Impact of trametinib on the neuropsychological profile of NF1 patients.

PURPOSE: The use of trametinib in the treatment of pediatric low-grade gliomas (PLGG) and plexiform neurofibroma (PN) is being investigated in an ongoing multicenter phase II trial (NCT03363217). Preliminary data shows potential benefits with significant response in the majority of PLGG and PN and an overall good tolerance. Moreover, possible benefits of MEK inhibitor therapy on cognitive functioning in neurofibromatosis type 1 (NF1) were recently shown which supports the need for further evaluation. METHODS: Thirty-six patients with NF1 (age range 3-19 years) enrolled in the phase II study of trametinib underwent a neurocognitive assessment at inclusion and at completion of the 72-week treatment. Age-appropriate Wechsler Intelligence Scales and the Trail Making Test (for children over 8 years old) were administered at each assessment. Paired t-tests and Reliable Change Index (RCI) analyses were performed to investigate change in neurocognitive outcomes. Regression analyses were used to investigate the contribution of age and baseline score in the prediction of change. RESULTS: Stable performance on neurocognitive tests was revealed at a group-level using paired t-tests. Clinically significant improvements were however found on specific indexes of the Wechsler intelligence scales and Trail Making Test, using RCI analyses. No significant impact of age on cognitive change was evidenced. However, lower initial cognitive performance was associated with increased odds of presenting clinically significant improvements on neurocognitive outcomes. CONCLUSION: These preliminary results show a potential positive effect of trametinib on cognition in patients with NF1. We observed significant improvements in processing speed, visuo-motor and verbal abilities. This study demonstrates the importance of including neuropsychological evaluations into clinical trial when using MEK inhibitors for patients with NF1.

Behavioral-play familiarization for non-sedated magnetic resonance imaging in young children with mild traumatic brain injury.

BACKGROUND: Mild traumatic brain injury (mTBI) sustained in early childhood affects the brain at a peak developmental period and may disrupt sensitive stages of skill acquisition, thereby compromising child functioning. However, due to the challenges of collecting non-sedated neuroimaging data in young children, the consequences of mTBI on young children's brains have not been systematically studied. In typically developing preschool children (of age 3-5years), a brief behavioral-play familiarization provides an effective alternative to sedation for acquiring awake magnetic resonance imaging (MRI) in a time- and resource-efficient manner. To date, no study has applied such an approach for acquiring non-sedated MRI in preschool children with mTBI who may present with additional MRI acquisition challenges such as agitation or anxiety. OBJECTIVE: The present study aimed to compare the effectiveness of a brief behavioral-play familiarization for acquiring non-sedated MRI for research purposes between young children with and without mTBI, and to identify factors associated with successful MRI acquisition. MATERIALS AND METHODS: Preschool children with mTBI (n=13) and typically developing children (n=24) underwent a 15-minutes behavioral-play MRI familiarization followed by a 35-minutes non-sedated MRI protocol. Success rate was compared between groups, MRI quality was assessed quantitatively, and factors predicting success were documented. RESULTS: Among the 37 participants, 15 typically developing children (63%) and 10 mTBI (77%) reached the MRI acquisition success criteria (i.e., completing the two first sequences). The success rate was not significantly different between groups (p=.48; 95% CI [-0.36 14.08]; Cramer's V=.15). The images acquired were of high-quality in 100% (for both groups) of the structural images, and 60% (for both groups) of the diffusion images. Factors associated with success included older child age (Β=0.73, p=.007, exp(B)=3.11, 95% CI [1.36 7.08]) and fewer parental concerns (Β=-1.56, p=.02, exp(Β)=0.21, 95% CI [0.05 0.82]) about the MRI procedure. CONCLUSION: Using brief behavioral-play familiarization allows acquisition of high-quality non-sedated MRI in young children with mTBI with success rates comparable to those of non-injured peers.

Longitudinal white matter microstructural changes in pediatric mild traumatic brain injury: An A-CAP study.

