Repetitive transcranial magnetic stimulation/ deep brain stimulation

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-Explore your reactions to use of the repetitive transcranial magnetic stimulation and deep brain stimulation modalities, discussed in this unit. Are you in favor of or opposed to these modalities? Provide a rationale. 

– This modalities have been used to treat some psychiatric diseases with great results, put examples of patients or diseases for what it can be useful, and what considerations need to be taken into account. 

-There has been a recent increased interest in do-it-yourself brain stimulation as a means of improving cognitive ability (Lumosity). Explain your opinion regarding do-it-yourself brain stimulation.

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Brain Stimulation (2010) 3, 36–41

Repetitive transcranial magnetic stimulation treats
postpartum depression

Keith S. Garcia,a Patricia Flynn,a Katherine J. Pierce,a Marty Caudlea

aDepartment of Psychiatry, Washington University School of Medicine, St. Louis Missouri

Postpartum depression (PPD) is a prevalent illness, affecting 10-15% of new mothers. PPD is the most
common complication of childbirth and is a significant public health concern. It is known to adversely
impact maternal-infant bonding, childrearing practices, and can lead to suicide and infanticide. The current
treatment approaches to PPD are suboptimal. Many mothers are reluctant to take medication because of
concerns about side effects or exposure of their newborn infant through breastfeeding. The specific aims of
this study were to (1) examine acute treatment effectiveness, (2) examine response durability, and (3) assess
an effect of repetitive transcranial magnetic stimulation (rTMS) on maternal bonding.

Nine antidepressant-free women with PPD were given 20 rTMS treatments over 4 weeks (10 Hz, 120%
motor threshold, left dorsolateral prefrontal cortex). Multiple characteristics were assessed at baseline
and throughout treatment. Duration of effect was assessed at 30 days, 3 months and 6 months posttreatment.

Friedman’s tests were conducted on Hamilton Rating Scale for Depression-24 item (HRSD-24),
Edinburgh Postnatal Depression Scale (EPDS), Inventory of Depressive Symptomatology-Self-Report
(IDS-SR) and Clinical Global Impressions-Severity (CGI-S) scores to compare performances at four
time points (baseline, end of Week 2, end of Week 4, and 180-day follow-up). Overall, these results
revealed a significant reduction in depressive symptoms by the end of Week 2 of treatment. Analyses
yielded a medium effect size (r 5 0.68) on the primary outcome variable (HRSD-24). Of note, all nine
patients remained in treatment for the complete 4 weeks, did not miss any treatment sessions and eight
participants achieved remission of symptoms, defined as a HRSD , 10 and a CGI-S 5 1. Analysis of
follow-up data indicated robustness of the rTMS treatment over time. At 6-month follow-up, of the
eight women that remitted, seven remained in remission without further psychiatric intervention,
including the addition of medication and one was lost to follow-up. Results also indicated a significant
improvement in bonding.

the project was awarded by the B.J.C. Townley fund

tigator-initiated protocols.

ests: Katherine J. Pierce, PhD, Washington University

cine, Department of Psychiatry, Campus Box 8134, 660

e., St. Louis, MO 63110.

E-mail address: [email protected]

Submitted March 10, 2009; revised April 11, 2009. Accepted for

publication June 1, 2009.

-see front matter � 2010 Elsevier Inc. All rights reserved.

rTMS treats PPD 37

Our results demonstrate promising results for the use of rTMS in the treatment of PPD. Further
randomized, sham-controlled studies need to be completed.
� 2010 Elsevier Inc. All rights reserved.

Keywords repetitive transcranial magnetic stimulation; postpartum depression; transcranial magnetic

Postpartum depression (PPD) is reported to occur in
10-15% of delivering women.1,2 It is the most common
complication of childbirth and is a significant public health
concern.3,4 PPD disrupts maternal homeostasis and has an
insidious impact on the lives of families by affecting
maternal-infant bonding, breastfeeding, child-rearing prac-
tices, and overall child well-being.5-8 Furthermore, PPD has
been shown to place children at significant risk of impaired
cognitive and emotional development.7 Unfortunately, PPD
is associated with both maternal suicide and infanticide.9,10

Treatment options for PPD are currently limited to
psychotherapy, pharmacotherapy, and electroconvulsive
therapy (ECT). Studies have found psychotherapeutic inter-
ventions to be an accepted intervention for PPD. Treatment in
the form of individual therapy, peer support, and/or group
therapy has been found to be helpful in alleviating the
anxiety, irritability, and feelings of detachment experienced
by women who have PPD.

11-13 Specifically, interpersonal
psychotherapy (IPT) is a proven, effective treatment for
mild-to-moderate PPD and an alternative to pharmaco-
therapy, especially for women who are breastfeeding.
However, IPT may not be the treatment of choice for women
who have moderate-to-severe symptoms and/or have
a history of severe depression in the past, or have had
previous reproductive-related depressive disorders.

14 In
addition, only limited information regarding the durability
of IPT exists and it has been shown that its beneficial effects
may be time limited.15

Physicians generally prefer pharmacotherapy to treat
women with PPD.16 However, patient acceptance of the use
of psychotropic medication for the treatment of PPD is
limited by maternal concerns regarding infant exposure
through breastfeeding and the unknown future effects of
such exposure.17,18 As a consequence of the perceived
risk of breastfeeding while on medication, as well as other
concerns, such as the potential impact of medication side
effects on late night child care, a significant number of
women report that they would not consider using psycho-
tropic medication to treat their PPD.19 The end result is
that many women choose to expose their infant to the
adverse effects of PPD rather than receive treatment.

ECT has been the primary device-based therapy for
treating unremitting major depression for over 6 decades,
and is perhaps the most broadly effective treatment for major

20 Although there are no systematic trials of ECT
in PPD, case literature supports its effectiveness in postpartum
psychiatric states.21 ECT, however, has well-documented

adverse effects, including headache, muscle pain, and
memory deficits.22-24 In addition, recovery time from each
ECT treatment may take several hours, which can limit the
ability of a new mother to care for her infant.

Repetitive transcranial magnetic stimulation (rTMS) is
a recently US Food and Drug Administration-approved
depression therapy,25,26 which uses briefly pulsed, powerful
magnetic fields to induce focused electrical currents in the
brain, depolarizing neurons. Recent meta-analyses have
shown that rTMS is superior to sham conditions in the
treatment of patients with major depressive disorder
(MDD).27-29 Unlike psychotherapeutic interventions, patients
receiving rTMS respond rapidly, often within 2-4 weeks, and
the response can be sustained.30 Repetitive TMS is unique
compared with other somatic depression therapies because
there are no systemic side effects that would interfere with
child care and no risk of exposure to the infant through breast-
feeding. Thus, the use of rTMS for the treatment of PPD
would address many of the short comings of medication.

We have completed an open-label rTMS treatment trial
(pilot) of unmedicated mothers with PPD in an attempt to
estimate the utility of rTMS in this population. Outcome
measures included investigator-administered, as well as
self-reported, measures of depression, and response dura-
bility was monitored for 6 months. In addition, we
examined the effects of rTMS on maternal bonding.


Human Research Protections protocol approval was
obtained from the Washington University School of
Medicine Human Research Protections Office before
enrolling subjects. Informed consent was obtained during
an appointment with the principal investigator before
performing any protocol procedures.


Recruitment material was displayed in more than 50
obstetrics/gynecology offices and in local businesses
frequented by women in a large metropolitan Midwestern
community. Physicians in the community were encouraged
to make referrals to the study through marketing methods,
including presentations by the study nurse coordinator and
principal investigator and mailings that informed them
about inclusion requirements.

38 Garcia et al

The entrance criteria included women with clinically
diagnosed PPD, age 18-50 years old, who had experienced
an uncomplicated pregnancy and delivery that resulted in
a healthy, single infant. A score greater than nine points on
the Edinburgh Postnatal Depression scale (EPDS),31,32 as
well as documentation of meeting DSM-IV-TR criteria
for a major depressive episode (completed by study psychi-
atrist/principal investigator, K.S.G.) was required for entry.
Patients with a history of psychosis or bipolar disorder were
excluded from participation.

A total of 39 women were screened by telephone. Of
these, 27 women did not meet the inclusion criteria or were
unable to participate because of other issues (two were
calling for their daughters; two preferred medication; two
had child care issues; two had a history of drug or ethyl
alcohol dependence; one had transportation issues; three had
a time commitment; one had a multiparous birth; one had an
adopted infant; two were teenaged; one stated medical
reasons; three were bipolar and on medication; seven gave
no reason [three of whom were scheduled for in-person
informational appointments but did not show up]). Inter-
views were conducted for the remaining women and resulted
in 12 signed informed consents. After the signing of the
consent form, the principal investigator (K.S.G.) performed
a protocol-specific interview that involved a discussion of the
participant’s options for treatment, as stated in the consent
form. Three participants consented and then withdrew their
consent after the initial interview with the principal investi-
gator. One woman was returning to work full time and was

Table 1 Demographic characteristics of nine PPD patients


89% White
11% Indian

Marital status
67% Married
33% Single

Employment status
67% Employed

Breastfeeding status
50% Breastfeeding

Age (y)
34.11 (6.05)

Level of education
16.89 (2.47)

EPDS baseline score
18.22 (4.52)

HRSD-24 baseline score
22.67 (6.44)

IDS-SR baseline score
41.22 (11.69)

PPD 5 postpartum depression; EPDS 5 Edinburgh Postnatal Depression Scale;

HDRS-24 5 Hamilton Rating Scale of Depression-24-point scale; IDS-

SR 5 Inventory of Depressive Symptomatology-Self-Report; SD 5 standard

deviation. Data are given as mean (SD).

not sure her job would allow the time off for treatment. The
other two women preferred the option of returning to their
primary care physician for medication therapy. Nine women
who completed the selection process were enrolled. Baseline
characteristics for the participants are summarized in Table 1.

