Transcranial Magnetic Stimulation In Humans
Transcranial magnetic stimulation (TMS) was patented in 1903 for the treatment of depression. Research investigating this treatment has exploded recently, as evidenced by the fact that only 1 paper on TMS was published in 1985 whereas 192 were published in 1997. This technique involves running electrical current through a coil, which creates a magnetic field. This magnetic field can penetrate the skull and reach cortical tissue to a depth of approximately 2 cm. It is speculated that this magnetic field causes a biologic current in the neurons that it makes contact with. There is an enormous variability from patient to patient as to how powerful this magnetic field should be. Placing the coil over the motor strip in area 4 of the brain and increasing the power until the thumb on the contralateral side moves determines the calibration. This is referred to as the motor-evoked potential or motor threshold, and the treatment dose is usually given at a range of 80% to 100% of this. Exercise usually increases this response, and depression and chronic fatigue syndrome have been noted to decrease it in a state-dependent fashion.
Many variables have yet to be determined in treatment with TMS. One of these is the frequency with which the treatment is applied, measured in cycles per second. There has been some evidence that high-frequency treatment (20 cycles per second) can create an excitable state in the patients and that low-frequency treatments (1 cycle per second) can be "quenching," causing long-term potentiation of depression. There is also some controversy about which hemisphere of the brain the treatment should be applied to. While the treatment is almost always applied to the prefrontal cortex, there has been some evidence that treatment of the left side decreases happy mood and treatment of the right side decreases sad mood. In a study of 1-cycle-per-second treatment of both the left and right side in 19 normal subjects, the authors found absolutely no difference in any mood, cognitive, or physiologic variable at this low-frequency treatment, except a statistically significant difference in diastolic blood pressure (subjects treated on the left side had a decrease of 9 mm Hg, and no blood pressure effect was seen with right-sided treatment). The authors doubt whether this finding is of any significance.
Ebmeier and colleagues did a study randomizing 15 patients with major depression into 1 of 3 groups: 5 cycles per second, 10 cycles per second, or 20 cycles per second. Patients were treated twice per day with 500 stimulations for a total of 1000 stimulations per day for 5 days. They achieved a reduction of 44% on Hamilton depression scales, with no significant differences in treatment effects across the 3 groups. They then looked at the motor-evoked potentials both before and after treatment and found no significant changes.
Finally, this group of authors did some neuroimaging studies using single photon emission computed tomography (SPECT) both before and after TMS treatments and found the primary change to be an increase in activity in the medial prefrontal cortex.
ECT and TMS
The similarities and differences between TMS and electroconvulsive therapy (ECT) offer some interesting perepectives on treatment. Clinical similarities between the 2 treatments include their apparent effectiveness in the treatment of depression, mania, and Parkinson's disease. Unlike TMS, ECT requires administration of anesthesia and induction of a seizure and usually causes some memory impairment, but its efficacy is extremely well documented in the literature. The first controlled trial of TMS was done in 1986, and there have been fewer than 10 known controlled trials since then, so its efficacy has not been as well documented.
Biologic similarities between the 2 treatments include an anticonvulsant effect for both, increased apomorphine stereotypy in animal models, and downregulation of beta-adrenergic receptors. Although both treatments precipitate early gene expression in the brain, they do so in different areas. With ECT, early gene expression occurs most often in the hippocampus, whereas with TMS, early gene expression occurs primarily in the paraventricular nucleus of the thalamus.
Recent studies have shown new growth of neurons in the brain throughout life. These authors have demonstrated that ECT causes new neuronal growth in the hippocampus, and that this new growth increases with the number of ECT treatments. This growth is also sustained; it is not subject to apoptosis (programmed cell death). These findings are consistent with current research findings that show that chronically depressed patients have decreased brain volume, particularly in the hippocampus. Finally, these authors speculate that TMS may be effective by resetting circadian dysthymia by the growth of new sympathetic neurons from the paraventricular nucleus to the pineal gland.