In the largest sample studied to date, white matter microstructural trajectories and their relation to persistent symptoms were examined after pediatric mild traumatic brain injury (mTBI). This prospective, longitudinal cohort study recruited children aged 8-16.99 years with mTBI or mild orthopedic injury (OI) from five pediatric emergency departments. Children's pre-injury and 1-month post-injury symptom ratings were used to classify mTBI with or without persistent symptoms. Children completed diffusion-weighted imaging at post-acute (2-33 days post-injury) and chronic (3 or 6 months via random assignment) post-injury assessments. Mean diffusivity (MD) and fractional anisotropy (FA) were derived for 18 white matter tracts in 560 children (362 mTBI/198 OI), 407 with longitudinal data. Superior longitudinal fasciculus FA was higher in mTBI without persistent symptoms relative to OI, d (95% confidence interval) = 0.31 to 0.37 (0.02, 0.68), across time. In younger children, MD of the anterior thalamic radiations was higher in mTBI with persistent symptoms relative to both mTBI without persistent symptoms, 1.43 (0.59, 2.27), and OI, 1.94 (1.07, 2.81). MD of the arcuate fasciculus, -0.58 (-1.04, -0.11), and superior longitudinal fasciculus, -0.49 (-0.90, -0.09) was lower in mTBI without persistent symptoms relative to OI at 6 months post-injury. White matter microstructural changes suggesting neuroinflammation and axonal swelling occurred chronically and continued 6 months post injury in children with mTBI, especially in younger children with persistent symptoms, relative to OI. White matter microstructure appears more organized in children without persistent symptoms, consistent with their better clinical outcomes.

Size-adaptable 13-channel receive array for brain MRI in human neonates at 3 T.

Neonatal brain injury suffered by preterm infants and newborns with some medical conditions can cause significant neurodevelopmental disabilities. MRI is a preferred method to detect these accidents and perform in vivo evaluation of the brain. However, the commercial availability and optimality of receive coils for the neonatal brain is limited, which in many cases leads to images lacking in quality. As extensively demonstrated, receive arrays closely positioned around the scanned part provide images with high signal-to-noise ratios (SNRs). The present work proposes a pneumatic-based MRI receive array that can physically adapt to infant head dimensions from 27-week premature to 1.5 months old. Average SNR increases of up to 68% in the head region and 122% in the cortex region, compared with a 32-channel commercial head coil, were achieved at 3 T. The consistent SNR distribution obtained through the complete coil size range, specifically in the cortex, allows the acquisition of images with similar quality across a range of head dimensions, which is not possible with fixed-size coils due to the variable coil-to-head distance. The risks associated with mechanical pressure on the neonatal head are minimal and the head motion is restricted. The method could be used in coil designs for other age groups, body parts and subjects.

Correlations between near-infrared spectroscopy, perfusion index, and cardiac outputs in extremely preterm infants in the first 72 h of life.

Haemodynamic assessment during the transitional period in preterm infants is challenging. We aimed to describe the relationships between cerebral regional tissue oxygen saturation (CrSO2), perfusion index (PI), echocardiographic, and clinical parameters in extremely preterm infants in their first 72 h of life. Twenty newborns born at < 28 weeks of gestation were continuously monitored with CrSO2 and preductal PI. Cardiac output was measured at H6, H24, H48, and H72. The median gestational age and birth weight were 25.0 weeks (24-26) and 750 g (655-920), respectively. CrSO2 and preductal PI had r values < 0.35 with blood gases, lactates, haemoglobin, and mean blood pressure. Cardiac output significantly increased over the 72 h of the study period. Fifteen patients had at least one episode of low left and/or right ventricular output (RVO), during which there was a strong correlation between CrSO2 and superior vena cava (SVC) flow (at H6 (r = 0.74) and H24 (r = 0.86)) and between PI and RVO (at H6 (r = 0.68) and H24 (r = 0.92)). Five patients had low SVC flow (≤ 40 mL/kg/min) at H6, during which PI was strongly correlated with RVO (r = 0.98). CONCLUSION: CrSO2 and preductal PI are strongly correlated with cardiac output during low cardiac output states. What is Known: • Perfusion index and near-infrared spectroscopy are non-invasive tools to evaluate haemodynamics in preterm infants. • Pre- and postductal perfusion indexes strongly correlate with left ventricular output in term infants, and near-infrared spectroscopy has been validated to assess cerebral oxygenation in term and preterm infants. What is New: • Cerebral regional tissue oxygen saturation and preductal perfusion index were strongly correlated with cardiac output during low cardiac output states. • The strength of the correlation between cerebral regional tissue oxygen saturation, preductal perfusion index, and cardiac output varied in the first 72 h of life, reflecting the complexity of the transitional physiology.

