Magnetic seizure therapy: development of a novel intervention

for treatment resistant depression

Oscar G. Moralesa,b, Harold A. Sackeima,b, Robert M. Bermana,b, Sarah H. Lisanbya,b,*

aMagnetic Brain Stimulation Laboratory, Department of Biological Psychiatry, New York State Psychiatric Institute,

1051 Riverside Drive, Unit 126, New York, NY 10032, USAbDepartment of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA

Abstract

Electroconvulsive therapy (ECT) is the most effective and most rapidly acting treatment for severe treatment resistant major depression,

but its use is limited by its cognitive side effects. Magnetic seizure therapy (MST) is a new form of convulsive therapy using high-dosage

repetitive transcranial magnetic stimulation (rTMS) to induce focal cortical seizures under anesthesia. MST is under study as a means of

reducing the side effects of ECT through the enhanced control over the sites of seizure initiation and topography of seizure propagation

afforded by the relative focality of rTMS. This review traces the stages in the development of MST, from device development, to preclinical

testing, to clinical trials. The results of a study on the comparative safety of chronic MST and electroconvulsive shock in non-human primates

support the safety of both interventions, and indicate that the seizures induced by MST are more focal and have less impact on deeper brain

structures. This non-human primate model and a controlled clinical trial in patients with major depression, suggest that MST may induce

fewer side effects and less amnesia than ECT. Ongoing work will yield the first data on the antidepressant efficacy of MST. If ultimately

shown to be effective, MST could represent a new, less invasive option for patients with severe treatment resistant depression or other

disorders who would otherwise require ECT.

q 2004 Elsevier B.V. All rights reserved.

Keywords: Electroconvulsive therapy; Magnetic seizure therapy; Repetitive transcranial magnetic stimulation; Depression; Seizure

1. Introduction

Electroconvulsive therapy (ECT) is the most effective

and rapidly acting treatment for Major Depressive Episode

(MDE) [1]. While modernization of ECT technique has

dramatically improved its risk/benefit ratio, some degree of

retrograde amnesia remains a significant risk of the

procedure. Research shows that the efficacy and side effects

of ECT are determined by the site of seizure initiation and

patterns of seizure spread [2–4], but these factors cannot be

adequately controlled with current ECT technique [5]. A

form of convulsive therapy that retains the therapeutic

efficacy of ECT, but with a better side effect profile, should

substantially improve the quality of life for patients needing

convulsive therapy and should increase access to effective

treatment. Magnetic seizure therapy (MST) is under

development as a means of achieving that goal [6–9].

Technology has advanced to the stage where it is now

possible to perform convulsive therapy by using a magnetic

stimulus, rather than an electrical stimulus, to induce the

seizure. Magnetic fields pass through tissue without the

impedance encountered by the direct application of

electricity, making it possible to focus the site and extent

of stimulation more precisely than could be achieved with

conventional ECT. MST entails the use of repetitive

transcranial magnetic stimulation (rTMS) to trigger a

seizure from superficial cortex. While both MST and ECT

induce seizures through electrical stimulation of the

brain, the electric field induced by MST is far more focal

[7]. Because magnetic fields pass through tissue unimpeded

[10,11], there is greater control over the site and extent of

stimulation with MST. The treatment can be targeted to key

cortical structures thought to mediate antidepressant

response, with relative sparing of medial temporal structures

implicated in the amnestic side effects of ECT.

The idea of using rTMS to induce seizures was first

raised in the field of neurology as a means of confirming

diagnosis, localizing seizure focus, and presurgical planning

in epileptic patients [12–15]. It was soon discovered that

1566-2772/$ - see front matter q 2004 Elsevier B.V. All rights reserved.

doi:10.1016/j.cnr.2004.06.005

Clinical Neuroscience Research 4 (2004) 59–70

www.elsevier.com/locate/clires

* Corresponding author. Address: Magnetic Brain Stimulation

Laboratory, Department of Biological Psychiatry, New York State

Psychiatric Institute, 1051 Riverside Drive, Unit 126, New York, NY

10032, USA. Tel.: þ1-212-543-5568; fax: þ1-212-543-6056.

E-mail address: slisanby@columbia.edu (S.H. Lisanby).

using rTMS to produce seizures on demand in epileptic

patients was exceedingly difficult, especially in patients on

anticonvulsant medications. Studies on the safety of rTMS

demonstrated that, at sufficient dosages, rTMS could induce

generalized seizures inadvertently in normal human subjects

who were not on anticonvulsants [16,17]. Sackeim proposed

the idea of using rTMS to deliberately induce seizures under

anesthesia as a means of improving ECT, providing greater

control over sites of seizure onset and patterns of seizure

spread [18]. Commercially available rTMS devices were

underpowered to overcome the anticonvulsant action of the

general anesthesia used during ECT, but several years of

developmental work in an animal model has resulted in a

device capable of reliable seizure induction under anesthe-

sia in humans.

