Near-infrared light scattering and water diffusion in newborn brains.

OBJECTIVE: MRI provides useful information regarding brain maturation and injury in newborn infants. However, MRI studies are generally restricted during acute phase, resulting in uncertainty around upstream clinical events responsible for subtle cerebral injuries. Time-resolved near-infrared spectroscopy non-invasively provides the reduced scattering coefficient ( µ s ' ), which theoretically reflects tissue structural complexity. This study aimed to test whether µ s ' values of the newborn head reflected MRI findings. METHODS: Between June 2009 and January 2015, 77 hospitalised newborn infants (31.7 ± 3.8 weeks gestation) were assessed at 38.8 ± 1.3 weeks post-conceptional age. Associations of µ s ' values with MRI scores, mean diffusivity and fractional anisotropy were assessed. RESULTS: Univariable analysis showed that µ s ' values were associated with gestational week (p = 0.035; regression coefficient [B], 0.065; 95% confidence interval [CI], 0.005-0.125), fractional anisotropy in the cortical grey matter (p = 0.020; B, -5.994; 95%CI, -11.032 to -0.957), average diffusivity in the cortical grey matter (p < 0.001; B, -4.728; 95%CI, -7.063 to -2.394) and subcortical white matter (p = 0.001; B, -2.071; 95%CI, -3.311 to -0.832), subarachnoid space (p < 0.001; B, -0.289; 95%CI, -0.376 to -0.201) and absence of brain abnormality (p = 0.042; B, -0.422; 95%CI, -0.829 to -0.015). The multivariable model to explain µ s ' values comprised average diffusivity in the subcortical white matter (p < 0.001; B, -2.066; 95%CI, -3.200 to -0.932), subarachnoid space (p < 0.001; B, -0.314; 95%CI, -0.412 to -0.216) and absence of brain abnormality (p = 0.021; B, -0.400; 95%CI, -0.739 to -0.061). INTERPRETATION: Light scattering was associated with brain structure indicated by MRI-assessed brain abnormality and diffusion-tensor-imaging-assessed water diffusivity. When serially assessed in a larger population, µ s ' values might help identify covert clinical events responsible for subtle cerebral injury.

Foetal growth, birth transition, enteral nutrition and brain light scattering.

If the brain structure is assessed at neonatal intensive care units, covert clinical events related with subtle brain injury might be identified. The reduced scattering coefficient of near-infrared light (µS') obtained using time-resolved near-infrared spectroscopy from the forehead of infants is associated with gestational age, body weight and Apgar scores, presumably reflecting subtle changes of the brain related to foetal growth and birth transition. One hundred twenty-eight preterm and term infants were studied to test whether µS' obtained from the head at term-equivalent age is associated with foetal growth, birth transition and nutritional status after birth, which are key independent variables of developmental outcomes. As potential independent variables of µS', birth weight, Apgar scores, age at full enteral feeding and post-conceptional age at the study were assessed to represent foetal growth, birth transition and nutritional status after birth. Subsequently, higher µS' values were associated with higher Apgar scores (p = 0.003) and earlier establishment of enteral feeding (p < 0.001). The scattering property of near-infrared light within the neonatal brain might reflect changes associated with birth transition and nutritional status thereafter, which might be used as a non-invasive biomarker to identify covert independent variables of brain injury in preterm infants.

Physiological and pathological clinical conditions and light scattering in brain.

MRI of preterm infants at term commonly reveals subtle brain lesions such as diffuse white matter injury, which are linked with later cognitive impairments. The timing and mechanism of such injury remains unclear. The reduced scattering coefficient of near-infrared light (µs') has been shown to correlate linearly with gestational age in neonates. To identify clinical variables associated with brain µs', 60 preterm and full-term infants were studied within 7 days of birth. Dependence of µs' obtained from the frontal head on clinical variables was assessed. In the univariate analysis, smaller µs' was associated with antenatal glucocorticoid, emergency Caesarean section, requirement for mechanical ventilation, smaller gestational age, smaller body sizes, low 1- and 5-minute Apgar scores, higher cord blood pH and PO2, and higher blood HCO3(-) at the time of study. Multivariate analysis revealed that smaller gestational age, requirement for mechanical ventilation, and higher HCO3(-) at the time of study were correlated with smaller µs'. Brain µs' depended on variables associated with physiological maturation and pathological conditions of the brain. Further longitudinal studies may help identify pathological events and clinical conditions responsible for subtle brain injury and subsequent cognitive impairments following preterm birth.

