Cytochrome c oxidase response to changes in cerebral oxygen delivery in the adult brain shows higher brain-specificity than haemoglobin

Abstract

The redox state of cerebral mitochondrial cytochrome c oxidase monitored with near-infrared spectroscopy (Δ[oxCCO]) is a signal with strong potential as a non-invasive, bedside biomarker of cerebral metabolic status. We hypothesised that the higher mitochondrial density of brain compared to skin and skull would lead to evidence of brain-specificity of the Δ[oxCCO] signal when measured with a multi-distance near-infrared spectroscopy (NIRS) system. Measurements of Δ[oxCCO] as well as of concentration changes in oxygenated (Δ[HbO2]) and deoxygenated haemoglobin (Δ[HHb]) were taken at multiple source-detector distances during systemic hypoxia and hypocapnia (decrease in cerebral oxygen delivery), and hyperoxia and hypercapnia (increase in cerebral oxygen delivery) from 15 adult healthy volunteers. Increasing source-detector spacing is associated with increasing light penetration depth and thus higher sensitivity to cerebral changes. An increase in Δ[oxCCO] was observed during the challenges that increased cerebral oxygen delivery and the opposite was observed when cerebral oxygen delivery decreased. A consistent pattern of statistically significant increasing amplitude of the Δ[oxCCO] response with increasing light penetration depth was observed in all four challenges, a behaviour that was distinctly different from that of the haemoglobin chromophores, which did not show this statistically significant depth gradient. This depth-dependence of the Δ[oxCCO] signal corroborates the notion of higher concentrations of CCO being present in cerebral tissue compared to extracranial components and highlights the value of NIRS-derived Δ[oxCCO] as a brain-specific signal of cerebral metabolism, superior in this aspect to haemoglobin.

Optimal wavelength combinations for near-infrared spectroscopic monitoring of changes in brain tissue hemoglobin and cytochrome c oxidase concentrations

“…It has been claimed that chromophore cross-talk, insufficient separability due to physical noise, and any concurrent changes in scattering can all give rise to spurious ∆[oxCCO] traces [12,22]. Yet, recent studies disprove these claims and establish ∆[oxCCO] as a NIRS-derived indicator of the redox state of mitochondrial cytochrome c oxidase and hence as a brain-specific optical biomarker of cerebral metabolic status [5,[8][9][10][11]14,15,32,33]. Also note that our study employs a restrictive wavelength range of 780-900 nm; exclusion of shorter wavelengths helps to enhance the contribution of cytochrome c oxidase to attenuation signals [14].…”

“…Numerous experimental and clinical studies have been carried out to delineate the biological basis of optical signals obtained from healthy and injured brain. These studies present sound evidence that NIRS-derived changes in chromophore concentrations can act as markers of cerebral physiology and pathology; the results offer significant insights into the feasibility of NIRS for observation of functional activation [5,6], detection of autoregulation or metabolic failure during routine surgery or after brain injury [7,8], and assessment of impending neurological damage due to hypoxia-ischemia (HI) in adults or neonates [9][10][11].…”

“…Since the total concentration of cytochrome c oxidase remains constant over the time course of our experiments [5,10,15], this law can be formulated as…”

Event-related changes of the prefrontal cortex oxygen delivery and metabolism during driving measured by hyperspectral fNIRS

“…The total concentration of CCO in the short term is almost constant and it interconverts between reduced and oxidized states. The concentration changes of oxidized CCO (Δ[ox-CCO]) that can be monitored by NIRS represent changes in the CCO redox state and reflect the balance between cerebral oxygen delivery and utilization [4,5]. The brain cells have the highest mitochondrial density among all other body cells thus the concentration of CCO is significantly higher and easier to measure within brain tissue.…”

Advanced Perfusion Techniques - Flow versus Pressure

“…[8] In a study that was published in 2013 which points the influence of the variations in blood flow and pressure on systemic and cerebral oxygen saturation during CPB found that the maintenance of flow and thus DO2 was more important than the maintenance of mean arterial pressure (MAP). [9] In the same study, a phenylephrine-induced increase in MAP led to the decrease of cerebral oxygen saturation (Sco2) and thus to the DO2 to the brain.…”