Download Transcranial magnetic stimulation

Transcranial magnetic stimulation: using
a law of physics to treat psychopathology
Gary M. Hasey, MD, MSc
J Psychiatry Neurosci 1999;24(2):97-101
Department of Psychiatry, McMaster University, Hamilton, Ont.
Correspondence to: Dr. Gary M. Hasey, Clinical Director, Mood Disorders
Program, Hamilton Psychiatric Hospital, 100 West 5th St., Hamilton ON L8N 3K7;
fax 905 575-6014
Medical subject headings: depressive disorder; electroconvulsive therapy;
electromagnetic fields; prefrontal cortex; stimulation, electric
Submitted Dec. 1, 1998
Accepted Jan. 4, 1999
© 1999 Canadian Medical Association
Contents
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Introduction
Harnessing magnetic fields
TMS as a treatment modality
Comparing TMS with ECT
Side effects and safety
Unknown mechanism
Conclusion
References
Introduction
Galvani and Volta demonstrated in the 1790s that electric currents could influence
the activity of muscle and nerve. However, this knowledge was not used effectively
in psychiatry until 1938, when Cerletti and Bini1 first described electroconvulsive
therapy (ECT). More than 60 years later, ECT remains one of the most powerful
antidepressant treatments. Apart from the addition of anesthesia and some
relatively minor technical refinements, the procedure is essentially the same as
Cerletti and Bini described it. This could be seen as scientific inertia and lack of
progress, or probably more accurately, as an indication of the fundamental
soundness of the strategy of using electromagnetic energy to modulate neuronal
activity.
Despite its often-remarkable efficacy, ECT remains a crude technique, analogous
to sculpting rock with explosive charges. With some skill and attention to energy
output, the end result may be very acceptable, but control is difficult and unwanted
effects are common. We have now been given a newer and more easily controlled
tool: transcranial magnetic stimulation (TMS). For the first time, we have a
noninvasive way to change the firing rate or electrochemical excitability of neurons
in relatively small regions of the cerebral cortex.
[Contents]
Harnessing magnetic fields
The notion that magnetic fields can be used to modulate brain activity is not new.
D'Arsonval2 in 1896 and Thompson3 in 1910 built large electromagnetic
stimulators, but they could not produce magnetic fields intense enough with the
available technology. They succeeded only in activating retinal neurons to create
"phosphenes" -- perceived light flashes -- in volunteers. It was not until 1985 that
Barker4 developed an electromagnetic field generator with sufficient power to
activate cortical neurons. Barker's TMS device consisted of a stimulation coil made
up of wire loops encased in insulating material and connected to a capacitor
capable of passing a large electrical current through the coil over a very brief time
interval. This design is the basis of all modern devices. As the current flows
through the coil, a short-lived but very powerful (1 to 2 Tesla) magnetic field is
generated around the coil. When the coil of Barker's device was placed over the
scalp overlying the motor cortex and the current turned on, sufficient voltage was
induced within cortical neurons to result in depolarization, causing observable
involuntary movement of the finger and hand.
The physical principle involved is known as Faraday induction. When an electric
current is passed through a coil, a magnetic field is generated. If another coil or
length of conductive material such as a nerve fibre is exposed to a changing
magnetic field, a secondary electrical field is induced within the exposed coil or
fibre. The size of the current induced depends on the strength and rate of change
of the magnetic field and on the number of loops in the secondary coil or, in the
case of TMS, the anatomical conformation of underlying nerve fibres. Neurons with
bent or curved axonal processes, passing at right angles to the lines of force of the
magnetic field, are most easily activated. The size and shape of the magnetic field
are readily determined. However, the precise brain structures stimulated, and the
resulting physiological effect of magnetic stimulation, cannot be inferred directly
from available mathematical models because the head and brain are irregularly
shaped, inhomogeneous volume conductors, and because the spatial orientation
and anatomical configuration of underlying nerve fibres are variable.
