Pei-Yi Lin

Cerebral oxygen metabolism in neonatal hypoxic ischemic encephalopathy during and after therapeutic hypothermia

Pathophysiologic mechanisms involved in neonatal hypoxic ischemic encephalopathy (HIE) are associated with complex changes of blood flow and metabolism. Therapeutic hypothermia (TH) is effective in reducing the extent of brain injury, but it remains uncertain how TH affects cerebral blood flow (CBF) and metabolism. Ten neonates undergoing TH for HIE and seventeen healthy controls were recruited from the NICU and the well baby nursery, respectively. A combination of frequency domain near infrared spectroscopy (FDNIRS) and diffuse correlation spectroscopy (DCS) systems was used to non-invasively measure cerebral hemodynamic and metabolic variables at the bedside. Results showed that cerebral oxygen metabolism (CMRO 2i ) and CBF indices (CBF i ) in neonates with HIE during TH were significantly lower than post-TH and age-matched control values. Also, cerebral blood volume (CBV) and hemoglobin oxygen saturation (SO 2 ) were significantly higher in neonates with HIE during TH compared with age-matched control neonates. Post-TH CBV was significantly decreased compared with values during TH whereas SO 2 remained unchanged after the therapy. Thus, FDNIRS–DCS can provide information complimentary to SO 2 and can assess individual cerebral metabolic responses to TH. Combined FDNIRS–DCS parameters improve the understanding of the underlying physiology and have the potential to serve as bedside biomarkers of treatment response and optimization.

Regional and Hemispheric Asymmetries of Cerebral Hemodynamic and Oxygen Metabolism in Newborns

Understanding the evolution of regional and hemispheric asymmetries in the early stages of life is essential to the advancement of developmental neuroscience. By using 2 noninvasive optical methods, frequency-domain near-infrared spectroscopy and diffuse correlation spectroscopy, we measured cerebral hemoglobin oxygenation (SO(2)), blood volume (CBV), an index of cerebral blood flow (CBF(i)), and the metabolic rate of oxygen (CMRO(2i)) in the frontal, temporal, and parietal regions of 70 premature and term newborns. In concordance with results obtained using more invasive imaging modalities, we verified both hemodynamic (CBV, CBF(i), and SO(2)) and metabolic (CMRO(2i)) parameters were greater in the temporal and parietal regions than in the frontal region and that these differences increased with age. In addition, we found that most parameters were significantly greater in the right hemisphere than in the left. Finally, in comparing age-matched males and females, we found that males had higher CBF(i) in most cortical regions, higher CMRO(2i) in the frontal region, and more prominent right-left CBF(i) asymmetry. These results reveal, for the first time, that we can detect regional and hemispheric asymmetries in newborns using noninvasive optical techniques. Such a bedside screening tool may facilitate early detection of abnormalities and delays in maturation of specific cortical areas.

Perioperative cerebral hemodynamics and oxygen metabolism in neonates with single-ventricle physiology

Congenital heart disease (CHD) patients are at risk for neurodevelopmental delay. The etiology of these delays is unclear, but abnormal prenatal cerebral maturation and postoperative hemodynamic instability likely play a role. A better understanding of these factors is needed to improve neurodevelopmental outcome. In this study, we used bedside frequency-domain near infrared spectroscopy (FDNIRS) and diffuse correlation spectroscopy (DCS) to assess cerebral hemodynamics and oxygen metabolism in neonates with single-ventricle (SV) CHD undergoing surgery and compared them to controls. Our goals were 1) to compare cerebral hemodynamics between unanesthetized SV and healthy neonates, and 2) to determine if FDNIRS-DCS could detect alterations in cerebral hemodynamics beyond cerebral hemoglobin oxygen saturation (SO 2). Eleven SV neonates were recruited and compared to 13 controls. Preoperatively, SV patients showed decreased cerebral blood flow (CBFi ), cerebral oxygen metabolism (CMRO 2i ) and SO 2; and increased oxygen extraction fraction (OEF) compared to controls. Compared to preoperative values, unstable postoperative SV patients had decreased CMRO 2i and CBFi , which returned to baseline when stable. However, SO 2 showed no difference between unstable and stable states. Preoperative SV neonates are flow-limited and show signs of impaired cerebral development compared to controls. FDNIRS-DCS shows potential to improve assessment of cerebral development and postoperative hemodynamics compared to SO 2 alone.

