Diffuse optical imaging of brain activation: approaches to optimizing image sensitivity, resolution, and accuracy

Near-infrared spectroscopy (NIRS) and diffuse optical imaging (DOI) are finding widespread application in the study of human brain activation, motivating further application-specific development of the technology. NIRS and DOI offer the potential to quantify changes in deoxyhemoglobin (HbR) and total hemoglobin (HbT) concentration, thus enabling distinction of oxygen consumption and blood flow changes during brain activation. While the techniques implemented presently provide important results for cognition and the neurosciences through their relative measures of HbR and HbT concentrations, there is much to be done to improve sensitivity, accuracy, and resolution. In this paper, we review the advances currently being made and issues to consider for improving optical image quality. These include the optimal selection of wavelengths to minimize random and systematic error propagation in the calculation of the hemoglobin concentrations, the filtering of systemic physiological signal clutter to improve sensitivity to the hemodynamic response to brain activation, the implementation of overlapping measurements to improve image spatial resolution and uniformity, and the utilization of spatial prior information from structural and functional MRI to reduce DOI partial volume error and improve image quantitative accuracy.

Introduction

Near-infrared spectroscopy (NIRS) and diffuse optical imaging (DOI) are emerging techniques used to study neural activity in the human brain. DOI employs safe levels of optical radiation in the wavelength region 650–950 nm, where the relatively low attenuation of light accounts for an optical penetration through several centimeters of tissue. As a result, it is possible to noninvasively probe the human cerebral cortex using near-infrared light and to monitor the cerebral concentration of hemoglobin, which is the dominant near-infrared absorbing species in the brain. Furthermore, the difference in the near-infrared absorption spectra of oxyhemoglobin (HbO₂) and deoxyhemoglobin (HbR) allows the separate measurement of the concentrations of these two species. To achieve this goal, it is sufficient to perform NIRS measurements at two wavelengths. The sum of the concentrations of oxy- and deoxyhemoglobin provides a measure of the cerebral blood volume (CBV), while the individual concentrations of the two forms of hemoglobin are the result of the interplay between physiological parameters such as regional blood volume, blood flow, and metabolic rate of oxygen consumption. NIRS thus offers an advantage over BOLD–fMRI which cannot disentangle blood flow and oxygen consumption changes without also acquiring blood flow images (Davis et al., 1998, Hoge et al., 1999). This ability is potentially important for a wide range of brain studies particularly of the developing and diseased brain. Extension of a spectroscopic measurement in a single location to include a large number of sources and detectors enables reconstruction of diffuse optical images of a large area of the brain.

Since the mid-1990s, an increasing number of researchers have used near-infrared spectroscopy and diffuse optical imaging for human functional brain studies. They have employed the technique to study cerebral response to visual (Heekeren et al., 1997, Meek et al., 1995, Ruben et al., 1997), auditory (Sakatani et al., 1999), and somatosensory (Franceschini et al., 2003, Obrig et al., 1996) stimuli; other areas of investigation have included the motor system (Colier et al., 1999, Hirth et al., 1996, Kleinschmidt et al., 1996) and language (Sato et al., 1999). Still other researchers have addressed the prevention and treatment of seizures (Adelson et al., 1999, Sokol et al., 2000, Steinhoff et al., 1996, Watanabe et al., 2000) and psychiatric concerns such as depression (Eschweiler et al., 2000, Matsuo et al., 2000, Okada et al., 1996b), Alzheimer disease (Fallgatter et al., 1997, Hanlon et al., 1999, Hock et al., 1996), and schizophrenia (Fallgatter and Strik, 2000, Okada et al., 1994), as well as stroke rehabilitation (Chen et al., 2000, Nemoto et al., 2000, Saitou et al., 2000, Vernieri et al., 1999).

While NIRS and DOI hold great promise as tools for cognition and the neurosciences, there are limitations to their application, as well as technological advances that will enhance their application.

Estimation of the oxy- and deoxyhemoglobin concentrations is sensitive to random measurement error and systematic errors arising from incorrect model parameters. Of significant concern is cross-talk in the estimate of the oxy- and deoxyhemoglobin concentrations. These errors can be partially reduced by judicial choice of measurement wavelengths (Sato et al., 2004, Strangman et al., 2003, Uludag et al., 2002, Yamashita et al., 2001).

The diffuse nature of photon migration through the tissue limits the penetration depth and thus the sensitivity to brain activation occurring subcortically. The sensitivity to brain activation is further compromised by contamination from several systemic physiological signals, which can have a larger percent signal variation than that of the brain activation and in some cases may even phase-lock with the stimulation (Franceschini et al., 2003, Obrig et al., 2000, Toronov et al., 2000).

DOI can potentially achieve spatial resolution of 1 cm in the axes parallel to the scalp in the adult human brain close to the skull (resolution degrades rapidly with increasing depth in the brain). However, current measurement strategies primarily utilize nonoverlapping geometric arrangements of sources and detectors, and thus spatial resolution is no better than the typical source-detector separation of 3 cm (Boas et al., in press). Spatial resolution in the depth axis is significantly worse in adult humans due to the small source-detector separations that can be used (<5 cm). Depth resolution could be improved if transmission measurements were made. However, while this is possible in newborn babies (Hintz et al., 1999), it is generally not possible in adult humans.

The limited depth resolution of DOI causes significant partial volume error and prevents absolute amplitude accuracy in the estimates of the hemoglobin concentration response to brain activation. As a result, quantitative comparison of response amplitudes from different brain regions within a subject and from the same brain region between subjects is compromised. Prior spatial information is required to overcome the partial volume problem. This information can be provided by fMRI if the brain activations measured by fMRI and DOI are correlated in space and time.

Again, NIRS has demonstrated the promise and feasibility of diffuse optical methods as tools for cognition and neuroscience. To realize their full potential, however, diffuse optical imaging methods need further development and implementation. In this paper, we review the current technological issues with diffuse optical imaging and the progress being made towards resolving these issues with example results from our laboratory. Specifically,

• We review the recent discussion on choosing optimal wavelengths for minimizing noise and cross-talk in the estimate of the hemoglobin concentrations.

• We discuss the strong presence of systemic physiological signals in the optical data, which interferes with estimates of the hemodynamic response to brain activation, and then present examples of how straightforward signal processing can help to distinguish the different systemic physiological components from the brain activation signal, to ultimately improve the contrast-to-noise ratio estimate of the hemodynamic response function.

• We review the significant improvement in spatial resolution and relative amplitude accuracy provided by overlapping measurements of the tissue.

• We emphasize that partial volume error leads to an underestimate of the concentration changes. While this is well known, many papers still report quantitative units for concentrations changes, although only the relative units are accurate. Generally, the relative accuracy is sufficient for brain activation studies.

• Absolute DOI amplitude accuracy requires better spatial resolution, particularly in depth, as can be provided by spatial prior information from, for example, MRI. We review progress in the spatial-temporal correlation of fMRI and DOI that will provide more insight into the biophysics of their respective signals. Ultimately, the routine combination of fMRI and DOI will provide high spatial-temporal resolution of brain activation with quantitative measures of the hemodynamic, metabolic, and neuronal response to brain activation.