Stimulating Neural Pathways to Reduce Mechanical Ventilation-associated Neurocognitive Dysfunction.

To the Editor:

We read the article by Bassi and colleagues with great interest, which provided insightful evidence to reduce ventilation-associated brain injury (VABI) by applying temporary transvenous diaphragm neurostimulation (1). Their innovative neurostimulation approach was based on the idea that diaphragm contraction by preserving lung homogeneity during mechanical ventilation (MV) activates pulmonary stretch receptors and pulmonary afferent signals, leading to the alleviation of VABI. In a porcine model, they demonstrated that diaphragm neurostimulation, synchronized with ventilator-delivered breaths, has neuroprotective effects against VABI. They suggested that VABI is mediated through a neural pathway independent of lung injury and systemic inflammation. Their study provides valuable knowledge about VABI pathophysiology and an innovative therapeutic approach to overcome this problem.

Notwithstanding, physiological breathing compensation could not be fully achieved by phrenic nerve stimulation and triggering diaphragmatic movements alone during MV. Another essential element of physiological ventilation is nasal breathing—the effects of which on the brain during MV need to receive more attention. In this way, another primary function of diaphragm contraction is rhythmically to draw air into the lungs during inspiration, mainly through nasal cavities. In nasal breathing, the airflow activates mechanosensitive olfactory sensory neurons (OSNs) of the nasal epithelium and entrains oscillatory neural activity in the olfactory bulb (OB) (2). Besides processing odorant information, OSNs also respond to mechanical stimulation of airflow passage (2). Rhythmic OB activation by nasal breathing generates respiration-coupled oscillations propagating throughout the cortical and subcortical regions implicated in cognitive functions such as learning and memory (3). Interestingly, nasal breathing diversion to the oral root as well as OB inhibition or OSN ablation abolishes these respiration-entrained brain rhythms, which are subsequently associated with cognitive impairments (3–5). Notably, intubation and tracheotomy obliterate hippocampal respiration-coupled rhythm, which can be restored by rhythmic air-puff delivery into nasal cavities (6). Furthermore, eliminated OB activity (e.g., by interrupting sensory inputs to OSNs or OB deafferentation) can impair the OB-related neurogenesis and induce oxidative and inflammatory conditions, particularly in the hippocampus (7, 8).

Altogether, we presumed that eliminated OB activity and respiratory-coupled oscillations might provoke cognitive dysfunctions observed in patients under prolonged MV. We recently applied rhythmic air-puffs into nasal cavities, synchronized with ventilator-delivered breaths, in endotracheal intubated animals under MV (9). This neurostimulation approach could restore respiration-coupled oscillations in the brain and, importantly, prevent memory impairments that are typically seen after recovery from MV (9). We proposed the rhythmic nasal air-puffs as a noninvasive stimulation approach to reduce or prevent MV-associated adverse neurological events.

Therefore, it seems that stimulating neural pathways of physiological breathing, such as diaphragm and OSNs, synchronized with ventilator-delivered breaths can improve neural homeostasis and notably reduce MV-associated neurocognitive dysfunction. However, manipulating other possible neural pathways needs to be addressed to mimic physiological breathing during MV. These preclinical experiments provide novel information for translational approaches in critical settings. Although further studies are required in human subjects, these findings can open a window for our knowledge to reduce neurological dysfunctions in critical patients, particularly those under long-term MV.