Stimulation Tests Rationale

Peripheral nerve, spinal, or cortical stimulation, either by implanted electrodes (for peripheral nerves) or by externally applied electric or magnetic fields, elicit relatively synchronized activation of motor units at reproducible and predictable levels. The resulting compound action potentials and subsequent muscle contraction allow for measurement of the efficiency of neural and neuromuscular transmission. The muscle responses to stimulation are discussed in Phrenic Nerve Stimulation in Section 2 of this Statement.

Scientific Basis

For practical purposes, human respiratory motor nerves are not accessible over a sufficient length to permit phrenic or other respiratory nerve conduction velocities to be measured. However, motor latency can be measured. Included in the latency are the times required for (1) initiation of action potentials in the axons, (2) rapid saltatory conduction through myelinated axons, (3) slow conduction along the thinner terminal twigs, and (4) chemical transmission across the neuromuscular junctions.

Equipment

Nerve stimulation. Stimulation of respiratory nerves can be accomplished with electrical or magnetic stimulators (Table 3). The former are less expensive, less cumbersome, more rugged, and more precisely controllable; the latter are easier to apply and less painful for patients. For electrical stimulation, the phrenic nerve is stimulated transcutaneously by surface electrodes at the posterior border of the sternomastoid, or with implanted needle, wire, or hook electrodes. The phrenic nerve(s) can also be stimulated magnetically, via a dorsal cervical approach, which stimulates the lower cervical nerve roots; via an anterior presternal approach, which stimulates both phrenic nerves; or, using one or two figure-of-eight coils, unilaterally or bilaterally over the anterior neck to stimulate one or both phrenic nerves.

Several other respiratory nerves and muscles can also be stimulated, either transcutaneously or by needle or wire electrodes. Pradhan and Taly (28) have demonstrated a technique for stimulating lower intercostal nerves via probe electrodes for latency measurements. The ventral roots of intercostal nerves have been stimulated either by high-voltage stimulation over the spine (64-66) or by surgically implanted wire elec-

TABLE 3. TYPES OF RESPIRATORY MUSCLE STIMULATION

Type of Stimulation Advantages

Disadvantages

Electrical Implanted

Transcutaneous Magnetic

Less uncomfortable during stimulation Precise control of stimuli

Inexpensive

Requires little preparation

Does not require contact with skin Painless

Difficult to place Painful

Difficult to maintain contact during voluntary effort

Expensive and cumbersome Relatively unselective Difficult to stimulate repetitively Precise location of stimulus uncertain (so latency measurements may be problematic)

trodes (67). The rectus abdominus and oblique muscles can also be stimulated with large surface area electrodes (68), and abdominal muscle stimulation has been shown to be effective enough to facilitate cough in tetraplegic patients with impaired expiratory muscle function (66). The abdominal muscles can be activated by magnetic stimulation of nerve roots at the level of T10.

In most cases, it is important to be sure that the delivered stimulus is strong enough to activate maximally all motor units in the muscle of interest. To that end, elicited CMAP amplitude is measured as a function of stimulus intensity, and, for subsequent measurements, stimulus intensity is set to be supramaximal, 20-50% above that required for maximal response. During long experiments, it should be regularly verified that stimulus intensity is supramaximal.

Cortical stimulation. It is now possible to stimulate cortical and subcortical neural pathways in human subjects, using highvoltage (up to 1,500 V) electrical stimulators (69) and magnetic stimulators (up to 3.0 T) (70). Electrical stimulation of the cortex requires saline-soaked gauze pads (or silver-silver chloride electrodes) on the scalp with the anode positioned over the relevant region of the motor cortex. For the diaphragm and intercostal muscles, the optimal site is close to the midline at or just anterior to the vertex (71). The cathode can either be a single electrode 6-8 cm anterior to the anode, a ring of electrodes placed around the scalp, or an electrode several centimeters lateral to the anode at the vertex. Commercially available magnetic stimulation coils consist of several circular coils in a single housing (usually > 10 cm in diameter) positioned (usually tan-gentially) with their edges close to the scalp region of interest. Positioning of large circular coils slightly anterior or posterior to the vertex will routinely activate corticofugal output from the medial parts of both hemispheres, including major inspiratory and expiratory muscles in normal subjects, and structures as lateral as the hand area are also activated. More focal stimulation can be achieved with double or "butterfly" coils. There are several nonstandard coils, but their properties must be carefully determined before their clinical utility can be assessed.

To obtain minimal latencies for response to transcranial stimulation, and thereby to avoid coming to the erroneous conclusion that there is a deficit in corticospinal conduction, it is best to record them during voluntary (or reflex) contractions producing at least 10% of maximal force. Responses can be obtained without a background contraction, but the latencies are more variable.

