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J Appl Physiol 88: 126-134, 2000;
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Vol. 88, Issue 1, 126-134, January 2000

Magnetic stimulation of the human motor cortex evokes skin sympathetic nerve activity

David H. Silber1, Lawrence I. Sinoway1,2, Urs A. Leuenberger1, and Vahe E. Amassian3

1 Section of Cardiology, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey 17033; 2 Lebanon Veterans Affairs Medical Center, Lebanon, Pennsylvania 17042; and 3 Departments of Physiology and Neurology, State University of New York, Health Science Center of Brooklyn, Brooklyn, New York 11203


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Single-pulse magnetic coil stimulation (Cadwell MES 10) over the cranium induces without pain an electric pulse in the underlying cerebral cortex. Stimulation over the motor cortex can elicit a muscle twitch. In 10 subjects, we tested whether motor cortical stimulation could also elicit skin sympathetic nerve activity (SSNA; n = 8) and muscle sympathetic nerve activity (MSNA; n = 5) in the peroneal nerve. Focal motor cortical stimulation predictably elicited bursts of SSNA but not MSNA; with successive stimuli, the SSNA responses did not readily extinguish (94% of discharges to the motor cortex evoked SSNA responses) and had predictable latencies [739 ± 33 (SE) to 895 ± 13 ms]. The SSNA responses were similar after stimulation of dominant and nondominant sides. Focal stimulation posterior to the motor cortex elicited extinguishable SSNA responses. In three of six subjects, anterior cortical stimulation evoked SSNA responses similar to those seen with motor cortex stimulation but without detectable movement; in the other subjects, anterior stimulation evoked less SSNA discharge than that seen with motor cortex stimulation. Contrasting with motor cortical stimulation, evoked SSNA responses were more readily extinguished with 1) peripheral stimulation that directly elicited forearm muscle activation accompanied by electromyograms similar to those with motor cortical stimulation; 2) auditory stimulation by the click of the energized coil when off the head; and 3) in preliminary experiments, finger afferent stimulation sufficient to cause tingling. Our findings are consistent with the hypothesis that motor cortex stimulation can cause activation of both alpha -motoneurons and SSNA.

central command; motor cortex; muscle sympathetic nerve activity; autonomic nervous system


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

WHEN HUMANS EXERCISE, the sympathetic nervous system is activated by a variety of mechanisms (12, 17, 22, 23, 31, 42). One mechanism has been termed central command and involves the "central activation" of sympathetics in concert with motor outflow (12, 42). The precise location of central command remains unclear because a number of subcortical areas when electrically or chemically stimulated can evoke locomotion and sympathoexcitation (14, 26, 27, 43, 44). Bedford et al. (7) and Eldridge et al. (9, 10), utilizing decerebrate animal preparations, demonstrated locomotion and a rise in blood pressure when electrically stimulating the mesencephalic locomotor region (7, 9, 10). The rise in blood pressure still occurred with paralysis, suggesting that this rise was not due to a peripheral mechanism. Microejection of gamma -aminobutyric acid elicited the response, suggesting that electrical stimulation of cell bodies, and not the excitation of fibers of passage, was occurring. Additionally, prior reports in animals have suggested that cortical areas when stimulated may evoke autonomic responses. The motor cortex may be especially important in this regard (13).

The introduction of magnetic coil stimulation by Barker et al. (6) provided a painless method of stimulating the motor cortex transcranially and peripheral nerves transcutaneously. With the magnetic coil centered at the vertex, the elicited hand muscle responses were 1-2 ms later than with anodic electrical stimulation over motor cortex (30). Given that the shortest latency muscle responses were invariably obtained with anodic stimulation, the accepted interpretation was that anodic stimulation directly excited corticospinal neurons, whereas magnetic coil stimulation (centered at the vertex) evoked transynaptic activation of corticospinal neurons (30). Subsequently, when using near-maximal magnetic output with the coil oriented lateral-sagitally over motor cortex, arm muscle responses to magnetic and anodic electrical stimulation were shown to have equal latencies. That is, magnetic coil stimulation with this orientation could directly activate corticospinal neurons (1, 48). A study of corticocortical activation of cortical spinal neurons in animals (4) and a modeling study (3) implied the importance of such activation in motor responses by appropriately oriented magnetic stimuli.