Arterial Spin Labeling Perfusion Magnetic Resonance Imaging Performed in Acute Perinatal Stroke Reveals Hyperperfusion Associated With Ischemic Injury.

BACKGROUND AND PURPOSE: Perfusion-weighted imaging in adults with acute stroke often reveals hypoperfusion in the ischemic core and in a surrounding area of nondiffusion-restricted penumbral tissue. Perinatal stroke is common, but the perfusion pattern is rarely documented. We aimed to describe the perfusion pattern in newborns with perinatal stroke. METHODS: Neonates with clinical features of acute stroke underwent magnetic resonance imaging. Perfusion data were obtained using pseudocontinuous arterial spin labeling. Strokes were classified as arterial, venous, or both. Core infarction was determined by the presence of restricted diffusion on diffusion-weighted imaging. Perfusion-weighted imaging and susceptibility-weighted imaging signal in the ischemic area were visually compared with the homologous region in the contralesional hemisphere. Electroencephalogram data were evaluated for seizure activity. RESULTS: In 25 neonates with acute stroke, 8 of 11 (73%) with arterial ischemic stroke demonstrated hyperperfusion, 1 of 9 (11%) with venous stroke, and 4 of 5 (80%) with both. Hypoperfusion was observed in 3 of 9 (33%) with venous and none with arterial ischemic stroke. Perfusion was normal in 4 of 9 (45%) with venous and 1 of 5 (20%) with both. Twenty-one of 24 patients (88%) with electroencephalogram data had either electrographic seizures or focal sharp waves in the ipsilesional hemisphere (11/11 arterial ischemic stroke, 6/9 venous, and 4/5 both). CONCLUSIONS: Perfusion-weighted imaging can be obtained in neonates with acute stroke and often reveals hyperperfusion in the infarct core. Penumbra in arterial ischemic stroke is seldom found. Hyperperfusion may be caused by poststroke reperfusion or to neuronal hyperexcitability of stroke-associated seizure. Its identification may be useful for consideration of therapy for acute neonatal stroke.

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.

MCOCT: an experimentally and numerically validated, open-source Monte Carlo simulator for optical coherence tomography.

Here, we present MCOCT, a Monte Carlo simulator for optical coherence tomography (OCT), incorporating a Gaussian illumination scheme and bias to increase backscattered event collection. MCOCT optical fluence was numerically compared and validated to an established simulator (MCX) and showed concordance at the focus while diverging slightly with distance to it. MCOCT OCT signals were experimentally compared and validated to OCT signals acquired in tissue-mimicking phantoms with known optical properties and showed a similar attenuation pattern with increasing depth while diverging beyond 1.5 mm and proximal to layer interfaces. MCOCT may help in the design of OCT systems for a wide range of applications.

Development of a semi-automatic segmentation technique based on mean magnetic resonance imaging intensity thresholding for volumetric quantification of plexiform neurofibromas.