TMS -- Treatment or Research Tool
Recent efforts by George to combine functional MRI scans with TMS have presented new and interesting challenges. Since both use magnetism at fairly high power, this presented an engineering challenge. One important difference is that the MRI scanner is essentially always on, but the TMS coil is only activated for brief pulses of energy. These authors were able to develop the equipment so that the image and the pulse magnetism would alternate, allowing them to image what is going on in the brain while TMS is taking place. One of the first things they looked at is the motor threshold calibration phenomenon. It is the distance between the cortex and the coil that determines the electricity required to move the thumb. They determined this energy to be approximately 60% of what is needed, with the patient's physiology providing the other 40%. They could find no difference between volitional and TMS thumb movement on a functional scan. They found that TMS-induced movements involve a very focused response of the neurons involved, and not a "blob of tissue" being activated by the coil. They also speculated that contralateral movement of the other hand would dampen the effect of the TMS-induced movements, since this is a physiologic phenomenon of attenuation of electrical activity in the contralateral side of the brain, where movement is taking place. To their surprise, they found no such effect. They were also curious as to whether repeated pulses of TMS would have a plateau effect on motor threshold; the 2 studies they conducted to resolve this issue yielded contradictory results. Finally, they found some increases in blood flow in a dose-dependent fashion at 120% of the motor threshold.
It is important to review what is and is not known about TMS. There is a newfound acceptance of the idea that changes in mood can occur with subseizure stimulation. With only 2 cm or less of direct effect, we are unable to access deep brain structures, but there may be a "prefrontal window" to allow us to get reasonably close.
In the future, further combinations of imaging technology and TMS may allow us real-time focusing on specific brain structures during treatment. These combinations may also allow us to look at specific neurotransmitters during treatment. A study by George on efficacy of TMS showed a difference of only 5 points on the Hamilton depression scale. This result is of interest from a research standpoint but is less than clinically relevant. Looking at all of the controlled studies of TMS together, he draws the following conclusions:
1. The speed of onset is a minimum of 2 weeks.
2. The location seems to be the prefrontal areas of the skull. There is some contradiction in the laterality data, but there is some evidence for better effect on the right side.
3. The treatments seem to have more of a direct antidepressant effect than a stimulant effect.
4. Although there are little data indicating that TMS is effective in bipolar depression, data have shown that it is not particularly effective in older populations, psychotic patients, or those patients whose anatomy makes for a distance of more than 16 mm between their cortex and the coil during treatments (ie, a thick skull).
We have no definitive data on the best frequency, ideal hemisphere, or optimum power for TMS. We also have no definitive safety data, although it is important to note that the seizure risk with TMS is lower than that associated with any known antidepressant medication. In conclusion, what we need are better clinical trials of longer duration to fully assess the viability of this exciting new treatment.
Antidepressant Properties of ECT and TMS
It is interesting to note that there are antidepressant properties of both ECT and TMS. These 2 treatments clearly have different mechanisms of action and may have different clinical utility. Although the effectiveness of ECT is extremely well established, TMS is, at best, still being developed, but holds great promise for having significantly fewer side effects. One of the most clinically important unanswered questions about this comparison is which types of patients will benefit from which therapy.
A new approach to combining the properties of both of these mechanisms is seen in the recent development of convulsive magnetic stimulation treatment (MST) and an analysis of why such treatment may be of clinical utility. Although the fact that TMS does not involve seizure induction is seen as a great advantage, it is believed that the seizure in ECT is what imparts a great deal of its efficacy. There are some serious problems with convulsive therapy initiated with electricity. There is remarkable variability of seizure threshold in ECT, with recent data showing a 100-fold difference between patients (Sackeim). The human skull is not particularly even with regard to electrical conduction, and it has multiple "current sinks." ECT has a dose-response relationship for both efficacy and side effects, and regional changes in the brain are responsible for both the effects of the treatment and the adverse events. Finally, it is very difficult to stop the spread of electrical activity to vulnerable areas of the brain.