Participants were 30 days to 1-year postpartum. Fifty
percent of our study’s subjects were breastfeeding, which
reflected a section of the PPD population known to be
unwilling to expose their infants to antidepressant medica-

17,18 Before treatment, participants were queried as to
their primary reason for choosing rTMS. The predominant
response was ‘‘I was concerned about medication side
effects.’’ Eight of the nine participants had a previous
history of major depressive disorder, and two of the eight
with a postpartum onset. Of these eight, four received
successful pharmacologic intervention, two were intolerant
of medication side effects, and two were not treated. Partic-
ipants were antidepressant-free at study entry and other
than one participant taking seven 2-mg doses of diazepam
over the course of the 4 weeks of treatment for Meniere-
related vertigo, no psychotropic or central nervous system
medications were consumed.

Study design

This study was an open-label, single-arm 4-week pilot of
the use of high-frequency, high-intensity, left dorsolateral
prefrontal cortex (DLPFC) rTMS for the treatment of PPD.

Repetitive TMS treatment

Twenty rTMS treatments (10 Hz applied at 120% of the
motor threshold for 4 seconds of stimulation and 26
seconds off for a total of 75 trains or 3000 pulses) (Neuro-
netics Model 2100 CRS TMS System, Neuronetics, Inc.,
Malvern, PA) were delivered five times per week over the
left DLPFC. Motor threshold testing was performed weekly
by the principal investigator to modify dosing if required.
Treatment was administered by an rTMS-experienced
registered nurse or physician assistant.

Clinical ratings/measures

Assessment of depressive symptoms included a clinical
interview, Edinburgh Postnatal Depression Scale
(EPDS),31,32 Hamilton Rating Scale of Depression-24
(HRSD-24),33 Inventory of Depressive Symptomatology-
Self Report (IDS-SR),34 and Clinical Global Impressions-
Severity (CGI-S)35 that occurred weekly throughout treatment
and at 1-, 3- and 6-months posttreatment. In addition,
a measure of bonding was administered before and immedi-
ately after the 4 weeks of treatment (Postpartum Bonding
Questionnaire [PBQ]).

The PBQ consists of 25 items

Table 2 Friedman’s test results for baseline, week 2, week 4, and 6-month follow-up scores for clinical outcome measures (n 5 7)

Mean/SD Mean/SD Mean/SD Mean/SD
c2 Significance

Scale Baseline score 2-wk score 4-wk score 6-mo score value level (P)

HRSD-24 23.43 (6.00) 9.00 (3.70) 2.14 (3.19) 2.00 (3.32) 19.50 , .0005
IDS-SR 42.43 (11.89) 20.71 (7.48) 7.29 (6.42) 4.29 (5.25) 19.97 , .0005
EPDS 18.29 (4.68) 9.14 (2.12) 3.43 (3.21) 2.71 (2.43) 19.35 , .0005
CGI-S 4.00 (0.00) 2.57 (0.79) 1.14 (0.38) 1.29 (0.49) 19.82 , .0005

HDRS-24 5 Hamilton Rating Scale of Depression-24-point scale; IDS-SR 5 Inventory of Depressive Symptomatology-Self-Report; EPDS 5 Edinburgh Postnatal

Depression Scale; CGI-S 5 Clinical Global Impressions-Severity; SD 5 standard deviation. Data are given as mean (SD).

rTMS treats PPD 39

rated on a scale of 0-5. The PBQ has 25 statements, each fol-
lowed by six responses ranging from ‘‘always’’ to ‘‘never.’’
Positive responses, such as ‘‘I enjoy playing with my baby,’’
are scored from zero (always) to 5 (never). Negative responses,
such as ‘‘I am afraid of my baby,’’ are scored from 5 (always) to
zero (never). The sum of scores for all the 25 items is calcu-
lated, with a high score indicating pathology.

Statistical analysis

The primary outcome measure for the study was the
HRSD-24.33 Secondary outcome variables included the
EPDS,31,32 IDS-SR (self-report),34 and CGI-S.35 Treatment
response was defined as a . 50% reduction in HRSD-24
scores from baseline. Remission was defined as a HRSD-
24 , 10 and a CGI-S 5 1.

Friedman’s tests were conducted on HRSD-24, EPDS,
IDS-SR, and CGI-S scores to compare depressive symp-
tomatology at four time points (baseline, end of treatment
Week 2, end of treatment Week 4, and 180-day follow-up).
Friedman’s test was chosen because the assumption of
normality could not be verified and the sample size was
small. In the presence of a significant overall test, post hoc
comparisons were performed by using the Wilcoxon
signed-ranks test. The critical alpha level was adjusted by
using Bonferroni’s correction to take into account the
potential for increased Type I error (critical alpha 5 .008).
Effect size (r) was calculated by completing a Wilcoxon
signed-ranks test comparing baseline to the end of Week






HDRS-24 Means Across Study

Figure 1 Hamilton Rating Scale of Depression-24 items
(HRSD-24) means across study duration.

4 HDRS-24 scores (a priori analysis point). The resulting
Z score was then entered into the following formula: where
r 5 Z/ON. Wilcoxon signed-ranks test was used to examine
changes in mother-infant bonding from pretreatment to
posttreatment as measured by the PBQ.



The results of the Friedman’s tests indicated that there was
a significant improvement in depressive symptomatology
(Table 2). Post hoc analyses (i.e., Wilcoxon signed-ranks
test) with adjustment of the two-tailed level to .008 to
accommodate increased Type I error indicated that the
significant decrease in symptoms occurred at the end of
the second week of treatment (HRSD-24 baseline Md
5 23.00, Week 2 Md 5 10.00, P 5 .008; EPDS baseline
Md 5 19.00, Week 2 Md 5 9.00, P 5 .008; IDS-SR
baseline Md 5 45.00, Week 2 Md 5 21.00, P 5 .008). A
Wilcoxon signed-ranks test comparing baseline with the
end of week 4 HDRS-24 scores (a priori analysis point)
yielded a medium effect size (r 5 0.68). Of note, all nine
patients remained in treatment for the complete 4 weeks
and did not miss any treatment sessions. Eight participants
achieved remission of symptoms, defined as a HRSD , 10
and a CGI-S 5 1. Analysis of follow-up data indicated
robustness of the rTMS treatment over time (Figures 1-3).
At 6-month follow-up, of the eight who remitted, seven re-
mained in remission at the 6-month follow-up without
further psychiatric intervention, including the addition of


IDS-SR Means Across Study

Figure 2 Inventory of Depressive Symptomatology-Self-Report
(IDS-SR) means across study duration.


EPDS Means Across Study

Figure 3 Edinburgh Postnatal Depression Scale (EPDS) means
across study duration.

40 Garcia et al

medication, and one was lost to follow-up. In addition,
a Wilcoxon signed-ranks test was conducted to evaluate
the impact of the intervention on women’s bonding with
their infants (as measured by the PBQ).

There was

a statistically significant improvement in bonding scores
from pretreatment (Md 5 20.00) to posttreatment
(Md 5 7.00, P 5 .010) assessment.

Repetitive TMS was safe and well tolerated. A patient
satisfaction questionnaire given at the end of treatment
indicated that eight of nine preferred rTMS to medication,
but only six of nine believed it was convenient. Minor
adverse events included headache, treatment site pain (both
of which were relieved with pretreatment over-the-counter
analgesics), and facial stimulation (which resolved with
magnetic repositioning). There were no drop outs because
of adverse events and there were no observed serious
adverse events.


This is the first open-label rTMS pilot group study of PPD
to address the question of the use of rTMS as a treatment
for PPD (three previous case studies existed).38-40 Treat-
ment response was rapid, robust, and durable suggesting
that rTMS could be used as a treatment bridge that would
allow mothers with PPD to remain medication free until
a time when they are no longer breastfeeding and the use
of medication maintenance becomes more acceptable, if

As with any small pilot, these results should be viewed
as highly preliminary. Shortcomings of the study include
small sample size and the lack of a sham control arm. In
addition, although psychotherapy was not administered,
daily contact with the professional psychiatric research
staff administering rTMS treatments could have influenced
the outcome. Depression was recurrent in eight of nine of
our treatment population and, of these, four of six of our
treatment population had been successfully treated with
medication for previous episodes (two received no treat-
ment). The patients in the study were not treatment
refractory, but rather unwilling to pursue other systemic

treatments such as medication during their postpartum
period. Thus, rTMS appears to be ideally targeted toward
mothers with PPD who are treatment responsive, but would
otherwise forgo treatment because of concerns about the
adverse impacts of medication.