MST is presently at a very early stage of development

(for reviews, see Refs. [6,9,19]). As of this writing, a total of

17 non-human primates and 36 human patients with major

depression have received MST worldwide. The field is just

beginning to explore its potential utility in psychiatry. This

manuscript presents the rationale for MST, the course of its

development, and the present state of knowledge from

preclinical and clinical trials concerning its mechanisms of

action and potential therapeutic role in psychiatry.

2. Definition and description of the MST procedure

rTMS is a non-invasive means of stimulating the cortex

using rapidly alternating magnetic fields applied to the scalp

via an electromagnetic coil [10]. Rapidly alternating

magnetic fields induce electrical current in the cortical

tissue underlying the coil. In addition to being a useful

means of probing brain circuitry, rTMS is under investi-

gation for its therapeutic potential in a number of psychiatric

and neurologic disorders (for reviews, see Refs. [20–23]).

In clinical trials, rTMS is typically given in sessions lasting

up to 30 min/day, repeated 5 days a week, over a period of

2–6 weeks. The subject is alert during the procedure and no

anesthesia is required.

MST refers to the use of high intensities of rTMS to

induce a seizure for therapeutic purposes. MST is presently

performed under general anesthesia so that the motor

manifestations of the seizure can be blocked, as is done with

ECT. However, future versions of the procedure may not

involve motor convulsion that could obviate the need for

muscle relaxants. Like ECT, the MST procedure is

performed once a day, three times a week, although the

optimal dosing schedule has not yet been studied system-

atically. The device used to perform MST is a modified

version of an rTMS device (Fig. 1), with an extended

parameter range in order to overcome the anticonvulsant

effects of anesthesia. Like rTMS, MST is investigational

(i.e. not FDA approved) and is currently only performed in

the context of approved research studies.

3. Rationale for developing a new convulsive treatment

3.1. The need for new interventions for treatment resistant

depression

Despite a wide variety of available antidepressant

medications and psychotherapies, a disturbing number of

patients do not achieve remission, either because they are

resistant or intolerant to treatment side effects. In recog-

nition of this fact, recent work has focused on developing

algorithms or guidelines for managing depressed patients

for whom treatment attempts have been unsuccessful [24].

ECT is presently the only treatment with proven efficacy in

treatment resistant patients, but this highly effective and

rapidly acting treatment is usually relegated to the later steps

of these algorithms and, in practice, is often used only as a

treatment of last resort, due both to its stigma and its well-

recognized cognitive side effects [25–27]. A novel treat-

ment that could capture the efficacy of ECT, while

minimizing its cognitive side effects, would bring the

most effective intervention yet available to more patients

earlier in the course of treatment. This should enhance both

the effectiveness and acceptability of this treatment strategy

for the most disabled group of depressed patients.

3.2. Cognitive effects of ECT

The cognitive side effects of ECT reduce its tolerability

and deter many patients from receiving this potentially life

saving treatment. Retrograde amnesia is the most persistent

adverse effect of ECT [28–31]. Shortly after ECT, most

patients have gaps in memory for events that occurred close

in time to ECT, but retrograde amnesia may extend back

several months or years. While retrograde amnesia often

improves during the first few months following ECT, for

many patients recovery is incomplete, with prolonged

amnesia for events that occurred close to the time of

treatment [32].

Reducing the side effects of ECT would represent a

special benefit for the elderly, who are especially vulnerable

to its amnestic effects. Pre-existing cognitive impairment is

one of the few predictors of ECTs adverse effects, and is

more likely with advancing age [33]. Coffey et al. found that

elderly depressed patients referred for ECT exhibit a higher

frequency of subcortical white matter hyperintensities on

MRI, and these structural changes predicted increased

cognitive side effects of the treatment and increased

frequency of post-ECT delirium [34,35]. Sparing targeted

regions from induced current and seizure spread by

controlling the pathway the electrical current traverses

might be expected to reduce cognitive side effects.

Variations in ECT technique (e.g. right unilateral (RUL),

ultrabrief pulse width) can lower its side effects substan-

tially [2,3,36]. For example, autobiographical memory

loss at 6 months is greater with bilateral (BL) than RUL

ECT. However, the use of externally applied electrodes

O.G. Morales et al. / Clinical Neuroscience Research 4 (2004) 59–7060

intrinsically limits the capacity to control the intracerebral

spatial distribution of the ECT stimulus and its intracerebral

current density [5,18]. Modifications in ECT technique have

substantially reduced, but they have not yet resolved, the

problem of cognitive side effects.

