Nadege Roche-Labarbe

Noninvasive optical measures of CBV, StO2, CBF index, and rCMRO2 in human premature neonates' brains in the first six weeks of life

With the causes of perinatal brain injuries still unclear and the probable role of hemodynamic instability in their etiology, bedside monitoring of neonatal cerebral hemodynamics with standard values as a function of age are needed. In this study, we combined quantitative frequency domain near infrared spectroscopy (FD‐NIRS) measures of cerebral tissue oxygenation (StO2) and cerebral blood volume (CBV) with diffusion correlation spectroscopy (DCS) measures of a cerebral blood flow index (CBFix) to test the validity of the CBV‐CBF relationship in premature neonates and to estimate cerebral metabolic rate of oxygen (rCMRO2) with or without the CBFix measurement. We measured 11 premature neonates (28–34 weeks gestational age) without known neurological issues, once a week from one to six weeks of age. In nine patients, cerebral blood velocities from the middle cerebral artery were collected by transcranial Doppler (TCD) and compared with DCS values. Results show a steady decrease in StO2 during the first six weeks of life while CBV remains stable, and a steady increase in CBFix. rCMRO2 estimated from FD‐NIRS remains constant but shows wide interindividual variability. rCMRO2 calculated from FD‐NIRS and DCS combined increased by 40% during the first six weeks of life with reduced interindividual variability. TCD and DCS values are positively correlated. In conclusion, FD‐NIRS combined with DCS offers a safe and quantitative bedside method to assess CBV, StO2, CBF, and rCMRO2 in the premature brain, facilitating individual follow‐up and comparison among patients. A stable CBV‐CBF relationship may not be valid for premature neonates. Hum Brain Mapp, 2010.

NIRS-measured oxy- and deoxyhemoglobin changes associated with EEG spike-and-wave discharges in children

Purpose:  Absence epilepsy is characterized by 3‐Hz generalized spike‐and‐wave discharges (GSWD) on the electroencephalogram, associated with behavioral arrest. It may be severe, and even in childhood benign absence epilepsy cognitive delay is frequent, yet the metabolic/hemodynamic aspects of this kind of epilepsy have not been established. We aimed to determine if the GSWD were related to hemodynamic changes by using a new technique with high temporal resolution: near infrared spectroscopy (NIRS).

Coupled oxygenation oscillation measured by NIRS and intermittent cerebral activation on EEG in premature infants.

Electroencephalography of premature neonates shows a physiological discontinuity of electrical activity during quiet sleep. Near infrared spectroscopy (NIRS) shows spontaneous oscillations of hemoglobin oxygenation and volume. Similar oscillations are visible in term neonates and adults, with NIRS and other functional imaging techniques (fMRI, Doppler, etc.), but are generally thought to result from vasomotion and to be a physiological artifact of limited interest. The origin and possible relationship to neuronal activity of the baseline changes in the NIRS signal have not been established. We carried out simultaneous EEG-NIRS recordings on six healthy premature neonates and four premature neonates presenting neurological distress, to determine whether changes in the concentration of cerebral oxy- and deoxy- and total hemoglobin were related to the occurrence of spontaneous bursts of cerebral electric activity. Bursts of electroencephalographic activity in neonates during quiet sleep were found to be coupled to a transient stereotyped hemodynamic response involving a decrease in oxy-hemoglobin concentration, sometimes beginning a few seconds before the onset of electroencephalographic activity, followed by an increase, and then a return to baseline. This pattern could be either part of the baseline oscillations or superimposed changes to this baseline, influencing its shape and phase. The temporal patterns of NIRS parameters present an unique configuration, and tend to be different between our healthy and pathological subjects. Studies of physiological activities and of the effects of intrinsic regulation on the NIRS signal should increase our understanding of these patterns and EEG-NIRS studies should facilitate the integration of NIRS into the set of clinical tools used in neurology.

High-resolution electroencephalography and source localization in neonates.

