Origins of abnormal excitability in biceps brachii motoneurons of spastic-paretic stroke survivors

Abstract

Stroke survivors often exhibit abnormal motoneuron excitability, manifested clinically as spasticity with exaggerated stretch reflexes in resting muscles. We examined whether this abnormal excitability is a result of increased activation of intrinsic voltage-dependent persistent inward currents (PICs) or whether it is a result of enhanced synaptic inputs to the motoneuron. This distinction was made by recording firing rate profiles of pairs of motor units during isometric contractions of elbow flexor muscles. To estimate PIC amplitude, the discharge of the lower-threshold (reporter) motor unit of the pair was used to estimate the synaptic input to the higher-threshold (test) motor unit. The estimated synaptic input required to recruit the test unit was compared with the synaptic input when the test unit was derecruited (DeltaF) and this served as an estimate of the intrinsic (PIC) contribution to motoneuron firing. We found that PIC estimates were not larger in spastic-paretic motoneurons (DeltaF = 4.0 +/- 1.6 pps) compared with contralateral (4.6 +/- 1.4 pps) and age-matched healthy control motoneurons (3.8 +/- 1.7, all P > 0.1). Instead, following the voluntary contractions, the majority of lower-threshold motor units in spastic-paretic muscles (83%) exhibited spontaneous discharge, compared with 14% of contralateral and 0% of control motor units. Furthermore, there was strong co-modulation of simultaneously active units in spastic muscle. The presence of ongoing, correlated unit activity at "rest," coupled with firing behavior at recruitment unique to lower-threshold motor units in spastic muscles, suggested that firing changes are likely a result of a low-level depolarizing synaptic drive to the resting motoneuron pool.

Fig. 1.

Lowering of estimated synaptic drive at derecruitment compared with recruitment (delta firing rate; ΔF) during volitional contractions was similar in the spastic-paretic (A) and contralateral (B) limb of a stroke survivor and matched limb of a healthy control subject (C). A: 2 biceps brachii motor units recorded during a triangular isometric contraction with the elbow flexor muscles for the spastic-paretic limb of a stroke survivor. Vertical dashed lines indicate times of recruitment and derecruitment of the test unit; horizontal lines indicate the corresponding reporter unit firing rates at these times. Bottom panels denote representative trains of action potentials (APs) for the reporter and test units with corresponding overlayed waveforms; middle panels denote the instantaneous frequency of the reporter (bottom) and test (top) units; top panel denotes force of elbow flexor muscles during the voluntary ramp contractions. B and C: 2 biceps brachii motor units recorded from the contralateral limb of the stroke survivor (B) and from the limb of an age- and sex-matched healthy control subject (C) during the same protocol as that in A. Note the similar lowering of estimated synaptic drive at derecruitment compared with recruitment (ΔF) for the spastic-paretic (A; 3.8, pulses/s [pps]) and contralateral limb of the stroke survivor (B; 4.1 pps), and the limb of an age- and sex-matched control subject (C; 4.3 pps). Insets above figures: reporter and test unit firing profiles plotted against one another in 500-ms bins during the duration of the test unit firing for the ascending (red dots) and descending (blue dots) portion of the ramp contractions. The arrows and circles pointing to or surrounding the dots respectively indicate nonlinear startup frequencies that were not included in the calculation of the coefficient of determination (r²) from the linear regression fit through the rate–rate plots.

Fig. 2.

The reporter motor unit in spastic-paretic muscle continued to fire following the voluntary ramp contraction, whereas the test unit did not. Top: force of the elbow flexor muscles from a spastic-paretic stroke survivor during and following the voluntary ramp contraction. Middle: instantaneous frequency of the test motor unit during the voluntary ramp contraction. Bottom: instantaneous frequency of the reporter motor unit during and following the voluntary ramp contraction. Note the continuation of force and reporter motor unit firing for about 60 s following the ramp contraction despite verbal cuing from the investigator to relax the muscle and the subject's report that he was relaxed. The higher-threshold test motor unit ceased firing before the end of the voluntary ramp contraction.

Fig. 3.

Firing frequency profiles of 2 low-threshold motor units (below threshold of test unit) that continued to fire after a voluntary contraction in a spastic-paretic muscle. Overlayed waveforms denote the accuracy in discrimination of the motor units. Note that the firing rates of the 2 low-threshold units were modulated in a parallel manner. Inset shows the firing rate of the 2 motor units plotted against one another in 500-ms bins during the duration that they were firing in parallel. Note the high r² value from the linear regression fit through the rate–rate plot, confirming that the 2 motor units were modulated in parallel (P < 0.001, r² = 0.64).

Fig. 4.

Acceleration in firing rate of the reporter motor unit following recruitment was less in the lower-threshold (reporter; middle panel) than that in the higher-threshold (test; top panel) unit in the spastic-paretic muscle of a stroke survivor (A). The acceleration in firing rate was quantified as the increment in firing rate from onset to maximal discharge within the first 5 discharges. The bottom panel portrays the force of the elbow flexor muscles during the rising phase of the contraction for one spastic-paretic stroke survivor, whereas the middle and top panels show the reporter and test unit firing profiles, respectively, that accompany the rising force profiles. Note the 5th-order polynomial fit through the firing rate data does not rise at contraction onset in the lower-threshold (reporter) motor unit in the spastic-paretic muscle, whereas it does in the higher-threshold (test) motor unit in the spastic-paretic, muscle (A). B: the average acceleration in firing rate following recruitment was less in the lower-threshold (reporter) than that in the higher-threshold (test) motor unit in spastic-paretic muscle. Each circle represents the average value from repeated trials of voluntary ramp contractions for each spastic-paretic muscle of the 10 subjects; wider horizontal bars denote the average value for the group data for the reporter and test units; smaller horizontal bars denote 1SE above and below mean values. Acceleration in the reporter unit firing rate (2.2 ± 1.8 pps) was less than the acceleration in the test unit firing rate (4.5 ± 3.3 pps) for the spastic-paretic muscle. *P = 0.02 compared with the test unit.