4. Potential advantages of magnetic seizure induction

relative to ECT

MST offers a means of controlling the two key factors

that determine the efficacy and side effects of ECT (site of

seizure initiation and pattern of seizure spread) [37–41],

neither of which can be adequately controlled with ECT

techniques currently in use. Both MST and ECT induce

seizures through electrical stimulation of the brain. In the

case of ECT, the electricity is applied directly to the scalp,

whereas with MST the electricity is indirectly induced in the

brain by a magnetic stimulus. With ECT, the high

impedance of the skull shunts 80–95% of the electrical

stimulus away from the brain [42]. A small portion of the

electrical stimulus causes neuronal depolarization. The

shunting produces a non-focal, widespread intracerebral

current distribution [5]. The topography of shunting varies

considerably among individuals, due to differences in skull

thickness and anatomy.

MST offers precise control over the site of seizure

initiation and the capacity to limit seizure spread because

Fig. 1. Prototype MST device consisting of 16 charging units feeding a single capacitor.

O.G. Morales et al. / Clinical Neuroscience Research 4 (2004) 59–70 61

magnetic fields pass through tissue without impedance [10].

The electrical field induced by MST is capable of neural

depolarization at a depth of #2 cm below the scalp (i.e.

gray–white matter junction), so direct effects are limited to

the superficial cortex [43–46]. Coil geometry allows the

magnetic field to be spatially targeted, offering further

control over intracerebral current paths. Measurements in

non-human primates with intracerebral multicontact elec-

trodes support the hypothesis that MST-induced current and

the resulting seizure are more focal than that obtained with

ECT [7]. This enhanced control represents a means to focus

the treatment in targeted cortical structures thought to

mediate antidepressant effects and to reduce spread to

medial temporal structures implicated in the amnestic side

effects of ECT.

5. Importance of focality and dosage of stimulation

to clinical outcome

Remission rates with ECT can range from 20 to over

70%. This variation has been tied to differences in the sites

and dosage of stimulation—factors not well controlled with

ECT. Double-masked, randomized trials demonstrate

powerful interactions between site of seizure initiation and

electrical dosage in efficacy and side effects [2,3,47].

Dosage relative to seizure threshold strongly modulates

the efficacy of RUL ECT and the speed of response for RUL

and BL ECT [2,48–50]. Electrode placement and electrical

dosage are also strongly associated with the magnitude of

cognitive side effects. Several studies have found that high

dose RUL ECT is as effective as BL ECT, with the

advantages of lower cognitive side effects, especially at

long-term follow-up [2,3].

ECT changes regional functional brain activity, based on

quantitative assessment of regional cerebral blood flow,

cerebral metabolic rate for glucose, and the induction of

electroencephalographic slow wave activity (increased delta

and theta power) [39–41,51,52]. The magnitude and

regional distribution of these changes have replicable

relationships to the efficacy and cognitive side effects of

ECT. ECT causes highly significant decreases in regional

cerebral metabolism, with the largest reductions in BL

superior, dorsolateral and medial prefrontal cortices. Other

regions heavily involved include BL parietal cortex,

posterior cingulate, and left medial and inferior temporal

lobe.

It is thought that ECT-induced prefrontal changes are

associated with antidepressant effects, while temporal lobe

changes are associated with key amnestic side effects.

Supporting this notion, antidepressant response is strongly

associated with prefrontal cerebral blood flow reductions

and increases in prefrontal slowing on EEG [40]. Further-

more, measures of retrograde amnesia for autobiographical

memories were correlated with increased left frontotem-

poral EEG theta power. These findings suggest that one may

be able to dissociate the antidepressant effects from the

cognitive side effects of ECT by improved focusing and

control over the induced seizure.

It is logical to look to the field of epilepsy for further

support for the notion that the cognitive and behavioral

consequences of seizures have topographical specificity.

Temporal lobe epilepsy (TLE) is associated with hippo-

campal atrophy and cognitive deficits, possibly through

secondary neuronal metabolic and structural deterioration in

this region. Generalized cognitive impairment with global

decline in attention, memory, and general intelligence are

also more likely to be seen with increasing seizure

frequency and epilepsy duration. However, few studies

have examined the relationship between memory disorders

in patients with epilepsy and seizure type and location of the

focus. Hendriks et al. reported in a study of 252 patients

with epilepsy that seizure-related factors (seizure type,

location and lateralization) do not contribute to the degree of

memory complaints patients have in daily life [53]. More

systematic study of cognitive deficits in relationship to

focality and localization of the seizure may help to guide the

development of focal seizure induction methods that retains

antidepressant effect without disturbance of cognitive

function.