Hemodynamic Measurements of the Human Adult Head in Transmittance Mode by Near-Infrared Time-Resolved Spectroscopy.

Using a near-infrared time-resolved spectroscopy (TRS) system, we measured the human head in transmittance mode to obtain the optical properties and the hemodynamic changes of deep brain tissues in seven healthy adult volunteers during hyperventilation. For six out of seven volunteers, we obtained the optical signals with sufficient intensity within 10 sec. of sampling. We confirmed that it is possible to non-invasively measure the hemodynamic changes of the human head during hyperventilation, even in the transmittance measurements by the developed TRS system. These results showed that the level of deoxygenated hemoglobin was significantly increased, and the level of oxygenated and total hemoglobin and tissue oxygen saturation were also significantly decreased during hyperventilation. We expect that this TRS technique will be applied to clinical applications for measuring deep brain tissues and deep biological organs.

Measurement of maternal cerebral tissue hemoglobin on near-infrared time-resolved spectroscopy in the peripartum period.

AIM: To measure cerebral tissue hemoglobin in uncomplicated and complicated pregnant women during the peripartum period. METHODS: Time-resolved spectroscopy (TRS-20) can measure absolute concentration of oxygenated, deoxygenated, and total tissue hemoglobin based on the transit time of individual photons. Therefore, we used TRS-20 to measured tissue hemoglobin in the hemi-prefrontal lobes of normotensive pregnant women with (n = 51) or without (n = 19) epidural anesthesia, hypertensive pregnant women with pre-eclampsia (n = 10), a pregnant woman with acute onset of hypertension soon after delivery, and a hypertensive woman after hemorrhagic stroke in delivery. RESULTS: Cyclic labor concomitant with intra-abdominal pressure caused synergistic elevation in cerebral tissue hemoglobin. In contrast, epidural anesthesia reduced the amplitude of the cyclic increase of cerebral tissue hemoglobin in normotensive pregnant women. Hypertension in labor due to pre-eclampsia increased the amplitude of synergistic elevation of cerebral tissue hemoglobin caused by cyclic labor and intra-abdominal pressure. A prolonged high basal level of cerebral tissue hemoglobin was observed in a case of acute onset of hypertension soon after delivery. A decrease in cerebral tissue hemoglobin in the hemi-prefrontal lobe was observed in a woman 2 h after the onset of hemorrhagic stroke in labor. CONCLUSIONS: TRS-20 can detect specific changes in maternal cerebral tissue hemoglobin level in response to physiological and pathophysiological changes in delivery. Thus, it represents a promising new conventional tool for maternal cerebral monitoring in the peripartum period.

Sensitivity correction for the influence of the fat layer on muscle oxygenation and estimation of fat thickness by time-resolved spectroscopy.

Near-infrared spectroscopy (NIRS) has been used for noninvasive assessment of oxygenation in living tissue. For muscle measurements by NIRS, the measurement sensitivity to muscle (S(M)) is strongly influenced by fat thickness (FT). In this study, we investigated the influence of FT and developed a correction curve for S(M) with an optode distance (3 cm) sufficiently large to probe the muscle. First, we measured the hemoglobin concentration in the forearm (n=36) and thigh (n=6) during arterial occlusion using a time-resolved spectroscopy (TRS) system, and then FT was measured by ultrasound. The correction curve was derived from the ratio of partial mean optical path length of the muscle layer 〈L(M)〉 to observed mean optical path length 〈L〉. There was good correlation between FT and 〈L〉 at rest, and 〈L〉 could be used to estimate FT. The estimated FT was used to validate the correction curve by measuring the forearm blood flow (FBF) by strain-gauge plethysmography (SGP_FBF) and TRS (TRS_FBF) simultaneously during a reactive hyperemia test with 16 volunteers. The corrected TRS_FBF results were similar to the SGP_FBF results. This is a simple method for sensitivity correction that does not require use of ultrasound.

