Some thoughts on transcranial magnetic stimulation (TMS)

First, what is transcranial magnetic stimulation?

TMS has been available for the last 15 years (introduced by Anthony Barker) and has been used primarily as a research tool. It’s based on Faraday’s principles of electromagnetic inductions. A pulse of current flowing through a coil of wire generates a magnetic field. If the magnitude of this magnetic field changes in time, it induces a current in a nearby conductor, like neurons. So the stimulating coil is held over a subject’s head and as a brief pulse of current is passed, a magnetic field is generated that passes through the subject’s scalp and skull. This stimulates the neural tissue, causing neuronal depolarization. In many experiments, single pulses of stimulation are applied, which is similar to conventional electric stimulation of peripheral nerves. To date, single-pulse techniques appear completely safe when applied to healthy individuals. In addition, repetitive pulses (repetitive TMS, or rTMS) can also be applied. With repetitive pulses, one must be careful of potential harmful effects, including seizure induction. So, the parameters that are used are very important, and depending on the parameters, one can inhibit or stimulate neurons. Applied as single pulses appropriately delivered in time and space, or applied in trains of repetitive stimuli at an appropriate frequency and intensity, TMS can transiently disrupt the function of a given cortical area, creating a temporary ‘virtual brain lesion.’

This method is still in its infancy and much is not understood of its mechanisms. The precise depth of stimulation has not been ascertained, although it does not appear to go below the cortical level, the spatial resolution is not known, it is not known which neural elements are the most sensitive to stimulation in a particular brain area, and it is not known whether all of the effects of stimulation are attributable to activity at the site of the stimulus or whether activity spreads though neural pathways to more distant sites.

How has TMS and rTMS been used?

It has been used primarily as a tool in cognitive neuroscience, to help study localization of function (see Pascual-Leone, 2000 for review). For example, one can witness a striking effect of TMS when a single TMS pulse of sufficient intensity is placed over the primary motor cortex and produces movements. The magnetic field intensity needed to produce this varies considerably across individuals, and this is known as the motor threshold. Subjectively, this stimulation feels much like a tendon reflex movement. Over the primary visual cortex, TMS can produce the perception of flashes of light. One could certainly use this technology to examine re-mapping after amputation and injury. It can also be used to examine motor neuron conduction velocity.

Other immediate behavioral effects are generally disruptive, particularly when the TMS pulses are delivered rapidly and repetitively. In this capacity, rTMS can act as temporary virtual lesions, which may be used to assess the causal significance between focal brain activity and behavior. For example, Pascual-Leone has examined the effects of rTMS to relate cortical function with Braille reading in early blind subjects. Kosslyn (1999) has used it to examine the neurobiology of visual imagery, and Zangaladze (1999) has utilized it to examine neural substrates of tactile discrimination. Further, the timing of neural events during a task may be identified with presenting single pulses of TMS at varying times relative to sensory stimuli.

TMS as a therapeutic tool

Most of the research has focused on the effects of rTMS as a therapy for depression; however, it is being studied as a therapeutic agent in OCD, schizophrenia, Parkinson’s disease, tic disorders, and epilepsy (see Wassermann & Lisanby, 2001).

As Dimitri mentioned, we do know that depression seems to be associated with dysfunction of the prefrontal cortex and its connections with other cortical and subcortical regions. There also appears to be an imbalance in left/right prefrontal activation. So, it is reasonable to postulate that stimulation may influence this dysfunction.

However, unlike pharmaceutical testing, where a drug undergoes preclinical testing prior to use, the reverse seems to be the case with TMS. There are surprisingly few animal studies on the basic mechanisms of action of rTMS. Because of the coil size, rTMS cannot be administered focally to rodents and it likely affects the entire brain, rather than a more focal region, as observed in humans. Animal studies that have been conducted have been promising for the potential antidepressant effects. These studies have found neurochemical changes, including alterations in dopamine, serotonin, and possibly BDNF, as well as altered gene expression, and have found some behavioral changes consistent with antidepressant effects. Basically, they are seeing effects that are similar to electroconvulsive shock therapy (see Lisanby & Belmaker, 2000). But given the intensities of stimulation used in these studies, one must be cautious of the findings.

Several studies have examined the effects of rTMS on depression. For example, in 1996, Pascual-Leone reported that 5 daily rTMS treatment to the left prefrontal cortex had marked antidepressant effects, but that antidepressant effect began to relapse within 1-2 weeks after stopping rTMS. Berman et al (2000) found a modest antidepressant efficacy of rTMS to the left prefrontal cortex. Others have reported that slow rTMS presented to the right prefrontal cortex may be effective, whereas others (i.e. Loo et al (1999)) have not found any difference. Studies that have compared the efficacy of rTMS with electroconvulsive shock therapy (ECT) (Pridmore et al., 2000), have not found rTMS is more effective. Again, it may be that the optimal dose is not known. In summary, the key findings in depression have not been systematically replicated and effect sizes have often been small and variable. In much of this work, the magnitude of antidepressant effects has been below the threshold of clinical usefulness.

Problems with the clinical studies.

As Dimitri noted, there is little consistency in placement of the coil and, in fact, there is no independent confirmation that the locations hit are the optimal locations or that the cortex is being reliably or effectively stimulated. Many of the studies are also wrought with poor designs, lacking appropriate controls. For example, as mentioned in class, blinding is difficult if not impossible, and since placebo response rates in depression trials range from 30 to 50%, it is difficult to evaluate the efficacy of this treatment. One could easily imagine that placebo effects may be particularly large for these studies, with the impressiveness of the rTMS device and procedure. Not only may the subject detect the treatment, but the individual administering the TMS has to be aware of the treatment condition. In addition, none of the key effects has been rigorously replicated and the positive findings are based on small samples in short (1-2-week) trials. The persistence of antidepressant effects beyond the 1-2 week treatment period have rarely been examined. Thus, it is still not known if TMS on the region target will produce local and distant effects that serve to normalize activity in the circuit on a lasting basis. Finally, given that there are so many potential parameters, systematic studies must be conducted to determine whether it is truly effective.

Does it hold potential?

Possibly. It certainly is an effective investigative tool for basic and clinical neuroscience research (given the proper parameters). Could it be therapeutic? We will have to see. Perhaps when we have a better idea of the effects of stimulus parameters and mechanisms, it will be very useful.

Problems with rTMS

Since very few combinations of the magnetic stimulation parameters have been tested experimentally, the issue of safety places stringent boundaries on the stimulation that can be used in human studies. Single and low frequency applications are certainly safer than high frequency and intensity applications.

While transcranial magnetic stimulation is a promising research tool, and may be a therapeutic tool, again, the technique is still in its infancy. The side effects and long-term effects of repetitive TMS have not been fully delineated. Difficulties occur because the procedure has several dosing parameters (frequency, intensity, train duration, etc.), the benefit of guiding preclinical data is lacking, and the procedure is often used without clear hypotheses about the mechanisms of action. (By the way, the absence of a large-scale commercial backing that usually supports the testing of proprietary drugs for therapeutic use has made research in this area relatively slow and lacking in standardization.) So, the work is still preliminary and the future is far from certain as to whether rTMS will serves as an effective clinical antidepressant intervention.

There is an increase in the number of studies of rTMS and, yes, they are starting to use other functional imaging techniques to evaluate the effects of rTMS treatment (e.g. research by T. Paus). This may assist in placement of the coil and in the mechanisms of action. To date, results as to the action of rTMS have been inconsistent, but the field is advancing rather quickly.

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