Rationale and objectives: Plexiform neurofibromas (PNs) are peripheral nerve tumors that occur in 25-50 % of patients with neurofibromatosis type 1. PNs may have complex, diffused, and irregular shapes. The objective of this work was to develop a volumetric quantification method for PNs as clinical assessment is currently based on unidimensional measurement. Materials and methods: A semi-automatic segmentation technique based on mean magnetic resonance imaging (MRI) intensity thresholding (SSTMean) was developed and compared to a similar and previously published technique based on minimum image intensity thresholding (SSTMini). The performance (volume and computation time) of the two techniques was compared to manual tracings of 15 tumors of different locations, shapes, and sizes. Performance was also assessed using different MRI sequences. Reproducibility was assessed by inter-observer analysis. Results: When compared to manual tracing, quantification performed with SSTMean was not significantly different (mean difference: 1.2 %), while volumes computed by SSTMini were significantly different (p < .0001, mean difference: 13.4 %). Volumes quantified by SSTMean were also significantly different than the ones assessed by SSTMini (p < .0001). Using SSTMean, volumes quantified with short TI inversion recovery, T1-, and T2-weighted imaging were not significantly different. Computation times used by SSTMean and SSTMini were significantly lower than for manual segmentation (p < .0001). The highest difference measured by two users was 8 cm3. Conclusion: Our method showed accuracy compared to a current gold standard (manual tracing) and reproducibility between users. The refined segmentation threshold and the possibility to define multiple regions-of-interest to initiate segmentation may have contributed to its performance. The versatility and speed of our method may prove useful to better monitor volumetric changes in lesions of patients enrolled in clinical trials to assessing response to therapy.

Longitudinal Functional Connectome in Pediatric Concussion: An Advancing Concussion Assessment in Pediatrics Study.

Advanced magnetic resonance imaging (MRI) techniques indicate that concussion (i.e., mild traumatic brain injury) disrupts brain structure and function in children. However, the functional connectivity of brain regions within global and local networks (i.e., functional connectome) is poorly understood in pediatric concussion. This prospective, longitudinal study addressed this gap using data from the largest neuroimaging study of pediatric concussion to date to study the functional connectome longitudinally after concussion as compared with mild orthopedic injury (OI). Children and adolescents (n = 967) 8-16.99 years with concussion or mild OI were recruited from pediatric emergency departments within 48 h post-injury. Pre-injury and 1-month post-injury symptom ratings were used to classify concussion with or without persistent symptoms based on reliable change. Subjects completed a post-acute (2-33 days) and chronic (3 or 6 months via random assignment) MRI scan. Graph theory metrics were derived from 918 resting-state functional MRI scans in 585 children (386 concussion/199 OI). Linear mixed-effects modeling was performed to assess group differences over time, correcting for multiple comparisons. Relative to OI, the global clustering coefficient was reduced at 3 months post-injury in older children with concussion and in females with concussion and persistent symptoms. Time post-injury and sex moderated group differences in local (regional) network metrics of several brain regions, including degree centrality, efficiency, and clustering coefficient of the angular gyrus, calcarine fissure, cuneus, and inferior occipital, lingual, middle occipital, post-central, and superior occipital gyrus. Relative to OI, degree centrality and nodal efficiency were reduced post-acutely, and nodal efficiency and clustering coefficient were reduced chronically after concussion (i.e., at 3 and 6 months post-injury in females; at 6 months post-injury in males). Functional network alterations were more robust and widespread chronically as opposed to post-acutely after concussion, and varied by sex, age, and symptom recovery at 1-month post-injury. Local network segregation reductions emerged globally (across the whole brain network) in older children and in females with poor recovery chronically after concussion. Reduced functioning between neighboring regions could negatively disrupt specialized information processing. Local network metric alterations were demonstrated in several posterior regions that are involved in vision and attention after concussion relative to OI. This indicates that functioning of superior parietal and occipital regions could be particularly susceptibile to the effects of concussion. Moreover, those regional alterations were especially apparent at later time periods post-injury, emerging after post-concussive symptoms resolved in most and persisted up to 6 months post-injury, and differed by biological sex. This indicates that neurobiological changes continue to occur up to 6 months after pediatric concussion, although changes emerge earlier in females than in males. Changes could reflect neural compensation mechanisms.

Quantitative effect of the neonatal fontanel on synthetic near infrared spectroscopy measurements.

