Evaluation of cerebral energy demand during graded hypercapnia

The cerebral metabolic rate of oxygen (CMRO2) is a physiological parameter closely linked to neural activation as well as to various disease states. Hypercapnic calibration is used to calibrate the BOLD-CBF-CBV relationship under the assumption of iso-metabolic blood flow increase during CO2 inhalation [1]. At the same time, simultaneous measurements of cerebral blood volume (CBV), hemoglobin oxygen saturation (SO2) and blood flow (CBF) necessary to calculate CMRO2 changes can be obtained non-invasively using near infrared optical spectroscopy with the caveat of reduced spatial resolution and depth sensitivity. In this study we used optical measurements obtained during graded hypercapnia (2.5-5-7.5% CO2, Fig. 2) to test the iso-metabolic assumption, and demonstrated an apparent increase in brain metabolism at higher inhaled CO2 levels. MATERIALS AND METHODS Four normal healthy Sprague-Dawley rats (~300g) were used to record hemodynamic parameters during stepped CO2 breathing gas changes. A combined optical/MR probe assembly (Figure 1) was fabricated to fit in the animal holder of a small-bore 9.4T MRI system (Bruker). In this submission, we only report the results from the optical measurements. The optical system consisted of a frequency domain spectrometer (FD-NIRS) that provided absolute optical properties at 7 near-infrared wavelengths between 670 and 830 nm at 12.5 Hz [2] and a diffuse correlation spectrometer (DCS) that provided the time-resolved temporal auto-correlation of the diffusely reflected light at ~1 Hz [3,4]. Hemoglobin concentration and oxygenation were calculated by fitting the optical absorption coefficient at the 7 wavelengths to the known oxy and deoxy-hemoglobin spectra and a correlation diffusion model was used to extract a blood flow index from the temporal auto-correlation functions. Both optical measures were obtained at 4 probing depths, determined by the distance between the source and detection optical fibers (5,8,11,14 mm, respectively). An average of all distances was used for subsequent CMRO2 computation. The relative CMRO2 during gas changes compared to baseline was calculated as rCMRO2=rCBF.rCBV.rOEF, where rCBF was measured directly with the DCS instrument, rCBV was obtained from rHbT (the ratio of total hemoglobin concentration) and rOEF=(Sa,O2-SO2final)/(Sa,O2-SO2initial) , with Sa,O2 the arterial hemoglobin oxygen saturation, SO2 the tissue averaged hemoglobin saturation. Fig. 1. Optical-MR probe Fig. 3. Example blood flow, volume, Hb saturation and metabolism. References. 1. Mandeville J.B., et al., MRM, 1999, 42: p 944-951. 2. Fantini S., et al., Opt. Exp., 1999, 4: p 308-314. 3. Boas, D.A., L.E. Campbell, and A.G. Yodh,. Phys. Rev. Lett., 1995. 75: p. 1855-1858. 4. Culver, J.P., et al.,. J Cereb Blood Flow Metab, 2003. 23(8): p. 911-24. RESULTS AND DISCUSSION Figure 3 shows sample time-traces of optical total hemoglobin (HbT), tissue hemoglobin saturation (SO2), cerebral blood flow (CBF) and CMRO2 during stepped increases from 0 to 2.5% (cyan highlight), 5% (green) and 7.5% (red) respectively of the amount of CO2 in the breathing gases. Progressive increases in both CBV and CBF are noted, with a simultaneous decrease in the oxygen extraction fraction. Initial results appear to indicate increased CMRO2 during the hypercapnic episodes (Fig .4). Further investigation is warranted. Fig.4 Relative metabolism from all animals time (min) Fig. 2. Protocol 0 2.5 5 7.5 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 CO2 (%) Proc. Intl. Soc. Mag. Reson. Med. 18 (2010) 1210