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PHYSICAL SCIENCES / BIOLOGICAL SCIENCES / ENGINEERING / NEUROSCIENCE
Retinotopic mapping of adult human visual cortex with high-density diffuse optical tomography
*Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110; Department of Physics and School of Medicine, Washington University, St. Louis, MO 63130; and Department of Physics, University of Exeter, Exeter EX4 4QJ, United Kingdom
Edited by Marcus E. Raichle, Washington University School of Medicine, St. Louis, MO, and approved May 29, 2007 (received for review December 19, 2006)
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functional brain mapping | near-infrared spectroscopy | neuroimaging | retinotopy
HbO2), deoxygenated hemoglobin (HbR), and total hemoglobin (HbT), whereas the BOLD signal is mainly dependent on HbR (8). The ability to simultaneously image these contrasts allows DOI to distinguish differences in their magnitude (3, 4, 9), timing (3, 10–12), and localization (13–15), forming a more complete picture of neurovascular function. In contrast to positron emission tomography (PET), which uses ionizing radiation, DOI uses safe, infrared light for imaging. Despite unique strengths, however, DOI as a standard tool for functional mapping has been limited by low spatial resolution, a lack of volumetric localization, and instrument complexity. We have developed an optical imaging system with superior contrast-to-noise characteristics that overcomes many previous limitations to provide higher resolution imaging while maintaining simple instrumentation. The vast majority of DOI studies have been performed in topographic mode, in which the image is synthesized from measurements at a single source–detector pair (SD pair) separation and without overlapping measurements. Topographic DOI has been used extensively, for example, to map functional responses in the human visual (16–18), sensorimotor (13), and auditory cortex (19, 20); to study language lateralization in the prefrontal cortex (21); to record brain activity in infants (3, 17, 19, 20, 22–24); and even to measure cerebral blood volume during seizures (25, 26). Topographic DOI has limited lateral resolution and no depth-sectioning capability, precluding spatial separation of superficial and brain signals. Because of these limitations, topography studies of the visual cortex have been limited to distinguishing contralateral activations, an imaging task requiring no greater than 4-cm resolution.
A more advanced optical imaging method, diffuse optical tomography (DOT), relies on a variety of measurement strategies to improve lateral resolution and acquire depth information. Time-resolved measurements, for example, use time-gating to profile different tissue depths (27–31). However, the complexity and cost of time-resolved systems impose practical limits and require tradeoffs between channel count, optode density, coverage (field of view), and frame rate. Another strategy is to use high-density DOT grids, which use overlapping measurements at multiple SD pair separations (32, 33); different measurement distances provide information about different depths, and the use of overlapping measurements improves lateral resolution and localization. However, due to the large range in measured light levels, this approach places very stringent requirements on dynamic range and channel cross-talk. Despite these challenges, initial reports on DOT of the human brain demonstrate the feasibility of detecting lateralization of motor cortex activation (24, 27, 34), cerebral hemorrhage, decreased brain oxygenation in neonates after acute stroke (35), and vascular responsivity during the Valsalva maneuver (36). The breadth of these applications highlights the promise of the tomographic approach to optical neuroimaging.
In this paper, we report functional mapping of the adult human visual cortex made possible by a high-density DOT imaging system. The visual cortex is ideal for testing new neuroimaging techniques because its structure and function have been comprehensively mapped with invasive anatomical and electrical studies in mammals (37–39) and in humans (40–42). Visual cortex activations were used extensively in early evaluations of PET and fMRI as functional brain mapping tools (43–46). More recently, the visual cortex was used as a model system to establish fMRI procedures for comparative mappings of adults and children in a common stereotactic space (47). Whereas previous optical imaging studies of the visual cortex have focused on discriminating contralateral activations (15, 18), here we report functional features of the human visual cortex that were previously inaccessible to optical imaging, such as eccentricity within quadrants of the visual field. These retinotopic mappings are repeatable and are consistent with previous fMRI and PET mappings. A high contrast-to-noise ratio allows us to measure individual activations, enabling us to move beyond repetitive block design stimulus paradigms. We present imaging of an angular sweep of the visual field that highlights these capabilities. The imaging improvements of this high-density DOT system, as demonstrated in these retinotopic maps, constitute a large step toward the full realization of optical imaging for mapping brain function in humans.
