Cerebral Hemodynamics in High-Risk Neonates Probed by Diffuse Optical Spectroscopies

Advances in medical and surgical care of the critically ill neonates have decreasedmortality, yet a significant number of these neonates suffer from neurodevelopmentaldelays and failure in school. Thus, clinicians are now focusing on prevention ofneurologic injury and improvement of neurocognitive outcome in these high-risk infants. Assessment of cerebral oxygenation, cerebral blood volume, and the regulation of cerebral blood flow (CBF) during the neonatal period is vital for evaluating brain health. Traditional CBF imaging methods fail, however, for both ethical and logistical reasons. In this dissertation, I demonstrate the use of non-invasive optical modalities, i.e., diffuse optical spectroscopy and diffuse correlation spectroscopy, to study cerebral oxygenation and cerebral blood flow in the critically ill neonatal population. The optical techniques utilize near-infrared (NIR) light to probe the static and dynamic physiological properties of deep tissues. Diffuse correlation spectroscopy (DCS) employs the transport of temporal correlation functions of diffusing light to extract relative changes in blood flow in biological tissues. Diffuse optical spectroscopy (DOS) employs the wavelength-dependent attenuation of NIR light to assess the concentrations of the primary chromophores in the tissue, namely oxy- and deoxy-hemoglobin. This dissertation presents both validation and clinical applications of novel diffuse optical spectroscopies in two specific critically ill neonatal populations: very-low birth weight preterm infants,and infants born with complex congenital heart defects. For validation of DCS in neonates, the blood flow index quantified by DCS is shown to correlate well with velocity measurements in the middle cerebral artery acquired by transcranial Doppler ultrasound. In patients with congenital heart defects DCS-measured relative changes in CBF due to hypercapnia agree strongly with relative changes in blood flow in the jugular veins as measured by phase-encoded velocity mapping magnetic resonance. For applications in the clinic, CO2 reactivity in patients with congenital heart defects prior to various stages of reconstructive surgery was quantified; our initial results suggest that CO2 reactivity is not systematically related to brain injury in this population. Additionally, the cerebral effects of various interventions, such as blood transfusion and sodium bicarbonate infusion, were investigated. In preterm infants, monitoring with DCS reveals a resilience of these patients to maintain constant CBF during a small postural manipulation

Upcoming Neurophotonics Status Report

Forthcoming status report articles provide updates on microscopy and on diffuse optical imaging in neurophotonics

Microvascular cerebral hemodynamics in pediatric sickle cell disease with Diffuse Correlation Spectroscopy

Sickle cell disease is a genetic blood disorder that has profound effects on the brain. Chronic anemia combined with both macro- and micro-vascular perfusion abnormalities that arise from stenosis or occlusion of blood vessels, increased blood viscosity, adherence of red blood cells to the vascular endothelium, and impaired autoregulatory mechanisms in sickle cell disease patients all culminate in susceptibility to cerebral infarction. Indeed, the risk of stroke is 250 times higher in children with sickle cell disease than in the general population. Unfortunately, while transcranial Doppler ultrasound (TCD) has been widely clinically adopted to longitudinally monitor macrovascular perfusion in these patients, routine clinical screening of microvascular perfusion abnormalities is challenging with current modalities (e.g., positron emission tomography, magnetic resonance imaging) given their high-cost, requirement for sedation in children \u3c 6y, and need for trained personnel. In this pilot study, we first assess the feasibility of a low-cost, noninvasive optical technique known as Diffuse Correlation Spectroscopy (DCS) to quantify an index of resting-state cortical cerebral blood flow in 11 children with SCD along with 11 sex- and age-matched healthy controls. As expected, blood flow index was significantly higher in sickle subjects compared to healthy controls (p \u3c 0.001). Within sickle subjects, blood flow index was inversely proportional to resting-state arterial hemoglobin levels (p = 0.012), consistent with expected anemia-induced compensatory vasodilation that aims to maintain adequate oxygen delivery to the tissue. Further, in a subset of patients measured with transcranial Doppler ultrasound, DCS-measured blood flow was correlated with TCD-measured blood flow velocity in middle cerebral artery (Rs = 0.68), although the trend was not statistically significant (p=0.11). These results are consistent with those of several previous studies using traditional neuroimaging techniques to quantify cerebral blood flow, suggesting that DCS may be a promising low-cost tool for assessment of tissue-level cerebral blood flow in pediatric sickle cell disease. Finally, given that sickle cell disease is often associated with severe anemia, we next assessed the potentially confounding effects of hematocrit on the DCS-measured blood flow index using a microfluidic tissue-simulating phantom. For a fixed flow rate in the microfluidic channels, we show that blood flow index is inversely correlated with hematocrit, and we present a means to correct the measured blood flow index for hematocrit in anemic conditions