The current controversy between unilateral vs bilateral ECT adds to these problems. Unilateral ECT is thought of as having fewer side effects but also less efficacy. Right unilateral ECT at high dose may be as effective as bilateral ECT. Seizures, however, may lack antidepressant efficacy but create enough of an insult to the brain for adverse effects to occur. Current paths, and not intensity of seizure, determine efficacy. The key to ECT efficacy is enhancing inhibition in the prefrontal cortex, particularly on the right side. Bilateral ECT tends to concentrate current in the anterior frontal cortex, while unipolar ECT tends to be even over the anterior two thirds of the cortex it is applied to. As the dose increases, unipolar ECT's current distribution more closely resembles bilateral ECT. ECT responders have been shown to have a state-dependent 80% increase in seizure threshold, a decrease in cerebral blood flow in the anterior cortex, an increase in delta waves in the frontal cortex, and an increase in theta waves in the medial temporal cortex.
The comparison between ECT and MST may show MST solving some of these problems. The pulse of energy used to give ECT is between 1 and 2 milliseconds, which is supraphysiologic and certainly inefficient. MST (and TMS) has pulses at 0.15 milliseconds given at variable frequencies. MST may give us the opportunity to do focal inductions of seizures with active inhibition of vulnerable areas.
Both left and right unilateral ECT works in many patients. Right unilateral ECT may be better for depression, and left unilateral ECT may be more effective for mania. Laterality may be more critical for TMS, as may be frequency or the site of the treatment. ECT may resemble low-frequency TMS more than high-frequency TMS in its inhibitory qualities.
Repetitive Transcranial Magnetic Stimulation (rTMS) in the Elderly
Elderly depressed patients are often treatment resistant or intolerant of medication. Since TMS may be effective for depression and has no known cognitive side effects, it may be a good treatment for this population. Unfortunately, there are data showing a decreased response rate to TMS in the elderly.
Mosimann and colleagues conducted a controlled double-blind study of depressed patients over the age of 40 in which 9 patients underwent sham TMS and 14 received real TMS. The patients in the treatment group were given 9 days of treatment at 100% of motor threshold at 20 cycles per second for 16,000 pulses per day. Sham TMS was done by tilting the coil at 90 degrees away from the patient during treatment. Patients were assessed for mood and cognitive status on days 1 and 9, and for mood on day 5. The results of this study showed a response rate to sham TMS of 17% and a response rate to real TMS of 20.4%, with no significant difference. It did, however, show a small improvement in cognitive function. While the study was disappointing, it does indicate an interesting potential for this treatment in the elderly, given its cognitive results.
1. Steele JD, Glabus MF, Shajahan PM, Ebmeier KP. Increased cortical inhibition in depression: a prolonged silent period with transcranial magnetic stimulation. Psychol Med. 2000;30:565-570.
2. Ebmeier KB, Shajahan PM, Glabus MF. Neuroimaging of TMS effects in humans. Int J Neuropsychopharmacol. 2000;3:S26. Abstract: S.16.1.
3. Bolwig T. ECT and TMS - Similarities and dissimilarities in their development as antidepressive treatment modality. Int J Neuropsychopharmacol. 2000;3(suppl 1):S27. Abstract: S.16.2.
4. George MS, Nahas Z, Avery D. TMS-treatment or research tool - where are we 5 years after the beginning? Int J Neuropsychopharmacol. 2000;3(suppl 1):S27. Abstract: S.16.3.
5. George MS, Lisanby SH, Sackeim HA. Transcranial magnetic stimulation: applications in psychiatry. Arch Gen Psychiatry. 1999;56:300-311.
6. Sackeim HA. Antidepressant properties of ECT and TMS: modulation of prefrontal cortex function. Int J Neuropsychopharmacol. 2000;3(suppl 1):S27. Abstract S.16.4.
7. Mosimann UP, Schlaepfer TE. rTMS in the elderly - cognitive enhancer, antidepressant or research tool? Int J Neuropsychopharmacol. 2000;3(suppl 1):S28. Abstract: S.16.5.