreckenberger M, et al. Regional cerebral
blood flow and negative/positive symptoms in 24 drug-naive
schizophrenics. J Nucl Med. 1997;8:181Y188.
56. Cordes J, Thunker J, Agelink MW, et al. Effects of 10 Hz repetitive
transcranial magnetic stimulation (rTMS) on clinical global impression
in chronic schizophrenia. Psychol Res. 2010;177:32Y36.
57. Mittrach M, Thunker J, Winterer G, et al. The tolerability of rTMS
treatment in schizophrenia with respect to cognitive function.
Pharmacopsychiatry. 2010;43:110Y117.
58. Freitas C, Fregni F, Pascual-Leon A. Meta-analysis of the effects
of repetitive transcranial magnetic stimulation (rTMS) on negative and
positive symptoms in schizophrenia. Schizophr Res. 2009;108:11Y24.
59. Dlabac-de Lange JJ, Knegtering R, Aleman A. Repetitive transcranial
magnetic stimulation for negative symptoms of schizophrenia: review
and meta-analysis. J Clin Psychiatry. 2010;71:411Y419.
60. Stanford AD, Sharif Z, Corcoran C, et al. rTMS strategies for the
study and treatment of schizophrenia: a review. Int J
Neuropsychopharmacol. 2008;11:563Y576.
61. George MS, Padberg F, Schlaepfer TE, et al. Controversy: repetitive
transcranial magnetic stimulation or transcranial direct current
stimulation shows efficacy in treating psychiatric diseases (depression,
mania, schizophrenia, obsessive-compulsive disorder, panic,
posttraumatic stress disorder). Brain Stimulation. 2009;2:14Y21.
62. Kirkpatrick B, Conley RC, Kakoyannis A, et al. Interstitial cells of
the white matter in the inferior parietal cortex in schizophrenia:
an unbiased cell-counting study. Synapse. 1999;34:95Y102.
63. Kirkpatrick B, Buchanan RW, Ross DE, et al. A separate disease within
the syndrome of schizophrenia. Arch Gen Psychiatry.
2001;58:165Y171.
64. Kay SR, Fiszbein A, Opler L. The positive and negative syndrome scale
(PANSS) for schizophrenia. Schizophr Bull. 1987;13:261Y276.
65. Brebion G, Amador X, Smith M, et al. Depression, psychomotor
retardation, negative symptoms, and memory in schizophrenia.
Neuropsychology, Neuropsychiatry, and Behavioral Neurology.
2000;13:177Y183.
66. Nakaya M, Ohmori K, Komahashi T, et al. Depressive symptoms in
acute schizophrenic inpatients. Schizophr Res. 1997;25:131Y139.
67. Andreasen NC. Negative symptoms in schizophrenia. Definition and
reliability. Arch Gen Psychiatry. 1982;39:784Y788.
68. McKenna PJ, Lund CE, Mortimer AM. Negative symptoms:
relationship to other schizophrenic symptom classes. Br J Psychiatry.
1987;104Y107.
69. Sax KW, Strakowski SM, Keck PE Jr, et al. Relationships
among negative, positive, and depressive symptoms in schizophrenia
and psychotic depression. Br J Psychiatry. 1996;168:68Y71.
70. Selemon LD, Goldman-Rakic PS. The reduced neuropil hypothesis:
a circuit based model of schizophrenia. Biol Psychiatry. 1999;45:17Y25.
71. Hamilton M. A rating scale for depression. J Neurol Neurosurg
Psychiatry. 1960;23:56Y62.
72. Hoffman R, Hampson M, Wu K, et al. Probing the pathophysiology of
auditory/verbal hallucinations by combining functional magnetic
resonance imaging and transcranial magnetic stimulation.
Cereb Cortex. 2007;17:2733Y2743.
73. Herwig U, Padberg F, Unger J, et al. Transcranial magnetic stimulation
in therapy studies: examination of the reliability of standard coil
positioning by neuronavigation. Biol Psychiatry. 2001;50:58Y61.
74. Schonfeldt-Lecuona C, Gron G, Walter H, et al. Stereotaxic rTMS for
the treatment of auditory hallucinations in schizophrenia.
Neuroreport. 2004;15:1669Y1673.
