Publications

2018
Sifre, R., Lasch, C., Fenoglio, A., Georgieff, M. K., Wolff, J. J., & Elison, J. T. (2018). Restricted, Repetitive, and Reciprocal Social Behavior in Toddlers Born Small for Gestation Duration. Journal of Pediatrics , 200, 118-124. Publisher's VersionAbstract

Objective

To characterize restricted and repetitive behaviors (RRBs) and reciprocal social behaviors(RSBs) in a large sample of toddlers who represent a range of birth weights and gestation durations.

Study design

A battery of questionnaires characterizing demographic information and measuring RRBs and RSBs were completed by parents of toddlers between the ages of 17-26 months (n = 1589 total; n = 98 preterm). The association between birth weight and/or gestation duration and the primary outcome measures (RRBs and RSBs as ascertained through the Repetitive Behavior Scale for Early Childhood and the Video-Referenced Rating of Reciprocal Social Behavior) were tested by using hierarchical multivariate multiple regression.

Results

Toddlers born preterm and full term did not differ on RRBs or RSBs. However, there were significant associations between birth weight percentile for gestation duration (BPGD) and RRBs (β = −2.1, P = .03), above and beyond the effects of age, sex, and vocabulary production. Similarly, there was a significant association between BPGD and RSBs (β = −1.8, P = .02), above and beyond the effects of age, sex, and vocabulary production.

Conclusions

These findings demonstrate that BPGD better predicted putative antecedents of adverse psychological outcomes—specifically, RRBs and RSBs—than gestation duration alone. These findings provide insight to the link between preterm birth and suboptimal behavioral/psychological outcomes and suggest that high birth weight, which may reflect a more optimal intrauterine environment, may serve as a protective factor irrespective of gestation duration.

2017
Fenoglio, A., Georgieff, M. K., & Elison, J. T. (2017). Social brain circuitry and social cognition in infants born preterm. Journal of Neurodevelopmental Disorders , 9 (27). Publisher's VersionAbstract

Preterm birth is associated with an increased risk of adverse neurologic, psychiatric, and cognitive outcomes. The brain circuits involved in processing social information are critical to all of these domains, but little work has been done to examine whether and how these circuits may be especially sensitive to prematurity. This paper contains a brief summary of some of the cognitive, psychiatric, and social outcomes associated with prematurity, followed by a description of findings from the modest body of research into social-cognitive development in infants and children born preterm. Next, findings from studies of structural and functional brain development in infants born preterm are reviewed, with an eye toward the distinctive role of the brain circuits implicated in social functioning. The goal of this review is to investigate the extent to which the putative “social brain” may have particular developmental susceptibilities to the insults associated with preterm birth, and the role of early social-cognitive development in later neurodevelopmental outcomes. Much work has been done to characterize neurobehavioral outcomes in the preterm population, but future research must incorporate both brain and behavioral measures to identify early biomarkers linked to later emerging social-cognitive clinical impairment in order to guide effective, targeted intervention.

2016
Lin, P. - Y., Hagan, K., Fenoglio, A., Grant, P. E., & Franceschini, M. A. (2016). Reduced cerebral blood flow and oxygen metabolism in extremely preterm neonates with low-grade germinal matrix-intraventricular hemorrhage. Scientific Reports , 6. Publisher's VersionAbstract

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.

2015
Dehaes, M., Cheng, H., Ferradal, S., Buckley, E., Lin, P. - Y., Vyas, R., Hagan, K., et al. (2015). Perioperative Cerebral Hemodynamics and Metabolism in Neonates with Single-Ventricle Physiology. Journal of Cerebral Blood Flow and Metabolism , 36, 162-163. Publisher's VersionAbstract
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 (SO2). Eleven SV neonates were recruited and compared to 13 controls. Preoperatively, SV patients showed decreased cerebral blood flow (CBFi), cerebral oxygen metabolism (CMRO2i) and SO2; and increased oxygen extraction fraction (OEF) compared to controls. Compared to preoperative values, unstable postoperative SV patients had decreased CMRO2i and CBFi, which returned to baseline when stable. However, SO2 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 SO2 alone.
2014
Dehaes, M., Aggarwal, A., Lin, P. - Y., Fortuno, R. C., Fenoglio, A., Roche-Labarbe, N., Soul, J. S., et al. (2014). Cerebral Oxygen Metabolism in Neonatal Hypoxic Ischemic Encephalopathy During and Following Therapeutic Hypothermia. Journal of Cerebral Blood Flow & Metabolism , 34, 87-94. LinkAbstract
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 (CMRO2i) and CBF indices (CBFi) 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 (SO2) 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 SO2 remained unchanged after the therapy. Thus, FDNIRS–DCS can provide information complimentary to SO2 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.
Joseph, R. M., Fricker, Z., Fenoglio, A., Lindgren, K. A., Knaus, T. A., & Tager-Flusberg, H. (2014). Structural asymmetries of language-related gray and white matter and their relationship to language function in young children with ASD. Brain Imaging and Behavior , 8 (1), 60-72. LinkAbstract
Children with autism spectrum disorder (ASD) are highly variable in their language abilities, but the neural bases of these individual differences are poorly understood. Structural magnetic resonance imaging (MRI) and magnetic resonance diffusion tensor imaging (DTI) tractography were used to examine asymmetries in language-related gray- and white-matter and their relationships to language ability in a sample of 20 children with ASD, aged 4–7 years, and a reference sample of 20 typically developing (TD) children, aged 6–11 years. Children with ASD did not differ significantly from TD children in gray matter asymmetries, but were significantly less left-lateralized than TD children in the volume and radial diffusivity (RD) of the arcuate fasciculus (AF). They did not differ in the fractional anisotropy (FA) or the mean or axial diffusivity of the AF. Within the ASD group, exploratory analyses revealed that decreased leftward/increased rightward asymmetry of pars opercularis was associated with higher language ability and bilaterally increased FA and decreased RD of the AF. In conclusion, children with ASD exhibited atypical asymmetry in language-related white-matter structure as well as an atypical pattern of brain-language relationships that suggest that they may meet language milestones and acquire normal language via a different neurodevelopmental trajectory from TD children.
2013
Lin, P. - Y., Roche-Labarbe, N., Dehaes, M., Carp, S., Fenoglio, A., Barbieri, B., Hagan, K., et al. (2013). Non-invasive Optical Measurement of Cerebral Metabolism and Hemodynamics in Neonates. The Journal of Visualized Experiments , 73. LinkAbstract

