AAEM MINIMONOGRAPH 35 ABSTRACT: Since 1985, when the technique of transcranial magnetic stimulation (TMS) was first developed, a wide range of applications in healthy and diseased subjects has been described. Comprehension of the physiological basis of motor control and cortical function has been improved. Modifications of the basic technique of measuring central motor conduction time (CMCT) have included measurement of the cortical silent period, paired stimulation in a conditioning test paradigm, repetitive transcranial magnetic stimulation (rTMS), and peristimulus time histograms (PSTH). These meth- ods allow dissection of central motor excitatory versus inhibitory interplay on the cortical motor neuron and its presynaptic connections at the spinal cord, and have proven to be powerful investigational techniques. TMS can be used to assess upper and lower motor neuron dysfunction, monitor the effects of many pharmacological agents, predict stroke outcome, document the plasticity of the motor system, and assess its maturation and the effects of aging, as well as perform intraoperative monitoring. The recent use of rTMS in the treatment of depression and movement disorders is novel, and opens the way for other potential therapeutic applications. © 2002 American Association of Electrodiagnostic Medicine. Muscle Nerve 25: 160–175, 2002 DOI 10.1002/mus.10038 MAGNETIC STIMULATION OF THE CENTRAL AND PERIPHERAL NERVOUS SYSTEMS MARKUS WEBER, MD,1 and ANDREW A. EISEN, MD, FRCP(C)2 1 Department of Neurology, Kantonsspital, CH-9007 St. Gallen, Switzerland 2 Neuromuscular Diseases Unit, Vancouver General Hospital, Vancouver, British Columbia, Canada Early experiments in humans used high-voltage, discusses methodological aspects, reviews the differ- short-duration electrical stimulation applied to the ent techniques and measurements in use, and criti- scalp overlying the motor cortex, a rather uncom- cally analyzes its utility in clinical practice and basic fortable procedure and inappropriate for routine neuroscience. clinical use. In 1985, Barker and colleagues5 intro- duced the technique of transcranial magnetic stimu- lation (TMS) which led to a new era of research in ANATOMY AND PHYSIOLOGY OF THE CORTICAL MOTOR NEURONAL SYSTEM motor control and cortical function. Since that time, interest in TMS has steadily increased and a vast lit- Motor function in humans is subserved by several erature has already accumulated. distinct yet interconnected anatomical regions. They This minimonograph considers current concepts include the primary motor cortex, also known as of the anatomical and physiological basis of TMS, Brodmann area 4, the premotor areas and supple- mentary motor cortex, basal ganglia, thalamus, cer- Abbreviations: AHC, anterior horn cell; ALS, amyotrophic lateral sclero- ebellum, brain stem, and reticular formation. The sis; CM, cortical motor neuronal; CMAP, compound muscle action poten- primary motor cortex is different from other regions tial; CMCT, central motor conduction time; EMG, electromyographic; GABA, gamma-aminobutyric acid; ISI, interstimulus interval; MEP, motor of the cerebral cortex in that it is thicker but has a evoked potential; MS, multiple sclerosis; PLS, primary lateral sclerosis; lower cell density. The main output cells are the PSTH, peristimulus time histograms; rTMS, repetitive transcranial mag- netic stimulation; SMNs, spinal motoneurons; T, tesla; TMS, transcranial large pyramidal cells in lamina V and smaller cells in magnetic stimulation lamina III. Their dendrites show a preferential ori- Key words: cortical function; cortical motor neuronal system; motor con- trol; motor evoked potential; peristimulus time histogram; transcranial entation parallel to the main axis of the precentral magnetic stimulation gyrus. Correspondence to: AAEM, 421 First Avenue SW, Suite 300 East, Roch- ester, MN 55902; e-mail: [email protected] The spinal motoneurons (SMNs) of the cord are © 2002 American Association of Electrodiagnostic Medicine. Published the “final common pathway” of the motor system to by John Wiley & Sons, Inc. which the higher centers and pyramidal cells make 160 Magnetic Stimulation MUSCLE & NERVE February 2002 direct or, more commonly, indirect connections via (Fig. 1, left).70 This results in a single descending multiple descending tracts. In non-human primates volley recordable from the pyramidal tract, which and other mammals, these descending tracts con- has been termed the D wave or direct wave.42,43,62,105 verge on the spinal motoneuron. In humans, the Increasing the stimulus intensity activates input cells, sophistication and complexity of motor control, par- causing indirect, transsynaptic activation of pyrami- ticularly in the face and distal aspects of the limbs, dal tract