Nevertheless, advances in coil design have led to stimulators capable of activating
a small enough region of the cortex to allow mapping of cortical functioning with a
degree of precision rivalling that achieved using direct electrode stimulation of the
brain. Coupled with other devices such as the electromyograph, Barker's stimulator
has become an important diagnostic tool in clinical neurology, as well as an
investigational tool for studying regional cortical involvement in processes as
diverse as motor functioning, vision and Braille reading. Application of TMS for
treatment of neuropsychiatric conditions is a more recent development.
The main technological innovations since Barker's first design are the repetitive
stimulator and the figure-of-8 coil. The repetitive stimulator (rTMS) is capable of
delivering not only single magnetic pulses, but also a very rapid series or "train" of
magnetic pulses (e.g., 5 to 30 pulses per second or Hz). This attribute may be
critical to the optimal use of TMS. A train of pulses appears to be capable of
producing more profound changes in neuronal activity than those produced by a
single pulse. As well, the nature of the neuronal response to TMS may ultimately
prove to be dependent upon stimulation frequency. The figure-of-8 coil is also
important because it creates a much more focused magnetic field than the original
round or teardrop-shaped coils. This permits greater stimulation precision, as a
smaller area of cortex is exposed to the most intense part of the magnetic field.
We are now equipped with a very powerful technology. Commercially available
devices can produce magnetic fields of intensity greatly exceeding the threshold for
depolarization of neurons, at least in the motor cortex, and advances in coil design
permit focused stimulation of small regions of cerebral cortex. The most immediate
challenge for users in psychiatry is to determine the optimal stimulation parameters
and anatomical stimulation site for different neuropsychiatric conditions. In the
process of working through these issues we will undoubtedly learn a great deal
about the neurophysiological underpinnings of various neuropsychiatric diseases.
[Contents]
TMS as a treatment modality
The earliest investigations of the potential of TMS as a therapeutic agent in
psychiatric disorders involved the use of single-pulse stimulators and round coils.
Hoflich et al5 treated 2 patients with major depressive psychosis refractory to
pharmacotherapy with 10 days of TMS using an open design. Somewhat later,
they treated 15 patients with major depressive disorder (MDD) with either high- or
low-intensity TMS or sham TMS.6 Although some patients showed improvement,
the results were generally disappointing and not statistically significant. However,
in both studies TMS was given as a series of single electromagnetic pulses (0.25
to 0.50 Hz) delivered with a circular coil over the vertex. We have since learned
that repetitive stimulation using a figure-of-8 coil and prefrontal cortex stimulation
sites may show considerably better results. Although Conca et al7 were able to
show improvement in patients with depression treated with single pulses (delivered
at 6-second intervals), they stimulated several sites, including prefrontal areas, and
all subjects received antidepressant medications concurrently.
George et al8 were the first to identify the left prefrontal cortex as an important
stimulation site in patients with depression. In an open trial, they treated 6 patients
with depression that was very resistent to pharmacotherapy with rTMS delivered to
the left dorsolateral prefrontal cortex (DLPFC). This site was chosen on the
grounds that depression was associated with hypoperfusion of this region. They
employed a repetitive stimulator set to deliver 20 Hz pulses through a figure-of-8
coil. Four of the 6 patients showed improvement, and 1 had a complete remission.
The importance of the prefrontal stimulation site was confirmed by Pasqual-Leone
et al9 in the first controlled, fully blind study of rTMS. They treated 17 patients with
depressive psychosis refractory to pharmacotherapy with genuine rTMS (10 Hz,
figure-of-8 coil) or sham stimulation administered to the left DLPFC, right DLPFC or
vertex in random sequence. There was a highly significant difference between
sham and genuine rTMS, and significantly more improvement of depression after
treatment delivered to the left DLPFC compared with other stimulation sites.