Optical imaging for monitoring tumor oxygenation response after initiation of single-agent bevacizumab followed by cytotoxic chemotherapy in breast cancer patients.

PURPOSE: Optical imaging techniques for measuring tissue hemoglobin concentration have been recently accepted as a way to assess tumor vascularity and oxygenation. We investigated the correlation between early optical response to single-agent bevacizumab and treatment outcome. METHODS: Seven patients with advanced or metastatic breast cancer were treated with single-agent bevacizumab followed by addition of weekly paclitaxel. Optical imaging of patient's breasts was performed to measure tumor total hemoglobin concentration (tHb) and oxygen saturation (stO2) at baseline and on days 1, 3, 6, 8, and 13 after the first infusion of bevacizumab. To assess early metabolic response, 2-deoxy-2-(18F)-fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT), 18F-fluoromisonidazole (FMISO)-PET/CT, and magnetic resonance imaging were performed at baseline and after two cycles of the regimen. RESULTS: Seven patients were grouped as responders (n = 4) and nonresponders (n = 3) on the basis of metabolic response measured by FDG-PET/CT. The responders showed remarkable tumor shrinkage and low accumulations of FMISO tracer relative to those of the nonresponders at the completion of two cycles of chemotherapy. Tumors of both groups showed remarkable attenuation of mean tHb as early as day 1 after therapy initiation. The nonresponders had lower baseline stO2 levels compared with adjacent breast tissue stO2 levels along with a pattern of steadily low stO2 levels during the observation window. On the other hand, the responders appeared to sustain high stO2 levels with temporal fluctuation. CONCLUSIONS: Low tumor stO2 level after single-agent bevacizumab treatment was characteristic of the nonresponders. Tumor stO2 level could be a predictor of an additional benefit of bevacizumab over that provided by paclitaxel.

Clinicopathological and prognostic impact of imaging of breast cancer angiogenesis and hypoxia using diffuse optical spectroscopy.

Near-infrared diffuse optical spectroscopy (DOS) imaging can non-invasively measure tumor hemoglobin concentration using high contrast to normal tissue, thus providing vascularity and oxygenation status. We assessed the clinical usefulness of DOS imaging in primary breast cancer. In all, 118 women with a histologically confirmed diagnosis of primary malignant tumor were enrolled. All participants underwent testing using time-resolved DOS before treatment initiation. Visual assessment of DOS imaging for detecting tumors was carried out by two readers blinded to the clinical data. Relative total hemoglobin (rtHb) and oxygen saturation (stO2 ) of the tumors was compared with clinicopathological variables and 10-year prognosis was calculated. Sensitivity for detecting a tumor based on the rtHb breast map was 62.7% (74/118). The sensitivity depended on T stage: 100% (7/7) for T3, 78.9% (45/57) for T2, 44.7% (17/38) for T1, and 31.3% (5/16) for Tis . Tumors showed unique features of higher rtHb with a wider range of stO2 than normal breast tissue, depending on histological type. There was a significant correlation of rtHb with tumor size, lymphatic vascular invasion, and histological grade, and of stO2 with age and tumor size. Neither rtHb nor stO2 correlated with intrinsic biomarkers such as estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2; rtHb inversely correlated with 10-year relapse-free survival and overall survival, with statistical significance. Diffuse optical spectroscopy imaging has limited utility for the early detection of breast cancer; nonetheless, the findings suggest that the degree of tumor angiogenesis and hypoxia may be associated with tumor aggressiveness and poor prognosis.

Optical imaging of tumor vascularity associated with proliferation and glucose metabolism in early breast cancer: clinical application of total hemoglobin measurements in the breast.