Non-invasive Optical Measurement of Cerebral Metabolism and Hemodynamics in Infants

Perinatal brain injury remains a significant cause of infant mortality and morbidity, but there is not yet an effective bedside tool that can accurately screen for brain injury, monitor injury evolution, or assess response to therapy. The energy used by neurons is derived largely from tissue oxidative metabolism, and neural hyperactivity and cell death are reflected by corresponding changes in cerebral oxygen metabolism (CMRO2). Thus, measures of CMRO2 are reflective of neuronal viability and provide critical diagnostic information, making CMRO2 an ideal target for bedside measurement of brain health. Brain-imaging techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) yield measures of cerebral glucose and oxygen metabolism, but these techniques require the administration of radionucleotides, so they are used in only the most acute cases. Continuous-wave near-infrared spectroscopy (CWNIRS) provides non-invasive and non-ionizing radiation measures of hemoglobin oxygen saturation (SO2) as a surrogate for cerebral oxygen consumption. However, SO2 is less than ideal as a surrogate for cerebral oxygen metabolism as it is influenced by both oxygen delivery and consumption. Furthermore, measurements of SO2 are not sensitive enough to detect brain injury hours after the insult 1,2, because oxygen consumption and delivery reach equilibrium after acute transients3. We investigated the possibility of using more sophisticated NIRS optical methods to quantify cerebral oxygen metabolism at the bedside in healthy and brain-injured newborns. More specifically, we combined the frequency-domain NIRS (FDNIRS) measure of SO2 with the diffuse correlation spectroscopy (DCS) measure of blood flow index (CBFi) to yield an index of CMRO2 (CMRO2i) 4,5. With the combined FDNIRS/DCS system we are able to quantify cerebral metabolism and hemodynamics. This represents an improvement over CWNIRS for detecting brain health, brain development, and response to therapy in neonates. Moreover, this method adheres to all neonatal intensive care unit (NICU) policies on infection control and institutional policies on laser safety. Future work will seek to integrate the two instruments to reduce acquisition time at the bedside and to implement real-time feedback on data quality to reduce the rate of data rejection.

Mayer waves reduce the accuracy of estimated hemodynamic response functions in functional near-infrared spectroscopy

Analysis of cerebral hemodynamics reveals a wide spectrum of oscillations ranging from 0.0095 to 2 Hz. While most of these oscillations can be filtered out during analysis of functional near-infrared spectroscopy (fNIRS) signals when estimating stimulus evoked hemodynamic responses, oscillations around 0.1 Hz are an exception. This is due to the fact that they share a common spectral range with typical stimulus evoked hemodynamic responses from the brain. Here we investigate the effect of hemodynamic oscillations around 0.1 Hz on the estimation of hemodynamic response functions from fNIRS data. Our results show that for an expected response of ~1 µM in oxygenated hemoglobin concentration (HbO), Mayer wave oscillations with an amplitude > ~1 µM at 0.1 Hz reduce the accuracy of the estimated response as quantified by a 3 fold increase in the mean squared error and decrease in correlation (R(2) below 0.78) when compared to the true HRF. These results indicate that the amplitude of oscillations at 0.1 Hz can serve as an objective metric of the expected HRF estimation accuracy. In addition, we investigated the effect of short separation regression on the recovered HRF, and found that this improves the recovered HRF when large amplitude 0.1 Hz oscillations are present in fNIRS data. We suspect that the development of other filtering strategies may provide even further improvement.

