Repetitive Transcranial Magnetic Stimulation/ Deep Brain Stimulation

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Theemerginguseofbrainstimulationtreatmentsforpsychiatricdisorders.pdf

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: paul.fi [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,

924 BRAIN STIMULATION IN PSYCHIATRY

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

options?

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.

REPETITIVE TRANSCRANIAL MAGNETIC

STIMULATION

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

P. B. FITZGERALD 925

although they have yet to be evaluated in substantive

trials.

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,

926 BRAIN STIMULATION IN PSYCHIATRY

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

required.

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

P. B. FITZGERALD 927

LOW INTENSITY MAGNETIC STIMULATION

APPROACHES

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.

LOW VOLTAGE ELECTRICAL STIMULATION

APPROACHES

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

928 BRAIN STIMULATION IN PSYCHIATRY

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.

CONVULSIVE STIMULATION THERAPIES

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

P. B. FITZGERALD 929

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

930 BRAIN STIMULATION IN PSYCHIATRY

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.

SURGICAL INTERVENTIONS

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

P. B. FITZGERALD 931

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.

932 BRAIN STIMULATION IN PSYCHIATRY

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].

NEW AND EMERGING APPROACHES

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.

SUMMARY

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

P. B. FITZGERALD 933

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with depression and possibly other psychiatric disorders.

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.

Acknowledgements

PBF is supported by a Practitioner Fellowship grant

from the National Health and Medical Research Council

(NHMRC).

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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