75. Langguth B, Eichhammer P, Zowe M, et al. Neuronavigated transcranial
magnetic stimulation and auditory hallucinations in a schizophrenic
www.ectjournal.com 73
Prikryl and Kucerova
patient: monitoring of neurobiological effects. Schizophr Res.
2006;84:185Y186.
76. Horacek J, Brunovsky M, Novak T, et al. Effect of low-frequency rTMS
on electromagnetic tomography (LORETA) and regional brain
metabolism (PET). in schizophrenia patients with auditory
hallucinations. Neuropsychobiology. 2007;55:132Y142.
77. Koutsouleris N, Gaser C, Jager M, et al. Structural correlates of
psychopathological symptom dimensions in schizophrenia: a voxel
based morphometric study. Neuroimage. 2008;39:1600Y1612.
78. Fujimoto T, Takeuch K, Matsumoto T, et al. Abnormal glucose
metabolism in the anterior cingulate cortex in patients with
schizophrenia. Psychiatry Res. 2007;154:49Y58.
79. Zetzsche T, Preuss UW, Frodl T, et al. White matter alterations in
schizophrenic patients with pronounced negative symptomatology and
with positive family history for schizophrenia. Eur Arch Psychiatry
Clin Neurosci. 2008;258:278Y284.
80. Torrey EF. Schizophrenia and the inferior parietal lobule. Schizophr
Res. 2007;97:215Y225.
81. Andreasen NC, Pierson R. The role of the cerebellum in schizophrenia.
Biol Psychiatry. 2008;64:81Y88.
82. Prikryl R, Ustohal L, Prikrylova Kucerova H, et al. Effect of sequential
frontotemporal repetitive transcranial magnetic stimulation (rTMS) on
schizophrenia. Activitas Nervosa Superior Rediviva. 2010;1:37Y41.
83. Nahas Z, Li X, Kozel FA, et al. Safety and benefits of distance-adjusted
prefrontal transcranial magnetic stimulation in depressed patients 55Y75
years of age: a pilot study. Depress Anxiety. 2004;19:249Y256.
84. Sanfilipo M, Lafargue T, Rusinek H, et al. Volumetric measure of the
frontal and temporal lobe regions in schizophrenia: relationship to
negative symptoms. Arch Gen Psychiatry. 2000;57:471Y480.
74 www.ectjournal.com
Copyright 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of ECT & Volume 29, Number 1, March 2013
85. Kozel FA, Nahas Z, deBrux C, et al. How coil-cortex distance relates
to age, motor threshold, and antidepressant response to repetitive
transcranial magnetic stimulation. J Neuropsychiatry Clin Neurosci.
2000;12:376Y384.
86. Stokes MG, Chambers CD, Gould IC, et al. Simple metric for scaling
motor threshold based on scalp-cortex distance: application to
studies using transcranial magnetic stimulation. J Neurophysiol.
2005;94:4520Y4527.
87. Loo CK, Taylor JL, Gandevia SC, et al. Transcranial magnetic
stimulation (TMS) in controlled treatment studies: are some sham
forms active? Biol Psychiatry. 2000;47:325Y331.
88. Lisanby SH, Gutman D, Luber B, et al. Sham TMS intracerebral
measurement of the induced electrical field and the induction
of motor-evoked potentials. Biol Psychiatry. 2001;49:460Y463.
89. Arana AB, Borckardt JJ, Ricci R, et al. Electrical stimulation as a sham
control for rTMS: does it truly mimic the cutaneous sensation and
pain of active prefrontal rTMS? Brain Stimulation. 2008;1:4Y51.
90. Borckardt J, Walker J, Branham RK, et al. Development and evaluation
of a portable sham tms system. Brain Stimulation. 2008;1:52Y59.
91. OReardon JP, Solvason HB, Janicak PG, et al. Efficacy and safety of
transcranial magnetic stimulation in the acute treatment of major
depression: a multi-site randomized controlled trial. Biol Psychiatry.
2007;62:1208Y1216.
92. Lieberman JA, Stroup S, McEvoy JP, et al, for the Clinical Antipsychotic
Trials of Intervention Effectiveness (CATIE) Investigators.
Effectiveness of antipsychotic drugs in patients with chronic
schizophrenia. N Engl J Med. 2005;353:1209Y1223.
* 2013 Lippincott Williams & Wilkins