6. MST in the context of other emerging brain

stimulation techniques in psychiatry

At present, the only device approved for the treatment of

depression is ECT. That status is likely change in the near

future as a number of brain stimulation techniques emerge

on the therapeutic horizon, including rTMS, vagus nerve

stimulation (VNS), and deep brain stimulation (DBS) [54].

These new modes of brain stimulation may provide more

specific and less invasive treatments and could also improve

our understanding of the neural circuitry underlying

psychiatric disorders.

The concept of using brain stimulation to study and treat

disorders is actually quite old, but recent technological

developments have enabled the vision of focal brain

stimulation to become a clinical reality. Experiments in

neurophysiology using electrical current began in 1786

when Galvani induced muscular contractions in the legs of

frogs. Penfield and Jasper (1954) [79] provided invaluable

information of the topography of a number of clinical and

EEG responses induced by direct electrical stimulation of

the cortex. The use of electricity for therapeutic brain

stimulation started over 65 years ago with ECT. In 1973,

DBS was attempted when Mazars stimulated various sites of

the thalamus, internal capsule and periventricular gray areas

to induce analgesia [55]. Barker first used TMS to non-

invasively induce electrical currents in the cortex in 1985

[10]. Changing brain activity through electrical stimulation

of the vagus nerve (VNS) was developed by Zabara for the

treatment of epilepsy [56]. The procedure for seizure

O.G. Morales et al. / Clinical Neuroscience Research 4 (2004) 59–7062

induction using rTMS (MST) was developed at Columbia

University in a non-human primate in 1998 and human

testing commenced in 2000 [57,58]. Finally, work this year

at Columbia has started to refine electrode shape and

stimulation parameters to permit focal electrical seizure

induction using electricity (FEAST).

Modern brain simulation techniques attempt to alter the

functioning of targeted neuronal networks through the

induction of seizures (MST, ECT and FEAST), or sub-

convulsively through the effect of the electrical stimulus on

neuronal depolarization (VNS, TMS and DBS). A

challenge facing both seizure-inducing and subconvulsive

forms of stimulation is the determination of the optimal

stimulus parameters. For example, the physiological

impact of rTMS can be excitatory or inhibitory depending

upon the frequency and site of stimulation. Also, seizure

threshold and ictal characteristics vary dramatically

depending upon the parameters of the stimulus that

induced the seizure [59]. The brain stimulation techniques

differ in their degrees of invasiveness, from minimally

invasive procedures such as TMS to more invasive

treatments as DBS (Table 1).

What makes the novel seizure-inducing forms of brain

stimulation (MST and FEAST) unique among other

treatment strategies under development is that they start

with the most effective treatment for severe depression

(ECT) and attempt to reduce or eliminate its cognitive side

effects. Compared to alternative treatments, ECT has

advantages with respect to speed of clinical improvement,

probability of achieving remission, and the quality of

remission (i.e. fewer residual symptoms) [60]. In contrast,

research to optimize subconvulsive treatments for

depression generally begins with an intervention that may

have modest antidepressant properties, and the goal is

enhancing efficacy and identifying factors that improve

efficacy to a level that is clinically useful.

7. Pre-clinical studies of MST

7.1. MST device development and testing in the non-human

primate

The initial step in the development of MST was to build a

device capable of reliable seizure induction under anesthe-

sia. This task was complicated by the anticonvulsant effects

of the general anesthetic agents typically used for ECT. Our

early work demonstrated that commercially available rTMS

devices were underpowered to achieve that goal. Develop-

ing a device capable of reliable seizure induction under

anesthesia required several years of developmental work in

an animal model.

Our work suggested that non-human primates were the

ideal animal model for MST due to their large brain size

relative to other commonly used experimental animals [57].

We have not found it possible to induce seizures with rTMS

in rodents (even with unanesthetized subjects) despite high

levels of stimulation (up to 60 Hz, 100% maximal

stimulator output, 6.6 s trains, small figure 8 or round

coils) [6]. This is likely due to the fact that the intensity of

the electric field induced in the brain is proportional to the

size of the brain (i.e. less current induced in smaller brains),

and to the ratio between coil size and brain size (i.e. smaller

brains need smaller coils to be efficiently stimulated) [61].

Pediatric-sized coils in monkeys became a practical means

of more closely approximating the coil-to-brain size ratio of

humans. Monkeys also offered the opportunity to test the

neuropathological safety of MST in the primate brain, and to

examine the cognitive side effects of MST relative to

electroconvulsive shock (ECS) with tasks that assess more

complex aspects of cognitive function, which is not possible

in rodents [62].

