Impaired Organization of Paired-Pulse TMS-Induced I-Waves After Human Spinal Cord Injury

Abstract

Paired-pulse transcranial magnetic stimulation (TMS) of the human motor cortex results in consecutive facilitatory motor-evoked potential (MEP) peaks in surface electromyography in intact humans. Here, we tested the effect of an incomplete cervical spinal cord injury (SCI) on early (first) and late (second and third) MEP peaks in a resting intrinsic finger muscle. We found that all peaks had decreased amplitude in SCI subjects compared with controls. The second and third peaks were delayed with the third peak also showing an increased duration. The delay of the third peak was smaller than that seen in controls at lower stimulation intensity, suggesting lesser influence of decreased corticospinal inputs. A mathematical model showed that after SCI the third peak aberrantly contributed to spinal motoneurone recruitment, regardless on the motor unit threshold tested. Temporal and spatial aspects of the late peaks correlated with MEP size and hand motor output. Thus, early and late TMS-induced MEP peaks undergo distinct modulation after SCI, with the third peak likely reflecting a decreased ability to summate descending volleys at the spinal level. We argue that the later corticospinal inputs on the spinal cord might be crucial for recruitment of motoneurones after human SCI.

Keywords: corticospinal volleys; primary motor cortex; spinal cord injury; transcranial magnetic stimulation; voluntary movement.

© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Experimental setup. (A) Schematics of the experimental setup showing the posture of the hand and the coil position during testing. (B) Group data in control subjects (n = 15) showing MEP peaks tested by paired-pulse TMS in the resting FDI muscle. The abscissa shows ISI between paired pulses (0.5 and 5.9 ms), and the ordinate shows the size of the conditioned MEP (expressed as a % of the Test MEP). Note that the conditioned MEP was largely facilitated at stimulus intervals corresponding to the I1, I2, and I3 waves from epidural recordings (Ziemann and Rothwell 2000). Error bars indicate SEs. *P < 0.05. (C). Curve fitting analysis using a 3 Gaussian model for each MEP peak to estimate individual properties. The vertical dotted lines indicate the onset latency of each MEP peak localized by the fitting model and the horizontal dashed line represents the size of the Test MEP (baseline). The horizontal arrow indicates the duration of MEP peaks.

Figure 2.

MEP peaks. (A) MEPs tested in the resting FDI muscle in a control (upper panel) and SCI subject (lower panel) at the peak amplitude interval for the first (left trace: Control, 1.3 ms; SCI, 1.3 ms), second (middle trace: Control, 2.7 ms; SCI, 3.1 ms), and third (right trace: Control, 4.3 ms; SCI, 5.1 ms) MEP peaks. Traces show the average of 20 test (black) and conditioned (gray) MEPs. Arrows indicate the test (S1) and conditioning (S2) stimulus. (B) Group data in controls (n = 15, circles) and subjects with SCI (n = 16, triangles). The abscissa shows the ISIs tested (0.5–5.9 ms, in 0.2-ms steps). The ordinate shows the size of the conditioned MEP (expressed as a % of the Test MEP, horizontal dashed line). Note that the amplitude of all peaks was decreased in subjects with SCI compared with controls. Also, note that the onset of the second and third MEP peaks was delayed in SCI subjects compared with controls and that the third MEP peak showed increased duration after SCI. Error bars indicate SEs. Filled symbol denotes statistical significance compared with baseline (P < 0.05). *P < 0.05 compared with SCI.

Figure 3.

MEP peaks onset latency and duration estimated by a Gaussian model. (A) Data estimated by a Gaussian model for each peak in controls (circles) and subjects with SCI (triangles). Each symbol shows the group mean of conditioned MEPs (expressed as a % of the Test MEP), with the solid line representing the respective curve fit. The vertical dotted lines indicate the onset localized by the fitting model. Note the delayed onset, as shown by the arrows, in SCI subjects compared with controls for the second and third MEP peak. The horizontal dashed line represents the size of the Test MEP. Group data (Controls, n = 14; SCI, n = 12) showing onset latency (B), duration (C), and discharge frequency (D) of each peak. The abscissa shows each MEP peak (1, 2, and 3). The ordinate shows the onset and duration (milliseconds), and discharge frequency (Hz) of each peak in SCI subjects (light bars) and controls (dark bars). Error bars indicate SEs. *P < 0.05.

Figure 4.

Differences across MEP peaks between groups. Left panel graphs show the difference in onset latency (A), discharge frequency (B), and duration (C) for the first (red), second (green), and third (blue) MEP peaks between SCI subjects and controls. Right panel graphs show individual data in each of the variables tested. The abscissa shows each MEP peak (1, 2, and 3). The ordinate shows the onset and duration (milliseconds), and discharge frequency (Hz) of each peak. Note that overall subjects with SCI showed more pronounced changes in duration, frequency discharge, and onset latency in the third compared with the second and first MEP peaks. Error bars indicate SEs. *P < 0.05.

Figure 5.

Proportion of spinal motoneurones recruited by MEP peaks. Graphs on the top row show the proportion of the spinal motoneurone pool recruited by the first (red), second (green), third (blue), and all MEP peaks together (black) as a function of the mean motor unit threshold in controls (A, n = 14) and SCI subjects (C, n = 12), and the difference between groups (E). Graphs on the bottom row show the quantified proportion of the spinal motoneurone pool recruited from the same subjects (Controls [B], SCI [D], and the difference between groups [F]). Note that the model revealed a pronounced contribution of the third peak to the recruitment of spinal motoneurones in subjects with SCI, regardless of the motor unit threshold tested. Error bars indicate SEs. *P < 0.05.

Figure 6.

Correlations in individuals with SCI. Correlation analysis between the maximum amplitude (upper left graph) and onset latency (upper right graph) of the second MEP peak with the coefficient of variation (A) and MEP maximum amplitude (B, see methods). Also, correlation analysis between the third MEP maximum amplitude (lower left graph) and duration (lower right graph) with index finger reaction time (C). In graphs showing amplitude, the abscissa shows the size of the conditioned MEP (expressed as a % of the Test MEP) and the ordinates show the coefficient of variation (CV) and reaction time (RT; milliseconds). In graphs showing onset latency and duration, the abscissa shows latency and duration values (milliseconds) and the ordinates show the CV and RT (milliseconds). Correlation analysis was Bonferroni corrected for multiple comparisons.