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We have developed an instrument for non-invasive optical imaging of the human brain that produces on-line images with a temporal resolution of 160 ms. The imaged quantities are the temporal changes in cerebral oxy-hemoglobin and deoxy-hemoglobin concentrations. We report real-time videos of the arterial pulsation and motor activation recorded on a 4×9 cm2area of the cerebral cortex in a healthy human subject. This approach to optical brain imaging is a powerful tool for the investigation of the spatial and temporal features of the optical signals collected on the brain. © 2000 Optical Society of America.

The American Pediatric Society and The Society for Pediatric Research 1999 Abstract Pediatric Research (1999) 45, 347A–347A; doi:10.1203/00006450-199904020-02066 First RealTime Optical Imaging of Experimental Brain Ischemia and Hemorrhage in Neonatal Piglets Miljan R Stankovic 1 , Dev Maulik 1 , Warren Rosenfeld 1 , Phillip G Stubblefield 1 , Maria Angela Franceschini 1 , Dennis Hueber 1 , Enrico Gratton 1 and Sergio Fantini 1 1 Winthrop Univ. Hospital, Mineola, NY, Boston Univ., Boston, MA, Dept Physics, Urbana, IL, ISS, Champaign, IL Abstract 2050 Poster Session II, Sunday, 5/2 (poster 229) Optical imaging, based on the ability of near infrared light to non-invasively penetrate through the intact scalp and skull, can monitor cerebral hemodynamics and oxygenation in real-time, assuming that images are acquired fast enough. Previously reported acquisition times of 5 s, 10 min, 2 h, or even 1 to 3 days per image, were far too slow to allow for real-time imaging, particularly in clinical settings where acute events are the focus of our attention. This study presents the first application of real-time optical imaging in the detection of experimental brain ischemia and hemorrhage and the accompanying cerebrovascular changes in newborn piglets. Optical imaging was performed on 7 anesthetized, instrumented, and ventilated newborn piglets secured within a stereotaxic instrument. We used a modified near-infrared oximeter and a custom-built 16 - light - source - 2 - detector optical probe rendering 64 pixel / 4 × 4 cm / 2-D brain absorption images with the acquisition time of 0.19 s per image (or 5.26 images per sec). Once the baseline was recorded (Fig 1), 0.3 cc of saline and 2 cc of blood were injected into the left frontal subcortical brain region aimed to induced focal and global anatomical and functional brain absorption changes. The imager readily detected: 1) focal changes in brain absorption caused by the appearance of the saline (white changes) and blood (dark changes) in the brain featuring brain ischemia and hemorrhage, respectively; 2) global bilateral ischemic changes (white changes) caused by the accompanying increase in intracranial pressure featuring brain ischemia followed by reperfusion and hyperemia; 3) five subcortical hematomas and two large bilateral subarachnoid hemorrhages with small subcortical hematomas, as confirmed on autopsy. The imaging detection limit was ~0.07 cc (5 mm in diameter) for saline and ~0.04 cc (4 mm in diameter) for blood at the estimated depth of 1 -1.5 cm. Our 1-min movie clip demonstrates the capability of optical imaging in detecting brain ischemia, hemorrhage, and reperfusion non-invasively and real-time, with high temporal and good spatial resolution. Fig 1. No caption Full figure and legend (64K)

We have experimentally investigated the meaning of the effective optical absorption @ma ~eff ! # and the reduced scattering @ms9 ~eff ! # coefficients measured on the surfaces of two-layered turbid media, using the diffusion equation for homogeneous, semi-infinite media. We performed frequency-domain spectroscopy in a reflectance geometry, using source‐detector distances in the range 1.5‐ 4.5 cm. We measured 100 samples, each made of one layer ~thickness in the range 0.08 ‐1.6 cm! on top of one semi-infinite block. The optical properties of the samples were similar to those of soft tissues in the near infrared. We found that the measured effective optical coefficients are representative of the underlying block if the superficial layer is less than ;0.4 cm thick, whereas they are representative of the superficial layer if it is more than ;1.3 cm thick. © 1998 Optical Society of America OCIS codes: 170.5280, 170.6510, 170.7050, 300.0300, 300.6340.

