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Krasnow Institute > Monday Seminars > Abstracts Transcranial Magnetic Stimulation in Neuropsychiatry Benjamin D. Greenberg Transcranial magnetic stimulation (TMS), a relatively noninvasive way to probe and potentially affect the functioning of the brain, can help researchers understand how activity in brain regions relates to symptoms of psychiatric disorders. Although proposals were made to use fluctuating magnetic fields to affect brain activity nearly one hundred years ago, magnetic devices capable of brain stimulation are a recent development. In repetitive TMS, or rTMS, a regularly pulsing magnetic field affects activity in the cerebral cortex underlying an electromagnetic coil placed on the scalp. Results of early studies suggest that the single or paired-pulse TMS techniques, and the newer repetitive method (rTMS), are potentially useful probes of cortical mechanisms involved in psychiatric illness, as in the larger number of earlier studies showing that rTMS can affect the control of movement, sensory perception, or cognitive processes like memory. For example, single-pulse TMS of motor cortex can produce muscle potentials or movement. Similarly, higher frequency repetitive stimulation (rTMS) of occipital cortex can produce phosphenes, and rTMS over Broca's area results in word finding difficulties or speech arrest. Available TMS devices can only directly affect neuronal activity in the cerebral cortex. To more fully probe, and possibly treat, psychiatric illness, it may be necessary to affect activity in subcortical structures as well. Current TMS techniques may do this, but only indirectly, through the functional connections the cerebral cortex has with underlying brain structures. In fact, initial studies indicate that rTMS will very likely become an important probe of functional connections in neuroanatomical circuits both in neuropsychiatric illness and in healthy individuals. rTMS is a very different technique from the use of electrical current directly applied to the scalp to stimulate the brain, as, for example, in electroconvulsive therapy or ECT, in which the treatment is intended to produce a seizure. This is not the case with rTMS, which is intended to affect the activity of the brain (and in some cases possibly produce therapeutic benefit) without causing a seizure (although a possible therapeutic use of convulsant rTMS in depression has been proposed by one group of investigators). Unintentional seizures have occurred, rarely, in individuals receiving rTMS. In almost all cases this appeared to result from stimulation at high intensities or frequencies, or from the use of very short intervals between trains of stimuli. A seizure also occurred in an individual receiving amitriptyline plus haloperidol, medications which can each lower the seizure threshold. Other potential adverse effects of rTMS include discomfort near the site of stimulation, due to superficial muscle contraction, and induction of tension-type headaches (and, in one case in our laboratory, a classic migraine in a patient with a migraine history). While there is little evidence that rTMS can produce lasting adverse effects on cognition, this area needs much further study. In exploratory studies, it was found that rTMS applied over prefrontal cortex produced relatively subtle but significant alterations in mood in healthy individuals. These findings, together with earlier, albeit inconclusive, European studies of single-pulse TMS in depression, suggested that rTMS might have antidepressant effects. Both open and controlled clinical studies in the U.S., including at the NIMH in Bethesda, Charleston (Medical Univ. So. Carolina), Atlanta (Emory Univ.) and in other countries (Israel, Germany, Spain and elsewhere) suggest that single-pulse TMS, and rTMS, may have antidepressant effects. Most of the controlled studies (in which depressed patients received both active treatment and sham rTMS not designed to stimulate the brain) have tended to show significant improvement in depression after stimulation over the left prefrontal cortex. While some studies in depression have been well-controlled, the design of optimal control conditions is a complex and not fully resolved issue. It is encouraging that improvement has been seen in severely depressed or in difficult to treat patients. In most patients, however, these beneficial effects have been transient, i.e., not lasting more than two weeks. The initial reports are nonetheless promising in that antidepressant effects were seen in a substantial percentage of treatment-refractory patients. For example, in one study of depressed patients who had been referred for ECT, nearly half of fifty-six patients (or 56% of the subgroup of patients under 65 years of age) responded to rTMS. Currently, there is great interest in this area, and at least twenty groups are studying rTMS as a possible treatment for depression worldwide. Before such a use of rTMS could be realized, however, much work remains to be done. This includes establishing optimal procedures (e.g., stimulation frequencies, intensities, and sites; coil design and "dosing regimens" are other key considerations. Selecting the patients who might benefit most is another important issue. rTMS might find a role in providing early symptom relief after initiation of antidepressant therapy, as a maintenance treatment, or as an augmenting procedure in partially medication-responsive patients. rTMS has also been studied, although to a much lesser extent, in other psychiatric illnesses such as obsessive-compulsive disorder (OCD, a particular interest of our group), PTSD, and mania. The rationale for the use of rTMS in these illnesses, as in depression, is that affecting the function of brain regions or circuits could possibly improve symptoms of these illnesses. It is possible that brain activity (or "excitability") can be increased or decreased by rTMS, by using different stimulation frequencies and locations, in therapeutically useful ways. The use of rTMS in some of these other patient populations is likely to pose particular challenges. For example, our group has noted some transient, regionally-specific, exacerbations of anxiety after rTMS in patients with various anxiety disorders. And a group in Israel has just reported that an individual with combat-related PTSD apparently had symptoms triggered simply by the acoustic artifact of rapid rTMS (which could in fact seem reminiscent of a machine-gun burst). Controlled trials of rTMS as a treatment in OCD and PTSD are ongoing at the NIMH and elsewhere. As this research goes forward, it will be important to understand more about just how rTMS might affect the brain, by increasingly combining rTMS with functional brain imaging and neuropsychological testing (also quite important in assessing the safety of rTMS) in clinical studies. When used as a probe instead of a treatment, TMS, including the "paired-pulse" TMS technique, may also be able to provide important information about possible abnormalities in brain circuits, and also about mechanisms of therapeutic drug action in the brain. Thus, TMS, while still relatively early in development, appears to be a relatively safe and quite promising technique for probing and possibly treating people with psychiatric illnesses. REFERENCES 1. Pascual-Leone A, Grafman J, Cohen LG, Roth BJ, Hallett M: Transcranial magnetic stimulation. a new tool for the study of higher cognitive function in humans, in Handbook of Neuropsychology. Edited by Grafman J, Boller, F. Amsterdam, Elsevier, 1997. 2. Pascual-Leone A, Catala MD, Pascual AP. Lateralized effect of rapid-rate transcranial magnetic stimulation on mood. Neurol 1996; 46: 499-502. 3. George MS, Wassermann EM, Williams W, Steppel J, Pascual-Leone A, Basser P, Hallett M, Post R. Changes in mood and hormone levels after rapid-rate transcranial magnetic stimulation (rTMS) of the prefrontal cortex. J Neuropsychiatry Clin Neurosci 1996; 8: 172-180. 4. Martin JD, George MS, Greenberg BD, Wassermann EM, Schlaepfer TE, Murphy DL, Hallett M, Post RM. Mood effects of prefrontal repetitive high frequency magnetic stimulation (rTMS) in healthy volunteers. CNS Spectrums 1997; 2: 53-54. 5. George MS, Speer AM, Wassermann EM, Kimbrell TA, Williams WA, Kellner CH, Risch SC, Stallings L, Post R. Repetitive TMS as a probe in health and disease. CNS Spectrums 1997; 2: 39-44. 6. Greenberg BD, George MS, Martin JD, Benjamin J, Schlaepfer TE, Altemus M, Wassermann EM, Post RM, and Murphy DL: Effect of prefrontal repetitive transcranial magnetic stimulation in obsessive-compulsive disorder: a preliminary study. Am J Psychiatry 1997; 154: 867-869.
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