Weakness is a major complication of critical illness that complicates recovery both during the first few weeks following illness as well as the quality of life 1 to 2 years after the illness. During the acute recovery period, weakness often prevents patient weaning from the ventilator, prolonging intensive care unit stays, and leading to greatly increased cost, complication rates and mortality. In a recently published paper we found, in both patients and rats, that difficulty in recruitment of motoneurons to fire is an important contributo to weakness triggered by critical illness. Preliminary data presented in this grant suggests difficulty recruiting motoneurons to fire may persist after recovery from critical illness and thus may contribute to long term weakness. Reduced motoneuron excitability as a mechanism of weakness has never been proposed and thus represents a novel area of research into weakness triggered by critical illness. In vivo intracellular recording from motoneurons in adult rats will be used in combination with modeling of motoneuron excitability to identify potential mechanisms underlying the reduction of excitability. Potential mechanisms will further be explored using dynamic clamp of motoneurons in vivo to correct the defect(s) in ion channels that underlie the reduction in excitability. Preliminary data suggests we have identified a class o drugs that can correct the defect in excitability. It is our hope that identification of drugs that improve motoneuron excitability will rapidly translate to new therapy that improves the rate of rehabilitation and the quality of life for patients after hospital discharge.

Public Health Relevance

Our work will be the first to determine the mechanism underlying a previously unsuspected contributor to weakness in critically ill patients: reduced motoneuron excitability. If successful we will develop novel therapy to promote recovery of strength following critical illness. By promoting recovery we hope to greatly reduce complication rates to improve outcome and quality of life after hospital discharge.

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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Nuckolls, Glen H
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Wright State University
Other Basic Sciences
Schools of Medicine
United States
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Wang, Xueyong; Rich, Mark M (2018) Homeostatic synaptic plasticity at the neuromuscular junction in myasthenia gravis. Ann N Y Acad Sci 1412:170-177
Hawash, Ahmed A; Voss, Andrew A; Rich, Mark M (2017) Inhibiting persistent inward sodium currents prevents myotonia. Ann Neurol 82:385-395
Rudnick, Noam D; Griffey, Christopher J; Guarnieri, Paolo et al. (2017) Distinct roles for motor neuron autophagy early and late in the SOD1G93A mouse model of ALS. Proc Natl Acad Sci U S A 114:E8294-E8303
Nardelli, Paul; Powers, Randall; Cope, Tim C et al. (2017) Increasing motor neuron excitability to treat weakness in sepsis. Ann Neurol 82:961-971
Nardelli, Paul; Vincent, Jacob A; Powers, Randall et al. (2016) Reduced motor neuron excitability is an important contributor to weakness in a rat model of sepsis. Exp Neurol 282:1-8
Barnes, Benjamin T; Confides, Amy L; Rich, Mark M et al. (2015) Distinct muscle apoptotic pathways are activated in muscles with different fiber types in a rat model of critical illness myopathy. J Muscle Res Cell Motil 36:243-53
Friedrich, O; Reid, M B; Van den Berghe, G et al. (2015) The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill. Physiol Rev 95:1025-109
Novak, Kevin R; Norman, Jennifer; Mitchell, Jacob R et al. (2015) Sodium channel slow inactivation as a therapeutic target for myotonia congenita. Ann Neurol 77:320-32