Frequency-domain optical mammography has been advocated to improve contrast and thus cancer detectability in breast transillumination. To the best of our knowledge, this report provides the first systematic clinical results of a frequency-domain laser scanning mammograph (FLM). The instrument provides monochromatic light at 690 and 810 nm, whose intensity is modulated at 110.0010 and 110.0008 MHz, respectively. The breast is scanned by stepwise positioning of source and detector, and amplitude and phase for both wavelengths are measured by a photomultiplier tube using heterodyne detection. Images are formed representing amplitude or phase data on linear gray scales. Furthermore, various algorithms carrying on more than one signal (amplitude ratio, phase difference, μa,μs',N) were essayed. Twenty visible cancers out of 25 cancers in the first 59 investigations were analyzed for their quantitative contrast with respect to the whole breast or to defined reference areas. Contrast definitions refer to the signal itself (definition 1), to the signal noise (definition 2), or were based on nonparametric comparison (definition 3). The amplitude signal provides better contrast than the phase signal. Ratio images between red and infrared amplitudes gave variable results; in some cases the tumor contrast was canceled. The algorithms to determine μa and μs' from amplitude and phase data did not significantly improve upon objective contrast. The N algorithm, using the phase signal to flatten the amplitude signal did significantly improve upon contrast according to contrast definitions 1 and 2, however, did not improve upon nonparametric contrast. Thus, with the current instrumentation, the phase signal is helpful to correct for the complex and variable geometry of the breast. However, an independent informational content for tumor differentiation could not be determined. The flat field algorithm did greatly enhance optical contrast in comparison with amplitude or amplitude ratio images. Further evaluation of FLM will have to be based on the N-algorithm images. © 1998 Society of Photo-Optical Instrumentation Engineers.

The Green's function for the diffusion equation is widely used to describe photon transport in turbid media. We have performed a series of spectroscopy experiments on a number of uniform turbid media with different optical properties (absorption coefficient in the range 0.03-0.14 cm-1, reduced scattering coefficient in the range 5-22 cm-1). Our experiments have been conducted in the frequency domain, where the measured parameters are the dc intensity (Idc), ac amplitude (Iac), and phase (Φ) of the light intensity wave. In an infinite medium, the Green's function predicts a linear dependence of ln(rIdc) and Φ on the source-detector separation r. Our measurements show that the intercepts of these straight lines predicted by the Green's function do not agree with the experimental results. To reproduce the experimental results, we have introduced an effective photon source whose spatial extent and source strength depend on the optical properties of the medium. This effective source term has no effect on the slopes of the straight lines predicted by the Green's function at large values of r. © 1997 Optical Society of America.

We have measured the optical absorption and scattering coefficient spectra of a multiple-scattering medium (i.e., a biological tissue-simulating phantom comprising a lipid colloid) containing methemoglobin by using frequency-domain techniques. The methemoglobin absorption spectrum determined in the multiple-scattering medium is in excellent agreement with a corrected methemoglobin absorption spectrum obtained from a steady-state spectrophotometer measurement of the optical density of a minimally scattering medium. The determination of the corrected methemoglobin absorption spectrum takes into account the scattering from impurities in the methemoglobin solution containing no lipid colloid. Frequency-domain techniques allow for the separation of the absorbing from the scattering properties of multiple-scattering media, and these techniques thus provide an absolute measurement of the optical absorption spectra of the methemoglobin/lipid colloid suspension. One accurately determines the absolute methemoglob in absorption spectrum in the frequency domain by extracting the scattering and absorption coefficients from the phase shift Φ and average light intensity DC (or Φ and the amplitude of the light-intensity oscillations AC) data with relationships provided by diffusion theory, but one determines it less accurately by using the Φ and modulation M (M ≡ AC/DC) data and the diffusion theory relationships. In addition to the greater uncertainty in the absorption and scattering coefficients extracted from the Φ and M data, the optical parameters extracted from the Φ and M data exhibit systematically inaccurate behavior that cannot be explained by random noise in the system. Possible reasons for the systematically lower accuracy of the methemoglobin absorption spectrum obtained from Φ and M data are discussed.

We have designed a multisource frequency-domain spectrometer for the optical study of biological tissues. Eight multiplexed, intensity-modulated LEDs are employed as the light sources. Four of them emit light at a peak wavelength of 715 nm (λ1); the other four, 850 nm (λ2). The frequency of intensity modulation is 120 MHz. This instrument measures the frequency-domain parameters phase, dc intensity, and ac amplitude at the two wavelengths λ1 and λ2 and for different distances between light source and detector. From these frequency-domain raw data, the absolute values of the absorption and reduced scattering coefficients of tissue at λ1 and λ2 are obtained. The oxy- and deoxyhemoglobin concentrations, and hence the hemoglobin saturation, are then analytically derived from the molar extinction coefficients. Acquisition times as short as hundreds of milliseconds provide real-time monitoring of the measured parameters. We performed a systematic test in vitro to quantify the precision and accuracy of the instrument reading. We also report in vivo measurements. This spectrometer can be packaged as a compact portable unit.