Near infrared spectroscopy (NIRS) is a functional imaging technique allowing measurement of local cerebral oxygenation. This modality is particularly adapted to critically ill neonates, as it can be used at the bedside and is a suitable and noninvasive tool for carrying out longitudinal studies. However, NIRS is sensitive to the imaged medium and consequently to the optical properties of biological tissues in which photons propagate. In this study, the effect of the neonatal fontanel was investigated by predicting photon propagation using a probabilistic Monte Carlo approach. Two anatomical newborn head models were created from computed tomography and magnetic resonance images: (1) a realistic model including the fontanel tissue and (2) a model in which the fontanel was replaced by skull tissue. Quantitative change in absorption due to simulated activation was compared for the two models for specific regions of activation and optical arrays simulated in the temporal area. A correction factor was computed to quantify the effect of the fontanel and defined by the ratio between the true and recovered change. The results show that recovered changes in absorption were more precise when determined with the anatomical model including the fontanel. The results suggest that the fontanel should be taken into account in quantification of NIRS responses to avoid misinterpretation in experiments involving temporal areas, such as language or auditory studies.

Speckle contrast reduction through the use of a modally-specific photonic lantern for optical coherence tomography.

A few-mode optical coherence tomography (FM-OCT) system was developed around a 2 × 1 modally-specific photonic lantern (MSPL) centered at 1310 nm. The MSPL allowed FM-OCT to acquire two coregistered images with uncorrelated speckle patterns generated by their specific coherent spread function. Here, we showed that averaging such images in vitro and in vivo reduced the speckle contrast by up to 28% and increased signal-to-noise ratio (SNR) by up to 48% with negligible impact on image spatial resolution. This method is compatible with other speckle reduction techniques to further improve OCT image quality.

Associations between neurological examination at term-equivalent age and cerebral hemodynamics and oxygen metabolism in infants born preterm.

Background: Infants born at 29-36 weeks gestational age (GA) are at risk of experiencing neurodevelopmental challenges. We hypothesize that cerebral hemodynamics and oxygen metabolism measured by bedside optical brain monitoring are potential biomarkers of brain development and are associated with neurological examination at term-equivalent age (TEA). Methods: Preterm infants (N = 133) born 29-36 weeks GA and admitted in the neonatal intensive care unit were enrolled in this prospective cohort study. Combined frequency-domain near infrared spectroscopy (FDNIRS) and diffuse correlation spectroscopy (DCS) were used from birth to TEA to measure cerebral hemoglobin oxygen saturation and an index of microvascular cerebral blood flow (CBF i ) along with peripheral arterial oxygen saturation (SpO2). In combination with hemoglobin concentration in the blood, these parameters were used to derive cerebral oxygen extraction fraction (OEF) and an index of cerebral oxygen metabolism (CMRO2i ). The Amiel-Tison and Gosselin Neurological Assessment was performed at TEA. Linear regression models were used to assess the associations between changes in FDNIRS-DCS parameters from birth to TEA and GA at birth. Logistic regression models were used to assess the associations between changes in FDNIRS-DCS parameters from birth to TEA and neurological examination at TEA. Results: Steeper increases in CBF i (p < 0.0001) and CMRO2i (p = 0.0003) were associated with higher GA at birth. Changes in OEF, CBF i , and CMRO2i from birth to TEA were not associated with neurological examination at TEA. Conclusion: In this population, cerebral FDNIRS-DCS parameters were not associated with neurological examination at TEA. Larger increases in CBF i and CMRO2i from birth to TEA were associated with higher GA. Non-invasive bedside FDNIRS-DCS monitoring provides cerebral hemodynamic and metabolic parameters that may complement neurological examination to assess brain development in preterm infants.

Functional brain connectivity after corrective cardiac surgery for critical congenital heart disease: a preliminary near-infrared spectroscopy (NIRS) report.