Previous rTMS studies have not demonstrated the
impressive remission rates and maintenance of remission
observed in this small pilot study.

28 This raises a concern
that these results might be spurious. Several factors could
account for this discrepancy. First, the study was open-
label, thus our patients were aware they were receiving
active treatment and may have experienced a placebo
response. However, recent studies have shown that
a placebo response is lower in rTMS trials in which it is
not used as an add-on therapy.

28,41 Second, our population
was not treatment refractory and many had responded
successfully to treatment in previous episodes. No current
rTMS treatment literature exists describing nontreatment-
resistant patients’ responses to rTMS. This is clearly an
area that needs to be further explored. Third, our treatment
protocol was more aggressive than most published proto-
cols with higher dosing over longer treatment periods.
Finally, PPD may be more responsive to rTMS than other
forms of MDD because it may be a unique form of MDD
or a form of MDD that may be more self-limiting. This
area of interest could also benefit from further examination.


This small pilot study is encouraging. Future large-scale,
sham-controlled studies are needed to confirm our obser-
vations. Feedback provided by participants highlighted the
need for onsite child care to enhance treatment convenience
and should be included in any future studies. The potential
use of rTMS as a prophylactic treatment for depression
occurring during pregnancy and during the postpartum
period, when medication management is undesirable,
represents an additional opportunity for the use of rTMS.
There is an urgency to develop an alternative therapy for
treating women who have PPD. We believe rTMS may
become a preferred treatment for PPD.

We express our sincere thanks to the women partici-
pating in this unique pilot program. Our appreciation is also
extended to Neuronetics, Inc., for supplying the
Neuronetics Model 2100 CRS TMS System.


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  • Repetitive transcranial magnetic stimulation treats postpartum depression
    • Methods
      • Patients
    • Study design
    • Repetitive TMS treatment
    • Clinical ratings/measures
    • Statistical analysis
    • Results
    • Discussion
    • Conclusions
    • References

Paul B. Fitzgerald, Professor (Correspondence)

Monash Alfred Psychiatry Research Centre, The Alfred and Monash
University School of Psychology and Psychiatry, The Alfred, First Floor
Old Baker Building, Commercial Road, Melbourne, Victoria, 3004,
Australia. Email: [email protected]

The emerging use of brain stimulation
treatments for psychiatric disorders

Paul B. Fitzgerald

Objective: The aim of this study was to review the current state of development and applica-

tion of a wide range of brain stimulation approaches in the treatment of psychiatric disorders.

Method: The approaches reviewed include forms of minimally invasive magnetic and elec-

trical stimulation, seizure induction, implanted devices and several highly novel approaches

in early development.

Results: An extensive range of brain stimulation approaches are now being widely used in

the treatment of patients with psychiatric disorders, or actively investigated for this use. Both

vagal nerve stimulation (VNS) and repetitive transcranial magnetic stimulation (rTMS) have

been introduced into clinical practice in some countries. A small body of research suggests

that VNS has some potentially long-lasting antidepressant effects in a minority of patients

treated. rTMS has now been extensively investigated for over 15 years, with a large body of

research now supporting its antidepressant effects. Further rTMS research needs to focus

on defi ning the most appropriate stimulation methods and exploring its longer term use in

maintenance protocols. Very early data suggest that magnetic seizure therapy (MST) has

promise in the treatment of patients referred for electroconvulsive therapy: MST appears to

have fewer side effects and may have similar efficacy. A number of other approaches includ-

ing surgical and alternative forms of electrical stimulation appear to alter brain activity in a

promising manner, but are in need of evaluation in more substantive patient samples.

Conclusions: It appears likely that the range of psychiatric treatments available for

patients will grow over the coming years to progressively include a number of novel brain

stimulation techniques.

Key words: deep brain stimulation , depression , electroconvulsive therapy , magnetic sei-

zure therapy , repetitive transcranial magnetic stimulation , transcranial direct current stimu-

lation , treatment resistant , vagus nerve stimulation.

Australian and New Zealand Journal of Psychiatry 2011; 45:923–938

DOI: 10.3109/00048674.2011.615294

It is well recognized that there are a variety of psychi-

atric disorders for which the current range of treatment

options are suboptimal. For example, major depressive

disorder (MDD) is extremely common, affecting approx-

imately 15% of people across their lifespan [1]. There are

a range of medication and non-medication treatments for

© 2011 The Royal Australian and New Zealand College of Psychiatrists

MDD, but in spite of frequent trials of therapy, approxi-

mately 30% of patients will continue to experience depres-

sion and be considered treatment resistant [2,3]. Similarly,

approximately a third of patients with schizophrenia are

considered treatment resistant and continue to experience

ongoing severe and disabling symptoms [4]. In addition,

there are psychiatric disorders such as autism for which

we completely lack any illness-specifi c treatments. It has

been hoped by many that the major advances in brain

sciences and genetics that have emerged over recent years

would result in the rapid development of new and highly

effective treatments for these disorders. Unfortunately,


this has not transpired. Developing drugs for central

nervous system (CNS) applications is more expensive,

time-consuming and less likely to succeed than develop-

ing drugs for any other class of illness [5]. Recent years

have seen the withdrawal of several major pharmaceuti-

cal companies from CNS development [5]. If new phar-

maceutical agents are not going to advance the treatment

of these disorders in the immediate future, are there other


One possibility is the burgeoning fi eld of brain stimu-

lation approaches to the treatment of neuropsychiatric

disorders. Psychiatry has a long history of the use of

a specifi c form of brain stimulation, electroconvulsive

therapy (ECT), which remains the most effective treat-

ment for depression: it is also, less frequently, used for

other disorders. A variety of other innovative brain stim-

ulation techniques are under intensive evaluation and

development; several of these are now transitioning into

clinical practice. The aim of this paper is to review the

current status of the development of a range of these

techniques. Reviewed approaches include convulsive tech-

niques similar to ECT, non-convulsive, non-invasive

forms of magnetic and electrical stimulation, and surgi-

cal interventions.



A technique that has progressed to one of the more

advanced stages of development is repetitive transcranial

magnetic stimulation (rTMS). Transcranial magnetic stim-

ulation (TMS) is a non-invasive means of stimulating nerve

cells in superfi cial areas of the brain. TMS involves using a

coil held over the scalp to induce a magnetic fi eld [6]. The

magnetic fi eld passes through the scalp without resistance

and induces an electrical fi eld in superfi cial areas of the

cortex. When provided at suffi cient intensity, the electri-

cal fi eld induced by the magnetic pulse produces depo-

larization of nerve cells [7]. This creates synchronous

fi ring of a group of nerve cells with effects specifi c to

the site of stimulation. This can include the activation of

a peripheral muscle during motor cortical stimulation,

the induction of visual sensations (phosphenes) during

visual cortex stimulation or the disruption of a cognitive

task [8].

When TMS pulses are applied repetitively (rTMS), the

repeated stimulation of nerve cells can progressively

change their activity over time. High-frequency rTMS

(stimulation at greater than 1 Hz and typically 5 to 20 Hz)

has been shown to increase cortical excitability [9]. Low

frequency stimulation (typically 1 Hz) has the opposite

effect, decreasing cortical excitability [9]. Single sessions

of stimulation produce effects on local cortical excitabil-

ity that can be measured for up to one hour and in thera-

peutic applications repeated sessions over time presumably

have some form of additive effect. However, although

considerable attention has been paid to the local effects

of rTMS stimulation, it is possible that the effects of

rTMS are not primarily local but induced through

strengthening of connectivity between the local area

stimulated and the area to which the projecting neurones

stimulated by the rTMS pulses connect.

Clinical studies of rTMS in depression

Due to the capacity of rTMS to induce changes in brain

activity over time, it has been considered in the treatment

of conditions where abnormal cortical activity is evident.

The therapeutic effects of rTMS have been explored now

in a range of neuropsychiatric disorders with the majority

of research focused on the treatment of MDD. This appli-

cation was fi rst proposed in the mid 1990s. The fi rst prom-

ising results were obtained when high frequency trains

were applied to the left dorsolateral prefrontal cortex

(DLPFC) [10,11]. This application was based on the

observation that left DLPFC was underactive in patients

who were depressed in resting positron emission tomog-

raphy (PET) studies [12]. Initial clinical trials were of

short duration but established that rTMS appeared to have

some antidepressant effects. Over 15 years, a large num-

ber of sham controlled clinical trials have been conducted.

However, many of these were small as there has been very

limited industry support available for trials of the magni-

tude that would be usually conducted for device or medi-

cation regulatory approval [13].

Trials investigating the use of high-frequency stimula-

tion applied to left DLPFC have been subject to several

substantive meta-analyses. For example, the meta-analysis

by Schutter et al . [14] involved 30 trials and 1164 patients.
This analysis showed a highly signifi cant effect of active

treatment compared to placebo on the average reduction

in depression severity scores (p � 0.00001). The effect
sizes seen in these analyses are similar to those seen in

trials of antidepressant medication, although many of

the trials have been conducted exclusively in patients

who are treatment resistant [14]. Notably, another meta-

analysis has clearly demonstrated that effect sizes seen

in more recent studies have been greater than those seen

in earlier research, supporting the idea that the increase

in rTMS dose seen in more recent trials has resulted in

improved treatment outcomes [15].