The size principle was first described for alpha -motoneurons (15); i.e., transynaptic activation of alpha -motoneurons favors excitation initially of the smallest members of the pool, presumably because of the higher input resistance and lower membrane capacity (38). Hypothetically, the size principle might be extended to other neurons. For example, it may be extended to pyramidal tract and corticospinal neurons related to skeletal muscle contraction and autonomic functions (45). If so, a general concept emerges that the fastest effector actions are mediated by rapidly conducting fibers, i.e., by the largest neurons compared with those neurons mediating the slower autonomic responses. By hypothesis, small corticocortical inputs might be expected to activate corticospinal neurons subserving autonomic functions more readily or as least as readily as those subserving skeletal muscle responses. This hypothesis was a consideration in the coil orientation utilized (see also METHODS); i.e., transynaptic activation would favor activation of smaller corticospinal neurons. Stein and Bertoldi (38) reviewed the literature related to mechanisms subserving the size principle. They concluded that input resistance (which was inversely related to axonal conduction velocity and hence size of the alpha -motoneuron) was directly related to size of both maximal compound and quantal excitatory postsynaptic potentials, i.e., to measures of ease of excitation and facilitation, respectively. Although comparable data are lacking for large and small corticospinal neurons, it seemed reasonable to extend the size principle to cortical neurons as a working hypothesis.

Significantly, when cortical areas involved in motor activity are stimulated by a magnetic coil, reproducible sudomotor responses are seen (29). Sudomotor responses are likely to represent one of the end organ responses to an increase in skin sympathetic nerve activity (SSNA). Furthermore, pathways exit from areas in frontal cortex to areas in the limbic system that are known to influence autonomic functions (11, 16, 28, 49). These frontal areas are accessible to magnetic stimulation in humans.

Prior work has suggested that the increases in SSNA seen during forearm exercise may be due to an increase in central command (42), although this concept is not universally accepted (32, 33). Muscle sympathetic nerve activity (MSNA) changes during exercise are thought to be due predominantly to increases in discharge from metabolic and mechanically sensitive muscle afferents (muscle reflex) (17, 33, 39), with central command playing a greater role during high intensity rhythmic exercise (41).

In the present study, we examined direct recordings of MSNA and SSNA in the peroneal nerve during magnetic coil stimulation. We hypothesized that motor and anterior cortical stimulation would be more likely to increase SSNA than MSNA. Our results suggest that stimulation of selected cortical areas can lead to an increase in SSNA; moreover, this activation is not due to a generalized "arousal" process or to peripheral feedback from skin or muscle afferents. Some of these findings were presented in preliminary form (35).


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Subjects. We studied 8 healthy male subjects, age 25 ± 1 yr; 2 subjects were studied on 2 separate occasions for a total of 10 sets of observations. In three, both SSNA and MSNA were examined, for a total of five MSNA and eight SSNA recordings. All subjects signed informed consent, and the Pennsylvania State University Hospital's Institutional Review Board reviewed the procedures.

Magnetic coil stimulation. With a polyphasic pulse, the Cadwell MES-10 stimulator (maximum output 2.2 T) energizes either a round magnetic coil (9.4-cm OD) or the smallest figure-eight coil that was then available (5 × 10-cm OD), which consisted of two coils joined at a junction. Under the junction, the induced electric field is two times that under the lateral edges of the coil; the properties of the induced electric fields are described elsewhere (18, 21).

