In spinal injury, the loss of descending input not only impairs motor commands but also damages descending control of spinal excitability. The goal of this proposal is to understand the cellular and synaptic mechanisms of the resulting distortions in the behavior of spinal circuits, which can generate aberrant muscle activation patterns and unintended movements like spasms. To achieve this goal, we use our chronic spinal cat preparation to develop a novel translational approach, in which we link cellular mechanisms to system behaviors. Our results potentially provide clear predictions for experiments to evaluate whether these same mechanisms occur in human spinal injured subjects. In the intact state, considerable data show that the effects of sensory inputs on motor outputs are focused, reciprocal and consistent. These effects are focused in the sense that sensory input from one joint primarily induces motor output at that same joint, reciprocal in that sensory inputs generate opposite actions on antagonists and consistent in that sensory inputs generate stable responses to repeated activations. The basic concept underlying this proposal is that the loss of descending control of spinal excitability induces precisely the opposite sensory processing state, one that is diffuse, co- active and inconsistent. Although likely overly simple this concept provides clearly testable hypotheses and moreover is supported by significant data, including our recent preliminary studies. The translational nature of our experimental design arises from two novel techniques that link intracellular measurements to the """"""""real world"""""""": 1) synaptic currents are measured during voltage clamp in response to precise movements of the entire hindlimb via a 6 degree of freedom robotic arm and 2) firing patterns from intracellular recordings are compared to firing patterns of populations of motor units recorded by a newly developed electrode array placed on muscle. Both the robotic and the array techniques are already in use in human subjects, thus providing the basis for our proposed predictions for human experiments.
Aim 1 seeks to identify the mechanisms of expanded receptive fields by identifying the types of sensory afferents involved.
Aim 2 examines the balance of excitation versus inhibition, primarily relying on intracellular recordings.
Aim 3 investigates wind-up, both n terms of quantifying its strength and in terms of determining its source in motoneurons versus interneurons. The proposed experiments will provide a new depth of understanding of the distortions in spinal processing of sensory input that emerge in spinal injury.
Each aim will provide information critical for developing specific therapeutic interventions, focusing on restoration of normal functional connections and minimization of wind- up.

Public Health Relevance

Loss of descending input in spinal injury not only affects motor commands but also the baseline excitability of spinal neurons. Our thesis is that a distorted state of processing of sensory input emerges, one that has diffuse effects, limited reciprocal inhibition and inconsistent responses to repeated inputs. Our aims focus on the cellular mechanisms of each of these distortions.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Jakeman, Lyn B
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Northwestern University at Chicago
Schools of Medicine
United States
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Thompson, Christopher K; Negro, Francesco; Johnson, Michael D et al. (2018) Robust and accurate decoding of motoneuron behaviour and prediction of the resulting force output. J Physiol 596:2643-2659
Johnson, Michael D; Frigon, Alain; Hurteau, Marie-France et al. (2017) Reflex wind-up in early chronic spinal injury: plasticity of motor outputs. J Neurophysiol 117:2065-2074
Johnson, Michael D; Thompson, Christopher K; Tysseling, Vicki M et al. (2017) The potential for understanding the synaptic organization of human motor commands via the firing patterns of motoneurons. J Neurophysiol 118:520-531