Two large multisite trials have been conducted to date:

one industry sponsored and one independently funded. A

privately held company, Neuronetics, sponsored a ran-

domized sham controlled trial involving 300 patients


although they have yet to be evaluated in substantive


The optimal method for targeting the DLPFC also

remains uncertain. Almost all trials have identifi ed and tar-

geted DLPFC by measuring 5 cm anterior to the scalp sur-

face corresponding to motor cortex, localized using single

TMS pulses [35]. However, this clearly results in inaccurate

targeting in the majority of patients, often with subsequent

stimulation being applied to premotor cortex [36]. It is pos-

sible that improved targeting of DLPFC utilizing structural

MRI may enhance clinical responses [37]. However, several

functional imaging-based targeting approaches have not

resulted in improved outcomes [38,39]. Imaging may not

be required to produce optimal response: better outcomes

may be obtained with a more anterior and lateral coil loca-

tion [40], or potentially through the use of electroencepha-

lography (EEG) coordinates [41].

Safety and tolerability

Generally speaking, rTMS approaches appear to be

relatively safe and well tolerated [42,43]. The main side

effects are discomfort on the scalp at the stimulation site

during treatment, or the development of a post-stimulation

headache [43]. These effects are highly variable between

subjects, but are seen more commonly with high stimula-

tion frequencies and intensities. Tolerability appears to

be greater when stimulation is introduced at a lower

intensity and gradually increased over time.

In regard to more severe possible consequences, rTMS

treatment in depression does not appear to have any del-

eterious effects on cognition, including memory [43].

There have been several case reports of the induction of

mania in patients with bipolar disorder [44] and an early

case report of what appeared to be new onset delusions

[45]. The major concern with rTMS has been the possi-

bility of seizure induction [42]. The occurrence of sei-

zures seems to have been dramatically limited by the use

of safety guidelines introduced in the late 1990s [46]

although there have been occasional reports. Few of these

have been in patients with depression treated within

established safety guidelines. The induction of a vasova-

gal episode is another possibility which can confound the

interpretation of a loss of consciousness and should be

suspected in patients with a history of fainting related to

other medical procedures.

Limited data is also accumulating on the safety of the

use of rTMS in a variety of special populations. Treat-

ment has been provided in small trials or case studies in

pregnancy [47], in adolescent depression [48,49], as well

as in patients with a variety of neurological complications

such as Parkinson ’ s disease [50 – 52], stroke [53,54] and

traumatic brain injury [55].

who had failed a least one antidepressant medication trial

[16]. The duration of treatment extended up to 6 weeks

(daily treatment 5 days per week) followed by a 3-week

taper. There was a signifi cant antidepressant effect of

active compared to sham treatment on most of the out-

come measures, though not all. The improvement was

most substantial in patients who had failed only one

medication, as compared to those who had failed more.

The results of this trial were utilized in an application for

device approval that was successful in the USA in 2008.

The second trial, funded by the National Institute of Men-

tal Health, involved 199 patients randomized to active or

sham treatment for up to 6 weeks [17]. There was a sta-

tistical advantage of active stimulation over sham in the

percentage of patients achieving remission, although the

overall rate was low (14.1 versus 5.1%).

Studies have also been conducted to directly compare

high frequency rTMS to ECT [18 – 23]. The majority of

these have found no differences between the treatments

although their power to fi nd differences was limited. One

study, incorporating patients with psychotic depression,

showed greater benefi t with ECT in the psychotic

group [21], while a second study has reported greater

effects of ECT [24]. One substantial issue with these tri-

als is that many of them have compared a fi xed course of

unilateral rTMS to a fl exible course of often uni and bilat-

eral ECT. This presumably biases somewhat towards the

likelihood of fi nding a better outcome with ECT.

Methods of rTMS administration

A number of substantial questions remain in regard to

optimal rTMS administration. The dose of stimulation,

typically refl ected in the number and intensity of pulses

applied, has progressively increased over time. Interest-

ingly, pilot data has recently suggested that antidepres-

sant effects might be achieved much more rapidly with

very high dose intensive protocols [25]: this requires

further evaluation. Conversely, it is possible that less

frequent treatment than the typical 5 days per week

scheduling may be of similar effi cacy [26].

Despite high-frequency left sided rTMS having been

the most extensively evaluated approach, it is not yet

clear whether this is the optimal method of rTMS deliv-

ery. Low frequency rTMS applied to the right DLPFC

appears to have similar effi cacy, may be better tolerated,

and safer [27 – 29]. Bilateral approaches have also shown

promise [30], although some recent studies have cast

doubt about whether they will prove more effective than

unilateral stimulation [31,32]. In addition, a range of

newer forms of rTMS including theta burst stimulation

[33] and priming stimulation [34] may prove more effec-

tive than the standard left side high frequency approach,


its clinical use was advocated in recent revisions of the

infl uential ‘ PORT ’ clinical guidelines [70]. However,

most of the studies to date have been short term; despite

some evidence of the persistence of therapeutic benefi ts

over time [66] the long-term impact of this form of treat-

ment on patients ’ clinical course remains uncertain.

A second approach has been the use of high frequency

stimulation applied to left (or bilateral) prefrontal cortex

in the treatment of negative symptoms. There have been

both positive [71 – 73] and negative [74 – 77] studies in this

regard; more substantive, larger and longer-term trials are


rTMS in other psychiatric disorders

The use of rTMS has also been evaluated in a number

of other psychiatric disorders. However, most of the stud-

ies have been small, and limited attempts have been made

at replication. Several studies have explored the use of

rTMS in mania. High frequency frontal stimulation on

the right was initially suggested to be superior to left

sided stimulation and sham [78]. However, this was not

confi rmed in a subsequent study of active versus sham

right sided stimulation [79].

In obsessive compulsive disorder (OCD) there has

been some inconsistency in the stimulation method

applied. Very early on, single rTMS sessions at high fre-

quency on the right DLPFC appeared to produce some

benefi ts [80]. These benefi ts were also seen in a small,

early, non-sham controlled trial with both left and right

sided stimulation [81]. However, subsequent studies of

both right and left sided (high and low frequency) rTMS

have not shown therapeutic benefi t [82 – 85].

Benefi ts have also been seen in post traumatic stress

disorder (PTSD) from single sessions of rTMS [86], as

well as in a sham controlled trial of high frequency right

PFC stimulation [87]. Negative effects were seen with

left sided stimulation [88].

In panic disorder there was initial promise in open

label data [89,90] but this has not been supported in a

small trial with serotonin reuptake inhibitor medication

resistant patients [91].

Finally, research is underway to establish if rTMS has

therapeutic potential in addictive disorders. Single ses-

sion studies have demonstrated that prefrontal rTMS can

reduce craving in cocaine or nicotine dependent subjects

[92,93]. Two more recent double-blind studies have

shown positive therapeutic effects of prefrontal rTMS in

alcohol dependence and in nicotine dependence [94,95].

Although both these studies involved longer periods of

stimulation, they used divergent rTMS methods; high

frequency stimulation was applied on the right in one

study, and to the left DLPFC in the other.

Effects over time

Depression is clearly a relapsing disorder and many

patients experience multiple episodes despite the effi cacy

of antidepressant medication in relapse prevention [56].

Unfortunately we continue to lack a comprehensive under-

standing of the long-term effects of rTMS treatment on the

course of depression. A recent study investigated relapse

rates from 204 patients treated over a number of years with

rTMS [57]. Event-free remission rates were 75.3% at 2

months, 60% at 3 months, 42.7% at 4 months, and 22.6%

at 6 months. Several studies have suggested that the rein-

stitution of rTMS treatment during depressive relapse is

successful in many patients [58,59]. Limited research has

also suggested that some benefi t may be obtained from

maintenance rTMS schedules (for example [60,61])

although substantial studies are lacking in this area.

rTMS in depression: summary of status

A substantive body of work has clearly established

that rTMS treatment has antidepressant effi cacy. This

effi cacy is likely to be similar to that seen with antide-

pressant medication. Although benefi cial effects with

rTMS appear greater in less treatment resistant patients,

those with a greater degree of treatment resistance have

clearly responded in a substantial number of clinical

trials. rTMS appears to be relatively safe and well toler-

ated. For these reasons, rTMS is being increasingly

applied in clinical practice internationally. It is likely to

be useful for patients who are not suitable for ECT, or

prefer to avoid that treatment due to concerns about side

effects or stigma. rTMS is not likely to replace ECT as

a rapidly and powerfully effective antidepressant, but is

certainly likely to reduce the need for ECT treatment in

a substantive number of patients.

rTMS in schizophrenia

A considerable number of trials have investigated the

use of rTMS in the treatment of patients with schizophre-

nia [62,63]. Quite a number of these studies have not had

a specifi c symptoms focus, and have not generated prom-

ising results. However, more hypothesis-driven approaches

have produced interesting fi ndings. For example, low fre-

quency stimulation applied to temporoparietal cortex has

been used in the potential treatment of refractory hallu-

cinations. The majority of trials of this application have

demonstrated benefi ts of active stimulation over sham

(e.g. [64 – 66]) or ongoing medication treatment only

[67], although there have been some negative studies

(e.g. [68]). The effi cacy of this form of stimulation has

been suggested by several meta-analyses (e.g. [69]), and




In contrast to rTMS where the magnetic fi eld is applied

only at suffi cient intensity to produce depolarization of

neurons, low intensity magnetic stimulation approaches

propose to change brain activity through magnetic stimula-

tion but not neuronal depolarization. The potential use of

low fi eld magnetic stimulation (LFMS) arose from a ser-

endipitous observation of mood change in bipolar patients

who were undergoing a specifi c type of magnetic reso-

nance imaging scan; echo planar imaging [96]. Following

this fi nding, a single session trial was conducted in which

a greater degree of mood improvement was seen in patients

who underwent echo planar imaging than those who

underwent a sham imaging session [96]. This was followed

with a rodent study demonstrating that LFMS produced

changes in the forced swim test consistent with antidepres-

sant activity [97]. A subsequent imaging study has dem-

onstrated that LFMS produces changes in brain metabolism

in healthy subjects, although no mood changes were

detected [98]. Echo planar imaging fi elds are at least 100

times weaker than the fi elds produced by rTMS, although

they are applied across the entire brain (at 1 kHz).