The induced electric field in the brain produces its physiological effects largely through stimulation of myelinated axons under or near the coil's windings, the axons stimulated being markedly affected by the orientation of the magnetic coil (2, 3, 48). For example, direct excitation of corticospinal neurons is favored by a lateromedial orientation of the induced electric field, but their indirect or synaptic excitation is favored by a posteroanterior orientation, which preferentially excites corticocortical axons. Low threshold points for axonal excitation are created by bends (3, 19), which are plentiful in the cerebral cortex and white matter. Although large-diameter corticospinal neurons monosynaptically excite alpha -motoneurons supplying hand (and other) muscles (25), it is likely that corticospinal and other corticofugal neurons eliciting autonomic effects are of small diameter. Therefore, we chose an orientation of the magnetic coil likely to favor excitation of corticocortical axons, which by the size principle (15), might preferentially excite small corticospinal (and other corticofugal) neurons. Thus, for synaptic stimulation of corticospinal neurons mediating skeletal muscle and autonomic effectors, the long axis of the figure-eight junction was located ~6 cm lateral to the midline and was centered at the posterior-anterior level of the vertex (Cz). Focal stimulation as evidenced by movement predominately of a single digit could be obtained by stimulating with the edge only of the round coil contacting the scalp (1). The advantage in focal stimulation of using the small figure of eight coil flat on the scalp was that it avoided the difficulty of maintaining the same tilt of the round coil over long periods. By utilizing such orientations, contralateral arm muscle activation could be elicited without cortical activation of muscles elsewhere.

The magnetic coil was also used to stimulate peripheral nerves in the forearm and fingers to examine the effect of afferent feedback from muscle and skin. Peripheral nerve stimulation is simpler to understand than is cortical stimulation and has been previously described (2, 5, 18, 19). Briefly, an electrical field is generated under the magnetic coil's windings, thereby exciting the axons, which, if straight, are excited by the negative spatial derivative of the electric field (19). Both motor and sensory axons can be stimulated in this way with less discomfort than by percutaneous electrical stimulation.

Recording SSNA and MSNA. The peroneal nerve recordings were obtained by using the microneurographic technique, a method well described in the literature (32-34, 39, 42). Briefly, the subject was placed supine with the right leg elevated at the level of the knee. The peroneal nerve just below the fibular head was electrically stimulated transcutaneously to determine its location. A 5-µm-tip tungsten microelectrode was then inserted within a sympathetic nerve fascicle subserving muscle or skin. A second electrode was placed in the subcutaneous tissue a few centimeters away as a reference. In all subjects the right peroneal nerve was used. The signal was then amplified (50-90 K), filtered (700-2,000 Hz), rectified, and integrated (Nerve Traffic Analyzer, Dept. of Bioengineering, University of Iowa) to obtain a mean voltage neurogram.

A signal was identified as SSNA when it was not linked to the QRS and was stimulated by arousal (40, 42). A signal was identified as MSNA when it bore a fixed relationship to the QRS complex (electrocardiogram). was not influenced by arousal stimuli (loud noise or question), and was stimulated by a fall in blood pressure, a Valsalva maneuver or voluntary apnea (40). Furthermore, a site was differentiated depending on whether electrical stimulation evoked parastesias (skin) or a twitch (muscle). Additionally before a recording was identified, the response to muscle stretch or skin tactile stimulation was noted. Recordings that contained mixed SSNA and MSNA were rejected. Each recording was reviewed by at least two of the authors. When a burst was identified, its height [amplitude, arbitrary units (AU)], duration (ms), and latency (ms) from the preceding magnetic coil stimulus artifact were noted. When a SSNA burst contained more than one peak, it was counted as multiple bursts if the decrease in voltage between peaks was >50% of the smaller peak. The area of a burst was then estimated as one-half the product of its duration and amplitude (AU).