Patients with congenital heart disease (CHD) requiring cardiac surgery in infancy are at high risk for neurodevelopmental impairments. Neonatal imaging studies have reported disruptions of brain functional organization before surgery. Yet, the extent to which functional network alterations are present after cardiac repair remains unexplored. This preliminary study aimed at investigating cortical functional connectivity in 4-month-old infants with repaired CHD, using resting-state functional near-infrared spectroscopy (fNIRS). After fNIRS signal frequency decomposition, we compared values of magnitude-squared coherence as a measure of connectivity strength, between 21 infants with corrected CHD and 31 healthy controls. We identified a subset of connections with differences between groups at an uncorrected statistical level of p < .05 while controlling for sex and maternal socioeconomic status, with most of these connections showing reduced connectivity in infants with CHD. Although none of these differences reach statistical significance after FDR correction, likely due to the small sample size, moderate to large effect sizes were found for group-differences. If replicated, these results would therefore suggest preliminary evidence that alterations of brain functional connectivity are present in the months after cardiac surgery. Additional studies involving larger sample size are needed to replicate our data, and comparisons between pre- and postoperative findings would allow to further delineate alterations of functional brain connectivity in this population.

Altered longitudinal structural connectome in paediatric mild traumatic brain injury: an Advancing Concussion Assessment in Paediatrics study.

Advanced diffusion-weighted imaging techniques have increased understanding of the neuropathology of paediatric mild traumatic brain injury (i.e. concussion). Most studies have examined discrete white-matter pathways, which may not capture the characteristically subtle, diffuse and heterogenous effects of paediatric concussion on brain microstructure. This study compared the structural connectome of children with concussion to those with mild orthopaedic injury to determine whether network metrics and their trajectories across time post-injury differentiate paediatric concussion from mild traumatic injury more generally. Data were drawn from of a large study of outcomes in paediatric concussion. Children aged 8-16.99 years were recruited from five paediatric emergency departments within 48 h of sustaining a concussion (n = 360; 56% male) or mild orthopaedic injury (n = 196; 62% male). A reliable change score was used to classify children with concussion into two groups: concussion with or without persistent symptoms. Children completed 3 T MRI at post-acute (2-33 days) and/or chronic (3 or 6 months, via random assignment) post-injury follow-ups. Diffusion-weighted images were used to calculate the diffusion tensor, conduct deterministic whole-brain fibre tractography and compute connectivity matrices in native (diffusion) space for 90 supratentorial regions. Weighted adjacency matrices were constructed using average fractional anisotropy and used to calculate global and local (regional) graph theory metrics. Linear mixed effects modelling was performed to compare groups, correcting for multiple comparisons. Groups did not differ in global network metrics. However, the clustering coefficient, betweenness centrality and efficiency of the insula, cingulate, parietal, occipital and subcortical regions differed among groups, with differences moderated by time (days) post-injury, biological sex and age at time of injury. Post-acute differences were minimal, whereas more robust alterations emerged at 3 and especially 6 months in children with concussion with persistent symptoms, albeit differently by sex and age. In the largest neuroimaging study to date, post-acute regional network metrics distinguished concussion from mild orthopaedic injury and predicted symptom recovery 1-month post-injury. Regional network parameters alterations were more robust and widespread at chronic timepoints than post-acutely after concussion. Results suggest that increased regional and local subnetwork segregation (modularity) and inefficiency occurs across time after concussion, emerging after post-concussive symptom resolve in most children. These differences persist up to 6 months after concussion, especially in children who showed persistent symptoms. While prognostic, the small to modest effect size of group differences and the moderating effects of sex likely would preclude effective clinical application in individual patients.