A second low intensity magnetic stimulation approach

involves the use of the transcranial application of low inten-

sity pulsed electromagnetic fi elds (T-PEMF) through a

purpose-built generator. A variety of lines of research out-

side of psychiatry had indicated that low intensity pulsed

magnetic fi elds can have substantive biological effects,

including altering angiogenesis and neurite growth [99,100].

Based on these observations and an open label pilot study

[101], Martiny et al . compared 5 weeks of active T-PEMF
with sham treatment in 50 patients with treatment resistant

depression [101]. Antidepressant effects emerged in the fi rst

week of treatment and greater than 50% of patients in the

active group met response criteria by study end. The T-PEMF

device used in this study involved seven separate induction

coils placed around the head generating alternating mag-

netic fi elds of approximately 1.9 milliTesla. The electric

fi elds induced in tissue from this level of stimulation would

be substantially lower than the 35 mV change typically

required for neuronal depolarization.

Low intensity magnetic stimulation:
summary of status

It is obviously early days for research into the brain
effects of low intensity magnetic stimulation. However,
the data gathered to date suggests that this form of stim-
ulation does have brain effects that may be relevant to
the modulation of mood. Further research to explore the
therapeutic capacity of these systems is justifi ed.



Transcranial direct current stimulation

An alternative, non-invasive way to modulate brain

activity is with the application of a low voltage electrical

current. Several forms of electrical stimulation have been

developed and tested to a greater or lesser degree in

psychiatric disorders.

Transcranial direct current stimulation (tDCS) is a

technique that involves the application of a low amplitude

(1 – 2 mA) direct current to the brain through two surface

electrodes placed on the scalp [102]. Rubber electrode

pads covered with sponges are connected to a low voltage

stimulation device. The technology for generating a tDCS

current is very basic, and the current itself may be gener-

ated with devices run by commonly available batteries.

Stimulation is usually applied continually for a period of

time, commonly between 15 and 20 minutes.

The notion of tDCS is a relatively old one, with

researchers proposing the application of this type of tech-

nique during the 1960s and 1970s. However, despite ini-

tial enthusiasm, interest in the fi eld faded until it was

rediscovered about 10 years ago, through the conduct of

a series of neurophysiological studies demonstrating the

capacity of tDCS to modulate brain activity [103 – 105].

This research, which has progressively expanded, has now

characterized a variety of aspects of the effect of tDCS on

the brain. Most importantly, it has become relatively clear

that anodal stimulation (stimulation under the positive

electrode) produces a localized increase in cortical excit-

ability [106]. In contrast, a localized decrease in cortical

excitability is produced under the cathode [106]. There-

fore, either uni-modal or bimodal effects may be produced

depending on whether both electrodes are placed on the

scalp, or if one is placed in a non-cephalic position.

The immediate effect of tDCS is likely to occur through

subtle changes in membrane polarization, related to a

small degree of the applied current passing into the brain

[107]. However, the effects of tDCS have been shown to

last for up to 1 hour after of a single session of stimula-

tion; these more persistent effects may well have a more

complicated origin in the brain [107]. For example, last-

ing effects have been shown to be dependent on activity

at the NMDA receptor, and to be modulated by a variety

of drugs that affect this receptor in addition to calcium

channels [107].

These persistent, but temporary tDCS effects are

increasingly being used as a way of non-invasively mod-

ulating brain function in a variety of cognitive neurosci-

ence experiments. There is also increasing interest in

their potential therapeutic capacity. Following on from


commercially available and are being marketed for the

treatment of a variety of disorders. There is also consider-

able variability in the stimulation provided by different

devices. For example, the ‘ Alpha-Stim SCS ’ has been

marketed for the treatment of conditions including anxiety

disorders, depression and insomnia, and supplies stimula-

tion with bipolar rectangular pulses, provided at low or

high frequency and adjusted across an amplitude range,

through electrode clips placed on the earlobes. Although

such CES devices are often marketed for a variety of indi-

cations, there is a very limited evidence base for most of

these applications. A variety of open label research trials

(for example Bystritsky et al. [119]) and studies in mixed

samples have been conducted; many have lacked consis-

tent or substantively validated methods. At this time, the

majority of the claims made about the effect of this form

of stimulation lack the required support of substantive

sham controlled trials in well characterized populations.

Electrical stimulation: summary of status

A small but emerging literature suggests that tDCS

may have antidepressant activity, although this requires

confi rmation in more substantial samples. It is a promis-

ing technique, as its low cost suggests it could be a use-

ful alternative treatment in developing countries. There

is little evidence to recommend the clinical use of CES

at this stage.


Electroconvulsive therapy

ECT remains a widely used and highly effective psy-

chiatric treatment. Its main indication continues to be in

the treatment of patients with resistant depression or

depression requiring a rapid antidepressant response. The

induction of cognitive side effects, particularly antero-

grade and retrograde amnesia, and the considerable

stigma associated with the treatment are ongoing issues

relating to the use of ECT. Resultant resistance to its use

exists within most communities.

ECT evolved out of pharmacological methods of

seizure induction, and different forms of ECT have sub-

stantially different effi cacy/side-effect profi les [120]. It

therefore seems likely that the therapeutic effects and

cognitive side effects of ECT are potentially dissociable.

It may therefore be possible to fi nd a method of seizure

induction that produces the therapeutic benefi ts associ-

ated with ECT without the same cognitive side-effect

profi le. However, this is not inevitable. The therapeutic

potency of ECT may not relate just to the induction of a

the prefrontal rTMS model, the main therapeutic possi-

bility assessed to date has been the use of anodal stimu-

lation applied to the left DLPFC in patients with

depression. Four out of fi ve patients responded to 1 week

of this form of stimulation in the fi rst clinical trial, com-

pared to no responders in a sham group [108]. In a larger

follow up study, active left prefrontal tDCS again resulted

in a greater clinical response than sham and occipital

stimulation [109]. Several other groups have now

explored tDCS effects. Ferrucci et al . applied tDCS twice
daily (20-minute sessions at 2 mA) in a group of 14

patients with severe MDD referred for ECT in an open

label manner. They found substantial antidepressant

effects that interestingly appeared to continue to accumu-

late after the end of the course of stimulation [110]. The

same parameters were then used in a larger sample of

both unipolar and bipolar depressed subjects with similar

results [111]. In contrast, Loo et al . provided a lower dose
stimulation (1 mA) over fi ve stimulation sessions to 40

patients in a sham controlled trial and found no antide-

pressant effects [112]. Several notable tDCS case reports

have also been published: in one patient, depression that

developed following stroke was treated and showed a

substantial antidepressant effect [113]. In a second case

report, mania was induced in a patient with bipolar dis-

order following frontal stimulation with an extra-cephalic

cathode [114].

Although no substantial studies have been conducted

to date, the safety profi le for tDCS looks relatively benign

[107,105]. Itching, tingling, headache and a burning sen-

sation are the most commonly reported side effects and

appear transient [115,116]. There has been some concern

about the possibility of brain stem effects on respiration

when non-cephalic electrodes are used; however, a recent

study investigating this issue could fi nd no evidence of

adverse events in healthy volunteers [117].

Cranial electrical stimulation

Another form of low voltage electrical brain stimulation

is cranial electrical stimulation (CES). CES describes a

variety of methods of stimulating the brain, typically com-

prising alternating, low voltage electrical currents. Forms

of CES have been applied to altering brain activity for

several centuries (see review in Stagg and Nitsche [107]),

but the use of a wide variety of stimulation parameters has

been included under the banner of CES, including tDCS

as described above. This degree of variability confounds

interpretation of the studies conducted to date. A consider-

able degree of the early development of CES techniques

occurred in the former USSR, with data not widely avail-

able in English [118]. In a number of countries, including

the USA and Australia, CES devices have become


ECT comparison study, similar antidepressant effects

were seen between MST and right unilateral ECT; MST

also appeared to have a favourable side-effect profi le

[131]. In a separate study, MST was shown to have anti-

depressant properties, and appeared to be associated with

a rapid return of orientation [131].

