Repetitive transcranial magnetic stimulation (rTMS) is a relatively new technique for activating the cerebral cortex through the scalp and skull. By inducing electrical currents in the brain, rTMS is able to produce a variety of effects, including muscle twitching, changes in motor performance, disruption of cognitive and perceptual processes, and changes in mood. Although the technique is noninvasive and easily tolerated by patients and normal subjects, rTMS can produce epileptic seizures and, potentially, other undesirable effects on brain function. Further studies will be required to fully define the safe ranges of the stimulation parameters.

In initial studies using animal models of depression, we primarily focused on the similarities of transcranial magnetic stimulation (TMS) to electroconvulsive therapy (ECT). However, our investigations show that TMS has its own, unique, potentially diagnostic and therapeutic effects, distinct from those of ECT. These effects need further exploration in animal and clinical studies.

Recent advances in functional neuroimaging (including positron emission tomography, single-photon emission tomography, and fast magnetic resonance imaging) have allowed better understanding of the brain regions involved in regulating normal and pathological moods. Repetitive transcranial magnetic stimulation (rTMS) has the ability to stimulate or temporarily impair brain regions, which makes it a powerful tool for directly testing theories of the neurologic basis of mood regulation.

The emergence of repetitive transcranial magnetic stimulation (rTMS) as a relatively noninvasive probe of cortical function provides an opportunity to explore the relationships between regional brain activity and symptomatology across neuropsychiatric illnesses. In this article, we briefly review evidence from functional neuroimaging studies (principally those using positron emission tomography [PET] or single-photon emission computed tomography [SPECT]) and other studies suggesting regional brain involvement in anxiety disorders, specifically obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD). We also review an initial controlled study conducted by our group using rTMS as a probe of prefrontal mechanisms in OCD. This discussion is not intended to be comprehensive, but rather to provide examples of disorders that, based on current knowledge, might be good candidates for the use of rTMS as a probe. In addition, we present case reports from pilot studies of rTMS in three patients with different primary anxiety disorder diagnoses, which illustrate some of the issues involved in such studies, as well as the effects observed. The possibility that rTMS may have therapeutic potential in anxiety disorders is also discussed.

Kindling involves repeated administration of brief high-frequency electrophysiological stimulation of the brain at initially subthreshold intensities that eventually evoke full-blown seizures. It has thus been used not only as a model of epileptogenesis, but of long-term neuronal memory. Quenching is a phenomenon that utilizes low-frequency stimulation for much longer periods of time (eg, 1 Hz for 15 minutes), and appears to exert preventive effects on the development of kindling and inhibit the manifestation of full-blown kindled seizures by markedly increasing the amygdala afterdischarge and seizure threshold. (See also “Kindling and Quenching: Conceptual Implications for rTMS,” by Weiss and Post, page 32). The parameters of kindling and quenching with intracerebral stimulation of the amygdala in vivo are highly similar to those achieved in vitro in hippocampai slice preparations for inducing long-term potentiation (LTP) and longterm depression (LTD), respectively. These neuroplastic changes are relatively long lasting and appear reversible at the level of synaptic function with either LTD or LTP capable of countering the effects of the other.

Unlike the other articles in this series on rTMS, this paper will not include clinical research or magnetic stimulation experiments. Instead, we will focus on an animal model of epilepsy called kindling and a procedure that we have recently developed to inhibit kindled seizures called quenching. Both procedures involve direct intracerebral electrical stimulation of the brain. We demonstrate that low-frequency stimulation, which does not disrupt ongoing behavior, can have profound and long-lasting effects on both seizure development and fully kindled seizures.

At this point, we do not know how well these models relate, either mechanistically or phenomenologically, to the effects of repeated transcranial magnetic stimulation (rTMS); however, we believe that at the very least, some of the principles emerging from studying these phenomena may be relevant to our thinking about rTMS and its potential treatment utility. Specifically, we discuss the possible relationship between quenching and rTMS with regards to parameters of induction, possible common mechanisms, and potential treatment implications.