Additional support for the involvement of the prefrontal cortex in mood regulation
comes from studies in healthy control subjects. Pasqual-Leone et al,10 and George
et al11 separately demonstrated in volunteer subjects that rTMS administered to the
left prefrontal region increased sadness scores, while right prefrontal rTMS
increased happiness scores. Stimulation of other brain regions had no significant
effect. Interestingly, these effects are the opposite of those seen in patients with
depression, for whom high-frequency rTMS has antidepressant effects only when
administered to the left side. In keeping with these "lateralized" findings, Grisaru et
al12 demonstrated, in 16 patients, that rTMS (20 Hz) administered to the right
DLPFC has a greater antimanic effect than rTMS to the left DLPFC.
The duration of the improvement of mood after successful treatment with rTMS has
not yet been clearly established, but appears to be at least in the order of weeks to
months. There is some evidence that longer remission of depression can be
obtained with higher rTMS stimulus energies (J.M. Tormos et al: unpublished
data). In all likelihood, relapse rates for depression similar to those seen with ECT
will be revealed over future studies, and maintenance TMS or antidepressant drug
prophylaxis will be necessary. Mood stabilizers may also play a role, even in
unipolar depression. Tormos et al,13 for example, reported that patients treated with
rTMS for major depression had a longer-lasting improvement when the rTMS was
given together with the mood stabilizer and anticonvulsant gabapentin.
[Contents]
Comparing TMS with ECT
ECT and TMS are the only techniques that use electrical energy to induce
neuropsychiatric change, and this naturally invites comparison of the two. In
animals, rTMS can produce behavioural and biological effects that are qualitatively
similar though slightly less robust than those seen after electroconvulsive shock
(ECS). These effects include enhanced apomorphine-induced stereotypy, reduced
immobility in the Porsolt swim test, increased seizure threshold,14 increased brain
dopamine and serotonin levels15 and ß-adrenoreceptor down-regulation.16 To date,
there is only one open trial comparing ECT with rTMS in patients with depression.
In this study, Grunhaus et al17 treated 26 subjects with severe major depression
with either left prefrontal rTMS (10 Hz) or right unilateral ECT. Patients in the ECT
group who did not show improvement by the seventh ECT were switched to
bilateral ECT. As expected, the researchers observed clinically and statistically
significant improvement in both the groups receiving ECT and rTMS. There were
no significant differences in antidepressant response between the groups, except
that sleep improved more completely among the patients in the ECT group.
[Contents]
Side effects and safety
The roughly equivalent efficacy of ECT and TMS is all the more striking given the
apparently benign side-effect profile and procedural simplicity of TMS. TMS may
be slightly uncomfortable, but is certainly not painful, and anesthesia is not
required. Patients remain alert throughout the procedure, can walk and function
immediately afterward and do not require any special post-treatment supervision.
There appears to be no significant cognitive impairment associated with the
treatment. In some patients rTMS causes what may be muscle-tension headache,
which can persist for some hours after the end of the stimulation session.
Special precautions must be taken to prevent hearing damage. Deformation of the
coil with the passage of the electrical current results in a deceptively unimpressive
"click"; however, the frequency is one at which the human ear is especially
vulnerable to acoustic injury, so foam earplugs should be worn both by the subject
and operator during rTMS.
There is no evidence of neuronal histotoxicity resulting from TMS, but there is a
theoretical risk of heat injury in poorly perfused areas such as cysts or infarcts, and
patients with such lesions should be excluded, as should all patients with
intracranial metal objects such as surgical clips. The functioning of cardiac
pacemakers can be altered by TMS; hence, patients with pacemakers should not
be treated.