MST: summary of status

It is clearly too early to make conclusions about the

potential role of MST. However, if direct head-to-head

trials prove that it has similar effi cacy to ECT, MST could

be relatively rapidly rolled out into clinical practice; the

infrastructure for the provision of MST largely already

exists in the form of standard ECT suites. Although MST

has many similarities to ECT, the alternative method of

seizure induction and lack of a problematic history will

most likely result in substantially less stigma being asso-

ciated with this treatment. As a consequence, there may

be greater patient and community acceptance of MST.

Although head-to-head MST – ECT studies are already

underway, considerable further research is required to

defi ne the optimal methods of MST stimulation; half a

century of ECT research has yet to allow us to fully

understand the best way to provide this treatment. Factors

that require exploration include the optimal frequency/

intensity combination, the most effective target site and

coil type, and whether the optimal characteristics for sei-

zure induction are the same as the optimal characteristics

for antidepressant effi cacy.

Focal electrically administered convulsive therapy

Since its inception there has been a progressive

improvement in the risk – benefi t profi le achieved with

ECT; a long series of studies have refi ned knowledge in

regard to a variety of parameters of ECT application. For

example, changes in the type of pulse applied, the elec-

trode placement and more recently the pulse width have

improved the application of ECT [120,132]. However, a

number of ECT parameters have not been systematically

explored, such as the direction of electrical current

and the size and shape of stimulation electrodes. In addi-

tion, the focality of ECT stimulation remains very poor

due to the shunting of current across the skull. Focal elec-

trically administered convulsive therapy (FEAST) has

been proposed as an alternative convulsive or non-

convulsive therapy with substantially greater capacity for

focused brain stimulation [132].

To date, FEAST involves the use of a unidirectional

electrical current provided between two electrodes that

vary substantially in size [121,133]. The current passes

between a small anterior and large posterior electrode,

seizure, but may also be dependent on the actual electrical

stimulation of brain structures. This question can only be

answered through the implementation of trials of alterna-

tive seizure induction techniques that do not produce the

same degree of direct, widespread electrical stimulation of

brain areas. It may be possible to reduce the spread through

the brain of electrical activation produced with ECT with

the use of more focal methods of electrical stimulation

[121]. However, some degree of shunting across the scalp

will occur with any directly applied electrical current,

reducing the focal extent of the stimulation.

Magnetic seizure therapy

An alternative method of seizure induction without

any diffusion of the stimulus is through the use of a high-

powered transcranial magnetic stimulation device. Mag-

netic seizure therapy (MST) uses high frequency and

high intensity magnetic fi elds to generate a seizure,

applying a highly focused magnetic fi eld which repeat-

edly stimulates local cortical neurones until seizure activ-

ity is induced [122]. There is a spread of the seizure

through the brain, but no spread of the stimulation fi eld.

As with ECT, MST is administered under a general

anaesthetic and utilizes similar procedures.

Following the initial proposition of the possibility of

MST, early studies focused on establishing whether it

would have a more advantageous side-effect profi le while

attempting to understand the stimulation characteristics

capable of seizure induction. These studies were limited

by the capability of available stimulators which could

only provide short stimulus trains at high power at

approximately 50 Hz [123]. This equipment was not able

to induce seizures in all subjects, and there was limited

capacity for stimulating above an individual subject ’ s

seizure threshold [123].

Despite these limitations, the initial MST studies pro-

vided some important information. In rhesus monkeys,

MST was shown to produce no problematic histological

changes [124,125] and appeared to have less cognitive

side effects than the animal ECT equivalent [126]. Initial

human studies also indicated that MST appeared to have

a favourable side-effect profi le [127,128]. Initial effi cacy

data indicated MST had antidepressant properties, but that

these may be less than those produced with ECT [129].

A second generation of MST studies has now com-

menced, utilizing newly developed equipment capable of

stimulating at higher intensities up to 100 Hz [123]. Pri-

mate studies have shown much more reliable seizure

induction with high frequency MST than lower frequency

stimulation, whilst still demonstrating fewer cognitive

side effects than conventional ECT [130]. Initial human

data is also emerging. In the fi rst direct 100 Hz MST and


achieved clinical response appeared to maintain it with-

out other changes in antidepressant treatment, despite

high levels of chronicity and treatment resistance. In a

small additional sample of patients, a � 50% response
rate was seen (6 of 11) over 12 months [142]. However,

treatment resulted in persistent vocal cord palsies in two

patients lasting 2 and 6 months respectively, and a non-

responding patient committed suicide.

Vocal cord effects are one of the main side effects of

VNS. An alteration to voice, neck discomfort, cough,

dysphagia and shortness of breath can all occur, with

vocal changes potentially persisting over time [139].

However, VNS does not appear to cause cognitive impair-

ment [143].

VNS therapy was approved by the Food and Drug

Administration (FDA) in the USA in 2005 for the treatment

of depression (uni- or bipolar) which has not responded to

at least four medication trials. Since device registration, the

VNS device manufacturing company has conducted a dou-

ble-blind randomized dose study in 331 patients enrolled

across 29 centres in the USA. Response to three levels of

stimulation dose was compared during a 22 week acute

phase and after 1 year of follow up. The results of this study

have not been published in the peer-reviewed literature, but

company materials describe a 12 month response rate of

between 25 and 50% depending on the rating scale used or

level of stimulation intensity [144].

In addition to the use of VNS in depression, several

other applications have been proposed. A small open

label trial has suggested that VNS may have some effi –

cacy in refractory anxiety disorders [145], and its poten-

tial use in obesity and pain management have been

suggested but not yet evaluated [146,147].

VNS: summary of status

The data collected and published to date supporting the

use of VNS in the treatment of depression is quite limited.

However, VNS does appear to have some antidepressant

effects and the profi le of response to this treatment is sub-

stantially and promisingly different from that produced

with a variety of other treatment techniques. Antidepres-

sant effects appear to accumulate slowly over time and to

persist, with little suggestion in the data so far of the prob-

lematic relapse rates common after other acute interven-

tions. However, given the relatively low overall response

rate, approaches to better defi ne which patients are likely

to respond to VNS are urgently required.

Deep brain stimulation

Deep brain stimulation (DBS) is the second surgical

intervention for psychiatric disorders that has evolved

both placed on the same hemisphere. This type of

electrical stimulation appears capable of producing local

seizure activity that does not generalize into a tonic

clonic seizure [132]. At higher stimulation voltages a

generalized convulsion may be produced [132]. To date,

research has only established the feasibility of this type

of stimulation in non-human primates and it is yet to be

determined if either convulsive or non-convulsive forms

of FEAST have clinical utility.


Vagal nerve stimulation

Vagal nerve stimulation (VNS) involves the surgical

implantation of a pulse generator, similar to a pacemaker,

in the chest. This is connected to a stimulating electrode

which is attached to the vagus nerve in the neck [134,135].

Stimulation is applied to the vagus nerve continuously,

although the stimulation parameters may be adjusted.

The main existing indication for VNS is in the treatment

of refractory epilepsy; VNS stimulation can reduce sei-

zure frequency but does not commonly allow patients to

cease anticonvulsant medication treatment [136].

The fi rst potential use of VNS in psychiatry arose from

the observation that patients treated with VNS for epi-

lepsy occasionally experienced mood improvement and

that VNS produced changes in brain activation in depres-

sion relevant brain regions [134,137]. The report from the

initial open label trial of VNS for depression involved 30

patients stimulated for 10 weeks [138]. Between 40 and

50% of the patients achieved clinical response criteria and

this response appeared to persist or improve during follow

up [139]. Results with a larger sample of 59 patients were

more modest (30.5% responders after 10 weeks of treat-

ment, 15.3% remitted), and VNS was found to be less

successful for patients who had failed a greater number

of medication trials [140].

Subsequently, a multicentre randomized trial was con-

ducted with intended device registration. The pivotal D02

trial was a 10 week double-blind trial [140]. The response

rate in the double-blind phase was low and not statisti-

cally different between the active and sham groups [140].

When all subjects were followed up at 9 months, the

response rate was approximately 30%.

In parallel to the double-blind trial, a group of patients

receiving treatment as usual were also evaluated over

12 months. In this analysis, a greater proportion of

patients receiving VNS (27%) achieved response by

12 months than in the treatment as usual group (13%)

[140]. In a more recent analysis of data from the early

studies, Sackeim et al . [141] found that patients who


A series of subsequent reports have described predom-

inately open label OCD DBS trials. For example,

Greenberg et al . found that four of eight patients followed
for 3 years had responded to treatment with persistence

of clinical effects [162]. A paper published in 2010

described the experience of four DBS centres from

around the world, up until that time [163]. This report

included 26 patients with treatment refractory OCD and

a high incidence of comorbid major depression. A clear

benefi t in OCD symptoms that persisted over time was

demonstrated, and there was a parallel improvement in

comorbid depressive symptoms. This paper also described

how the DBS implantation site progressively shifted over

time to a more posterior target, adjacent to the anterior

commissure. The more posterior site produced better

clinical responses [163]. In regard to side effects, two

patients experienced small intracerebral haemorrhages,

both of which had no long-lasting adverse consequences.

One patient experienced an intraoperative seizure and

one a wound infection. A variety of adverse events related

to the process of stimulation were also described, includ-

ing increased depression and hypomania. Adverse cogni-

tive effects were described, but reversed with alteration

of certain stimulation parameters.