In the SSNA recordings, because of their irregular occurrence, criteria had to be developed to determine whether given SSNA bursts were elicited by a magnetic stimulus. The following criteria were used. 1) A discrete, easily identified SSNA burst followed the stimulus artifact. 2) For each subject we estimated a minimum onset latency for a magnetic-elicited SSNA burst; any burst occurring at an earlier latency was considered unrelated to the magnetic stimulus. The minimum evoked latency was estimated as follows: the delay in the preganglionic portion of the pathway was assumed to contribute a negligible amount to the onset latency. We then estimated the length of the postganglionic portion of the pathway and assumed that the conduction velocity was no greater than 2.5 m/s, thus setting the shortest possible latency for an evoked SSNA discharge. This value was chosen because postganglionic sympathetic impulses are carried by unmyelinated fibers. 3) To determine the upper value of an acceptable onset latency, two of the four authors (L. I. Sinoway and D. H. Silber) examined all SSNA bursts that followed magnetic coil motor cortex stimuli and the respective onset latency value. Each onset latency was recorded, and only those latencies greater than the shortest latency possible were considered. The investigators then determined whether a given onset latency was much longer than the other obtained values. If the latency was so long as to be considered physiologically improbable, then the magnetic coil stimulation was considered not to be linked to a SSNA discharge. Once a criterion range of latencies for the individual subject was determined, bursts after magnetic coil stimulation of sites other than the motor cortex could be defined as either elicited by or unrelated to the magnetic coil stimulus. All latencies were measured from the onset of the stimulus artifact to the onset of the rising deflection in the SSNA burst.

Experimental protocol. After the subjects had the procedure explained and signed an informed consent, they were placed supine. Electrocardiograms (heart rate; beats/min) was recorded via chest patch electrodes. Blood pressure (mean arterial pressure; mmHg) was obtained with an automated finger cuff device that uses the modified volume clamp method (Finapres, Ohmeda, Fort Lee, NJ). Respiratory movements were recorded from a pneumograph around the upper abdomen. Electromyograms (EMGs) were obtained via patch electrodes over the forearm digit flexors and displayed both on an oscilloscope and a chart recorder. All other data, including MSNA or SSNA, were simultaneously recorded on a multichannel chart recorder at speeds permitting the accurate timing of events (model TA4000, Gould, Valley View, OH).

Although heart rate, blood pressure, and respiration after magnetic coil stimulation of the various cortical and noncortical regions were recorded, the data were not collected on tape or stored digitally, making statistical assessment of the heart rate and blood pressure responses unreliable.

Once the subjects had been instrumented and a MSNA or SSNA site obtained, an external cortical map was made. The point "Cz" on the midsagittal line was defined according to the International 10-20 EEG System (21). Reference points were drawn on the scalp at 2-cm intervals along the midsagittal line, posterior and anterior (i.e., P4, 4 cm posterior; A4, 4 cm anterior). A second perpendicular line connecting each auditory canal and passing through Cz was then drawn. Two-centimeter intervals were then marked off on this line (i.e., R6, 6 cm right lateral). In those individuals in whom the scalp was obscured by hair, the map was made on a cloth tightly fitted to the head. Stimuli were then made to motor cortical areas (R4, L4, R6, L6) that elicited a forearm (hand, finger) and/or leg (foot) movement.

We also stimulated areas anterior (e.g., R6, A4) or posterior to the motor cortex; both the left and right motor cortex were separately stimulated to evaluate lateralization of effects. Magnetic coil stimulation was also done over the forearm yielding forearm flexor activation (via peripheral motor axons) and over fingers yielding a "tingling" sensation reported by the subjects. Finally, the magnetic coil was placed a short distance away; when it was energized a loud click was produced without transcranial stimulation.