Preliminary studies indicated that the commercially

available rTMS devices (peak output 25 Hz, 100% intensity,

10 s) could not reliably induce seizures in any organism

Table 1

Comparison of brain stimulation techniques

ECT MST TMS VNS DBS

FDA approved Yes No No Yes-epilepsy Yes-movement disorder

FDA approved for

psychiatric indication

Yes No No Under review Under investigation

Primary indication Major depression Investigational Investigational Epilepsy Movement disorder

Indications under investigation Major

depression

Major depression,

schizophrenia

Major

depression

Obsessive compulsive

disorder, major depression

Seizure-induction modality Yes Yes No No No

Anticonvulsive activity Yes Yes Under investigation Yes Under investigation

Focal stimulation No Yes Yes No Yes

Anesthesia required Yes Yes No No No

Surgery required No No No Yes Yes

Brain surgery required No No No No Yes

Magnetic induction No Yes Yes No No

Electricity induced in the brain Yes Yes Yes No Yes

Site of direct stimulation Brain Brain (superficial cortex) Brain Cranial nerve Brain

Reaches deep brain structures Yes No No Yes (indirectly) Yes (directly)

O.G. Morales et al. / Clinical Neuroscience Research 4 (2004) 59–70 63

under anesthesia. Two factors needed to be modified to

permit reliable seizure induction: (1) the width of the

magnetic pulse needed to be lengthened to approximately

0.5 ms, and (2) the output frequency needed to be boosted

by increasing the number of charging units. We found PWs

longer than 0.5 ms to be less efficient, presumably due to a

slower rise time to peak field strength. A device capable of

sustaining 40 Hz, 100% output, for 6.3 s, succeeded in

performing the first deliberate seizure induction under

general anesthesia in November, 1998 [57]. Generalized

tonic-clonic seizures were induced with a round coil

positioned on the vertex in rhesus monkeys, using the

same anesthetic protocol as conventional ECT. Since these

initial trials, the MST device has undergone numerous

upgrades and enhancements to increase its output up to

100 Hz. Subsequent work, reviewed below, has character-

ized the neurophysiological and neuroanatomical effects of

MST, and compared them with ECS in the monkey.

7.2. Spatial distribution of the MST-induced electric field

and resultant seizure

Two aspects of the biophysical and physiological

response to MST and ECS have been compared in monkeys:

(a) the distribution of the electric field induced in the brain,

and (b) the characteristics of the seizures induced. In both

domains, the physiological effects of MST were more

localized to superficial cortex and show a relative sparing of

hippocampus [7].

Intracerebral measurements of the electric field induced

in the brain of rhesus monkeys show that MST delivers

7-fold less induced charge per pulse than ECS at the site of

stimulation [7] (Fig. 2). MST showed negligible spread to

contralateral prefrontal or ventral regions, while ECS-

induced substantial voltage at most recording sites, includ-

ing ventral regions and extending to parietal and occipital

cortex. More focal stimulation would be expected to lead to

more focal seizure expression. As expected, compared with

ECS, MST showed more differentiation in ictal expression

as a function of the site of stimulation (e.g. BL and midline

placements inducing more ictal activity in prefrontal cortex

than unilateral placements) (Fig. 3). Seizure expression was

as robust in hippocampus as prefrontal cortex with ECS, but

markedly less robust in hippocampus than prefrontal cortex

with MST. These results support the rationale for attempting

seizure induction with MST as a means of limiting exposure

of key brain regions to the direct effects of the induced

electric field and resultant seizure.

7.3. Safety of MST

MST exposes the brain to magnetic fields, induced

electric fields, and seizures. The safety of magnetic field

exposure is well documented by the extensive safety record

of MRI scanning at field strengths of 1.5–2 T (and higher).

The magnitude and distribution of the electric fields and

seizures induced in the brain by MST are substantially lower

in magnitude and more circumscribed than those seen with

ECT, and the charge density delivered with ECT is well

below levels associated with neuropathological damage

[63]. Therefore, MST would be expected to be as safe, or

safer, than ECT. To test that hypothesis, we tested the

cognitive side effects of MST (compared to ECS

and anesthesia-alone sham) in non-human primates,

Fig. 2. Intracerebral recordings of current induced in rhesus monkey brain

with TMS, MST and ECS. TMS and MST deliver less charge per pulse than

ECS.

Fig. 3. Intracerebral recordings of ictal EEG power with MST and ECS

(right unilateral and bilateral) in monkeys. MST seizures are less robust

overall than ECS, and spread less to hippocampus.

O.G. Morales et al. / Clinical Neuroscience Research 4 (2004) 59–7064

and performed neuropathological examinations following

chronic treatment.