Recently, the DBS experience of 16 patients in a single

site in the Netherlands has also been published [164].

Stimulation in the sample was predominately targeted to

the nucleus accumbens at the ventral end of the ALIC.

Nine of 16 patients met response criteria and there was

a signifi cant difference between active and sham stimula-

tion during a double-blind phase. No substantial ongoing

adverse events were reported although mild forgetfulness

and word fi nding problems were described.

DBS in major depressive disorder

Partially motivated by the mood benefi ts seen with

DBS in OCD patients, and partially by the identifi cation

of viable targets in neuroimaging studies, recent attention

has been given to the possible use of DBS in the treat-

ment of highly refractory depression. Although a range

of targets in depression have been proposed, only a lim-

ited number have been the subject of investigation.

The fi rst of these targets is in the white matter adjacent

to the subgenual anterior cingulate cortex. The initial

report of DBS at this site described clinical response in

four of six patients with treatment refractory depression

[165]. Notably, depression returned in patients when

stimulation was removed in a blinded procedure, and

resolved with reinstitution of stimulation. A more sub-

stantial series of patients have subsequently been operated

on and their follow up data recently reported [166].

Response rates seen 3 years post stimulation remained

from a neurological indication. DBS was developed for

the treatment of Parkinson ’ s disease; it is now relatively

widely used in this illness as well as in dystonia and

tremor disorders [148 – 152]. DBS also involves the

implantation of a pulse generator, like a cardiac pace-

maker, in the chest. This is connected to stimulation

electrodes which are placed in localized brain regions.

Standard DBS equipment involves four closely spaced

electrodes at the end of electrode wire; it is likely that

a greater variety of hardware alternatives will emerge

over time. The treating clinician is able to control the

electrodes between which the current fl ows, as well as

current parameters such as voltage, frequency and

pulse width. The placement of the electrodes deter-

mines their effects: in movement disorders implanta-

tion is usually in basal ganglia nuclei such as the

subthalamic nucleus or the globus pallidus [153].

Although DBS has been widely conceptualized as pro-

ducing a ‘ reversible lesion ’ , the mechanism of action

of DBS continues to remain unclear. It is possible that

DBS actually produces functionally relevant changes

through synchronization of local and distal activity,

rather than just a lesion affect [154,155].

DBS in obsessive – compulsive disorder

The initial application of DBS in psychiatry was in the

potential treatment of severe treatment resistant OCD. In

the development of this application it was proposed that

DBS could be used as a reversible alternative to ablative

lesions placed in the anterior limb of the internal capsule

(ALIC). Lesional psychosurgery at the ALIC site contin-

ues to be conducted for severe OCD in some countries

[156,157], however in many it has now been replaced by

DBS approaches. Surgical interventions at this site aim

to disrupt connections between thalamus and anterior

regions of the frontal lobe.

The fi rst small series of OCD patients treated with

DBS were reported by Nuttin et al . in 1999 [158]. Three
patients in this series responded to treatment, and four of

six in a later report by the same group [159]. This initial

DBS application involved the implantation of widely

spaced electrodes to try and ensure disruption of activity

throughout the ALIC. This was based on the observation

from lesional studies that larger lesions were required to

gain greater therapeutic effects [160]. An early interest-

ing case report involved DBS implantation in a patient

with comorbid OCD and depression. An initial antide-

pressant response was achieved with stimulation of the

distal electrodes placed around the nucleus accumbens,

without any change in OCD symptoms [161]. OCD

symptoms subsequently improved when more proximal

electrodes in the ventral caudate were activated.


of potential indications where modulating cortical activ-

ity may have therapeutic benefi t, including in movement

disorders and chronic pain [172,173]. Very limited

research on the therapeutic benefi t of prefrontal ECS in

refractory depression has been conducted to date. Some

benefi cial effects for six patients in an industry sponsored

trial were reported in abstract form in 2008 [174] but have

not yet been published in detail. In a small open label

series of fi ve patients, Nahas et al . reported antidepressant
effects: three patients achieved remission with persistence

of antidepressant response at 7 month follow up [175].


There are a number of techniques that are in the early

stages of exploration as potential ways of modulating

brain activity: none of these are yet to move into the

clinical domain. For example, recent research has dem-

onstrated that low intensity ultrasound has the capacity

to produce neuronal depolarization; possibly through the

mechanical stimulation of ion channels [176]. This poten-

tial application of ultrasound differs from the use of high

intensity ultrasound as a means to ablate tissue [177] and

involves intensities not associated with tissue damage.

Considerable research is required to defi ne optimal

parameters to ensure suffi cient brain penetration and

maximize safety.

An alternative approach is the use of optogenetic stimu-

lation (see review in Carter and de Lecea [178]). This

involves the use of a virus to insert a specifi c channel (for

example rhodopsin) into specifi c neurones. These channels

are stimulated with a particular wavelength of light

resulting in ion fl ows creating highly focused neuronal

depolarization. Covington et al . used this method to over-
express a light-activated cation channel in mouse prefron-

tal cortex [179]. Some antidepressant-like effects were

produced with optogenetic stimulation of this brain region

in this model. There has been a rapid expansion of interest

in the use of optogenetic tools in neuroscience, although

considerable research will be required before these tools

can be practically applied to human populations.


A wide range of new brain stimulation techniques

have been developed for the potential treatment of psy-

chiatric and neurological disorders. Several of these have

progressed through the traditional research stages and are

now being increasingly applied in clinical practice. For

example, repetitive transcranial magnetic stimulation is

increasingly fi nding a role in the treatment of patients

high (75%), with no evidence of deterioration in response

over time. In addition, no substantive side effects emerged

during the period of follow up, which for some patients

extended to 6 years.

The other main DBS site involves variations on the

ALIC site used in OCD: research groups have either tar-

geted the white matter tract or, more specifi cally, the grey

matter of the nucleus accumbens at its ventral end. The

major report targeting the ALIC described the clinical

outcomes of 15 patients [167]. Forty per cent met clinical

response criteria at 6 month follow up and 53% at fi nal

follow up. Adverse events were limited; one case of

hypomania and one of DBS lead fracture. Stimulation

focused more specifi cally to the nucleus accumbens

has been reported only in a small number of patients.

Schlaepfer et al . described improvements in an initial
study of three patients [168]. Other groups have targeted

this site but have not yet reported substantive data.

Clearly DBS is an invasive treatment for psychiatric

disorders with a range of potential side effects. Potential

procedural side effects include haemorrhage, seizure induc-

tion, infection (usually superfi cial) and other anaesthetic

complications. However, the incidence of these appears to

be related to surgical experience [148,169]. Side effects

can also occur secondary to stimulation, including the

induction of fear and anxiety [170]. However, DBS has a

number of signifi cant potential advantages over lesional

psychosurgical procedures. In particular, as stimulation is

adjustable, controlled and minimally destructive of tissue,

it is considered relatively reversible.

DBS: summary of status

DBS is clearly a treatment that will be reserved for the

most refractory patients due to its invasive nature. How-

ever, it appears to have signifi cant therapeutic promise. In

2009, the US FDA granted humanitarian device exemption

for the use of a DBS stimulation device in the treatment

of OCD. This provides access to DBS therapy for patients

with OCD without the conduct of a large-scale placebo-

controlled trial by the sponsoring company, a development

that has been somewhat controversial [171]. Further

research is clearly required to understand the optimal tar-

gets for DBS stimulation and also to better understand the

optimal stimulation profi les, long-term outcomes and

whether likely treatment responders can be preselected.

Epidural cortical stimulation

Epidural cortical stimulation (ECS) is a third surgical

option, but one with a very limited research base. ECS

involves the implantation of a series of electrodes across

the cortical surface. It has been investigated for a number


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Over the next 5 to 10 years we are likely to see an ongo-

ing progression of trials in this area. As the development

of various brain stimulation techniques progress it will

be critical to adequately defi ne the optimal treatment

approaches for individual patients, and how these can be

integrated into feasible evidence-based clinical practice.

Hopefully this will ultimately result in improved patient

outcomes, especially in functioning and quality of life.

Due to the highly specifi c nature of many of these tech-

niques, they are ideally suited to a personalized medicine

approach. In such an approach, an individual ’ s treatment

is based on neuroimaging or other assessment of their

brain function. Whether or not this ideal can be met will

be dependent on whether the substantive trials required to

support this approach can be conducted, and whether our

neuroscience tools are sophisticated and specifi c enough

to generate these types of individualized results.


PBF is supported by a Practitioner Fellowship grant

from the National Health and Medical Research Council


Declaration of interest: PBF has received equipment for

research from Magventure, Brainsway and Medtronic

Inc. PBF alone is responsible for the content and writing

of the paper.


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Topic 1. Repetitive Transcranial Magnetic Stimulation

Repetitive Transcranial Magnetic Stimulation (rTMS) is a noninvasive way to stimulate nerve cells in areas of the brain. rTMS therapy, a cost-effective, noninvasive, nondrug outpatient treatment administered under the supervision of a doctor. The FDA-approved treatment is administered in a device that resembles a comfortable dentist’s chair, which has a headrest and reclines. The patient remains awake during the treatment; it does not require any sedation or anesthesia. Except for the initial treatment, the sessions last about a half-hour. The typical course of therapy consists of five treatments per week for four to six weeks. With this outpatient treatment, patients can immediately return to normal activities after treatment and can even drive home.

