Elsevier

Biological Psychiatry

Volume 49, Issue 5, 1 March 2001, Pages 460-463
Biological Psychiatry

Techniques and Methods
Sham TMS: intracerebral measurement of the induced electrical field and the induction of motor-evoked potentials

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Abstract

%Testing the therapeutic potential of transcranial magnetic stimulation (TMS) in controlled trials requires a valid sham condition. Sham TMS is typically administered by tilting the coil 45–90° off the scalp, with one or two wings of the coil touching the scalp. Lack of cortical effects has not been verified. mWe compared sham manipulations in their thresholds for eliciting motor-evoked potentials (MEPs) in human volunteers and in intracerebral measurements of voltage induced in the prefrontal cortex of a rhesus monkey. mThree types of sham (one-wing 45° and 90° and two-wing 90° tilt) induced much lower voltage in the brain than active TMS (67–73% reductions). However, the two-wing 45° sham induced values just 24% below active TMS. This sham was about half as potent in inducing MEPs over the motor cortex as active TMS. mSome sham TMS conditions produce substantial cortical stimulation, making it critical to carefully select the sham manipulation for clinical trials.

Introduction

Several controlled trials have found that transcranial magnetic stimulation (TMS) exerts antidepressant or antimanic effects George et al 1997, Grisaru et al 1998, Klein et al 1999, Lisanby and Sackeim 2000, Pascual-Leone et al 1996. However, effect sizes have varied considerably, and some studies found no difference between active TMS and sham stimulation (Loo et al 1999). In the Loo et al (1999) study, the lack of a differential effect between the active and sham treatments was seen in the presence of a substantial therapeutic response in the sham condition. Variability in therapeutic effects across studies may reflect differences in the biological activity of the sham manipulations employed. Validating the sham condition is key to determining whether TMS has therapeutic properties.

A valid sham should simulate the ancillary aspects of TMS (acoustic artifact, scalp muscle stimulation, daily experimenter contact, expectations about efficacy and side effects) but not result in cortical stimulation. The most common sham conditions angle the coil 45° or 90° off the head so that the magnetic field stimulates scalp muscles and produces an acoustic artifact, but presumably does not induce current in the cortex (Figure 1). In vivo validation of sham is critical. Indeed, Loo et al (2000) reported that a 45° sham was about half as potent as standard TMS in stimulating the motor cortex.

In this study, electrical voltage induced in the brain with active and four types of sham TMS was measured intracerebrally in a rhesus monkey, representing the first in vivo measurements of TMS-induced intracerebral electric fields. We also titrated the threshold for excitation of the motor cortex in normal volunteers (motor threshold [MT]) as a noninvasive index of the cortical activity of various “inactive” sham conditions.

Section snippets

Intracerebral measurement of TMS-induced voltage

This study was approved by our Institutional Animal Care and Use Committee. A nickel-chromium multicontact electrode (10 0.5-mm contacts, 6 mm apart) was stereotaxically implanted in an anesthetized maleMacaca mulatta. A remote occipital skull entry site was used to minimize the effect of the skull defect on TMS-induced current pathways in the prefrontal cortex. A postimplantation three-dimensional magnetic resonance image (GE [Milwaukee] Signa 1.5 T, contiguous 1.5-mm slices) was obtained to

Intracerebral measurement of TMS-induced voltage

Conforming to predictions (Cerri et al 1995), there was a rapid fall-off in the amplitude of the induced voltage with increasing distance from the coil. Amplitude was linearly related to TMS intensity (r2 = .9,p < .0001).

Induced voltage differed as a function of TMS condition (Figure 2). Individual pulses within each 5-sec train showed extremely little amplitude variation (coefficient of variation = 2.4%). All sham conditions induced substantially lower voltage than active TMS, and there was

Discussion

The 45° sham conditions elicited substantial cortical stimulation at levels corresponding to 48–76% of active TMS, as evidenced by both MEPs in human subjects and measurements of intracerebral voltage in a nonhuman primate. In agreement with Loo et al (2000), the effects of the 45° sham were most marked for the two-wing condition. Although Loo et al (2000) tested only the 45° sham, we demonstrate that the 90° sham (both one and two wing) conditions are devoid of biological effects as measurable

Acknowledgements

Supported in part by National Institute of Mental Health Grant No. MH01577 and a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression.

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