Longitudinal Gray Matter Trajectories in Pediatric Mild Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: This prospective, longitudinal cohort study examined trajectories of brain gray matter macrostructure after pediatric mild traumatic brain injury (mTBI). METHODS: Children aged 8-16.99 years with mTBI or mild orthopedic injury (OI) were recruited from 5 pediatric emergency departments. Reliable change between preinjury and 1 month postinjury symptom ratings was used to classify mTBI with or without persistent symptoms. Children completed postacute (2-33 days) and/or chronic (3 or 6 months) postinjury T1-weighted MRI, from which macrostructural metrics were derived using automated segmentation. Linear mixed-effects models were used, with multiple comparisons correction. RESULTS: Groups (N = 623; 407 mTBI/216 OI; 59% male; age mean = 12.03, SD = 2.38 years) did not differ in total brain, white, or gray matter volumes or regional subcortical gray matter volumes. However, time postinjury, age at injury, and biological sex-moderated differences among symptom groups in cortical thickness of the angular gyrus, basal forebrain, calcarine cortex, gyrus rectus, medial and posterior orbital gyrus, and the subcallosal area all corrected p < 0.05. Gray matter macrostructural metrics did not differ between groups postacutely. However, cortical thinning emerged chronically after mTBI relative to OI in the angular gyrus in older children (d [95% confidence interval] = -0.61 [-1.15 to -0.08]); and in the basal forebrain (-0.47 [-0.94 to -0.01]), subcallosal area (-0.55 [-1.01 to -0.08]), and the posterior orbital gyrus (-0.55 [-1.02 to -0.08]) in females. Cortical thinning was demonstrated for frontal and occipital regions 3 months postinjury in males with mTBI with persistent symptoms vs without persistent symptoms (-0.80 [-1.55 to -0.05] to -0.83 [-1.56 to -0.10]) and 6 months postinjury in females and younger children with mTBI with persistent symptoms relative to mTBI without persistent symptoms and OI (-1.42 [-2.29 to -0.45] to -0.91 [-1.81 to -0.01]). DISCUSSION: These findings signal little diagnostic and prognostic utility of postacute gray matter macrostructure in pediatric mTBI. However, mTBI altered the typical course of cortical gray matter thinning up to 6 months postinjury, even after symptoms typically abate in most children. Collapsing across symptom status obscured the neurobiological heterogeneity of discrete clinical outcomes after pediatric mTBI. The results illustrate the need to examine neurobiology in relation to clinical outcomes and within a neurodevelopmental framework.

A quantitative method for correlating observations of decreased apparent diffusion coefficient with elevated cerebral blood perfusion in newborns presenting cerebral ischemic insults.

In patients presenting with cerebral ischemic injury, the outcome of injured brain tissue quantified as decreased apparent diffusion coefficient (ADC) may depend on associated alterations in cerebral blood perfusion (CBP). This study proposes a non-biased method to quantify associations between ADC and CBP in newborns with global or focal cerebral ischemia. The study population consisted of nine neonates (age: 0 to 3 days) presenting with clinical and imaging evidence of ischemia (seven with global hypoxic ischemia, and two with focal arterial ischemic stroke) with decreased ADC. Six newborns without diffusion abnormalities on magnetic resonance (MR) imaging served as a comparative cohort (age: 0 days to 4 weeks). All patients underwent MR imaging including diffusion weighted imaging (DWI) to determine ADC and axial arterial spin labeling (ASL) to determine CBP. An algorithm was developed that uses the B0 volume from the DWI raw data as a reference, co-registers the ADC and ASL-CBP data to the B0, generates mask filters, and finally performs a statistical analysis to automatically select regions of interest (ROIs) with ADC or ASL-CBP values that deviate significantly from the rest of the brain. If ROIs are identified in this analysis, the algorithm then evaluates correlation based on ROI location and volume. A significant correlation was found between decreased ADC and elevated ASL-CBP with regions of elevated ASL-CBP typically larger than the corresponding ADC abnormality. The association between decreased diffusivity and increased ASL-CBP suggests that, for this cohort, cerebral ischemia is associated with hyperperfusion.

Quantification of the cortical contribution to the NIRS signal over the motor cortex using concurrent NIRS-fMRI measurements.