During rTMS, an electrical current passes through a wire coil placed over the scalp. The current induces a magnetic field that produces an electrical field in the brain that then causes nerve cells to depolarize, resulting in the stimulation or disruption of brain activity.

The exact details of how TMS functions are still being explored. Researchers have investigated rTMS as an option to treat auditory hallucinations, Major Depressive Disorder (MDD), as an add-on to drug therapy, and, in particular, as an alternative to electroconvulsive therapy (ECT) for patients with treatment-resistant depression.

The advantages of rTMS over ECT for patients with severe refractory depression   are that general anesthesia  s not needed, it is an outpatient procedure, it requires less energy, the   simulation is specific and targeted, and convulsion is not required. The advantages of rTMS as an add-on treatment to drug therapy may include hastening of the clinical response when used with antidepressant drugs.

TMS is generally not painful, but can be uncomfortable insofar as a tingling or knocking sensation is produced against the scalp. Scalp muscle contractions sometimes occur during the treatment. There is a very small risk of seizure associated with TMS, but for the frequency of stimulation used in this study (one stimulation per second) the risk is significant only for patients who have a prior history of seizures. We remain concerned regarding any risk to concentration or memory, although the occurrence of concentration and memory problems in our studies has been very rare (occurring in less than 5% of participants). If we encounter such problems the trial is stopped. In those few patients where such difficulties seem to have emerged, these complaints have disappeared following the halt of the trial. No difficulties in perceiving speech have arisen from TMS in any of our studies to date.


Croarkin, P. E., & MacMaster, F. P. (2019). Transcranial Magnetic Stimulation for Adolescent Depression. Child and adolescent psychiatric clinics of North America28(1), 33–43.

Aleman, A. (2013) Use of Repetitive Transcranial Magnetic Stimulation for Treatment in Psychiatry. Clinical Psychopharmacology and Neuroscience. 11(2) Retrieved from

Wexler A. (2017). The Social Context of “Do-It-Yourself” Brain Stimulation: Neurohackers, Biohackers, and Lifehackers. Frontiers in human neuroscience11, 224.

Topic 2. Deep Brain Stimulation

Deep brain stimulation (DBS) is a surgical treatment in which a device called a neurostimulator delivers tiny electrical signals to the areas of the brain that control movement.

The DBS system consists of three parts:

· A thin, insulated wire called a lead, or electrode that is placed into the brain

· The neurostimulator, similar to a heart pacemaker, which is usually placed under the skin near the collarbone, but may be placed elsewhere in the body

· Another thin, insulated wire called an extension that connects the lead to the neurostimulator

DBS requires surgery to correctly place each part of the neurostimulator system. DBS in adults usually involves two separate surgeries.

Stage 1 is usually performed under local anesthesia, meaning the patient is awake but pain-free. (If the procedure is done in children, general anesthesia is given.)

· The patient’s head is placed in a special frame using screws to keep it still during the procedure. Numbing medicine is applied where the screws contact the scalp. Sometimes, the procedure is done in the MRI and a frame is not used around your head.

· Numbing medicine is also applied to the scalp at the site where the surgeon drills a small opening in the skull and places the lead into a specific area of the brain.

· If both sides of the brain are being treated, the surgeon will make an opening on both sides of the skull, and two leads will be inserted.

· The surgeon may need to send small electrical impulses over the lead to make sure it is connected to the area of the brain responsible for the patient’s symptoms. Different neurological tests may be done.

Stage 2 is done under general anesthesia, meaning the patient is asleep and pain-free. The timing of this stage of surgery depends on where in the brain the stimulator will be placed.

· The surgeon makes a small opening, usually just below the collarbone and implants the neurostimulator. (Sometimes it is placed under the skin in the lower chest or belly area.)

· The surgeon makes another small opening behind the ear and passes the extension wire under the skin of the head, neck, and shoulder.

· The extension wire connects the lead to the neurostimulator.

· The skin is closed, and the device and wires cannot be seen outside the body.

Once connected, electrical pulses travel from the neurostimulator, along the extension wire, to the lead, and into the brain. These tiny pulses interfere with and block the electrical signals that cause tremors and movement disorder symptoms, such as those that occur with Parkinson’s disease, essential tremor, or obsessive-compulsive disorder.

Why is DBS Procedure is Performed?

This surgery may be an option for patients with very severe Parkinson’s disease symptoms that cannot be controlled by medications. The surgery does not cure Parkinson’s disease, but can help make reduce the severity of symptoms such as:

· Tremors

· Rigidity

· Stiffness

· Slow movements

· Walking problems

DBS may also be used to treat the following conditions:

· Essential tremor

· Dystonia

· Arm tremors related to multiple sclerosis

· Tourette syndrome (in rare cases)

· Obsessive-compulsive disorder

· Major drepression that does not respond well to medicines

· Epilepsy


DBS is considered to safe and effective when performed in properly selected patients. Risks associated with deep brain stimulation placement may include:

· Allergic reaction to the DBS parts

· Difficulty concentrating

· Dizziness

· Infection

· Leakage of cerebrospinal fluid, which can lead to headache or meningitis

· Loss of balance

· Reduced coordination

· Shock-like sensations

· Slight loss of movement

· Speech or vision problems

· Temporary pain or swelling at the site where the device was implanted

· Temporary tingling in the face, arms, or legs

Problems may also occur if parts of the DBS system break or move. For example, this may include:

· Breakage of the device, lead, or wires, which can lead to another surgery to replace the broken part

· Failure of the battery, which would cause the device to stop working properly (the battery normally lasts 3 to 5 years)

· The wire that connects the stimulator to the lead in the brain breaks through the skin (this usually only occurs in very thin people)

· The part of the device places in the brain may break off or move to a different place in the brain (this is rare)

Possible risks of any brain surgery are:

· Blood clot or bleeding in the brain

· Brain swelling

· Coma

· Confusion, usually lasting only for days or weeks at most

· Infection in the brain, in the wound, or in the skull

· Problems with speech, memory, muscle weakness, balance, vision, coordination, and other functions, which may be short-term or permanent

· Seizures

· Stroke

· Risks of general anesthesia are:

· Reactions to medications

· Problems breathing

Before the Procedure

The patient will have a complete physical exam.

The patient’s doctor will order many laboratory and imaging tests, including a CT or MRI scan. These imaging tests are done to help the surgeon pinpoint exact what part of the brain is responsible for the tremor and movement disorder symptoms. The images will be used to help the surgeon place the lead in the brain during surgery.

The patient may have to see more than one specialist (neurologist, neurosurgeon, psychologist, etc.) to make sure that the procedure is right for him/her and has the best chances of success.

Before surgery, the patient should tell the doctor or nurse:

· If one could be pregnant

· What drugs he/she are taking, including medicines, herbs or supplements, and vitamins you bought over-the-counter without a prescription

· If one has been drinking a lot of alcohol

During the days before the surgery:

· The patient’s health care provider may tell the patient to stop taking drugs that make it hard for the blood to clot, such as warfarin (Coumadin), aspirin, ibuprofen, naproxen, and other nonsteroidal anti-inflammatory drugs (NSAIDs) .

· If the patient is taking other medications, he/she should ask the doctor if it is okay to take them on the day of or in the days before the surgery.

· Always try to stop smoking. Ask the doctor for help.

· The doctor or nurse may ask the patient to wash his/her hair with a special shampoo the night before surgery.

On the day of the surgery:

· The patient will usually be told not to drink or eat anything for 8 to 12 hours before the surgery.

· Take the drugs the doctor told you to take with a small sip of water.

· Arrive at the hospital at the time specified by the doctor or nurse.

After the procedure

Most people who have DBS are in the hospital for about 3 days. The doctor may prescribe antibiotics to prevent a possibly infection.

The patient will return to your doctor’s office a few weeks after surgery so that the stimulator can be turned on, and the amount of stimulation can be adjusted, if necessary. This can easily be done, without further surgery. It is often referred to as “programming.”

The patient is instructed to notify the doctor if he/she develops any of the following after DBS surgery:

· Fever

· Headache

· Itching or hives

· Muscle weakness

· Nausea and vomiting

· Numbness or tingling on one side of the body

· Pain

· Redness, swelling, or irritation at any of the surgery sites

· Trouble speaking

· Vision problems

Outlook (Prognosis)

DBS is generally well tolerated and does not damage nerve cells like other surgical treatments for Parkinson’s disease. Many patients report significant improvement in their symptoms after having this treatment. However, most of them still need to take medication, although at lower doses, which improves their quality of life.

This surgery, and surgery in general, is riskier in people over age 70 and those with health conditions such as high blood pressure and diseases that affect blood vessels in the brain. You and your doctor should carefully weigh the benefits of this surgery against the potential risks.

The DBS procedure can be reversed, if needed.

Alternative Names

Globus pallidus deep brain stimulation; Subthalamic deep brain stimulation; Thalamic deep brain stimulation; DBS


Graat, I., Figee, M., & Denys, D. (2017). The application of deep brain stimulation in the treatment of psychiatric disorders. International review of psychiatry (Abingdon, England), 29(2), 178–190.


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