The cognitive side effects of MST and ECS were

compared using the Columbia University Primate Cognitive

Profile (CUPCP), which was developed to model the

cognitive parameters affected by ECT through the use of

visual stimuli presented to monkeys on a touch screen

monitor. The CUPCP and has been shown to be sensitive to

the effects of ECS [62]. Rhesus macaques were trained on

an orientation task, an anterograde learning and memory

task, and a combined anterograde and retrograde task where

learning and memory were evaluated for new and

previously trained 3-item lists. Across all tasks, ECS

consistently produced deficits in performance accuracy

and task-completion times that were significantly impaired

compared to either sham or MST conditions. Monkeys were

more accurate and faster to complete tasks following MST,

as compared to ECS [64].

Careful neuropathological examination revealed a com-

plete absence of acute or remote neuropathological lesions

associated with ECS or MST in this primate model closely

mimicking clinical conditions of ECT [65]. This evidence

for neuropathological safety in the primate brain supported

further clinical work with MST.

7.4. Hippocampal plasticity in response to MST

While ECS does not induce clinically apparent neuro-

pathological damage, it does impact certain aspects of

neural plasticity. Specifically, ECS has been reported in

rodents to profoundly affect mossy fiber sprouting (MFS)

and neurogenesis. MFS, the aberrant growth of collaterals of

granule cell axons into the inner molecular layer of the

dentate gyrus and CA3 of the hippocampus, is not seen with

antidepressant medications and is thought to contribute to

cognitive impairment in epilepsy models [66]. Neurogen-

esis is seen with antidepressant medications and has been

hypothesized to play a role in antidepressant response [67],

though some recent work yet to be published may challenge

this link. Neurogenesis is also seen in response to seizure-

induced injury and in that context is thought to contribute to

the abnormal hyperexcitability and memory disturbance

associated with chronic epilepsy [68–70]. Contrasting MST

and ECS in their effects on these two measures should be

informative regarding the mechanisms underlying these

effects of seizures, and the feasibility of dissociating these

effects through enhanced control over seizure initiation and

expression.

We found that ECS, but not MST, produces significant

MFS and increases in dentate cellular proliferation in the

monkey, consistent with the hypothesis that MST has less

impact on medial temporal lobe structures [71,72]. These

preliminary studies suggest that merely inducing a seizure is

insufficient to affect these measures of hippocampal

plasticity, and that the spatial distribution of the induced

electrical field and/or the pattern of seizure propagation may

be critical to these effects. The clinical significance of these

differences between MST and ECS will need to be

determined in the context of a controlled clinical trial. If

MST is found to have clinical efficacy, that would call into

question the role of hippocampal plasticity in antidepressant

action. On the other hand, should MST be found ineffective

in the clinical setting, this would support the view that an

impact on hippocampal plasticity is important for the

antidepressant action of seizures. A limitation of this work

was that it was performed at moderately suprathreshold

levels (2.5 times seizure threshold) using a non-focal round

coil positioned on the vertex. The effects of focal prefrontal

MST at more robust suprathreshold dosages, which would

be expected to be more optimal for efficacy, are currently

under study.

8. Clinical trials with MST

8.1. Case studies of MST in the treatment of major

depression

The first human MST was performed in 2000, in a

woman with treatment resistant depression referred for

ECT. The patient had a 50% drop in Hamilton Depression

Ratings Scale (HRSD24) scores following 4 MST sessions

[58]. MST was well tolerated with no significant side

effects. A second case with medication resistant depression

was treated with a longer MST course (12 treatments) and

experienced remission, with an 82% drop in HRSD24 and

final HRSD24 ¼ 6 [73]. These case reports demonstrated

feasibility, and provided suggestions of efficacy in an open,

uncontrolled setting.

8.2. Randomized comparison of the acute side effects

of MST and ECT

We conducted a double-masked, randomized, within-

subject trial contrasting MST with ECT in acute cognitive

side effects [8]. Ten depressed patients received a course of

convulsive therapy in which two of the first four treatments

were MST, and the remaining treatments were ECT. To

provide a robust test of the safety of MST, the ECT

comparator condition for 9 of the 10 patients was ultrabrief

pulse RUL ECT, the form of ECT with the fewest cognitive

side effects yet observed. MST was well tolerated, with

fewer subjective side effects than ECT (Fig. 4) and faster

recovery of orientation, a measure that predicts the

magnitude of long-term retrograde amnesia [30].

Masked neuropsychological assessments revealed

advantages of MST relative to ECT. Consistent with the

differential impact of MST and ECT on seizure expression

and hippocampal synaptic plasticity, the cognitive domains

where ECT showed greater impairment than MST were

those subserved at least partly by temporal lobe structures

(i.e. memory for recent events, new list learning, category

O.G. Morales et al. / Clinical Neuroscience Research 4 (2004) 59–70 65

fluency). In contrast, MST and ECT did not differ in their

effects on tasks more heavily dependent on prefrontal lobe

function (i.e. memory for temporal order, verbal fluency),

consistent with the view that MST would retain effects on

prefrontal structures important for efficacy.