BACKGROUND: Near-infrared optical imaging targeting the intrinsic contrast of tissue hemoglobin has emerged as a promising approach for visualization of vascularity in cancer research. We evaluated the usefulness of diffuse optical spectroscopy using time-resolved spectroscopic (TRS) measurements for functional imaging of primary breast cancer. METHODS: Fifty-five consecutive TNM stage I/II patients with histologically proven invasive ductal carcinoma and operable breast tumors (<5 cm) who underwent TRS measurements were enrolled. Thirty (54.5%) patients underwent 18F-fluoro-deoxy-glucose (FDG) positron emission tomography with measurement of maximum tumor uptake. TRS was used to obtain oxyhemoglobin, deoxyhemoglobin, and total hemoglobin (tHb) levels from the lesions, surrounding normal tissue, and contralateral normal tissue. Lesions with tHb levels 20% higher than those present in normal tissue were defined as "hotspots," while others were considered "uniform." The findings in either tumor type were compared with clinicopathological factors. RESULTS: "Hotspot" tumors were significantly larger (P= 0.002) and exhibited significantly more advanced TNM stage (P=0.01), higher mitotic counts (P=0.01) and higher levels of FDG uptake (P=0.0004) compared with "uniform" tumors; however, other pathological variables were not significantly different between the two groups. CONCLUSIONS: Optical imaging for determination of tHb levels allowed for measurement of tumor vascularity as a function of proliferation and glucose metabolism, which may be useful for prediction of patient prognosis and potential response to treatment.

Changes of evoked cerebral blood oxygenation and optical pathlength in the frontal lobe during language tasks: a study by multi-channel, time-resolved near-infrared spectroscopy and functional MRI.

To determine the alterations in optical characteristics and cerebral blood oxygenation (CBO) in the frontal lobe during language tasks, we evaluated the changes in mean optical pathlength (MOP) and CBO induced by a verbal fluency task (VFT) in the right and left frontal lobes in normal adults (n = 9, mean age = 29.6 +/- 4.8 years). We employed a newly developed 8-channel time-resolved near-infrared spectroscopy (TRS) instrument. The results demonstrated differences in MOP in the fronto-temporal areas with subject and wavelength; however, there was no significant difference between the right and left sides (p > 0.05). Also, the VFT did not affect the MOP significantly as compared to that before the tasks (p > 0.05). In all of the recording regions, the VFT caused increases in concentration of oxyhemoglobin and total hemoglobin associated with a decrease in deoxyhemoglobin concentration, indicating that these cortical areas were activated by the VFT. However, the mean concentration changes of oxyhemoglobin and total hemoglobin on the left side were larger than those on the right side. In addition, functional MRI demonstrated that the inferior frontal gyrus on the left side was activated in the subjects who exhibited increases in oxyhemoglobin concentration in these areas. These results suggest that TRS may be useful to study language function and to assess hemispheric dominance for language.

Bedside assessment of cerebral vasospasms after subarachnoid hemorrhage by near infrared time-resolved spectroscopy.

We examined the usefulness of near infrared time-resolved spectroscopy (TRS) for detection of vasospasm in subarachnoid hemorrhage (SAH). We investigated seven aneurysmal SAH patients with poor clinical conditions (WFNS grade V) who underwent endovascular coil embolization. Employing TRS, we measured the oxygen saturation (SO(2)) and baseline hemoglobin concentrations in the cortices. Measurements of TRS and transcranial Doppler sonography (TCD) were performed repeatedly for 14 days after SAH. In four of the seven patients, the SO(2) and hemoglobin concentrations measured in the brain tissue of the middle cerebral artery territory remained stable after SAH. However, in three patients, TRS revealed abrupt decreases in SO(2) and total hemoglobin between 5 and 9 days after SAH. Cerebral angiography performed on the same day revealed severe vasospasms in these patients. Although TCD detected the vasospasm in two of three cases, it failed to do so in one case. TRS could detect vasospasms after SAH by evaluating the cortical blood oxygenation.

Clinical evaluation of time-resolved spectroscopy by measuring cerebral hemodynamics during cardiopulmonary bypass surgery.

