Systematic investigation of changes in oxidized cerebral cytochrome c oxidase concentration during frontal lobe activation in healthy adults

Using transcranial near-infrared spectroscopy (NIRS) to measure changes in the redox state of cerebral cytochrome c oxidase (Δ[oxCCO]) during functional activation in healthy adults is hampered by instrumentation and algorithm issues. This study reports the Δ[oxCCO] response measured in such a setting and investigates possible confounders of this measurement. Continuous frontal lobe NIRS measurements were collected from 11 healthy volunteers during a 6-minute anagram-solving task, using a hybrid optical spectrometer (pHOS) that combines multi-distance frequency and broadband components. Only data sets showing a hemodynamic response consistent with functional activation were interrogated for a Δ[oxCCO] response. Simultaneous systemic monitoring data were also available. Possible influences on the Δ[oxCCO] response were systematically investigated and there was no effect of: 1) wavelength range chosen for fitting the measured attenuation spectra; 2) constant or measured, with the pHOS in real-time, differential pathlength factor; 3) systemic hemodynamic changes during functional activation; 4) changes in optical scattering during functional activation. The Δ[oxCCO] response measured in the presence of functional activation was heterogeneous, with the majority of subjects showing significant increase in oxidation, but others having a decrease. We conclude that the heterogeneity in the Δ[oxCCO] response is physiological and not induced by confounding factors in the measurements. © 2012 Optical Society of America

Investigation of in vivo measurement of cerebral cytochrome-c-oxidase redox changes using near-infrared spectroscopy in patients with orthostatic hypotension

We have previously used a continuous four wavelength near infrared spectrometer to measure changes in the cerebral concentrations of oxy- (Δ[HbO2] and deoxy- haemoglobin (Δ[HHb]) during head-up tilt in patients with primary autonomic failure. The measured changes in light attenuation also allow calculation of changes in the concentration of oxidised cytochrome c oxidase (Δ[oxCCO]), and this paper analyses the Δ[oxCCO] during the severe episodes of orthostatic hypotension produced by this experimental protocol. We studied 12 patients during a passive change in position from supine to a 60º head-up tilt. The challenge caused a reduction in mean blood pressure of 59.93 (±26.12) mmHg (Mean (±SD), p<0.0001), which was associated with a reduction in the total concentration of haemoglobin (Δ[HbT]= Δ[HbO2]+Δ[HHb]) of 5.02 (±3.81) μM (p<0.0001) and a reduction in the haemoglobin difference concentration (Δ[Hbdiff]= Δ[HbO2]-Δ[HHb]) of 14.4 (±6.73) μM (p<0.0001). We observed a wide range of responses in Δ[oxCCO]. 6 patients demonstrated a drop in Δ[oxCCO] (0.17 ±0.15μM ); 4 patients demonstrated no change (0.01 ±0.12 μM ) and 2 patients showed an increase in Δ[oxCCO] (0.21 ±0.01 μM ). Investigation of the association between the changes in concentrations of haemoglobin species and the Δ[oxCCO] for each patient show a range of relationships. This suggests that a simple mechanism for crosstalk, which might produce artefactual changes in [oxCCO], is not present between the haemoglobin and the oxCCO NIRS signals. Further investigation is required to determine the clinical significance of the changes in [oxCCO]

From Jöbsis to the present day: a review of clinical near-infrared spectroscopy measurements of cerebral cytochrome-c-oxidase

Near-infrared spectroscopy (NIRS) measurements of cytochrome-c-oxidase (CCO) have the potential to yield crucial information about cerebral metabolism at the patient bedside. Developments in instrumentation and the analytical methods used to resolve changes in CCO have led to many clinical applications of the measurement since its first demonstration in 1977 by Jöbsis. There is a substantial literature of work on measures of CCO in animal and in vitro studies; however, this review focuses on translational studies. Almost 40 years from the advent of the first measurement of CCO using NIRS, this signal continues to hold significant interest in our understanding of the human brain in health and disease. We discuss methodologies for obtaining NIRS measurements of CCO in the clinic and review studies in neonates and adults

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

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

A Model of Brain Circulation and Metabolism: NIRS Signal Changes during Physiological Challenges