The most serious adverse effect appears to be seizures during treatment. To my
knowledge, fewer than 10 seizures have been reported among the thousands of
patients who have received this treatment. The already very low risk of seizure can
be further reduced by excluding patients with a personal or family history of seizure
disorder, and by keeping the stimulation parameters within currently recommended
safety guidelines. Although TMS has been used safely together with mood
stabilizers, neuroleptics and many antidepressants, one patient had a seizure
during TMS after taking a combination of amitriptyline and haloperidol without the
investigators' knowledge.18 "Kindling" -- a process by which repeated
subconvulsive stimuli eventually lower the seizure threshold so that seizures occur
without stimulation -- is also a theoretical possibility. However, kindling has not
been observed in humans. In animals, low-frequency electrical stimulation has
been reported to raise the seizure threshold or "quench" seizures kindled by highfrequency stimulation of the amygdala.19 It is possible that low-frequency rTMS
may have similar anticonvulsant effects.
Admittedly, the long-term biological effects of TMS are not yet well understood.
Concerns have been raised about the possible carcinogenic effect of long-term
exposure to magnetic fields generated by electrical cables or appliances in the
workplace or home,20 but the evidence for this is weak and the nature of the
exposure very different from that of TMS. The period of exposure during TMS is
very brief, the field strength high and the frequency usually 20 Hz or less. The
exposure to the fields induced by power lines and electrical equipment is of many
years' duration, the field strength weak and the frequency generally 50 to 60 Hz.
[Contents]
Unknown mechanism
The mechanism by which TMS alters neuropsychiatric functioning is unknown.
However, there is some evidence that high-frequency rTMS (10 to 20 Hz) may
increase cortical excitability, while low-frequency TMS (1 Hz) may reduce cortical
excitability. Speer et al21 demonstrated that high-frequency rTMS (20 Hz) applied
to the left DLPFC increases cerebral blood flow over this region in patients with
depression, while low-frequency rTMS (1 Hz) produces the opposite effect. In
accordance with this indirect evidence, Chen et al22 found that low-frequency rTMS
(0.9 Hz) reduced the excitability of the motor cortex for at least 15 minutes after the
end of rTMS in healthy volunteers, while Tergau et al23 observed enhanced cortical
excitability after TMS trains with frequencies of 10 Hz or more in their subjects.
This apparent capacity to either increase or decrease cortical excitability and
neuronal metabolic activity may be central to the efficacy of TMS treatment for
mood disorders and other neuropsychiatric diseases. As an example, PasqualLeone24 has demonstrated that depression may be alleviated by either highfrequency rTMS over the left DLPFC or low-frequency rTMS over the right DLPFC.
We may have, for the first time, a way to selectively and noninvasively "tune" the
cerebral cortex to correct or compensate for the neuronal dysfunction that
produces psychopathology or neurological disease.
TMS is currently being tested for therapeutic effects in other psychiatric disorders,
with encouraging preliminary results. Greenberg et al25 have reported that
compulsive urges were improved for 8 hours in patients with obsessivecompulsive
disorder after right prefrontal rTMS. However, in a short case series, a patient with
panic disorder and another with generalized anxiety disorder showed increased
anxiety after right prefrontal rTMS.26 Other groups using a single session of 30 lowfrequency TMS treatments have observed transient improvement in patients with
post-traumatic stress disorder27 and schizophrenia.28 The open design, small
sample size and limited number of stimulation sites tested in these studies make
interpretation difficult; however, TMS may find major applications outside of
affective disorders.
[Contents]
Conclusion
Where will TMS take us in the future? Further experimentation with stimulation
parameters and sites using current technology will lead to greater therapeutic
efficacy for mood disorders and to delineation of other neuropsychiatric conditions
that may respond to TMS. Better understanding of the combined use of
pharmacotherapy with TMS may allow more rapid and longer-lasting improvement
in psychiatric conditions and in neurological diseases such as epilepsy and
Parkinson's disease. More powerful magnetic-field generators, new coil
conformations and arrays of several coils used simultaneously will allow stimulation
of currently inaccessible regions, such as the inferior orbital cortex, or deeper
structures, such as the basal ganglia. In the more distant future, miniaturization
may lead to more portable or even implantable magnetic neuromodulators.
Whatever the direction empirical research into this technology takes us, our
understanding of both pathophysiology and the functioning of the healthy brain will
inevitably grow.
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References
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