Behavioural Neurology 17 (2006) 149���157 149 IOS Press An ethics perspective on Transcranial Magnetic Stimulation (TMS) and human neuromodulation Judy Illesa,b,���, Marisa Galloa and Matthew P. Kirschena,b,c aStanford Center for Biomedical Ethics, Stanford University, CA, USA bDepartment of Radiology, Stanford University, CA, USA cProgram in Neuroscience, Stanford University, CA, USA Abstract. This paper concerns the ethics of human neuromodulation using transcranial magnetic stimulation (TMS). We examine the challenges of modulating the brain with TMS through the research ethics lens and in clinical medicine for treating frank pathology, primarily in psychiatric diseases. We also consider contemporary issues raised in the neuroethics literature about managing unexpected findings, and relate these to TMS and to other frontier neurotechnology that is becoming openly available in the public domain. We argue that safety and informed consent are of paramount importance for TMS, but that personal values and sociocultural factors must also be considered when examining the promise of this technology and applications that ought to be highlighted for extra precautions. 1. The dynamic evolution of TMS research Transcranial magnetic stimulation (TMS) involves a powerful and rapidly changing electrical current trans- mitted through a coil that is placed on the scalp. It pro- duces a magnetic field that passes unimpeded through the skull and induces a weaker electrical current in the brain [109] that transiently disrupts neural circuits at the stimulation site. The growing body of litera- ture on TMS (Fig. 1) suggests that TMS offers sev- eral advantages over other non-invasive neuroimaging techniques in the study of normal neural functioning. Techniques like functional magnetic resonance imag- ing (fMRI), positron emission tomography (PET), mag- netoencephalography (MEG) and electroencephalog- raphy (EEG) rely on correlations to establish brain- behavior relationships. Functional MRI, for exam- ���Corresponding author: Judy Illes, Ph.D., Senior Research Scholar, Director, Program in Neuroethics, Stanford Center for Biomedical Ethics, and Department of Radiology, Stanford, CA 94305-5748, USA. Tel.: +1 650 724 6393 Fax: +1 650 725 6131 E-mail: illes@stanford.edu. ple, correlates changes in hemodynamic signal with cognitive behavior. TMS, on the other hand, char- acterizes behavioral changes with selective disruption of normal neural signaling, revealing neural structures necessary for normal behavioral and cognitive func- tions. Compared to patient lesion studies ��� that is, studying patients with strokes or tumors ��� TMS has some advantages since compensatory mechanisms and functional rewiring over time can obscure understand- ing of the discrete function of the originally damaged tissue. In examining fundamental issues of research ethics covered in The Belmont Report issued by the Na- tional Commission for the Protection Human Subjects in Biomedical and Behavioral Research (1979), unique issues of safety, informed consent and disclosure stand out for TMS. 1.1. Considerations of safety Single-pulse TMS is thought to be extremely safe and has proven to be a valuable tool for investigating normal human neurophysiology. It has been used effectively over the past 20 years to help us gain detailed knowl- ISSN 0953-4180/06/$17.00 ��� 2006 ��� IOS Press and the authors. All rights reserved

150 J. Illes et al. / An ethics perspective on Transcranial Magnetic Stimulation (TMS) and human neuromodulation Fig. 1. Number of TMS articles published in the scientific literature per year between January 1985 and July 2004. edge about brain-behavior relationships in such areas as motor systems [16,19,96,111], visual and perceptual processing [7,50,51,68,93], language [30,33,92], ver- bal working memory [28,53,82] and memory guided saccades [15,26,35,42,59,83,85,86,91]. Several thou- sand individuals have participated as normal controls in these experiments with very few adverse reactions. A small percentage of research subjects describe non- specific symptoms like headache, nausea [99] or tinni- tus after several hundred TMS pulses during a single experimental session, but no serious adverse reactions have been reported. Enough single-pulse TMS safety studies have been conducted on both animals and humans to confidently state that there are no known short or long-term seque- lae to TMS stimulation [17,21,65,67]. In one study, non-human primates receiving 7,000 maximum inten- sity single TMS pulses delivered in daily increments over thirty days demonstrated no short or long term deficits of higher cerebral functions [112]. A subse- quent study administered 1,200 to 3,800 stimuli at 5��� 20 Hz over the visual cortex of eleven healthy volun- teers and did not provide any evidence of pathological changes on contrast MRI or diffusion scans, demon- strating that TMS does not adversely affect the blood- brain barrier or induce localized edema [90]. In lobec- tomy specimens obtained from two epileptic patients following repetitive TMS, no structural brain damage was found [61]. Compared to single-pulse TMS, repetitive TMS (rTMS) is a more powerful tool, capable of making a pronounced and possibly irreversible impact on neural functioning. It has been reported to induce seizures in a small percentage of healthy subjects [20,43,109], and is therefore more likely to have longer-term effects than single pulse TMS on neural functioning. In an effort to establish safe parameters for rTMS, Pascual-Leone et al. [94] evaluated the effect of varying frequency and intensity of rTMS on cortical excitability in healthy vol- unteers. Adverse reactions such as headaches, visual disturbances, vertigo, weakness, and paresthesias were not experienced by subjects. Blood pressure, pulse, and ECG levels remained unchanged after stimulation. One subject experienced a seizure after three stimuli to the left motor cortex. It was later discovered that the subject had elevated prolactin levels and a family history of seizures. Other studies have also found a rise in hormones, specifically thyroid stimulating hor- mone (TSH), following TMS [39,103]. A second sub- ject in Pascual-Leone et al.���s study experienced tinnitus in the left ear following rTMS, which lasted less than 30 minutes [94]. Seizures induced by TMS are esti- mated to occur in about 1 out of 1000 TMS and rTMS subjects [3,109]. Studies of TMS on children have identified side effects such as scalp discomfort, hand weakness, headache, neck and arm pain, and arm tingling [34,40, 80]. After surveying 28 TMS studies involving over 850 children, Gilbert et al. [40] recommended that in- stitutional review boards classify TMS as a minimal risk procedure, despite the noted adverse effects. In 1996, an international workshop was held to de- lineate the risks of rTMS and establish relevant guide- lines [109]. Workshop topics covered stimulation pa- rameters, physiological monitoring, neuropsychologi- cal monitoring, training and qualifications of rTMS op-