We developed a three-wavelength time-resolved spectroscopy (TRS) system, which allows quantitative measurement of hemodynamics within relatively large living tissue. We clinically evaluated this TRS system by monitoring cerebral circulation during cardiopulmonary bypass surgery. Oxyhemoglobin, deoxyhemoglobin, total hemoglobin and oxygen saturation (SO(2)) were determined by TRS on the left forehead attached with an optode spacing of 4 cm. We also simultaneously monitored jugular venous oxygen saturation (SjvO(2)) and arterial blood hematocrit (Hct) using conventional methods. The validity and usefulness of the TRS system were assessed by comparing parameters obtained with the TRS and conventional methods. Although the changes in SO(2) were lower than those in SjvO(2), SO(2) obtained by TRS paralleled the fluctuations in SjvO(2), and a good correlation between these values was observed. The only exceptions occurred during the perfusion period. Moreover, there was a good correlation between tHb and Hct values (r(2)=0.63). We concluded that time-resolved spectroscopy reflected the conditions of cerebral hemodynamics of patients during surgical operations.

Cerebral hemodynamics evaluation by near-infrared time-resolved spectroscopy: correlation with simultaneous positron emission tomography measurements.

We compared pharmacologically-perturbed hemodynamic parameters (cerebral blood volume; CBV, and flow; CBF) by acetazolamide administration in six healthy human subjects studied with positron emission tomography (PET) and near-infrared (NIR) time-resolved spectroscopy (TRS) simultaneously to investigate whether NIR-TRS could measure in vivo hemodynamics in the brain tissue quantitatively. Simultaneously with the PET measurements, TRS measurements were performed at the forehead with four different optode spacing from 2 cm to 5 cm. Total hemoglobin and oxygen saturation (SO2) measured by TRS significantly increased after administration of acetazolamide at any optode spacing in all subjects. In PET study, CBV and CBF were estimated in the following three volumes of interest (VOIs) determined on magnetic resonance images, VOI1: scalp and skull, VOI2: gray matter region, VOI3: gray and white matter regions. Acetazolamide treatment elevated CBF and CBV significantly in VOI2 and VOI3 but VOI1. TRS-derived CBV was more strongly correlated with PET-derived counterpart in VOI2 and VOI3 when the optode spacing was above 4 cm, although optical signal from cerebral tissue could be caught with any optode spacing. As to increase of the CBV, 4 cm of optode spacing correlated best with VOI2. To support the result of TRS-PET experiment, we also estimated the contribution ratios of intracerebral tissue to observed absorption change based on diffusion theory. The contribution ratios at 4 cm were estimated as follows: 761 nm: 50%, 791 nm: 72%, 836 nm: 70%. These results demonstrated that NIR-TRS with 4 cm of optode spacing could measure cerebral hemodynamic responses optimally and quantitatively.

Changes of cerebral blood oxygenation and optical pathlength during activation and deactivation in the prefrontal cortex measured by time-resolved near infrared spectroscopy.

To determine the alterations in optical characteristics and cerebral blood oxygenation (CBO) during activation and deactivation, we evaluated the changes in mean optical pathlength (MOP) and CBO induced by a verbal fluency task (VFT) and driving simulation in the right and left prefrontal cortex (PFC), employing a newly developed time-resolved near infrared spectroscopy, which allows quantitative measurements of the evoked-CBO changes by determining the MOP with a sampling time of 1 s. The results demonstrated differences in MOP in the foreheads with the subjects and wavelength; however, there was no significant difference between the right and left foreheads (p > 0.05). Also, both the VFT and driving simulation task did not affect the MOP significantly as compared to that before the tasks (p > 0.05). In the bilateral PFCs, the VFT caused increases of oxyhemoglobin and total hemoglobin associated with a decrease of deoxyhemoglobin, while the driving simulation task caused decreases of oxyhemoglobin and total hemoglobin associated with an increase of deoxyhemoglobin; there were no significant differences in evoked-CBO changes between the right and left PFC. The present results will be useful for quantitative measurement of hemodynamic changes during activation and deactivation in the adults by near infrared spectroscopy.