The crossed phrenic phenomenon

Abstract

The cervical spine is the most common site of traumatic vertebral column injuries. Respiratory insufficiency constitutes a significant proportion of the morbidity burden and is the most common cause of mortality in these patients. In seeking to enhance our capacity to treat specifically the respiratory dysfunction following spinal cord injury, investigators have studied the "crossed phrenic phenomenon", wherein contraction of a hemidiaphragm paralyzed by a complete hemisection of the ipsilateral cervical spinal cord above the phrenic nucleus can be induced by respiratory stressors and recovers spontaneously over time. Strengthening of latent contralateral projections to the phrenic nucleus and sprouting of new descending axons have been proposed as mechanisms contributing to the observed recovery. We have recently demonstrated recovery of spontaneous crossed phrenic activity occurring over minutes to hours in C₁-hemisected unanesthetized decerebrate rats. The specific neurochemical and molecular pathways underlying crossed phrenic activity following injury require further clarification. A thorough understanding of these is necessary in order to develop targeted therapies for respiratory neurorehabilitation following spinal trauma. Animal studies provide preliminary evidence for the utility of neuropharmacological manipulation of serotonergic and adenosinergic pathways, nerve grafts, olfactory ensheathing cells, intraspinal microstimulation and a possible role for dorsal rhizotomy in recovering phrenic activity following spinal cord injury.

Keywords: C1; C2; SCI; cervical; diaphragm; hemidiaphragm; hemisection; neuroplasticity; paralysis; phrenic; recovery; respiratory; spinal cord injury.

Figure 1

Dynamic changes in phrenic motor output following hemisection. Following readministration of isoflurane, there is a suppression of phrenic nerve (PhN) amplitude. Hemisection performed under isoflurane silences the ipsilateral PhN. Over the ensuing recovery period, spontaneous crossed phrenic activity returns and there is a marked increase in central respiratory drive. Phrenic nerve amplitude is shown in millivolts (mV). Timescale bar is shown in lower right hander corner. Modified with permission from Figure 3 of Ghali and Marchenko, 2015. HSx: Hemisection; PhL: left phrenic nerve; PhR: right phrenic nerve.

Figure 2

Anesthesia potently suppresses crossed phrenic activity. Two hours following a hemisection, isoflurane is readministered to the animal. There is a potent suppression of phrenic bursting bilaterally, with discharge of the phrenic nerve (PhN) ipsilateral to HSx (PhL) nearly eliminated by anesthesia. Phrenic nerve amplitude is shown in millivolts (mV). Timescale bar is shown in lower right hander corner. Modified with permission from Figure 6 of Ghali and Marchenko, 2015. HSx: Hemisection; PhL: left phrenic nerve; PhR: right phrenic nerve.

Figure 3

Bulbophrenic network organization. Color traces under phrenic neurograms indicate phase of activity (i.e., inspiratory, expiratory [post-I and E2], or tonically discharging units) of indicated excitatory (+) and inhibitory (–) synapses. The retrotrapezoid nucleus is a central chemoreceptor region which stimulated by low pH and provides tonic excitation to bulbar respiratory nuclei. The parafacial respiratory group and Bötzinger and pre-Bötzinger complexes generate the respiratory rhythm and control the output of pre-motor neurons in the ventral and dorsal respiratory groups. Pre-motor neurons in rVRG, in turn, PhMNs during inspiration, monosynaptically (pathways 1, 5, 6, and 7) and polysynaptically (pathways 2, 3, and 4) via C_1–2 pre-phrenic interneurons (pathways 2 and 3) and possibly via local phrenic interneurons (pathway 4). Medullophrenic rVRG units project both ipsi- (pathways 1, 2, 4, and 7) and contralaterally (pathways 5 and 6; decussating at medullary or spinal levels) in lateral and ventromedial funiculi. A subset of medullophrenic rVRG units (crossed-and-recrossed) may decussate in the medulla and subsequently in the spinal cord to ultimately supply ipsilateral PhMNs (pathway 7). Inhibitory control of PhMNs is provided by descending medullophrenic BötC units (pathway 8) as well as local phrenic interneurons (pathway 9), which may relay the former as well as contribute to tonic inhibition of PhMNs independent of extrinsic drive. C_1–2 pre-phrenic interneurons are concentrated in the C₁ and rostral half of C₂ spinal segments; C₁ hemisection would thus spare the majority of C_1–2 pre-phrenic interneurons, while a C₂ hemisection would dissociate these units from caudally-related ipsilateral PhMNs. Not shown are putative contralateral monosynaptic bulbophrenic projections decussating between above the classic C₂ hemisection and below our C₁ hemisection site. Pathways: 1, ipsilateral monosynaptic medullophrenic projection; 2, ipsilateral polysynaptic medullophrenic projection via C_1–2 pre-PhINs; 3, collaterals to C_1–2 pre-PhINs from rVRG pre-MNs; 4, ipsilateral polysynaptic medullphrenic pathway via PhINs; 5, contralateral monosynaptic spinal-decussating medullophrenic pathway; 6, contralateral monosynaptic medullary-decussating medullophrenic projection; 7, crossed-and-recrossed monosynaptic medullary- and spinal-decussating medullophrenic projection; 8, descending ipsilateral medullophrenic inhibitory projection; 9, intraspinal inhibitory interneurons. Modified with permission from Figure 10 of Ghali and Marchenko, 2016a. BötC: Bötzinger complex; C_1–2 pre-PhINs: C_1–2 pre-phrenic interneurons; cVRG: caudal ventral respiratory group; HSx: hemisection; pFRG: parafacial respiratory group; PhL: left phrenic nerve; PhNucl: phrenic nucleus; PhR: right phrenic nerve; pre-BötC: pre-Bötzinger complex; RTN: retrotrapezoid nucleus; rVRG: rostral ventral respiratory group.

Figure 4

Recovery of late-inspiratory activity ipsilateral to hemisection. Following a C₁ HSx, late-inspiratory activity is often observed to recover initially. Phrenic nerve amplitude is shown in millivolts (mV). Timescale bar is shown in lower right hander corner. Modified with permission from of Ghali and Marchenko, 2015. HSx: Hemisection; PhL: left phrenic nerve; PhR: right phrenic nerve; sec: second.