The presence of cardiac or other implanted electrical devices, including pacing wires and pulmonary artery catheters equipped with thermisters, is an absolute contraindication for magnetic stimulation and for high-voltage electrical stimulation of cranial or spinal structures. Epilepsy and known intra-cortical pathology are relative contraindications for cranial stimulation, as is the presence of intracranial clips.

Although transcranial stimulation has now been used for well over a decade with few reports of side effects, two issues deserve mention. First, there is a risk of induction of a seizure, particularly in those with pre-existing cortical pathology (such as a recent cerebrovascular accident). Although seizures have not been observed with repeated single stimuli, greater precautions are necessary for the newer rapid-rate stimulators (72, 73). Second, the use of some but not all transcranial magnetic stimulators has caused sustained elevations in auditory threshold, presumably due to the brief, but high-intensity "click" produced by the stimulus passing into the coil.

Data Analysis

Nerve stimulation is essential for measurements of nerve conduction velocity or latency. Furthermore, the electromyographic signal elicited by supramaximal nerve stimulation (CMAP) provides a different perspective than spontaneous EMG, with two distinct advantages: assurance of maximal activation, and a generally higher signal-to-noise ratio. CMAPs are detected, usually with surface electrodes applied over the costal margin, and the time between triggering of the stimulus and detection of the elicited CMAP is recorded. In most cases, CMAP amplitude and/or area are also recorded.

Latencies can also be measured after cortical stimulation (Figure 7). The "central" conduction time (CCT) is an indirect estimate of the time taken for the descending volley to travel from the motor cortex to the relevant motoneurons. The CCT can be measured by subtraction of the peripheral conduction time (estimated by stimulation over the relevant spinal segment or root) from the total conduction time, from stimulus to onset of the motor-evoked potential (MEP). The measured CCT, however, is not a true measurement of central conduction velocities, because the exact site and timing of the relevant descending corticofugal volleys show some variability and because stimulation over the spinal cord activates the motor axons at a variable distance from the motoneurons. The MEP observed in EMG recordings of most human trunk and neck muscles, including diaphragm, intercostals, scalene, and abdominal muscles (64), has an onset latency consistent with a rapidly conducting oligosynaptic pathway. There is no evidence that this MEP involves a contribution from bulbopon-tine respiratory neurons.

The MEP can also be assessed in terms of amplitude (and dispersion). Transcranial electrical stimulation via an anode over the appropriate scalp site evokes a direct corticospinal volley (D-wave) followed by a series of indirect trans-synapti-cally evoked corticospinal volleys (I-waves; interval between volleys, 0.8-1.0 milliseconds). With increased intensity of electrical stimulation, the site of activation along the corticospinal path is located deeper within the brain, reaching the level of the pyramidal decussation in the medulla with strong stimuli (74). The size of the D-wave increases with increased stimulus intensity, as does the size of I-waves. With transcranial magnetic stimulation, the precise corticospinal response depends on the location of the evoked currents. Hence, there are differences in the magnetic activation of the corticospinal output from the hand areas (lateral region of the primary motor cortical strip) compared with the leg areas (within the medial edge of the motor cortex) with different directions of stimulus current. With high-power nonfocal coils (which have the greatest diagnostic utility) transcranial magnetic stimuli evoke not only

DIAPHRAGM DELTOID

DIAPHRAGM DELTOID

Figure 7. Comparison of motor latencies and compound diaphragm or deltoid action potentials elicited by magnetic stimulation at the phrenic nerve, spinal level, and cortical level. The latencies are indicated in milliseconds. Bil. = bilateral; C4 = level of the 4th cervical root. Reprinted by permission from Reference 64.

Figure 7. Comparison of motor latencies and compound diaphragm or deltoid action potentials elicited by magnetic stimulation at the phrenic nerve, spinal level, and cortical level. The latencies are indicated in milliseconds. Bil. = bilateral; C4 = level of the 4th cervical root. Reprinted by permission from Reference 64.

Pi Left

Pi Left

Figure 8. Effects of cortical stimulation at rest and during voluntary inspiratory efforts of varying strength. Left: Transdiaphragmatic pressure (Pdi) twitches obtained by bilateral supramaximal phrenic nerve stimulation during relaxation (thick trace). The thin traces show twitches resulting from transcranial magnetic stimulation (stimulator set at 85% maximal) at rest (lowest trace, no twitch) and during three graded static inspiratory efforts. Note the facilitation of Pdi twitches at intermediate voluntary efforts and the partial occlusion at high effort. Right: Compound muscle action potentials (CMAPs) recorded from surface electrodes on right and left chest wall (over the diaphragm) during magnetic stimulation at the four levels of voluntary effort shown at left. Note the progressive facilitation in CMAP amplitude. Reprinted by permission from Reference 76.