Validation of Diffuse Correlation Spectroscopic Measurement of Cerebral Blood Flow Using Phase-Encoded Velocity Mapping Magnetic Resonance Imaging

Diffuse correlation spectroscopy (DCS) is a novel optical technique that appears to be an excellent tool for assessing cerebral blood flow in a continuous and non-invasive manner at the bedside. We present new clinical validation of the DCS methodology by demonstrating strong agreement between DCS indices of relative cerebral blood flow and indices based on phase-encoded velocity mapping magnetic resonance imaging (VENC MRI) of relative blood flow in the jugular veins and superior vena cava. Data were acquired from 46 children with single ventricle cardiac lesions during a hypercapnia intervention. Significant increases in cerebral blood flow, measured both by DCS and by VENC MRI, as well as significant increases in oxyhemoglobin concentration, and total hemoglobin concentration, were observed during hypercapnia. Comparison of blood flow changes measured by VENC MRI in the jugular veins and by DCS revealed a strong linear relationship, R = 0.88, p \u3c 0.001, slope = 0.91 ± 0.07. Similar correlations were observed between DCS and VENC MRI in the superior vena cava, R = 0.77, slope = 0.99 ± 0.12, p \u3c 0.001. The relationship between VENC MRI in the aorta and DCS, a negative control, was weakly correlated, R = 0.46, slope = 1.77 ± 0.45, p \u3c 0.001

Shedding light on the neonatal brain: probing cerebral hemodynamics by diffuse optical spectroscopic methods

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

The ENIGMA sports injury working group - an international collaboration to further our understanding of sport-related brain injury

Sport-related brain injury is very common, and the potential long-term effects include a wide range of neurological and psychiatric symptoms, and potentially neurodegeneration. Around the globe, researchers are conducting neuroimaging studies on primarily homogenous samples of athletes. However, neuroimaging studies are expensive and time consuming, and thus current findings from studies of sport-related brain injury are often limited by small sample sizes. Further, current studies apply a variety of neuroimaging techniques and analysis tools which limit comparability among studies. The ENIGMA Sports Injury working group aims to provide a platform for data sharing and collaborative data analysis thereby leveraging existing data and expertise. By harmonizing data from a large number of studies from around the globe, we will work towards reproducibility of previously published findings and towards addressing important research questions with regard to diagnosis, prognosis, and efficacy of treatment for sport-related brain injury. Moreover, the ENIGMA Sports Injury working group is committed to providing recommendations for future prospective data acquisition to enhance data quality and scientific rigor

The Canine Oral Microbiome

Determining the bacterial composition of the canine oral microbiome is of interest for two primary reasons. First, while the human oral microbiome has been well studied using molecular techniques, the oral microbiomes of other mammals have not been studied in equal depth using culture independent methods. This study allows a comparison of the number of bacterial taxa, based on 16S rRNA-gene sequence comparison, shared between humans and dogs, two divergent mammalian species. Second, canine oral bacteria are of interest to veterinary and human medical communities for understanding their roles in health and infectious diseases. The bacteria involved are mostly unnamed and not linked by 16S rRNA-gene sequence identity to a taxonomic scheme. This manuscript describes the analysis of 5,958 16S rRNA-gene sequences from 65 clone libraries. Full length 16S rRNA reference sequences have been obtained for 353 canine bacterial taxa, which were placed in 14 bacterial phyla, 23 classes, 37 orders, 66 families, and 148 genera. Eighty percent of the taxa are currently unnamed. The bacterial taxa identified in dogs are markedly different from those of humans with only 16.4% of oral taxa are shared between dogs and humans based on a 98.5% 16S rRNA sequence similarity cutoff. This indicates that there is a large divergence in the bacteria comprising the oral microbiomes of divergent mammalian species. The historic practice of identifying animal associated bacteria based on phenotypic similarities to human bacteria is generally invalid. This report describes the diversity of the canine oral microbiome and provides a provisional 16S rRNA based taxonomic scheme for naming and identifying unnamed canine bacterial taxa

Optical imaging and spectroscopy for the study of the human brain: status report.

This report is the second part of a comprehensive two-part series aimed at reviewing an extensive and diverse toolkit of novel methods to explore brain health and function. While the first report focused on neurophotonic tools mostly applicable to animal studies, here, we highlight optical spectroscopy and imaging methods relevant to noninvasive human brain studies. We outline current state-of-the-art technologies and software advances, explore the most recent impact of these technologies on neuroscience and clinical applications, identify the areas where innovation is needed, and provide an outlook for the future directions