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For the design of our continuous wave high-density DOT imager, we took a different approach, instead using isolated detector channels digitized with dedicated 24-bit ADCs. Dedicated control lines for each source are used for flexible software-configurable source encoding (frequency-, time-, and spatial-encoding). This design provides high instantaneous dynamic range (>106) and cross-talk rejection (<10–6), so that light levels over many orders of magnitude can be detected simultaneously. The instrument has two near-infrared wavelengths (750 and 850 nm) at each of 24 source positions. The sources are interleaved with 28 detectors in a high-density array (Fig. 1a) with overall dimensions of 13.2 x 6.6 cm. The optical fibers were coupled to the head with a flexible, plastic cap molded to fit the back of the head over the visual cortex (Fig. 1b). Each detector samples light from all sources, for a total of 672 possible measurements.
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Eccentricity Mapping.
As a result of the dense spatial sampling and the removal of global and superficial signals, functional activations had high contrast-to-noise ratios (CNR) (e.g., in Fig. 2, CNR = 12:1 without block averaging and CNR = 34:1 with block averaging), and activations due to even single stimuli could be imaged (Fig. 2). As evident in Fig. 2b, the activations are localized at depth with very little change in hemoglobin present in the outer layer. In Fig. 2c, a time series of cortical projection images are depicted for HbO2 concentration. Fig. 2d shows a time trace of HbO2, HbR, and HbT in a high-activation 1-cm3 region for nine individual stimuli, demonstrating strong activation. The measured hemoglobin time courses are in good agreement with previous fMRI and DOI studies (51). In a movie of nine individual functional activations from one imaging session (without block averaging) the localized activation is clearly visible in response to each presentation of the stimulus [supporting information (SI) Movie 1]. A typical time course (Fig. 2 c and d) shows a peak in the functional signal at t = 11 sec (stimulus presentation, t = 0–10 sec).
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HbO2 temporal response, t = 7–15 sec) for each subject (three stimuli in each of three sessions; the data from different scans within the same session were block-averaged together). The images for each subject were coregistered by applying a linear transformation to account for intersession variability in cap placement (see Methods). Threshold maps for each subject and contrast, averaged across all three sessions, are shown in SI Fig. 6 (coronal projection) and SI Fig. 7 (axial). In subjects 1, 3, 4, and 5, strong localized activations were seen in response to all three stimuli. In subject 2, the activation maps were less localized and had higher noise. The average centroids of the activations (HbO2) are (relative to the center of the imaging pad): central lower-right (stimulus A: x = –20 mm, z = 0 mm), peripheral lower-right (stimulus B: x = –20 mm, z = 5 mm), and central lower-left (stimulus C: x = 17 mm, z = 1 mm). Here, x denotes the horizontal axis and z represents the vertical axis. Intersubject variability is evident in the relative positions of mappings of the three stimuli. The centroids for the central lower-right and the central lower-left were separated by xAC = 37 ± 4 mm and zAC = 1 ± 5 mm (mean ± SD). The intersubject variability is more pronounced when examining the A–B shift. Relative to the centroid of activation A, the centroid of activation B is shifted by xAB = 0 ± 13 mm and zAB = 4 ± 7 mm. The variation is most easily understood if we express the A–B separation in polar coordinates with the origin being the centroid of activation A and 
= 0° corresponding to a positive horizontal (x) axis. Then the shift is a radial separation of rAB = 13 ± 7 mm over an angular range of 167° with AB = 83 ± 67°. So the radial separation of the two centroids is relatively constant with the majority of the variation coming from the angular component. This is consistent with visual inspection of Figs. 3 and 6, where (with the exception of noisy subject 2) the activations from the peripheral stimulus (B) are variable but appear in an annulus surrounding the activation from the central stimulus (A).