Not all of the cortical and peripheral areas mentioned were stimulated in all subjects. Additionally, the order and number of stimuli were varied in different subjects to reduce the potential for a statistical series effect. The responses to successive stimuli were carefully examined for reproducibility. When the responses were not reproducible to such successive stimuli they were defined as extinguishable. If the response occurred with every successive stimulus, it was said to have failed to extinguish. For each stimulus we determined whether a burst was elicited. The burst area was then approximated as one-half of the duration (ms) times the height (AU). Data are also presented as the burst incidence for each stimulus location. This was an ordered score of whether a burst occurred after magnetic coil stimulation with a score of +1 for a positive response and -1 for a negative response replacing the ordered classification of present or absent (37). Within a category of magnetically elicited responses, values for area and incidence were tallied, and means ± SE are reported. The Student's t-test was used to compare other areas of magnetic coil stimulation with motor cortex stimulation with P < 0.05 considered statistically significant. Statistics were done for each subject (acting as his own control), when sites of stimuli were compared and were done for the group, although a sufficient number of subjects did not always participate in similar comparisons.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

SSNA responses to motor cortical stimulation of dominant vs. nondominant hemispheres. SSNA was measured in eight subjects. Out of a total of 179 motor cortex stimuli delivered in these subjects, a burst of SSNA was noted 169 times (94.4%). The mean onset latencies varied in the eight volunteers from 739 ± 33 to 895 ± 13 ms, but the individual mean latencies did not correlate with the subject's height.

In general, SSNA responses did not extinguish with successive magnetic coil stimuli to the motor cortex. Stimuli delivered ipsilateral (right motor cortex) and contralateral (left motor cortex) to the SSNA recording site (right leg) yielded similar responses. In six of the six subjects in whom left and right motor corticies were compared, no statistical difference in incidence was found. However, it should be mentioned that in two of the subjects a greater SSNA area was seen when the right motor cortex was stimulated. Data for motor cortical stimulation for each individual are presented in Table 1. When these six subjects were analyzed as a group, no difference between left and right motor cortex for either incidence [0.81 ± 0.07 vs. 0.92 ± 0.04; P = not significant (NS)] or area (4,446 ± 403 vs. 5,471 ± 645 AU; P = NS) was found. For comparison, SSNA and MSNA responses are shown in Figure 1.

                              
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  		Table 1.   Motor cortex SSNA



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  		Fig. 1.   Five stimuli to motor cortex when muscle sympathetic nerve activity (MSNA; left) or skin sympathetic nerve activity (SSNA; right) was recorded. Whereas SSNA response failed to extinguish, no MSNA response was detected. Recordings at fast (1-s calibration) and slow speeds. Recordings are an integrated neurogram.

SSNA responses to stimulation of other cortical areas. In the first three subjects we stimulated nonmotor cortical areas with the round coil over the parietal and occipital lobes (Table 2). When we compared SSNA responses elicited by stimulation of motor and other cortical areas, we noted a smaller burst area in all three subjects after nonmotor cortical stimuli compared with motor cortex stimulation. Nonmotor cortical stimulation also evoked a lower burst incidence in two of the three subjects studied. Statistics for this group were not significant for area (1,963 ± 203 vs. 4,991 ± 365 AU) or incidence (0.14 ± 0.43 vs. 0.90 ± 0.03) because of the small sample size. In the next five subjects, the figure-eight coil was used for focal stimulation; stimuli were delivered 4 cm posterior to the motor cortex (Figures 2 and 3). In all five, the response incidence was statistically lower with posterior stimuli compared with motor cortex stimuli. The same finding was noted in four of five subjects when the area of the SSNA bursts was analyzed (Table 2). In summary, all eight subjects demonstrated either greater SSNA activity (area) or a more frequent response (incidence), or both, when the motor cortex was stimulated compared with stimulation of areas posterior to the motor cortex. When the entire group was analyzed (n = 8), posterior stimuli were less likely to produce SSNA (-0.15 ± 0.20 vs. 0.90 ± 0.03; P < 0.01) and led to smaller burst area (1,520 ± 246 vs. 4,991 ± 365 AU; P < 0.01) compared with motor cortex stimulation. When the group of five subjects in whom we performed the more focal posterior stimulation were compared, similar findings occurred for area (1,256 ± 332 vs. 4,991 ± 365 AU; P < 0.01) and incidence (-0.33 ± 0.18 vs. 0.90 ± 0.03; P < 0.01) compared with motor cortex stimulation.

