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Chronic, closed‐loop, cervical epidural stimulation elicits diaphragm motor plasticity after spinal cord injury
Author(s) -
Malone Ian,
Kelly Mia,
Nosacka Rachel,
Nash Marissa,
Mitchell Gordon,
Otto Kevin,
Dale Erica
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.04848
Subject(s) - medicine , spinal cord injury , stimulation , spinal cord , anesthesia , stimulus (psychology) , neuroplasticity , diaphragm (acoustics) , respiratory system , cardiology , psychology , physics , psychiatry , acoustics , loudspeaker , psychotherapist
Cervical spinal cord injury (cSCI) accounts for over half of all traumatic SCI (NSCISC, 2020). Unfortunately, respiratory insufficiency due to cSCI is the leading cause of mortality and morbidity after SCI. Electrical epidural stimulation (EES) can partially restore volitional locomotor function after SCI in humans while high‐frequency EES activates respiratory muscles (DiMarco and Kowalski, 2009) and may lead to at least short‐term plasticity (Gonzalez‐Rothi et al., 2017). We've shown that our model of cervical closed‐loop epidural stimulation (CL‐ES) in awake, freely‐behaving rats with C 2 hemisection (C 2 HS) elicits short term plasticity in diaphragm motor output (Malone et al., FASEB J 2020). Here we show that this expression of plasticity may be bimodal in that there are “responders” and “non‐responders” just as that seen in people with SCI (Tan et al., 2020; Lamy and Boakye, 2013). Rats were implanted with CL‐ES electrodes at C 4 and bilateral diaphragm EMG electrodes to record respiratory muscle activity in awake rats. Four groups were studied: C 2 HS + CL‐ES (n=8); C 2 HS + no stim (n=6); Sham + CL‐ES (n=6); Sham + no stim (n=6). As expected, increasing current (range: 50–750 μA; inspiratory‐triggered) increased the magnitude of evoked potentials. Further, four days of chronic (12‐20 hours/day) CL‐ES elicited facilitation of ipsilesional evoked responses in 6 of 8 animals with C 2 HS. Data were calculated as maximum percent change from baseline (‐/+) of the stimulus triggered averages at the current with the largest dispersion during sweeps. CL‐ES in C 2 HS rats elicited facilitation in max percent change in stimulus triggered average: 1) peak amplitude (pA; 879% ± 455%) vs. Sham + CL‐ES and Sham + no stim (109% ± 76%; p=0.04 and 92% ± 68% p=0.05, respectively) and 2) area under the curve (AUC; 555% ± 142%) vs. groups without stimulation (C 2 HS + no stim: 99% ± 52%, p=0.05; Sham + no stim: 73% ± 60%, p=0.038). The lack of robust facilitation in Sham + CL‐ES rats suggests the possibility of an intact inhibitory modulatory network in healthy rats. These results are preliminary and highly variable, thus we can only speculate about mechanisms giving rise to this form of respiratory neuroplasticity. Ongoing RTqPCR experiments utilizing correlative measures of spinal neurotrophic factor expression (e.g. brain derived neurotrophic factor) and siRNA knock‐down of relevant receptors on phrenic motor neurons (Dale et al., 2017) may give more insight. We hypothesize that facilitation of these evoked potentials may depend on activation of neurotrophic factor receptors within the phrenic motor network. This work demonstrates for the first time that CL‐ES can elicit respiratory motor plasticity after cSCI, demonstrating potential for a neuroceutical therapy to address breathing impairment in individuals with spinal cord injury. Data presented as mean ± SEM.