Marked differences in the nature of the seizures induced

by these two interventions were seen, although all seizures

(MST and ECT) generalized and resulted in motor

convulsion. Compared to ECT, MST seizures had shorter

duration ðP , 0:04Þ; lower ictal EEG amplitude

(F1;7 ¼ 43:51; P , 0:0003), and less postictal suppression

(F1;7 ¼ 13:26; P , 0:008). It will be important to determine

whether these electrophysiological differences have clinical

significance.

8.3. Antidepressant efficacy of MST

The antidepressant efficacy of MST is not yet known, but

is under active study. We conducted a randomized, double-

masked, two-center (Columbia University and University of

Texas Southwestern Medical Center) pilot study comparing

two forms of MST in their antidepressant properties and side

effects [74]. This dose-finding work is a needed precursor to

inform the selection of the optimal way to deliver MST and

to power a subsequent masked comparison with ECT.

Extensive neuropsychological testing is underway, and

patients are being followed for 6 months to examine the

persistence of any clinical benefits and/or side effects. Once

more experience is gained with optimizing the dosage of

MST, the next step will be to compare MST to conventional

antidepressant treatments in randomized clinical trials to

establish efficacy.

9. Potential neuroscience applications of MST as a focal

seizure induction model

Apart from its putative clinical value, MST may have

value as a means of probing the action of seizures, of

potential relevance to both the antidepressant action of ECT

and the pathophysiology of epilepsy. Differences between

ECT and MST along neurobiological variables may be

informative regarding the antidepressant action of seizures

and their impact on mood networks. For example, if seizures

of cortical origin that do not spread to the diencephalon or

hippocampus were found to be clinically effective, this

would have implications for our understanding of the action

of ECT. This would also provide an opportunity to test

whether MFS and neurogenesis are central to antidepressant

action (or cognitive side effects). MST also provides a

model for understanding how these actions of ECS come

about. Studies using ECS to trigger seizures cannot

distinguish whether the observed hippocampal effects are

secondary to the induced seizure, or due to the passage of

electricity through the temporal lobes. MST provides a

model free of this confound.

Prefrontal cortical involvement in ECT-induced seizures

is hypothesized to be key to enhanced efficacy, but with

ECT there is limited control over the generalization of

seizures in order to selectively test the role of prefrontal

involvement in clinical outcome. With MST, the efficacy

and side effects of more circumscribed prefrontal seizures

compared with those triggered from other cortical regions

could help to answer this question.

MST represents a new paradigm for studying the

consequences of seizures in the absence of direct electrical

effects on brain structures distant from the site of

stimulation. This may be a useful paradigm for modeling

the effects of focal epilepsy.

10. Future directions for MST research

10.1. MST device limitations

While the current MST device was adequate for

suprathreshold stimulation in monkeys, human work with

that device indicated that it is likely underpowered for

clinical applications. Nearly half of patients in work to date

had a seizure threshold at the maximal output of the device,

no patient could be treated at 6 times seizure threshold, a

dosage that increases the efficacy of RUL ECT, and no

seizures were able to be induced with the figure 8 coil (the

most focal of the available coils) over the prefrontal cortex,

even at the maximal output of the stimulator. This is

probably because focal coils stimulate a smaller region of

cortex and induce less current than non-focal coils, and the

seizure threshold of prefrontal cortex is higher than other

superficial cortical areas such as primary motor cortex.

Accentuating the problems of limited device output, MST

Fig. 4. Fewer subjective side effects with MST than ECT in depressed

patients.

O.G. Morales et al. / Clinical Neuroscience Research 4 (2004) 59–7066

threshold increases throughout the treatment course, as seen

with ECT. All of the clinical work to date employed a non-

focal cap coil, or a double cone coil positioned on the vertex,

which is not likely to be the target region for maximal mood

effects.

If the relationship between dosage above threshold and

efficacy for ECT pertains to MST, the available data in

humans and monkeys indicate that the current generation

MST device is incapable of providing stimulation at an

adequate percentage relative to seizure threshold to

maximize antidepressant efficacy. The next steps in the

development of MST will involve further coil and device

modifications to permit focal seizure induction in targeted

prefrontal regions, better control of coil heating and noise

(both of which are accentuated with MST relative to rTMS

due to the higher output levels), improved ease of use by

decreasing the number of power inlets required (currently

16 separate 20 A rated circuits), and improved reliability of

device operation. Device modifications are currently under

development and being piloted in an attempt to achieve

these goals.