Tissue glucose levels affect the refractive index of the extracellular fluid. The difference in refractive index between the extracellular fluid and the cellular components plays a role in determining the reduced scattering coefficient (micro(s)') of tissue. Hence a physical correlation may exist between the reduced scattering coefficient and glucose concentration. We have designed and constructed a frequency-domain near-infrared tissue spectrometer capable of measuring the reduced scattering coefficient of tissue with enough precision to detect changes in glucose levels in the physiological and pathological range.

We have studied light migration in highly scattering media theoretically and experimentally, using the We approximation in a semi-infinite-geometry boundary condition. Both the light source and the diffusion detector were located on the surface of a semi-infinite medium. Working with frequency-domain spectroscopy, we approached the problem in three areas: (1) we derived theoretical expressions for the measured quantities spectroscopy by applying appropriate boundary conditions to the diffusion equation; (2) in frequency-domain we experimentally verified the theoretical expressions by performing measurements on a macroscopically medium in quasi-semi-infinite-geometry conditions; (3) we applied Monte Carlo methods to homogeneous the semi-infinite-geometry boundary problem. The experimental results and the confirming Monte simulate Carlo simulation show that the diffusion approximation, under the appropriate boundary conditions, accurately estimates the optical parameters of the medium.

We measured hemodynamic responses using diffuse optical imaging simultaneouously with evoked magnetoencephalography signals using parametrically varied median nerve stimulation. The spatial locations of the DOI responses and MEG source estimates agreed with each other.

By combining diffuse optical imaging (DOI) and magnetoencephalography (MEG) we investigate neurovascular coupling non-invasively in human subjects using median-nerve stimulation. Previous fMRI studies have shown a habituation effect in the hemodynamic blood oxygen level-dependent (BOLD) response for stimulation periods longer than 2 s. With DOI and MEG we can test whether this effect in hemodynamic response can be accounted for by a habituation effect in the neural response. Our experimental results show that the habituation effect in the hemodynamic response is stronger than that in the earliest cortical neural response (N20). Using a linear convolution model to predict hemodynamic responses we found that including late neural components (≥ 30 ms) improves the prediction of the hemoglobin response. This finding suggests that in addition to the initial evoked-response deflections related to the talamic afferent input, later cortical activity is needed to predict the hemodynamic response.

OBJECTIVE: To study the V beta T-cell repertoire in peripheral blood lymphocytes (PBL) during acute HIV syndrome by using several anti-V beta monoclonal antibodies (MAb) and to analyse its functionality by stimulating PBL with superantigens (SAg) such as Staphylococcus aureus enterotoxins. METHODS: Cytofluorimetric analysis of V beta T-cell-receptor expression was performed on PBL from eight patients with symptomatic, acute HIV-1 primary infection, showing a dramatic decrease of CD4+ PBL accompanied by a marked increase in activated/memory CD8+ T cells, and on 12 age- and sex-matched healthy controls. PBL were then isolated, stimulated with different SAg, anti-CD3 MAb or phytohaemagglutinin and cultured for 3 days. PBL capability to progress through cell cycle was studied by the classic cytofluorimetric method of bromodeoxyuridine incorporation and DNA staining with propidium iodide. RESULTS: Despite the presence of a few expansions of some V beta families among CD8+ T lymphocytes, no gross alterations in T-cell repertoire were present in patients with acute HIV syndrome. Its functionality was maintained overall, as PBL responsiveness to SAg was well preserved. Interestingly, all CD8+ T cells, although bearing different V beta T-cell receptors, expressed marked signs of activation, i.e., CD45R0, CD38 and major histocompatibility complex class II molecules, and also high amounts of CD11a and CD18. CONCLUSIONS: Our data suggest, at least in the early phases and in the acute form of the infection, that HIV is not likely to act as a SAg. However, further studies are needed to analyse other sites, such as lymph nodes, where HIV could exert other, significant effects, and to study the expression of other V beta families than those investigated here.

Resting state connectivity aims to identify spontaneous cerebral hemodynamic fluctuations that reflect neuronal activity at rest. In this study, we investigated the spatial-temporal correlation of hemoglobin concentration signals over the whole head during the resting state. By choosing a source-detector pair as a seed, we calculated the correlation value between its time course and the time course of all other source-detector combinations, and projected them onto a topographic map. In all subjects, we found robust spatial interactions in agreement with previous fMRI and NIRS findings. Strong correlations between the two opposite hemispheres were seen for both sensorimotor and visual cortices. Correlations in the prefrontal cortex were more heterogeneous and dependent on the hemodynamic contrast. HbT provided robust, well defined maps, suggesting that this contrast may be used to better localize functional connectivity. The effects of global systemic physiology were also investigated, particularly low frequency blood pressure oscillations which give rise to broad regions of high correlation and mislead interpretation of the results. These results confirm the feasibility of using functional connectivity with optical methods during the resting state, and validate its use to investigate cortical interactions across the whole head.