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HbO2, HbR, and HbT). Fig. 4 highlights the resolution of the system. Activations have spreads (FWHM HbT) of 18 mm for activation A, 17 mm for activation B, and 20 mm for activation C. The separations of the centroids are xAC = 41 mm and zAC = 2 mm and xAB = 4 mm and zAB = 7 mm (due to the weighting, the separation of the means is not the mean of the separations of individual subjects). In our polar representation, we have rAB = 8 mm, AB = 56° (above the x axis). Individual activation maps for subjects 1 and 3–5 show better distinction between stimuli than the group average maps (SI Fig. 6). For the group-averaged data (Fig. 4), the overlap (number of voxels above half-maximum contrast common to both activation maps and normalized to the average extent of the individual maps) of stimuli A and B is 42% (overlaps for HbO2, HbR, and HbT are similar within ±2%). For the individual maps (Fig. 6), overlap values range from 0% to 42%, with a mean of 24%.
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xAC = 37 ± 4 mm and zAC = 2 ± 5 mm. These values are in good agreement with fMRI studies of the adult visual cortex (x = 42 mm and z = 4 mm, with SD values reported in the range 3–7 mm) (47). It is difficult to compare the relative mapping of the central and peripheral lower-right stimuli (xAB = 4 mm and zAB = 7 mm) to the common, unfolded space used in the visualization of fMRI data. However, the vertical shift of the activation is quantitatively in agreement with PET eccentricity maps (53) and qualitatively supported by angular and eccentricity maps performed with fMRI (54, 55). Heuristically, we can explain the DOT eccentricity maps as a shift from the perimacular retina, which maps with a large projection onto the lateral occipital cortex, to the peripheral retina, which is largely projected within the calcarine sulcus along the midline. In addition, one would expect a large anterior shift. Although such depth profiling may be possible in infants, the depth sensitivity of our current study does not readily reveal this shift. Interestingly, several of the maps show regions of apparent deactivation or negative contrast. For the polar mapping (Fig. 5), negative voxels are likely due to the temporal analysis that enforces a zero-mean value to the data. In the axial slices of Fig. 2b, negative voxels in the superficial layers are possibly the result of artifacts from the reconstruction process (e.g., ripples in the effective point spread function). In the time-course projection images of Fig. 2 a and d, the negative contrast may be due to either deactivation, residual image noise, or more subtle reconstruction artifacts. Future validation studies using coregistered MR structural and functional data are needed to resolve these issues (34, 56).
The high-density DOT system presented is able to reproduce activations within a subject over multiple imaging sessions. This reproducibility allowed us to detect significant intersubject variability, which has important consequences for more detailed cortical mapping problems (e.g., identifying borders of visual cortical areas). In addition, the robust intrasubject results show that DOT offers promise for single-subject mapping studies, where relying on an average map is insufficient, such as presurgical seizure focus localization or when optical contrasts are imaged intraoperatively on the cortical surface (57). High-density DOT arrays have the potential to map individual patients noninvasively. We look forward to application of the DOT imager to many of these interesting imaging problems.
For all of these applications, a necessary step in the development of DOT is the coregistration of DOT maps with anatomical images. In this study, in the interests of simplicity, DOT images were reconstructed in a hemispherical head model (see Methods), and, in the absence of anatomical data, we used the center of mass of the activation images for coregistration. A preferred approach would use a standard, MRI-derived head model for the forward light modeling to improve imaging accuracy and allow the DOT maps to be overlaid on an anatomical image (58, 59). Additionally, improving measurement of the placement of the DOT array relative to external landmarks on the head will allow the functional and anatomical images to be more accurately coregistered (24).
