TECHNIQUES AND METHODS The Transcranial Magnetic Stimulation Motor Threshold Depends on the Distance from Coil to Underlying Cortex: A Replication in Healthy Adults Comparing Two Methods of Assessing the Distance to Cortex Kathleen A. McConnell, Ziad Nahas, Ananda Shastri, Jeffrey P. Lorberbaum, F. Andrew Kozel, Daryl E. Bohning, and Mark S. George Using transcranial magnetic stimulation (TMS), a hand- held electrified copper coil against the scalp produces a powerful and rapidly oscillating magnetic field, which in turn induces electrical currents in the brain. The amount of electrical energy needed for TMS to induce motor movement (called the motor threshold [MT]), varies widely across individuals. The intensity of TMS is dosed relative to the MT. Kozel et al observed in a depressed cohort that MT increases as a function of distance from coil to cortex. This article examines this relationship in a healthy cohort and compares the two methods of assessing distance to cortex. Seventeen healthy adults had their TMS MT determined and marked with a fiducial. Magnetic resonance images showed the fiducials marking motor cortex, allowing researchers to measure distance from scalp to motor and prefontal cortex using two methods: 1) measuring a line from scalp to the nearest cortex and 2) sampling the distance from scalp to cortex of two 18-mm-square areas. Confirming Kozel’s previous finding, we observe that motor threshold increases as distance to motor cortex increased for both methods of measuring distance and that no significant correlation exists between MT and prefontal cortex distance. Distance from TMS coil to motor cortex is an important determinant of MT in healthy and depressed adults. Distance to prefontal cortex is not correlated with MT, raising questions about the common practice of dosing prefontal stimulation using MT determined over motor cortex. Biol Psychiatry 2001;49:454 – 459 © 2001 Soci- ety of Biological Psychiatry Key Words: Transcranial magnetic stimulation, motor threshold, motor cortex, prefrontal cortex, MRI, depression Introduction T ranscranial magnetic stimulation (TMS) is a powerful tool for brain research (George et al 1999; Ziemann et al, 2000). With TMS, an electromagnetic coil placed against a subject’s scalp sends a focal and rapidly chang- ing magnetic pulse through the skull with only minimal discomfort to the subject. Upon reaching the cortex, the magnetic field induces an electrical current that depolar- izes cortical neurons. Because the magnetic field declines exponentially with distance from the coil, any condition that would increase the distance between the scalp and the surface of the subject’s cortex theoretically might affect the intensity of magnetic stimulation (and thus induced electrical current) actually reaching the cortex. Over the motor cortex, TMS causes movement in the contralateral limb or body, a visible effect. The motor threshold (MT) is defined as the lowest level of stimula- tion capable of causing a twitch in the contralateral thumb, specifically, the abductor pollicis brevis (APB; Pascual- Leone et al 1992). The MT varies widely across individ- uals but is relatively stable within individuals over time (Ziemann et al, 2000). Because of the wide range of absolute TMS intensity needed to produce comparable stimulation across individuals, most TMS researchers have attempted to correct for this variability by dosing TMS intensity as a proportion of each individual’s motor threshold. Recently, Kozel et al (2000) examined the relationship between MT, age, and the distance from the scalp to both the motor cortex and the prefrontal cortex. In their cohort of 29 depressed subjects, MT strongly correlated with distance from scalp to motor cortex (p  .01). Interest- From the Functional Neuroimaging Division and the Brain Stimulation Laborato- ries, Departments of Psychiatry, Radiology, and Neurology, Medical Univer- sity of South Carolina, and the Department of Psychiatry, Ralph H. Johnson VA Medical Center, Charleston, South Carolina. Address reprint requests to Mark S. George, M.D., Radiology Department, MUSC, 171 Ashley Avenue, Charleston SC 29425. Received January 28, 2000; revised August 10, 2000; accepted August 21, 2000. © 2001 Society of Biological Psychiatry 0006-3223/01/$20.00 PII S0006-3223(00)01039-8