10.2. Clinical trials of the antidepressant efficacy of MST

Subsequent clinical studies of MST will need to address

the many as yet unanswered questions regarding its clinical

efficacy (both acute response and persistence of effects)

relative to ECT and antidepressant medications, parameters

of stimulation (including coil type, coil placement, dosage)

and treatment schedule (interval between treatments,

number of treatments, continuation and maintenance

schedule) to optimize its efficacy. Of note, the only form

of MST that has been tested to date involves generalization

to the motor cortex with a subsequent motor convulsion.

Future work may examine whether spread to motor cortex is

indeed necessary for clinical efficacy. If not, focal seizures

that do not generalize would obviate the need for muscular

paralysis during the treatment and significantly simplifying

the procedure.

The ultimate clinical role of MST will depend upon its

efficacy/side effect trade off. If MST is found to be more

tolerable than ECT, but less effective than ECT, it may still

have a clinical role if its efficacy shows advantages relative

to medications. Another potential role for MST could be in

post-ECT relapse prevention, on the theory that its

improved tolerability will enhance compliance with acute

and longer-term maintenance schedules.

10.3. Subconvulsive rTMS to modify or augment

conventional ECT

Another approach to enhancing the tolerability of

convulsive therapy using the technology of magnetic

stimulation would be to use subconvulsive levels of rTMS

in conjunction with conventional ECT. rTMS could be

given as a pretreatment to protect certain brain regions, or

on an ongoing basis throughout the ECT course to

accelerate or boost the anticonvulsant action of ECT.

rTMS in combination with ECT may prove promising,

given the effects of rTMS on cortical excitability. One small

trial has combined subconvulsive doses of rTMS with ECT

in an effort to improve clinical outcome and has shown

promising results [75]. Aside from that study, the utility of

rTMS augmentation of ECT remains unexplored.

The clinical efficacy of ECT appears to relate, at least in

part, to various measurable parameters of the induced

seizure, charge administered in relation to seizure threshold,

and, notably, the rise in seizure threshold induced by ECT

itself during a course of treatment. rTMS has been reported

to increase ST in rodent models [76] and is under study as a

treatment for epileptic seizures, especially those with a

cortical focus [77,78]. Subconvulsive rTMS can be applied

focally to determine the spatial specificity of effects on

seizure threshold from modulation of discrete cortical

structures. Depending on the frequency of stimulation and

perhaps brain location, rTMS may selectively increase or

decrease seizure threshold. Substantial work on ECT

indicates that the sites of seizure onset are especially

critical to its antidepressant response and cognitive side

effects. This suggests that rTMS may be able to modulate

ECT effects, either by augmenting ECT by selectively

increasing the rise in seizure threshold during a treatment

course, or by selectively inhibiting cortical excitability in

regions of the brain that are believed to contribute to the

cognitive side effects of ECT, such as the temporal lobe.

rTMS could also be employed as a research tool, to test

hypotheses about ECTs mechanism of action. For example,

blocking or reducing seizure spread in the frontal lobes

would test the recent hypothesis that ECT-induced suppres-

sion of frontal lobe activity is correlated with treatment

efficacy.

11. Conclusions

MST is under development as a means of lowering the

side effect burden of ECT and thereby improving the quality

of life for severely ill patients with major depression and

other disorders for whom ECT is presently the only

treatment option. Work with MST remains preliminary,

and the ultimate clinical role of MST is presently unknown.

The evidence to date, based upon a very small number of

patients, supports the safety of MST and suggests that its

acute side effect profile is more benign than ECT. Since

seizures are highly effective in treating major depression,

whether they are induced electrically or chemically, the

expectation would be that seizures triggered magnetically

would likewise be effective for depression. However, it is

possible to induce seizures with ECT that lack efficacy (e.g.

low dose RUL). Thus, it will be necessary to rigorously test

the clinical efficacy of MST in the context of

controlled clinical trials. Likewise, it will be important to

O.G. Morales et al. / Clinical Neuroscience Research 4 (2004) 59–70 67

systematically examine the parameters of stimulation with

MST to determine whether and how they interact in

determining efficacy and side effects. Such dose-finding

work is a necessary step prior to randomized comparisons

with ECT, and should prevent the premature abandonment

of this new technique due to under-dosing.

Acknowledgements

Presented in part at the 2003 Annual Meeting of the

ARMND. Supported by grants from NIMH (MH01577,

MH60884), NARSAD, Stanley Foundation, American

Federation for Aging Research, and Magstim Company.

Drs Lisanby and Sackeim have received research grants

and/or consulting fees from Magstim Company, Neuro-

netics, and Cyberonics.

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