We construct a model of brain circulation and energy metabolism. The model is designed to explain experimental data and predict the response of the circulation and metabolism to a variety of stimuli, in particular, changes in arterial blood pressure, CO2 levels, O2 levels, and functional activation. Significant model outputs are predictions about blood flow, metabolic rate, and quantities measurable noninvasively using near-infrared spectroscopy (NIRS), including cerebral blood volume and oxygenation and the redox state of the CuA centre in cytochrome c oxidase. These quantities are now frequently measured in clinical settings; however the relationship between the measurements and the underlying physiological events is in general complex. We anticipate that the model will play an important role in helping to understand the NIRS signals, in particular, the cytochrome signal, which has been hard to interpret. A range of model simulations are presented, and model outputs are compared to published data obtained from both in vivo and in vitro settings. The comparisons are encouraging, showing that the model is able to reproduce observed behaviour in response to various stimuli

Hyperspectral imaging solutions for brain tissue metabolic and hemodynamic monitoring: past, current and future developments

Hyperspectral imaging (HSI) technologies have been used extensively in medical research, targeting various biological phenomena and multiple tissue types. Their high spectral resolution over a wide range of wavelengths enables acquisition of spatial information corresponding to different light-interacting biological compounds. This review focuses on the application of HSI to monitor brain tissue metabolism and hemodynamics in life sciences. Different approaches involving HSI have been investigated to assess and quantify cerebral activity, mainly focusing on: (1) mapping tissue oxygen delivery through measurement of changes in oxygenated (HbO₂) and deoxygenated (HHb) hemoglobin; and (2) the assessment of the cerebral metabolic rate of oxygen (CMRO₂) to estimate oxygen consumption by brain tissue. Finally, we introduce future perspectives of HSI of brain metabolism, including its potential use for imaging optical signals from molecules directly involved in cellular energy production. HSI solutions can provide remarkable insight in understanding cerebral tissue metabolism and oxygenation, aiding investigation on brain tissue physiological processes

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

We analyze broadband near-infrared spectroscopic measurements obtained from newborn piglets subjected to hypoxia-ischemia and we aim to identify optimal wavelength combinations for monitoring cerebral tissue chromophores. We implement an optimization routine based on the genetic algorithm to perform a heuristic search for discrete wavelength combinations that can provide accurate concentration information when benchmarked against the gold standard of 121 wavelengths. The results indicate that it is possible to significantly reduce the number of measurement wavelengths used in conjunction with spectroscopic algorithms and still achieve a high performance in estimating changes in concentrations of oxyhemoglobin, deoxyhemoglobin, and oxidized cytochrome c oxidase. While the use of a 3-wavelength combination leads to mean recovery errors of up to 10%, these errors drop to less than 4% with 4 or 5 wavelengths and to even less than 2% with 8 wavelengths.Publisher's Versio

Development of optical instrumentation and methods to monitor brain oxygen metabolism: application to neonatal brain injury

Hypoxic ischemic encephalopathy (HIE) is a relatively common and potentially devastating form of perinatal brain injury, associated with neurodevelopmental problems and mortality. HIE is an evolving process. There is a need for real-time, in-vivo measurements of brain oxygenation and metabolism for clinical assessment in the first days of life, to detect those at risk of further brain injury who may benefit from redirection of care. This thesis describes the development of a broadband near-infrared spectroscopy (NIRS) system to monitor changes in metabolism and haemodynamics in HIE infants at the cotside. This system uses multiple wavelengths (λ=136,770-905nm) to monitor changes in concentration of the oxidation state of cytochrome-c-oxidase (oxCCO) as well as haemoglobin oxygenation. Changes in oxCCO are indicative of CCO redox state changes within mitochondria and therefore represent oxygen utilization. The 2-channel system incorporates a broadband source, optical fibres, spectrograph and CCD. This set up is flexible and robustly monitors changes in haemoglobin and oxCCO. The system was developed specifically for the neonatal intensive care unit (NICU) and has been demonstrated on 38 brain-injured newborn infants (28 with HIE). Data was continuously collected over the frontal lobe simultaneously with systemic data for multimodal analysis. This allows the study of cerebral changes in response to global pathophysiological events. HIE was assessed by magnetic resonance spectroscopy measurement of lactate to NAA ratio (Lac/NAA), the gold standard for neurodevelopmental outcome. Initially the analysis focussed on spontaneous hypoxias. The relationship between haemoglobin oxygenation and oxCCO during hypoxic events was significantly associated with Lac/NAA (n=22,r=0.51,p=0.02). Further investigation of the dynamics of the cerebral changes during hypoxias found oxCCO differences with injury severity (not observed in haemoglobins). Finally, the relationship between cerebral signals and systemic physiology was investigated with a multivariate statistical technique. A strong relationship between oxCCO and systemic changes indicated severe brain injury (n=12,p=0.04)