Serotonin affects movement gain control in the spinal cord

Abstract

A fundamental challenge for the nervous system is to encode signals spanning many orders of magnitude with neurons of limited bandwidth. To meet this challenge, perceptual systems use gain control. However, whether the motor system uses an analogous mechanism is essentially unknown. Neuromodulators, such as serotonin, are prime candidates for gain control signals during force production. Serotonergic neurons project diffusely to motor pools, and, therefore, force production by one muscle should change the gain of others. Here we present behavioral and pharmaceutical evidence that serotonin modulates the input-output gain of motoneurons in humans. By selectively changing the efficacy of serotonin with drugs, we systematically modulated the amplitude of spinal reflexes. More importantly, force production in different limbs interacts systematically, as predicted by a spinal gain control mechanism. Psychophysics and pharmacology suggest that the motor system adopts gain control mechanisms, and serotonin is a primary driver for their implementation in force production.

Keywords: efficient control; gain control; neuromodulation; pharmacology; serotonin; spinal cord.

Copyright © 2014 the authors 0270-6474/14/3412690-11$15.00/0.

Figures

Figure 1.

Experimental setup in Experiment 1 and its data. a, Hardware setup for wrist tendon vibration. The reflexive response is a wrist extension measured by a force transducer fitted on the middle finger. b, Results from Experiment 1. The average reflexive forces measured at the middle finger are plotted as a function of time in which time 0 is defined as 2 s before the vibration starts. The data from the escitalopram and the placebo control condition are plotted separately. Error bars denote mean ± SEM across n = 9 subjects. The force rate during ramp-up and the force level during the last 2 s of vibration were significantly larger in the escitalopram condition than in the control condition (p < 0.01 and 0.05, respectively).

Figure 2.

Results of Experiment 2 with individuals with chronic spinal cord injury (SCI). a, Tap forces and elicited EMG responses for quadriceps tendon reflexes in a typical subject with and without escitalopram intake. Muscles include VL, VM, and RF. b, Similar exemplary trials in the same subject as in a with administration of cyproheptadine. c, The peak-to-peak amplitude of the reflex response for RF is plotted against tap force, and the reflex gain is calculated as the slope of the linear regression of the linear portion of the reflex curve (filled circles). Data are from the same typical subject before and after escitalopram intake. d, Similar plot as in c from the same subject before and after cyproheptadine intake. e, Across all subjects, escitalopram intake produces an increase in amplitude of the tendon reflex, producing a median 56% increase in the RF, 20% increase in the VL, and 36% increase in the VM, whereas after cyproheptadine intake, the amplitude of the tendon reflex is decreased by 61, 48, and 59% in the RF, VL, and VM, respectively. f, The gain of the reflex was likewise modified by serotonergic agents. After escitalopram intake, the gain of the response was increased by 196, 283, and 116%, and after cyproheptadine intake, the gain of the response was decreased by 75, 70, and 65% in the RF, VL, and VM, respectively.

Figure 3.

Model of gain control. a, A hypothetical scenario with context-dependent gain control. To encode both 10 and 1 N target forces with only 10 spikes (B), the best resolution for the 1 N force is 0.5 N, with a gain of 1 N/spike, which is the lowest gain that make the 10 N force production possible. Allowing a context-dependent gain of 0.1 N/spike (A), the resolution can be 0.05 N for the 1 N force while leaving the solution for the 10 N force unaffected. b, Muscle force plotted as a function of synaptic input and gain according to our model. Depending on the gain, a fixed variance in synaptic inputs translates to different levels of variance in muscle force (variances shown as Gaussian distributions).

Figure 4.

Results from Experiment 3 and Control Experiments A-C. a, Experimental setup for Experiments 3–5 and the control experiments. The lines on the screen represent the force instructions for the precision force (red) and the power force (blue). b, Force signals from a typical subject during the medium power force task. Subjects were instructed to produce a precision force with their left index finger (mean shown in blue) while first holding and afterward removing the power force. The green trace depicts a typical power force recording, dropping to half of its amplitude at time 0. Gray shading denotes SDs across trials. c–e, Variance (CV) of the precision force during each second before and after switching off the power force produced by the palm (c), the finger (d), and the leg (e). The moment when the power force drops to its half amplitude is defined as time 0. On the time axis, 0.5 s means that the variance is calculated over the first second after time 0 (between 0 and 1 s). Significant differences have been found between power force intensity levels within the −1, 1, and 2 s (not marked in graph) for all effectors. f, Cross-correlation of the power force and the precision force is plotted as a function of time lag for three force levels separately. g, Results from Control Experiment A, presented in the same format as in c. The dashed lines represent the force instructions for the precision force (red) and the power force (blue), which are now in the reverse order as a. Significant differences have been found between power force intensity levels within the −1, 1, and 2 s (not marked in graph). There is no difference found within −7 s. h, Results from Control Experiments B and C, presented in the same format as in c. Significant differences have been found between power force intensity levels within the −1, 1, and 2 s (not marked in graph). *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 5.

Results from Experiments 4 and 5. a, Variance in the precision force plotted as a function of time, with or without cyproheptadine intake. The data from different power force conditions are plotted separately. b, Variance reduction (within the 1st second) induced by cyproheptadine intake is plotted as a function of the power force. c, Variance in the precision force as a function of time, with or without paroxetine intake. d, Variance increase (within the 1st second) induced by paroxetine intake is plotted as a function of the power force. Error bars denote mean ± SEM across n = 8 subjects. *p < 0.05.