Oxygen therapy attenuates neuroinflammation after spinal cord injury.

Acute hyperbaric O2 (HBO) therapy after spinal cord injury (SCI) can reduce inflammation and increase neuronal survival. To our knowledge, it is unknown if these benefits of HBO require hyperbaric vs. normobaric hyperoxia. We used a C4 lateralized contusion SCI in adult male and female rats to test the hypothesis that the combination of hyperbaria and 100% O2 (i.e. HBO) more effectively mitigates spinal inflammation and neuronal loss, and enhances respiratory recovery, as compared to normobaric 100% O2. Experimental groups included spinal intact, SCI no O2 therapy, and SCI + 100% O2 delivered at normobaric pressure (1 atmosphere, ATA), or at 2- or 3 ATA. O2 treatments lasted 1-h, commenced within 2-h of SCI, and were repeated for 10 days. The spinal inflammatory response was assessed with transcriptomics (RNAseq) and immunohistochemistry. Gene co-expression network analysis showed that the strong inflammatory response to SCI was dramatically diminished by both hyper- and normobaric O2 therapy. Similarly, both HBO and normobaric O2 treatments reduced the prevalence of immunohistological markers for astrocytes (glial fibrillary acidic protein) and microglia (ionized calcium binding adaptor molecule) in the injured spinal cord. However, HBO treatment also had unique impacts not detected in the normobaric group including upregulation of an anti-inflammatory cytokine (interleukin-4) in the plasma, and larger inspiratory tidal volumes at 10-days (whole body-plethysmography measurements). We conclude that normobaric O2 treatment can reduce the spinal inflammatory response after SCI, but pressured O2 (i.e., HBO) provides further benefit.

Hyperbaric Oxygen Therapy after Mid-Cervical Spinal Contusion Injury.

Hyperbaric oxygen (HBO) therapy is frequently used to treat peripheral wounds or decompression sickness. Evidence suggests that HBO therapy can provide neuroprotection and has an anti-inflammatory impact after neurological injury, including spinal cord injury (SCI). Our primary purpose was to conduct a genome-wide screening of mRNA expression changes in the injured spinal cord after HBO therapy. An mRNA gene array was used to evaluate samples taken from the contused region of the spinal cord following a lateralized mid-cervical contusion injury in adult female rats. HBO therapy consisted of daily, 1-h sessions (3.0 ATA, 100% O2) initiated on the day of SCI and continued for 10 days. Gene set enrichment analyses indicated that HBO upregulated genes in pathways associated with electron transport, mitochondrial function, and oxidative phosphorylation, and downregulated genes in pathways associated with inflammation (including cytokines and nuclear factor kappa B [NF-κB]) and apoptotic signaling. In a separate cohort, spinal cord histology was performed to verify whether the HBO treatment impacted neuronal cell counts or inflammatory markers. Compared with untreated rats, there were increased NeuN positive cells in the spinal cord of HBO-treated rats (p = 0.004). We conclude that HBO therapy, initiated shortly after SCI and continued for 10 days, can alter the molecular signature of the lesioned spinal cord in a manner consistent with a neuroprotective impact.

Restoration of breathing after opioid overdose and spinal cord injury using temporal interference stimulation.

Respiratory insufficiency is a leading cause of death due to drug overdose or neuromuscular disease. We hypothesized that a stimulation paradigm using temporal interference (TI) could restore breathing in such conditions. Following opioid overdose in rats, two high frequency (5000 Hz and 5001 Hz), low amplitude waveforms delivered via intramuscular wires in the neck immediately activated the diaphragm and restored ventilation in phase with waveform offset (1 Hz or 60 breaths/min). Following cervical spinal cord injury (SCI), TI stimulation via dorsally placed epidural electrodes uni- or bilaterally activated the diaphragm depending on current and electrode position. In silico modeling indicated that an interferential signal in the ventral spinal cord predicted the evoked response (left versus right diaphragm) and current-ratio-based steering. We conclude that TI stimulation can activate spinal motor neurons after SCI and prevent fatal apnea during drug overdose by restoring ventilation with minimally invasive electrodes.