DOI 10.1007/s00702-002-0804-6
J Neural Transm (2003) 110: 495–507
BOLD fMRI response to direct stimulation (transcranial magnetic
stimulation) of the motor cortex shows no decline with age
K. A. McConnell1, D. E. Bohning1, Z. Nahas2, A. Shastri1, C. Teneback2,
J. P. Lorberbaum2,4, M. P. Lomarev1, D. J. Vincent1, and M. S. George1–4
Departments of
1Radiology,
2Psychiatry, and
3Neurology, Center for Advanced Imaging Research and the Brain Stimulation
Laboratory, Medical University of South Carolina, and
4Ralph H. Johnson Veterans Hospital, Charleston, SC, U.S.A.
Received February 22, 2002; accepted December 4, 2002
Published online March 5, 2003; © Springer-Verlag 2003
Summary. Previous studies using BOLD fMRI to examine age-related
changes in cortical activation used tasks that relied on peripheral systems to
activate the brain. They were unable to distinguish between alterations due to
age-related changes in the periphery and actual changes in cortical physiol-
ogy. Transcranial magnetic stimulation (TMS), which allows direct, non-
invasive stimulation of cortical neurons, was interleaved with BOLD fMRI to
study 6 young and 5 old subjects. Three different tasks were compared: direct
stimulation by TMS, indirect active stimulation produced by a motor task, and
indirect passive stimulation produced by hearing the TMS coil discharge.
Direct neuronal stimulation by TMS produced similar fMRI signal in-
creases in both groups, suggesting that cortical physiology itself may not
necessarily decline with age.
Keywords: Transcranial magnetic stimulation, motor cortex, fMRI, blood
flow, imaging, aging.
Introduction
An important and still unanswered question is whether and to what degree
brain function declines as a function of normal aging. This question is compli-
cated by the combination of cognitive and neuromuscular processes underly-
ing the responses to most tests of brain function. Several researchers have
begun to use brain imaging, and particularly blood oxygenation level depen-
dent (BOLD) fMRI, to examine the effects of aging on cortical activation
patterns (Ross et al., 1997; D’Esposito et al., 1999; Buckner et al., 2000;

496 K. A. McConnell et al.
Huettel et al., 2001; Hesselman et al., 2001). In response to the increased
metabolic demands of neuronal activation, the brain’s microvasculature
floods the area of activation with oxygenated blood, thus locally decreasing
the ratio of deoxygenated to oxygenated hemoglobin and increasing the MR
signal. BOLD fMRI can detect areas of neuronal activation with a spatial
resolution of 1–2 millimeters and produce regional activation patterns for a
given task. BOLD fMRI is noninvasive and safe, making BOLD fMRI an
excellent tool for monitoring cortical physiology.
The results of these fMRI studies of the aging brain have been varied.
Significantly, all prior studies have used activation tasks that rely on periph-
eral systems to activate the brain (e.g. eyes, ears, and motor system). Thus,
they are unable to determine whether any age-related alterations in cortical
activation might have been the result of actual changes in cortical physiology,
or were due to age-related changes in the peripheral systems used to induce
brain changes. For example, photic stimulation studies might only be record-
ing age-related changes in visual acuity rather than changes in occipital cortex
physiology, while motor tasks might only be recording the activation changes
caused by having an aging musculoskeletal system or peripheral nervous
system, or both.
Transcranial magnetic stimulation (TMS) is a relatively new neuroscience
tool that allows stimulation of cortical neurons directly and non-invasively
using electromagnetic pulses from a coil placed on the subject’s scalp
(Barker et al., 1985). Stimulation occurs when the electric field induced by the
short magnetic pulse of the TMS coil is strong enough to depolarize neurons
in the brain’s cortex directly, without relying on peripheral systems. This
ability to directly stimulate neural networks makes TMS attractive as a probe
of the brain’s neural interconnections (George et al., 1996; Grafman et al.,
1994). This has led to a growing interest in combining TMS with functional
imaging methods to explore fundamental questions of brain circuitry (Paus et
al., 1997; Fox et al., 1997; Bohning et al., 1999, 2000; Siebner et al., 1999; Nahas
et al., 2001). We wondered if direct brain stimulation with TMS inside the
MRI scanner interleaved with the fMRI image acquisition might distinguish
age-related changes in cortical activation from actual changes in cortical
physiology without the confound of changes in the physiology of peripheral
systems (Bohning et al., 1999; Shastri et al., 1999). In this study we sought to
distinguish age-related changes in cortical sensitivity from age-related cogni-
tive and neuromuscular change by comparing the activations produced by
three different tasks: direct cortical stimulation produced by TMS, indirect
active cortical stimulation produced by a simple motor task, and indirect
passive stimulation produced by the auditory “task” of hearing the TMS
machine.
Methods and materials
Subjects
Fifteen healthy adults signed written informed consent in accord with a procedure ap-
proved by the Medical University of South Carolina Institutional Review Board and were