Near-Infrared Spectroscopy (NIRS) measures the functional hemodynamic response occurring at the surface of the cortex. Large pial veins are located above the surface of the cerebral cortex. Following activation, these veins exhibit oxygenation changes but their volume likely stays constant. The back-reflection geometry of the NIRS measurement renders the signal very sensitive to these superficial pial veins. As such, the measured NIRS signal contains contributions from both the cortical region as well as the pial vasculature. In this work, the cortical contribution to the NIRS signal was investigated using (1) Monte Carlo simulations over a realistic geometry constructed from anatomical and vascular MRI and (2) multimodal NIRS-BOLD recordings during motor stimulation. A good agreement was found between the simulations and the modeling analysis of in vivo measurements. Our results suggest that the cortical contribution to the deoxyhemoglobin signal change (ΔHbR) is equal to 16-22% of the cortical contribution to the total hemoglobin signal change (ΔHbT). Similarly, the cortical contribution of the oxyhemoglobin signal change (ΔHbO) is equal to 73-79% of the cortical contribution to the ΔHbT signal. These results suggest that ΔHbT is far less sensitive to pial vein contamination and therefore, it is likely that the ΔHbT signal provides better spatial specificity and should be used instead of ΔHbO or ΔHbR to map cerebral activity with NIRS. While different stimuli will result in different pial vein contributions, our finger tapping results do reveal the importance of considering the pial contribution.

Opioid analgesia and temperature regulation are associated with EEG background activity and MRI outcomes in neonates with mild-to-moderate hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia.

BACKGROUND: Therapeutic hypothermia (TH) without sedation may lead to discomfort, which may be associated with adverse consequences in neonates with hypoxic-ischemic encephalopathy (HIE). The aim of this study was to assess the association between level of exposure to opioids and temperature, with electroencephalography (EEG) background activity post-TH and magnetic resonance imaging (MRI) brain injury in neonates with HIE. METHODS: Thirty-one neonates with mild-to-moderate HIE who underwent TH were identified. MRIs were reviewed for presence of brain injury. Quantitative EEG background features including EEG discontinuity index and spectral power densities were calculated during rewarming and post-rewarming periods. Dose of opioids administered during TH and temperatures were collected from the medical charts. Multivariable linear and logistic regression analyses were conducted to assess the associations between cumulative dose of opioids and temperature with EEG background and MRI while adjusting for markers of HIE severity. RESULTS: Higher opioid doses (ß = -0.21, p = 0.02) and reduced skin temperature (ß = 0.14, p < 0.01) were associated with lower EEG discontinuity index recorded post-TH. Higher opioid doses (ß = 0.75, p = 0.01) and reduced skin temperature (ß = -0.39, p = 0.02) were also associated with higher EEG Delta power post-TH. MRI brain injury was observed in 14 patients (45%). In adjusted regression analyses, higher opioid doses (OR = 0.00; 95%CI: 0-0.19; p = 0.01), reduced skin temperature (OR = 41.19; 95%CI: 2.27-747.86; p = 0.01) and reduced cooling device output temperature (OR = 1.91; 95%CI: 1.05-3.48; p = 0.04) showed an association with lower odds of brain injury. CONCLUSIONS: Higher level of exposure to opioids and reduced skin temperature during TH in mild-to-moderate HIE were associated with improved EEG background activity post-TH. Moreover, higher exposure to opioids, reduced skin temperature and reduced device output temperature were associated with lower odds of brain injury on MRI.

All-fiber few-mode optical coherence tomography using a modally-specific photonic lantern.

Optical coherence tomography (OCT) was recently performed using a few-mode (FM) fiber to increase contrast or improve resolution using a sequential time-domain demultiplexing scheme isolating the different interferometric signals of the mode-coupled backscattered light. Here, we present an all-fiber FM-OCT system based on a parallel modal demultiplexing scheme exploiting a novel modally-specific photonic lantern (MSPL). The MSPL allows for maximal fringe visibility for each fiber propagation mode in an all-fiber assembly which provides the robustness required for clinical applications. The custom-built MSPL was designed for OCT at 930 nm and is wavelength-independent over the broad OCT spectrum. We further present a comprehensive coupling model for the interpretation of FM-OCT images using the first two propagation modes of a few-mode fiber, validate its predictions, and demonstrate the technique using in vitro microbead phantoms and ex vivo biological samples.