Figure 8. Effects of cortical stimulation at rest and during voluntary inspiratory efforts of varying strength. Left: Transdiaphragmatic pressure (Pdi) twitches obtained by bilateral supramaximal phrenic nerve stimulation during relaxation (thick trace). The thin traces show twitches resulting from transcranial magnetic stimulation (stimulator set at 85% maximal) at rest (lowest trace, no twitch) and during three graded static inspiratory efforts. Note the facilitation of Pdi twitches at intermediate voluntary efforts and the partial occlusion at high effort. Right: Compound muscle action potentials (CMAPs) recorded from surface electrodes on right and left chest wall (over the diaphragm) during magnetic stimulation at the four levels of voluntary effort shown at left. Note the progressive facilitation in CMAP amplitude. Reprinted by permission from Reference 76.

I-waves but also small D-waves (75). There is probably more trial-to-trial variability in the components of the descending volley to magnetic stimulation than to electrical stimulation.

During voluntary contraction, the minimal latency of responses is reduced, and the MEPs are increased in size compared with relaxation (Figure 8), reflecting increased excitability not only at the spinal level (76) but also at the motor cortex (77). For the diaphragm, this effect has been documented during both volitional efforts (35) and CO2-driven hyperpnea (78).

Interpretation of the results of motor cortical stimulation must be made with caution for several reasons. First, stimulation over the motor cortex activates both excitatory and inhibitory structures within the cortex. Second, a single stimulus as brief as 50 milliseconds evokes multiple descending corticospinal volleys. Third, the evoked motor response is elicited preferentially in a motoneurons that are close to firing threshold as a net result of voluntary, involuntary, and reflex inputs. Finally, change in MEP can be said to reflect a change in cortical physiology only if the excitability of the spinal cord has been proven to remain constant.

When cortical stimulation is delivered during voluntary effort, the MEP is followed by a period of near silence in the EMG recorded from the relevant muscle. The latter part of the silent period is due to inhibition of motor cortical output (79-81). The duration of the silent period grows with increasing intensity of cortical stimulation but does not vary greatly with the relative strength of voluntary contraction.

Applications

Normal phrenic nerve/diaphragm latencies, elicited by electrical stimulation at the neck, have been reported to average 6-8 milliseconds in adults (12, 16, 82, 83), with lower values in children (see Table 4). Because the right phrenic nerve is shorter than the left, latency is slightly shorter on the right side. CMAP amplitudes, recorded from chest wall surface electrodes, average 500-800 mV. Normal values for magnetic stimulation-induced phrenic nerve/diaphragm latency or for intercostal nerve/muscle latency have not been fully established (84, 85).

Phrenic nerve/diaphragm latencies are abnormally slow in demyelinating polyneuropathies, notably Guillain-Barre syndrome. They are usually nearly normal, but are associated with markedly depressed CMAP amplitude, in traumatic neuropathies, such as postcardiac surgery phrenic nerve palsy or the polyneuropathy of critical illness. In myasthenia gravis, a reversible decrement in diaphragm CMAP can be elicited by repetitive phrenic nerve stimulation.

CCTs from cortex to phrenic motoneurons are approximately 4 milliseconds in normal adults (35). Normal values for D- and I-wave amplitudes and the effects of disease are not yet established, but it is apparent that I-wave amplitude is reduced by general anesthetic agents.

Transcranial stimulation to determine CCT has been used in the assessment of a range of upper motor neuron disorders and particularly in the assessment of patients with possible CNS demyelination, including multiple sclerosis. It can be applied specifically to the respiratory muscles, or, more commonly, to muscles in both upper and lower limbs.

Compound muscle action potentials (CMAP) in response to electrical or magnetic nerve or cortical stimulation can also provide useful information. Lack of a CMAP after nerve stimulation is an indication of paralysis, with the lesion located proximal to or at the neuromuscular junction. Lack of a CMAP in response to cortical stimulation when a CMAP is elicited by phrenic nerve stimulation has been used to identify good candidates for phrenic nerve pacing.

Changes in CMAP amplitude, especially as compared with changes in elicited muscle twitch strength (such as phrenic stimulation-induced diaphragm CMAP as compared with transdiaphragmatic twitch pressure [Pdi,tw]) can be used as evidence for or against the development of neural or neuro-muscular transmission defects (when both Pdi,tw and CMAP decrease) or contractile defects (when Pdi,tw decreases but CMAP does not) (86).

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