                              
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  		Table 2.   Motor cortex and nonmotor cortex



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  		Fig. 2.   Magnetic coil stimulation during SSNA recording in 1 subject. Left: responses to 6 successive stimuli 4 cm posterior to motor cortex. Middle: responses to 6 stimuli to motor cortex. Right: responses to 6 stimuli 4 cm anterior to motor cortex. Note that stimulation of motor cortex and anterior site produces predictable SSNA of similar latencies that did not extinguish, unlike with posterior stimulation. Recordings are an integrated neurogram.



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  		Fig. 3.   Same SSNA integrated recordings as Fig. 2 superimposed. Note loss of amplitude with posterior site stimulation. Note that stimulating motor cortex and anterior site produces predictable SSNA that did not extinguish and had similar latencies, unlike posterior stimulation.

In these same five subjects we stimulated the cortex 4 cm anterior to the motor cortex (Table 2, Figs. 2 and 3), and in one subject (subject 2) we stimulated over the supplementary motor area with the round coil. In three of the six subjects, whether the frequency of a response (incidence) or the area of the SSNA induced was analyzed, there was statistically less SSNA with anterior stimuli compared with motor cortical stimuli. In the other three subjects similar responses were observed for magnetic coil stimulation over the motor cortex and more anterior portions of the cortex. As a group (n = 6), anterior stimuli led to less SSNA (area: 2,932 ± 916 vs. 4,991 ± 365 AU, P < 0.05: incidence: 0.28 ± 0.11 vs. 0.90 ± 0.03, P < 0.01).

SSNA responses to loud clicks. In six subjects, loud clicks frequently produced responses, which usually extinguished with repeated stimuli (Table 3, Fig. 4). The onset latencies for magnetic coil stimuli that evoked SSNA were very similar to those seen when the motor cortex was stimulated. In five of six subjects, burst incidence was less after audible clicks than after motor cortical stimulation; in only one subject (subject 6) did clicks elicit reproducible, but small, SSNA discharges. In all six subjects, there was a significant difference in the burst area that was elicited by clicks when compared with that by motor cortical stimulation. As a group (n = 6) both burst area and incidence were lower (area: 1,371 ± 339 vs. 4,991 ± 365 AU, P < 0.01; incidence: -0.18 ± 0.28 vs. 0.90 ± 0.03, P < 0.05) with clicks than with motor cortex stimulation.

                              
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  		Table 3.   SSNA response to magnetic coil stimulation



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  		Fig. 4.   SSNA integrated neurogram recording from 1 subject during 6 successive motor cortex stimuli (left) and 6 successive auditory click stimuli (right). Note SSNA response to click was rapidly extinguished.

SSNA responses to forearm muscle and finger stimulation. In five subjects, we also delivered forearm magnetic coil stimulation to the forearm of sufficient intensity to evoke muscle twitches (Table 3, Figs. 5 and 6). In all four of the subjects whose EMG responses were similar with motor cortex and forearm muscle stimuli, the SSNA burst incidence and area were less with the forearm stimuli. In subject 5, in whom EMGs after forearm stimuli were much larger than with motor cortex stimuli, both burst incidence and area were similar. As a group (n = 5), both burst area and incidence were reduced after forearm stimulation (area: 2,639 ± 826 vs. 4,991 ± 365 AU, P < 0.05; incidence: 0.07 ± 0.19 vs. 0.90 ± 0.03, P < 0.05).


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  		Fig. 5.   Six successive stimuli to either motor cortex (left) or forearm (right) in 1 subject. Note SSNA response to forearm stimulation rapidly extinguished. Recordings are an integrated neurogram.



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  		Fig. 6.   Single forearm (top) and motor cortex stimulation (bottom) in 1 subject. Note similar amplitude EMG with each stimulation. Nerve recordings are an integrated neurogram.