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Protocol. The research was approved by the Human Research Protection Office of the Washington University School of Medicine, and informed consent was obtained from all participants before scanning. Healthy adult subjects were recruited (two males and five females, ages 23–25). Of the recruited population, one subject (male) was excluded due to poor fit of the imaging cap, and one subject (female) was excluded due to high measurement noise.
Subjects were seated in an adjustable chair facing a 19-inch liquid crystal display at a 70-cm viewing distance. The DOT imaging cap was positioned with the optode array on the back of the head. The nasion-to-top optode row distance was measured to establish repeatable positioning. The cap was centered horizontally with the center of the imaging array near the inion (range across subjects, 0.3 cm below to 2.2 cm above). All presented visual stimuli were radial, reversing, black-and-white grids (10-Hz reversal) on a 50% gray background. The first paradigm consisted of blocks of a 10-sec stimulus followed by a 30-sec 50% gray screen. Stimuli were presented in the order A–B–C (Fig. 3a), repeated three times with a gray screen presented 15 sec before and after the stimulus sequence. Each subject returned for three sessions. The second paradigm was an angularly swept radial grid rotated 10 times at 10°/sec (Fig. 5) to complete a sweep of the entire visual field every 36 seconds. Gray screens were also presented for the 45 sec before and 15 sec after the complete sweep sequence.
Analysis.
An initial 0.02-Hz, high-pass filter removes long-term drift and all SD pair data were converted to a log-ratio data. Background signals were reduced by following approaches previously demonstrated with fMRI data (60) and simulated near-infrared optical data (61). A global signal derived from nearest-neighbor measurements was removed from SD pair data by linear regression. Starting with the log-ratio optode pair measurments (y'i), the mean of the first-nearest-neighbor measurements (y'nn) is removed from the all y'i through linear regression by using
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The resulting time traces yi are then used for reconstruction. Finally, a low-pass filter (0.5 Hz) removed residual pulse signals from the data.
For reconstruction, a two-layer, hemispheric head model (radius = 80 mm) was used with finite-element, forward-light modeling [NIRFAST (62)] to obtain a sensitivity matrix for the optode array. The inverted sensitivity matrix was used to convert time-series measurement data into time-series images of the differential absorption within the head model. HbR and HbO2 concentrations were obtained from the absorption coefficients by using spectral decomposition and the extinction coefficients of HbR and HbO2 at the two wavelengths (for further details, see SI Text).
In the eccentricity study (Figs. 3 and 4 and SI Figs. 6 and 7), the images for each subject were coregistered by applying a linear shift transformation to account for intersession variability in cap placement. For each session, the line connecting the centroids of the central lower-right (A) and central lower-left (C) activations was bisected to find the median point. The centroid of each activation was coregistered with a two-dimensional linear transformation. Information about the relative shifts between the activations remained. In the coronal projection view, the three activations have six major positional variables (x and y positions of the center of mass for each of three activations). After coregistration, four independent variables remained for comparative mapping evaluations. The average shift was 1 cm, with a SD of 6 mm. Due to higher noise, the coregistration was not performed for subject 2.
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Abbreviations: ADC, analog-to-digital converter; DOI, diffuse optical imaging; DOT, diffuse optical tomography; fMRI, functional MRI; PET, positron-emission tomography; SD pair, source–detector pair.
To whom correspondence should be addressed. E-mail: culverj{at}wustl.edu
Author contributions: B.W.Z., B.L.S., and J.P.C. designed research; B.W.Z., B.R.W., and J.P.C. performed research; B.W.Z. B.R.W., H.D., and J.P.C. contributed new reagents/analytic tools; B.W.Z., B.R.W., and J.P.C. analyzed data; and B.W.Z., B.R.W., B.L.S., H.D., and J.P.C. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0611266104/DC1.
© 2007 by The National Academy of Sciences of the USA
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10 image frames). All first-, second-, third-, and fourth-nearest-neighbor pairs were detected simultaneously and were well above the noise floor (dotted line).
