Optical coherence tomography (OCT) reveals depth-resolved dynamics during functional brain activation
Introduction
Optical imaging has become an important technique to investigate the neuronal and vascular responses to brain activation (Orbach et al., 1985, Grinvald et al., 1988, Villringer and Chance, 1997, Gratton and Fabiani, 2001, Franceschini et al., 2006, Hillman, 2007). Optical methods can offer both high spatial and temporal resolutions and are therefore particularly promising for measuring the hemodynamic, metabolic, and neuronal activity in vivo. Optical intrinsic signal imaging (OISI) is a well-established optical imaging method which utilizes a CCD camera to map the clustered activation of neurons. OISI can provide highly sensitive measures of neuronal (Rector et al., 2001, Rector et al., 2005) and vascular (Frostig et al., 1990, Tso et al., 1990) responses to brain activation, and is currently being used extensively for study of the neuro-vascular relationship (Devor et al., 2003, Devor et al., 2005, Sheth et al., 2004, Sheth et al., 2005). However, since CCD cameras integrate the back-scattered light from various depths, OISI cannot detect depth-resolved functional activation. To overcome this limitation, multiphoton microscopy has been used for functional neuronal imaging (Kleinfeld et al., 1998, Bacskai et al., 2003, Chaigneau et al., 2003, Svoboda and Yasuda, 2006). In addition, new methods such as laminar optical tomography (LOT) have been developed for depth-resolved tomographic imaging (Hillman et al., 2004, Hillman et al., 2007). Optical coherence tomography (OCT) is another promising method for depth-resolved imaging in highly scattering tissues such as the cerebral cortex. OCT is an emerging biomedical imaging method which can provide high-resolution, cross-sectional images in vivo and in real time (Huang et al., 1991, Schmitt, 1999). OCT enables the measurement of small, scattered signals over several orders of magnitude in dynamic range and can image deeper than multiphoton microscopy. Several groups have used OCT to study functional activation in neuronal tissues. Maheswari et al. demonstrated depth-resolved, stimulus-specific profiles during functional activation in the cat visual cortex (Maheswari et al., 2002, Maheswari et al., 2003), and showed a good agreement between the depth-integrated functional OCT signals and the OISI profiles (Rajagopalan and Tanifuji, 2007). They attributed these signals to variations in scattering due to localized structural changes such as capillary dilation and cell swelling. Lazebnik et al. (2003) demonstrated scattering changes corresponding to fast and slow signals triggered by action potential propagation in the sea slug abdominal ganglion. Satomura et al. (2004) observed the delayed swelling of the cortical surface in the somatosensory cortex following the electrical stimulation of the rat hind paw. Bizheva et al. (2006) and Srinivasan et al. (2006) reported depth-resolved functional OCT signals in the retina in response to visual stimulation. Recently, Wang et al. (2007) and Wang and Hurst (2007) demonstrated a new Fourier Domain OCT method termed optical angiography (OAG) to visualize the three-dimensional cerebral microcirculation of adult living mice through the intact cranium. Other groups have also explored low coherence interferometry methods for measurement of functional retinal activation (Yao et al., 2005) as well as nerve axon displacement (Akkin et al., 2004, Fang-Yen et al., 2004). In a previous study, we presented preliminary results using OCT to measure subsurface scattering changes due to functional activation in the rat somatosensory cortex (Aguirre et al., 2006). The rat somatosensory cortex is a well-established model system for neurophysiology, and these results demonstrated that OCT can provide high-resolution, cross-sectional measurement of functional hemodynamic response to electrical stimulation in the rat cortex. OCT data correlated well with simultaneously acquired OISI data. This allowed comparison of OCT results with extensively studied intrinsic optical signals. Our previous results suggested that OCT could have an important role in future studies of the functional neurovascular response. In this paper, we perform spatial and temporal correlations of OCT and OISI signals in order to gain further insights for interpretation of OCT results.
Section snippets
Experimental system
Simultaneous OCT and OISI were performed on the rat somatosensory cortex. Fig. 1(A) shows the schematic of the co-registered OCT and OISI system. The OCT system used time domain detection and consisted of a balanced interferometer configuration, a rapid linearly scanning reference delay line operating at 1140 Hz, and logarithmic demodulation. The light source was a Nd:Glass femtosecond laser generating ∼100 femtosecond pulses at 1060 nm center wavelength. The laser spectrum was broadened by a
Co-registration of functional OCT and OISI
Fig. 4 illustrates the co-registered OISI and OCT imaging in the region of functional activation. The functional signal was computed as a ratio of the reflectance at each time point to the mean reflectance in the pre-stimulus period and is therefore representative of a percent signal change from the baseline. Fig. 4(A) shows a representative ratio OISI image from the time window around the peak of maximal activation (t = 4–6 s). The region of functional activation corresponding to forepaw
OCT signal characteristics
In our experiments, OCT measures the depth-dependent scattering changes during the functional brain activation. The scattering signals measured here are different from the absorption changes measured by OISI, and also do not directly indicate blood flow values (however, Doppler OCT (Chen et al., 1997), an extension of OCT, is sensitive to blood flow). During the stimulation, a robust and highly localized OCT response is observed which is well-correlated with the stimulus and the hemodynamic
Conclusion
We presented depth-resolved functional OCT imaging of the neurovascular response to somatosensory stimulation in the rat. The time-course of the OCT response correlates well with OISI, suggesting that the OCT signal may reflect changes in hemodynamics. OCT signals include both positive and negative OCT functional changes. We also observe layer specific dynamic responses in the OCT signals which might indicate retrograde vessel dilation. Understanding the exact etiology of the OCT functional
Acknowledgements
The authors thank Drs. Elizabeth M. Hillman, Shuai Yuan, Chao Zhou, Sava Sakadzic, Qianqian Fang, and Guangyu Zhang for helpful discussions and technical assistance. Also we thank James Jiang and Alex Cable (Thorlabs Inc.) for providing the swept-source OCT system for obtaining the Fourier-domain OCT results. This research was supported by the Air Force Office of Scientific Research Medical Free Electron Laser Program FA9550-07-1-0101 and FA9550-07-1-0014, and the National Institutes of Health
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