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 transients 3. 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 (CMRO2i4,5.

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.

Roche-Labarbe, N., Fenoglio, A., Radakrishnan, H., Kocienski-Filip, M., Carp, S. A., Dubb, J., Boas, D. A., et al. (2013). Somatosensory evoked changes in cerebral oxygen consumption measured non-invasively in premature neonates. NeuroImage , 85, 279-286. LinkAbstract

The hemodynamic functional response is used as a reliable marker of neuronal activity in countless studies of brain function and cognition. In newborns and infants, however, conflicting results have appeared in the literature concerning the typical response, and there is little information on brain metabolism and functional activation. Measurement of all hemodynamic components and oxygen metabolism is critical for understanding neurovascular coupling in the developing brain. To this end, we combined multiple near infrared spectroscopy techniques to measure oxy- and deoxy-hemoglobin concentrations, cerebral blood volume (CBV), and relative cerebral blood flow (CBF) in the somatosensory cortex of 6 preterm neonates during passive tactile stimulation of the hand. By combining these measures we estimated relative changes in the cerebral metabolic rate of oxygen consumption (rCMRO(2)). CBF starts increasing immediately after stimulus onset, and returns to baseline before blood volume. This is consistent with the model of pre-capillary arteriole active dilation driving the CBF response, with a subsequent CBV increase influenced by capillaries and veins dilating passively to accommodate the extra blood. rCMRO(2) estimated using the steady-state formulation shows a biphasic pattern: an increase immediately after stimulus onset, followed by a post-stimulus undershoot due to blood flow returning faster to baseline than oxygenation. However, assuming a longer mean transit time from the arterial to the venous compartment, due to the immature vascular system of premature infants, reduces the post-stimulus undershoot and increases the flow/consumption ratio to values closer to adult values reported in the literature. We are the first to report changes in local rCBF and rCMRO(2) during functional activation in preterm infants. The ability to measure these variables in addition to hemoglobin concentration changes is critical for understanding neurovascular coupling in the developing brain, and for using this coupling as a reliable functional imaging marker in neonates.

2012
Roche-Labarbe, N., Fenoglio, A., Aggarwal, A., Dehaes, M., Carp, S., Franceschini, M. A., & Grant, E. P. (2012). Near infrared spectroscopy assessment of cerebral oxygen metabolism in the developing premature brain. Journal of Cerebral Blood Flow & Metabolism , 32 (3), 481-488. LinkAbstract

Little is known about cerebral blood flow, cerebral blood volume (CBV), oxygenation, and oxygen consumption in the premature newborn brain. We combined quantitative frequency-domain near-infrared spectroscopy measures of cerebral hemoglobin oxygenation (SO(2)) and CBV with diffusion correlation spectroscopy measures of cerebral blood flow index (BF(ix)) to determine the relationship between these measures, gestational age at birth (GA), and chronological age. We followed 56 neonates of various GA once a week during their hospital stay. We provide absolute values of SO(2) and CBV, relative values of BF(ix), and relative cerebral metabolic rate of oxygen (rCMRO(2)) as a function of postmenstrual age (PMA) and chronological age for four GA groups. SO(2) correlates with chronological age (r=-0.54, P value ≤0.001) but not with PMA (r=-0.07), whereas BF(ix) and rCMRO(2) correlate better with PMA (r=0.37 and 0.43, respectively, P value ≤0.001). Relative CMRO2 during the first month of life is lower when GA is lower. Blood flow index and rCMRO(2) are more accurate biomarkers of the brain development than SO(2) in the premature newborns.

Lin, P. - Y., Roche-Labarbe, N., Dehaes, M., Fenoglio, A., Grant, E. P., & Franceschini, M. A. (2012). Regional and Hemispheric Asymmetries of Cerebral Hemodynamic and Oxygen Metabolism in Newborns. Cerebral Cortex , 23 (2), 339-348. LinkAbstract

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 (SO2), blood volume (CBV), an index of cerebral blood flow (CBFi), and the metabolic rate of oxygen (CMRO2i) 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, CBFi, and SO2) and metabolic (CMRO2i) 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 CBFi in most cortical regions, higher CMRO2i in the frontal region, and more prominent right–left CBFi 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.