Afferent fibers in the fingers were stimulated in three subjects (Table 3, Fig. 7). In all three subjects, the finger stimulation elicited bursts that had a significantly lower incidence than those due to motor cortex stimulation. The number of subjects was too small to do a meaningful group statistic (n = 3) for both incidence and area. Nevertheless, a clear trend (P = 0.09 for area and incidence) was present, possibly suggesting less consistent SSNA (-0.33 ± 0.38 vs. 0.90 ± 0.03) or smaller area (1,698 ± 1,416 vs. 4,991 ± 365 AU) after magnetic coil stimulation of afferents in the fingers compared with motor cortex.


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  		Fig. 7.   Successive stimuli to motor cortex (left) and finger afferents (right) in 1 subject. Note SSNA response to finger stimulation rapidly extinguished. Time calibration of 1 s applies to faster writing speed. Recordings are an integrated neurogram.

MSNA response to motor cortical stimulation. MSNA was measured in five subjects. Fifty-eight magnetic coil stimuli delivered to the motor cortex did not predictably elicit discharges of MSNA at the latencies observed with SSNA (Fig. 1, left). These observations were made during periods when the blood pressure was increasing, constant, or diminishing.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Differentiation of motor cortical and other evoked SSNA responses. When responses were compared with successive single focal stimuli delivered to the motor cortex and those with other structures, a clear difference emerged. For example, motor cortex stimuli predictably elicited SSNA bursts with a consistent latency, whereas SSNA responses to the loud noise emitted by the energized coil or to muscle afferent stimulation rapidly became extinguished.

The three types of "peripheral" interventions (auditory, forearm muscle, and finger afferent stimulation) were also important because they ruled out that the motor cortex SSNA responses were due to afferent feedback. For example, we directly stimulated forearm muscle activity (similar EMG amplitude); motor cortex stimulation evoked greater SSNA responses that less readily extinguished. If SSNA responses after motor cortical stimulation were due to afferent feedback resulting from the muscle contracting, then forearm stimulation should have produced a similar response.

Differentiation of cortical areas eliciting SSNA responses. In this study we recorded SSNA responses to focal magnetic coil stimulation of different cortical areas. When successive magnetic stimuli were applied to the motor cortex, SSNA discharges were consistently evoked. This result was independent of the hemisphere stimulated and of whether movement occurred in the limb in which SSNA was recorded. Taking into account the afferent data mentioned previously, we conclude that in this study magnetic coil stimulation of the motor cortex evoked a feed-forward activation of SSNA.

Magnetic stimulation anteriorly in three of six subjects led to SSNA responses similar in incidence and area to those seen with motor cortex stimulation. However, such anterior stimulation did not evoke motor discharges. Frontal lobe areas anterior to the motor cortex are classically known to contain only small corticospinal neurons. Consistent with the size principle (15), such corticospinal neurons may be readily excited synaptically. Such small corticospinal neurons might project downward to SSNA efferents without eliciting movement. Alternatively, the anterior cortical stimulation might excite corticocortical afferents projecting to motor cortex (4). The size principle would favor the activation of the small corticospinal neurons, possibly related to autonomic function but not eliciting the magnetically induced short-latency movement, which depends on large corticospinal neurons. These anterior areas stimulated are believed to be related to the planning of movement (11, 49).

Posterior cortical stimulation was followed by a readily extinguishable SSNA response in direct contrast to motor cortical stimulation.

The overall topographical pattern of nonextinguished SSNA response just discussed may be compared with that described by Wall and Pribram (46) in monkeys. Changes in arterial pressure were elicited by repetitive electrical stimulation of many areas of exposed cerebral cortex, which were not secondary to movements because they persisted after curarization. Remarkably, after trigeminal neurotomy to eliminate the effect of meningeal afferent input, the responsive areas shrank to cerebral cortex adjoining the central sulcus and anterior to it. Those are similar areas to where we elicited nonextinguishable SSNA responses. We conclude from the similarity of topographical findings, including the failure to elicit nonextinguishable SSNA responses from posterior cortical stimulation, that our findings did not result from stimulation of meningeal afferents.

