Investigating the cerebral physiology of healthy term newborns' brains is important for better understanding perinatal brain injuries, of which the most common etiologies are hypoxia and ischemia. Hence, cerebral blood flow and cerebral oxygenation are important biomarkers of brain health. In this study, we employed a hybrid diffuse optical system consisting of diffuse correlation spectroscopy (DCS) and frequency-domain near infrared spectroscopy (FDNIRS) to measure hemoglobin concentration, oxygen saturation, and indices of cerebral blood flow and metabolism. We measured 30 term infants to assess the optical and physiological characteristics of the healthy neonatal brain in the frontal, temporal, and parietal lobes. We observed higher metabolism in the right hemisphere compared to the left and a positive correlation between gestational age and the level of cerebral hemoglobin concentration, blood volume, and oxygen saturation. Moreover, we observed higher cerebral blood flow and lower oxygen saturation in females compared to males. The delayed maturation in males and the sexual dimorphism in cerebral hemodynamics may explain why males are more vulnerable to perinatal brain injuries than females.

© 2019 Optical Society of America under the terms of the OSA Open Access Publishing Agreement Millimeter-depth sensitivity with frequency domain near-infrared spectroscopy has been challenging due to the breakdown of the diffusion equation for source-detection separations < 1cm. To overcome this challenge, we employ a Monte-Carlo lookup table-based inverse algorithm to fit small separation (3-6 mm) frequency-domain near-infrared spectroscopy (FDNIRS) data for absorption and reduced scattering coefficients. We verify this small separation FDNIRS method through a series of in vitro and in vivo studies. In vitro, we observed a root mean squared percent error (RMSE) in estimation of the reduced scattering coefficient and absorption coefficient of 2.8% and 7.6%, respectively, in liquid phantoms consisting of Intralipid and Indian ink, and a RMSE in estimation of oxygen saturation and total hemoglobin concentrations of 7.8 and 11.2%, respectively, in blood-mixed liquid phantoms. Next, we demonstrate one particularly valuable in vivo application of this technique wherein we non-invasively measure the optical properties of the mouse brain (n = 4). We find that the measured resting state cerebral oxygen saturation and hemoglobin concentration are consistent with literature reported values, and we observe expected trends during a hyper-/hypoxia challenge that qualitatively mimic changes in partial pressure of oxygen (pO2) measured simultaneously with an invasive pO2 sensor. Further, through simulations of the mouse head geometry, we demonstrate that the skull and scalp exert minimal influence on the estimate oxygen saturation, while leading to small but systematic underestimation of total hemoglobin concentration. In total, these results demonstrate the robustness of small separation FDNIRS to assess tissue optical properties at millimeter depth resolution.

Diffuse correlation spectroscopy (DCS) has shown promise as a means to non-invasively measure cerebral blood flow in small animal models. Here, we characterize the validity of DCS at small source-detector reflectance separations needed for small animal measurements. Through Monte Carlo simulations and liquid phantom experiments, we show that DCS error increases as separation decreases, although error remains below 12% for separations > 0.2 cm. In mice, DCS measures of cerebral blood flow have excellent intra-user repeatability and strongly correlate with MRI measures of blood flow (R = 0.74, p<0.01). These results are generalizable to other DCS applications wherein short-separation reflectance geometries are desired.

A correction to this article has been combined with the original pdf PDF versions of this paper and attached. Investigating the cerebral physiology of healthy term newborns’ brains is important for better understanding perinatal brain injuries, of which the most common etiologies are hypoxia and ischemia. Hence, cerebral blood flow and cerebral oxygenation are important biomarkers of brain health. In this study, we employed a hybrid diffuse optical system consisting of diffuse correlation spectroscopy (DCS) and frequency-domain near infrared spectroscopy (FDNIRS) to measure hemoglobin concentration, oxygen saturation, and indices of cerebral blood flow and metabolism. We measured 30 term infants to assess the optical and physiological characteristics of the healthy neonatal brain in the frontal, temporal, and parietal lobes. We observed higher metabolism in the right hemisphere compared to the left and a positive correlation between gestational age and the level of cerebral hemoglobin concentration, blood volume, and oxygen saturation. Moreover, we observed higher cerebral blood flow and lower oxygen saturation in females compared to males. The delayed maturation in males and the sexual dimorphism in cerebral hemodynamics may explain why males are more vulnerable to perinatal brain injuries than females.

Every heartbeat originates from a tiny tissue in the heart called the sinoatrial node (SAN). The SAN harbors only ≈10 000 cardiac pacemaker cells, initiating an electrical impulse that captures the entire heart, consisting of billions of cardiomyocytes for each cardiac contraction. How these rare cardiac pacemaker cells (the electrical source) can overcome the electrically hyperpolarizing and quiescent myocardium (the electrical sink) is incompletely understood. Due to the scarcity of native pacemaker cells, this concept of source–sink mismatch cannot be tested directly with live cardiac tissue constructs. By exploiting TBX18 induced pacemaker cells by somatic gene transfer, 3D cardiac pacemaker spheroids can be tissue-engineered. The TBX18 induced pacemakers (sphTBX18) pace autonomously and drive the contraction of neighboring myocardium in vitro. TBX18 spheroids demonstrate the need for reduced electrical coupling and physical separation from the neighboring ventricular myocytes, successfully recapitulating a key design principle of the native SAN. β-Adrenergic stimulation as well as electrical uncoupling significantly increase sphTBX18s' ability to pace-and-drive the neighboring myocardium. This model represents the first platform to test design principles of the SAN for mechanistic understanding and to better engineer biological pacemakers for therapeutic translation.

Optical studies of ex vivo brain slices where blood is absent show that neural activity is accompanied by significant intrinsic optical signals (IOS) related to activity-dependent scattering changes in neural tissue. However, the neural scattering signals have been largely ignored in vivo in widely-used IOS methods where absorption contrast from hemoglobin was employed. Changes in scattering were observed on a time scale of seconds in previous brain slice IOS studies, similar to the time scale for the hemodynamic response. Therefore, potential crosstalk between the scattering and absorption changes may not be ignored if they have comparable contributions to IOS. In vivo, the IOS changes linked to neural scattering have been elusive. To isolate neural scattering signals in vivo, we employed 2 implantable optodes for small-separation (2 mm) transmission measurements of local brain tissue in anesthetized rats. This unique geometry enables us to separate neuronal activity-related changes in neural tissue scattering from changes in blood absorption based upon the direction of the signal change. The changes in IOS scattering and absorption in response to up-states of spontaneous neuronal activity in cortical or subcortical structures have strong correlation to local field potentials, but significantly different response latencies. We conclude that activity-dependent neural tissue scattering in vivo may be an additional source of contrast for functional brain studies that provides complementary information to other optical or MR-based systems that are sensitive to hemodynamic contrast.