neurons. A series of recordable volleys, has largely sacrificed many of these indirect tracts named I waves to indicate their indirect origin, fol- with the expansion of the cortical motor neuronal low the initial D wave. The I waves are separated by (CM) system. This CM system originates from large intervals of about 1.5 to 2 ms. Anesthesia and cooling pyramidal cells in the primary motor cortex and is of the motor cortex have a profound depressant ef- the only descending motor pathway that makes fect on the I waves but not on the D wave.63 Epidural monosynaptic connections with the SMNs. (See Por- recordings of multiple descending volleys from the ter and Lemon,107 for a comprehensive review of spinal cord of conscious human patients have pro- corticospinal function in humans.) Each cortical mo- vided evidence that transcranial electrical stimula- tor neuron synapses with many SMNs, and each SMN tion activates the motor cortex in humans and ani- receives input from many different CM cells. This mals in the same way.19,49 arrangement of convergence and divergence is most The same experiments have also confirmed that abundant for the distal muscles—especially those of threshold transcranial magnetic stimuli over the the hand and facial musculature. It is what affords hand area of the motor cortex preferentially activate humans their amazing degree of fractionated con- the pyramidal cells indirectly (transsynaptically) trol and allows for a large repertoire of different through excitatory interneurons (Fig. 1, right). The movements served by the same muscle. CM control is onset latency of the compound muscle action poten- largely responsible for delicate control of force, pre- tial (CMAP) from small hand muscles is approxi- cision grip, angulation, rate of change of movement, mately 2 ms later (Fig. 1, bottom right, solid line) and muscle tension. It is likely that the CM system is than the electrically induced response. However, vital to the acquisition of new motor skills, which, with higher stimulus intensities or certain lateral coil once learned, are probably transferred to more cau- positions, the latency may shorten, consistent with D dal parts of the nervous system, including the spinal wave activation (Fig. 1, bottom right, dotted line). cord. Glutamate is the primary excitatory neuro- The different activation of pyramidal cells probably transmitter of the CM system. is related to the orientation of the induced current. The CM system is subject to excitatory and inhibi- Electrical stimulation causes the current to flow in all tory modulation. The stellate or basket cells are lo- directions parallel and radial to the surface, thus cated primarily in laminae III and V. Their axon penetrating the radially oriented pyramidal cells. terminals form predominantly inhibitory, gamma- TMS, however, induces current flow parallel to the aminobutyric acid (GABA) synapses on dendritic surface of the brain, preferentially exciting horizon- shafts, somata, and/or proximal axonal segment of tally oriented neurons. The result is that radially ori- the pyramidal neuron (cortical motor neuron)39 ented neurons will have a higher threshold for mag- and are horizontally orientated. These interneurons netic stimulation than electric stimulation. This is modulate the response of pyramidal neurons to ex- why coil orientation is important; even a slight posi- citatory inputs. tional change of the magnetic coil on the scalp can profoundly affect the size and latency of the motor NATURE OF TRANSCRANIAL evoked potential (MEP).14,85,96 The response of MAGNETIC STIMULATION lower limb muscles has a similar latency with electri- Since the introduction of TMS, there has been a cal and magnetic stimulation. This suggests that both debate over which structures are activated by the techniques have the same activation site in the ros- magnetic stimulus. A rapidly changing magnetic tral pyramidal axons as they leave the cortex and field is generated that induces electrical currents readily produce D wave activity.115 Whether TMS ac- within the cortex.5,43 Short-latency contractions are tivates a bi- or polysynaptic pathway in healthy sub- evoked in contralateral limb muscles. The latency is jects is presently unclear. Studies on monkeys have in keeping with a monosynaptic connection.4,43,61,86 failed to identify disynaptic excitation of motoneu- A single low-intensity anodal electrical stimulus rons from the pyramidal tract.83 delivered to the exposed surface of the cortex in TMS also activates the local circuit inhibitory in- monkeys preferentially activates pyramidal tract, terneurons. Several ipsi- and contralateral inhibitory neurons directly in the region of the axon hillock phenomena have been revealed with double (condi- Magnetic Stimulation