Niehaus et al. (24) recorded sympathetic skin responses related to sweating after transcranial magnetic stimulation. They used repetitive stimuli (2-5 pulses at 10 Hz) delivered through larger and therefore less focal coils than we utilized. Possibly the use of stronger, less focal magnetic contributed to their conclusion that the sympathetic skin responses were due to nonspecific arousal. Closer to our findings, Rossini et al. (29) found prominent sudomotor responses to magnetic stimulation of the motor cortex. Significantly, the amplitude of the sudomotor responses fell off markedly as the magnetic coil was moved to scalp locations that no longer effectively evoked motor twitches. Additionally, these responses were not seen with noise or cutaneous receptor stimulation.

Effectors activated by SSNA. Skin sympathetics innervate both skin vasculature and exocrine structures (32, 33). In the present report, we made no attempt to control for core, skin, and room temperature, variables known to affect the functional characteristics of SSNA responses (32, 33); therefore, our work does not allow us to define the distribution of end-organ responses to the SSNA discharges observed.

MSNA responses to motor cortical stimulation. When utilizing a single focal magnetic stimulation to the motor cortex we failed to observe an elicited MSNA response comparable to that evoked in SSNA. The lack of an excitatory response might be due to the greater importance of peripheral afferent feedback in the control of MSNA, but we did not examine for such influence, e.g., baroreceptor input. Macefield et al. (20) tested the effect on MSNA of magnetic stimuli to the motor cortex at various intervals after the QRS wave. When the stimulus delay was 200-400 ms, the averaged MSNA was reduced in amplitude. In the present report, we did not examine for inhibition of MSNA.

The relationship between successive magnetic stimuli to motor cortex and persistence of SSNA responses invites the question as to its possible significance. This relation also extended to one-half the subjects stimulated 4 cm anteriorly, i.e., probably the anterior portion of premotor cortex. Premotor cortex is known to be related to planning of the cued direction of future voluntary movements (47). A possible explanation of the association of these SSNA responses and voluntary motor activity is provided by the following findings: 1) motor cortical stimulation elicits sweating (29), and 2) the finger-grip force that is required to achieve a given load force is reduced if the skin is wet (8). In a further study, Smith et al. (36) found that hand dryness (induced by scopolamine patches placed behind the ears) led to an increase in static and peak forces required to maintain a given grip; i.e., frictional forces were reduced. The reduction of sweating was confirmed by the reduced psychogalvanic skin response. Thus sweating, somewhat counterintuitively, was shown not to reduce the coefficient of friction. In summary, the above suggests a function for SSNA in tactile exploration and grasping, and an explanation for the SSNA responses seen with magnetic stimulation of both motor cortex and premotor cortex in some subjects.

In conclusion, this study demonstrates that magnetic coil stimulation of the motor cortex leads to consistently evoked SSNA. This effect on SSNA is not due to feedback from muscle or skin afferents, nor is it secondary to auditory stimulation. Our data support a possible role for the motor cortex in skin sympathetic activation during exercise. Further studies are required to determine the role of the motor cortex in the parallel activation of motor and autonomic adjustments seen during exercise in humans.


    ACKNOWLEDGEMENTS

We appreciate the technical support of Kristen Gray and Michael Herr and also the expert typing of Jennifer Stoner.


    FOOTNOTES

This work was supported by National Institute on Aging Grant R01 AG-12227 (to L. Sinoway); National Heart, Lung, and Blood Institute Grant HL-02654 (to U. Leuenberger); and Division of Research Resources General Clinical Research Center Grant M01 RR-10732.

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Address for reprint requests and other correspondence: L. I. Sinoway, Sect. of Cardiology, MC H047, The Milton S. Hershey Medical Center, 500 University Dr., Hershey, PA 17033 (E-mail: lsinoway{at}psghs.edu).

Received 5 March 1999; accepted in final form 10 September 1999.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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