Component-level physiological attribution of paired-pulse modulation of polyphasic human motor evoked potentials

Transcranial magnetic stimulation (TMS) over the hand area of the human motor cortex evokes motor evoked potentials (MEPs) whose waveform is often discretely polyphasic during weak voluntary contraction. Kobayashi, Hyodo, Kurokawa and Ueno (1998) showed that when a subthreshold conditioning pulse from a vertex-centered round coil precedes a latero-medially oriented figure-eight test pulse, the second negative component (N2) of polyphasic MEPs is suppressed at interstimulus intervals below 5 ms while the first negative component (N1) is not suppressed, and they concluded that the first phase reflects direct (D-wave) corticospinal volleys, which are resistant to cortico-cortical inhibition. This interpretive conclusion did not establish the generator composition of the first component: later epidural recordings in conscious humans confirm that latero-medially oriented TMS recruits both D and earliest indirect ($I_1$) volleys that escape short-interval intracortical inhibition (Werhahn et al., 1994; Nakamura et al., 1996; Di Lazzaro et al., 1998). The relative D versus $I_1$ contribution to the N1 surface peak, and the stimulus conditions under which each dominates that waveform, remain unquantified.

Background

Transcranial magnetic stimulation (TMS) uses a brief, intense current in a scalp coil to induce an electric field in the underlying motor cortex and thereby discharge corticospinal neurons; the resulting muscle response recorded with surface electromyography (EMG) electrodes is the motor evoked potential (MEP). Since the classic recordings of Patton and Amassian (1954), the descending activity elicited by cortical stimulation is known to consist of a direct (D) wave, produced by direct activation of the axons of fast-conducting pyramidal tract neurons, followed by indirect (I) waves ($I_1$, $I_2$, and so on), produced by trans-synaptic activation of the same neurons through cortical circuits, at intervals of about 1.5 ms. In humans these volleys can be recorded directly by electrodes placed in the cervical epidural space (the space around the spinal cord's tough outer membrane) of conscious patients undergoing pain treatment. The volley composition depends strongly on the direction of the current induced in the brain: with a figure-eight coil (two adjacent circular windings whose induced currents add at the central junction) oriented so that the induced current flows posterior-to-anterior (PA), the earliest volley is $I_1$ and D waves appear only at high intensity; anodal transcranial electric stimulation (electric stimulation through scalp electrodes with the anode, the positive electrode, over the motor cortex) evokes a pure D wave at threshold; and with a latero-medial (LM) induced current, TMS evokes both D and $I_1$ activity already at active motor threshold (Werhahn et al., 1994; Nakamura et al., 1996; Di Lazzaro et al., 1998).

Paired-pulse TMS is the standard non-invasive assay of intracortical circuitry in humans: a subthreshold conditioning pulse is followed by a suprathreshold test pulse, and the ratio of conditioned to unconditioned MEP amplitude is measured as a function of the interstimulus interval (ISI). At ISIs of roughly 1-5 ms the test response is suppressed, which is termed short-interval intracortical inhibition (SICI; Kujirai et al., 1993); at ISIs of roughly 10-25 ms it is facilitated, which is termed intracortical facilitation (ICF; Kujirai et al., 1993). Epidural recordings show that SICI suppresses the late I waves while the $I_1$ wave is essentially unaffected (Nakamura et al., 1997; Di Lazzaro et al., 1998), and, paradoxically, that ICF facilitates the MEP without any measurable change in the number or amplitude of descending volleys (Di Lazzaro et al., 2006). A conditioning pulse over one hemisphere also changes the excitability of the opposite hemisphere through callosal pathways (the corpus callosum, the main fiber tract connecting the two cerebral hemispheres), a phenomenon termed interhemispheric inhibition (Ferbert et al., 1992), and interhemispheric facilitation and inhibition have been mapped with double magnetic stimulation (Salerno, 1996).

During weak voluntary contraction, MEPs from hand muscles are often discretely polyphasic, with separable negative peaks (conventionally N1, N2, and so on, referenced to positive peaks P1, P2). Kobayashi, Hyodo, Kurokawa and Ueno (1998) exploited this waveform structure. With a large round conditioning coil centered on the vertex (the midline point at the top of the skull, so that conditioning engages the motor cortices of both hemispheres) at 80% of motor threshold (the minimum stimulus intensity, determined separately for each coil, that evokes a just-detectable MEP in the target muscle during its slight voluntary contraction), and a figure-eight test coil over the right hand motor area whose coil current at the junction flowed medio-laterally (corresponding to a latero-medially directed induced current in the brain) at 130-140% of threshold, they evoked discretely polyphasic MEPs in the minimally contracted left first dorsal interosseous muscle (a hand muscle) of ten subjects, with conditioning stimuli followed by test stimuli at intervals of 1-10 and 15 ms. At interstimulus intervals below 5 ms, the second negative phase (N2) was suppressed compared with the unconditioned responses, whereas the first negative phase (N1) was not suppressed. They concluded that the first phase reflects direct corticospinal (D-wave) volleys, which are resistant to cortico-cortical inhibition. The study could not by itself settle the generator composition of the first component: with latero-medially oriented stimulation both D and $I_1$ volleys are recruited at threshold (Werhahn et al., 1994; Nakamura et al., 1996).

Problem Statement

The problem is to complete the physiological attribution of the first negative component (N1) of discretely polyphasic human MEPs in the paradigm introduced by Kobayashi et al. (1998): subthreshold conditioning via a round coil centered on the vertex at 80% of motor threshold, followed by suprathreshold test stimulation via a figure-eight coil over the contralateral hand motor area inducing a latero-medially directed current in the brain at 130-140% of threshold, with the target first dorsal interosseous muscle under minimal voluntary contraction and conditioning-test intervals of 1-10 and 15 ms. Specifically, the goal is to determine, for the fixed paradigm above, the relative contributions of the direct (D) volley and the earliest indirect ($I_1$) volley to the first negative peak (N1) of the polyphasic MEP; and, as a generalization beyond that paradigm (which holds test intensity and induced-current direction fixed), the stimulus conditions (test intensity and induced-current direction) under which each dominates the N1 waveform; replacing the source's interpretive conclusion that the first phase reflects direct corticospinal volleys with an evidence-based attribution of the first surface component that is justified from the cited physiology. "Each dominates the N1 waveform" is to be read as the larger share of the N1 deflection, not merely as the earlier volley in the descending train, whose composition the Background already states.

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