Common mechanisms of compensatory respiratory plasticity in spinal neurological disorders

Abstract

In many neurological disorders that disrupt spinal function and compromise breathing (e.g. ALS, cervical spinal injury, MS), patients often maintain ventilatory capacity well after the onset of severe CNS pathology. In progressive neurodegenerative diseases, patients ultimately reach a point where compensation is no longer possible, leading to catastrophic ventilatory failure. In this brief review, we consider evidence that common mechanisms of compensatory respiratory plasticity preserve breathing capacity in diverse clinical disorders, despite the onset of severe pathology (e.g. respiratory motor neuron denervation and/or death). We propose that a suite of mechanisms, operating at distinct sites in the respiratory control system, underlies compensatory respiratory plasticity, including: 1) increased (descending) central respiratory drive, 2) motor neuron plasticity, 3) plasticity at the neuromuscular junction or spared respiratory motor neurons, and 4) shifts in the balance from more to less severely compromised respiratory muscles. To establish this framework, we contrast three rodent models of neural dysfunction, each posing unique problems for the generation of adequate inspiratory motor output: 1) respiratory motor neuron death, 2) de- or dysmyelination of cervical spinal pathways, and 3) cervical spinal cord injury, a neuropathology with components of demyelination and motor neuron death. Through this contrast, we hope to understand the multilayered strategies used to “fight” for adequate breathing in the face of mounting pathology.

Does Trans-Spinal Direct Current Stimulation Alter Phrenic Motoneurons and Respiratory Neuromechanical Outputs in Humans? A Double-Blind, Sham-Controlled, Randomized, Crossover Study

“…Burst onset differences between PMN subtypes are likely to reflect intrinsic motoneuron properties (Berger, 1979): early-I PMNs are high-resistant small cells, whereas late-I PMNs are low-resistant large cells. Thus, during spontaneous ventilation, in which respiratory-related discharges of PMNs are primarily driven by bulbospinal inputs, early-I PMNs would be recruited before late-I PMNs according to the size principle of motoneuron recruitment established by Henneman et al (1965). Enhanced tidal volume after cathodal tsDCS is in line with previous reports demonstrating the potential of cathodal tsDCS stimulation to specifically facilitate spinal excitability (Alanis, 1953;Aguilar et al, 2011;Ahmed, 2011).…”

“…The amount of noise required to obtain this result is the "noise limit" (NL): NL Ͼ 0 indicates complexity within the signal; the higher the NL value, the more complex the signal (Wysocki et al, 2006). As ventilatory complexity is considered to originate in the brainstem respiratory pattern generators in animals and humans (Mangin et al, 2008;Hess et al, 2013), a putative effect of tsDCS at this level would result in NL variations. Tidal volume data were subsampled at 5 Hz and examined with a custom-written noise titration routine (MathWorks Inc) derived from the original routine of Poon and Barahona (2001) and modified for multiple dimension testing and repeated assessment (Roulin et al, 2011).…”

“…For these reasons, DC stimulation-induced aftereffects are thought to arise from synaptic changes via long-term potentiation-/ depression-like processes as well as nonsynaptic mechanisms involving changes in neural membrane function (Ardolino et al, 2005). In the light of our results and based on our current understanding of tsDCS mechanisms , it is conceivable that the mechanisms underlying enhanced DiMEPs after tsDCS could also involve changes in neurotransmission, which would be in line with the fact that (1) glutamate drives the pathway to PMNs during inspiration (McCrimmon et al, 1989;Chitravanshi and Sapru, 1996) and modulates synaptic strength in the short and long term via NMDA receptors (Rekling et al, 2000;McGuire et al, 2008); (2) GABA is intimately involved in respiratory motor control, as PMNs are inhibited by GABA A receptors during the expiratory phase of respiration (Fedorko et al, 1983;Merrill and Fedorko, 1984); and, (3) PMN NMDA receptors also contribute to excitatory neurotransmission (Chitravanshi and Sapru, 1996) and are implicated in many models of plasticity including phrenic LTF (Golder, 2009). This idea is also supported by recent arguments from animal studies: (1) both anodal and cathodal tsDCS increased glutamate analog D-2,3-3 H-aspartic acid release in vitro (Ahmed and Wieraszko, 2012), and (2) it has been proposed that cathodal tsDCS may act by directly inhibiting the spinal GABAergic system or by exerting overexcitation of postsynaptic neurons (Ahmed, 2013) likely through increased glutamate release (Ahmed and Wieraszko, 2012).…”

“…1). Short intracortical inhibition (sICI) was evoked using a paired-pulse technique with a subthreshold conditioning stimulus delivered 2 ms before a suprathreshold test stimulus of TMS, adjusted to evoke DiMEPs corresponding to 50% of DiMEP MAX (Kujirai et al, 1993). To avoid any ceiling effect, we first created an intensity curve for sICI by using intensities of 0.8, 0.7, 0.6, and 0.5 ϫ rMT (Stinear and Byblow, 2004).…”

Impact of unilateral denervation on transdiaphragmatic pressure

“…The coordination, and timing, of neural drive to the phrenic motoneuron pool is complex and integration may occur at various levels within the central nervous system. A compensatory increase in central respiratory drive or adaptations at the motor unit level all serve to preserve breathing capacity after perturbation (Butler, 2007; Johnson and Mitchell, 2013; Mantilla and Sieck, 2003, 2009; Miyata et al, 1995; Zhan et al, 1997). …”