Although Electroencephalography (EEG) source localization is being widely used in adults, this promising technique has not yet been applied to newborns because of technical difficulties, such as lack of data concerning the newborn skull conductivity, thickness, and homogeneity. Using a new type of EEG headcap molded on each babys head, we aimed to determine whether this technique could be adapted to neonates, and to evaluate the importance of these technical difficulties. We carried out EEG source reconstruction of the recordings of five neonates using dipole fit algorithm. We used four different head models for each neonate, obtained from individual MRI scans: normal skull thickness and conductivity of 0.0042 S/m; normal thickness and conductivity of 0.33 S/m; increased thickness and conductivity of 0.0042 S/m; and normal thickness and conductivity with a modeled bregma fontanel. Dipole locations were consistent with MRI and clinical data. The mean difference between the dipole locations in the 0.0042 and the 0.33 S/m skull layer models was 11.6 ± 2.5 mm, with an average 29.7% decrease in magnitude for the 0.33 S/m model but no significant changes for the dipoles orientation. Skull layer thickness had a large influence on magnitude, but no significant effect on position and orientation. The mean difference between the dipole locations induced by the modeled fontanel was 2.0 ± 2.1 mm, with an average 2.1% increase in magnitude. Our results show that EEG source localization is feasible in neonates. With further development, the technique may prove useful for neurological evaluation of neonates. Hum Brain Mapp, 2008.

Increased cerebral blood volume and oxygen consumption in neonatal brain injury

With the increasing interest in treatments for neonatal brain injury, bedside methods for detecting and assessing injury status and evolution are needed. We aimed to determine whether cerebral tissue oxygenation (StO2), cerebral blood volume (CBV), and estimates of relative cerebral oxygen consumption (rCMRO2) determined by bedside frequency-domain near-infrared spectroscopy (FD-NIRS) have the potential to distinguish neonates with brain injury from those with non-brain issues and healthy controls. We recruited 43 neonates ≤15 days old and >33 weeks gestational age (GA): 14 with imaging evidence of brain injury, 29 without suspicion of brain injury (4 unstable, 6 stable, and 19 healthy). A multivariate analysis of variance with Newman–Keuls post hoc comparisons confirmed group similarity for GA and age at measurement. StO2 was significantly higher in brain injured compared with unstable neonates, but not statistically different from stable or healthy neonates. Brain-injured neonates were distinguished from all others by significant increases in CBV and rCMRO2. In conclusion, although NIRS measures of StO2 alone may be insensitive to evolving brain injury, increased CBV and rCMRO2 seem to be useful for detecting neonatal brain injury and suggest increased neuronal activity and metabolism occurs acutely in evolving brain injury.

Near-infrared spectroscopy assessment of cerebral oxygen metabolism in the developing premature brain.

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 (SO2) and CBV with diffusion correlation spectroscopy measures of cerebral blood flow index (BFix) 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 SO2 and CBV, relative values of BFix, and relative cerebral metabolic rate of oxygen (rCMRO2) as a function of postmenstrual age (PMA) and chronological age for four GA groups. SO2 correlates with chronological age (r=−0.54, P value 0.001) but not with PMA (r=−0.07), whereas BFix and rCMRO2 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 rCMRO2 are more accurate biomarkers of the brain development than SO2 in the premature newborns.

Somatosensory evoked changes in cerebral oxygen consumption measured non-invasively in premature neonates

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 (rCMRO2). 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. rCMRO2 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 rCMRO2 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.

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.

Assessment of the frequency-domain multi-distance method to evaluate the brain optical properties: Monte Carlo simulations from neonate to adult

The near infrared spectroscopy (NIRS) frequency-domain multi-distance (FD-MD) method allows for the estimation of optical properties in biological tissue using the phase and intensity of radiofrequency modulated light at different source-detector separations. In this study, we evaluated the accuracy of this method to retrieve the absorption coefficient of the brain at different ages. Synthetic measurements were generated with Monte Carlo simulations in magnetic resonance imaging (MRI)-based heterogeneous head models for four ages: newborn, 6 and 12 month old infants, and adult. For each age, we determined the optimal set of source-detector separations and estimated the corresponding errors. Errors arise from different origins: methodological (FD-MD) and anatomical (curvature, head size and contamination by extra-cerebral tissues). We found that the brain optical absorption could be retrieved with an error between 8–24% in neonates and infants, while the error increased to 19–44% in adults over all source-detector distances. The dominant contribution to the error was found to be the head curvature in neonates and infants, and the extra-cerebral tissues in adults.

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.