Reduced cerebral blood flow and oxygen metabolism in extremely preterm neonates with low-grade germinal matrix- intraventricular hemorrhage

Low-grade germinal matrix-intraventricular hemorrhage (GM-IVH) is the most common complication in extremely premature neonates. The occurrence of GM-IVH is highly associated with hemodynamic instability in the premature brain, yet the long-term impact of low-grade GM-IVH on cerebral blood flow and neuronal health have not been fully investigated. We used an innovative combination of frequency-domain near infrared spectroscopy and diffuse correlation spectroscopy (FDNIRS-DCS) to measure cerebral oxygen saturation (SO2) and an index of cerebral blood flow (CBFi) at the infant’s bedside and compute an index of cerebral oxygen metabolism (CMRO2i). We enrolled twenty extremely low gestational age (ELGA) neonates (seven with low-grade GM-IVH) and monitored them weekly until they reached full-term equivalent age. During their hospital stay, we observed consistently lower CBFi and CMRO2i in ELGA neonates with low-grade GM-IVH compared to neonates without hemorrhages. Furthermore, lower CBFi and CMRO2i in the former group persists even after the resolution of the hemorrhage. In contrast, SO2 does not differ between groups. Thus, CBFi and CMRO2i may have better sensitivity than SO2 in detecting GM-IVH-related effects on infant brain development. FDNIRS-DCS methods may have clinical benefit for monitoring the evolution of GM-IVH, evaluating treatment response, and potentially predicting neurodevelopmental outcome.

A Pilot Randomized Controlled Trial of a New Supplementary Food Designed to Enhance Cognitive Performance during Prevention and Treatment of Malnutrition in Childhood

Abstract Background: Cognitive impairment associated with childhood malnutrition and stunting is generally considered irreversible. Objective: The aim was to test a new nutritional supplement for the prevention and treatment of moderate-acute malnutrition (MAM) focused on enhancing cognitive performance. Methods: An 11-wk, village-randomized, controlled pilot trial was conducted in 78 children aged 1–3 or 5–7 y living in villages in Guinea-Bissau. The supplement contained 291 kcal/d for young children and 350 kcal/d for older children and included 5 nutrients and 2 flavan-3-ol–rich ingredients not present in current food-based recommendations for MAM. Local bakers prepared the supplement from a combination of locally sourced items and an imported mix of ingredients, and it was administered by community health workers 5 d/wk. The primary outcome was executive function abilities at 11 wk. Secondary outcomes included additional cognitive measures and changes in z scores for weight (weight-for-age) and height (height-for-age) and hemoglobin concentrations at 11 wk. An index of cerebral blood flow (CBF) was also measured at 11 wk to explore the use of this measurement as a biological index of cognitive impairment. Results: There were no significant differences in any outcome between groups at baseline. There was a beneficial effect of random assignment to the supplement group on working memory at 11 wk in children aged 1–3 y (P < 0.05). This difference contrasted with no effect in older children and was not associated with faster growth rate. In addition, CBF correlated with task-switching performance (P < 0.05). Conclusions: These preliminary data suggest that cognitive impairment can be monitored with measurement of CBF. In addition, the findings provide preliminary data that suggest that it may be possible to improve poor cognitive performance in young children through changes in the nutritional formulation of supplementary foods used to prevent and treat MAM. Powered studies of the new supplement formulation are needed. This trial was registered at clinicaltrials.gov as NCT03017209.

Simultaneous Cerebral Hemodynamics and Blood Flow Measurements to Quantify Cerebral Metabolism in Infants by Near-infrared Spectroscopy

We combine a Continuous-wave NIRS (CWNIRS) system with a Diffuse Correlation Spectroscopy (DCS) system to simultaneously measure hemoglobin concentrations and blood flow to quantify cerebral metabolism changes in infants

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

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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.