Methodological considerations on diffusion MRI tractography in infants aged 0-2 years: a scoping review.

Diffusion MRI (dMRI) enables studying the complex architectural organization of the brain's white matter (WM) through virtual reconstruction of WM fiber tracts (tractography). Despite the anticipated clinical importance of applying tractography to study structural connectivity and tract development during the critical period of rapid infant brain maturation, detailed descriptions on how to approach tractography in young infants are limited. Over the past two decades, tractography from infant dMRI has mainly been applied in research settings and focused on diffusion tensor imaging (DTI). Only few studies used techniques superior to DTI in terms of disentangling information on the brain's organizational complexity, including crossing fibers. While more advanced techniques may enhance our understanding of the intricate processes of normal and abnormal brain development and extensive knowledge has been gained from application on adult scans, their applicability in infants has remained underexplored. This may partially be due to the higher technical requirements versus the need to limit scan time in young infants. We review various previously described methodological practices for tractography in the infant brain (0-2 years-of-age) and provide recommendations to optimize advanced tractography approaches to enable more accurate reconstructions of the brain WM's complexity. IMPACT: Diffusion tensor imaging is the technique most frequently used for fiber tracking in the developing infant brain but is limited in capability to disentangle the complex white matter organization. Advanced tractography techniques allow for reconstruction of crossing fiber bundles to better reflect the brain's complex organization. Yet, they pose practical and technical challenges in the fast developing young infant's brain. Methods on how to approach advanced tractography in the young infant's brain have hardly been described. Based on a literature review, recommendations are provided to optimize tractography for the developing infant brain, aiming to advance early diagnosis and neuroprotective strategies.

Assessment of Brain Injury and Brain Volumes after Posthemorrhagic Ventricular Dilatation: A Nested Substudy of the Randomized Controlled ELVIS Trial.

OBJECTIVE: To compare the effect of early and late intervention for posthemorrhagic ventricular dilatation on additional brain injury and ventricular volume using term-equivalent age-MRI. STUDY DESIGN: In the Early vs Late Ventricular Intervention Study (ELVIS) trial, 126 preterm infants ≤34 weeks of gestation with posthemorrhagic ventricular dilatation were randomized to low-threshold (ventricular index >p97 and anterior horn width >6 mm) or high-threshold (ventricular index >p97 + 4 mm and anterior horn width >10 mm) groups. In 88 of those (80%) with a term-equivalent age-MRI, the Kidokoro Global Brain Abnormality Score and the frontal and occipital horn ratio were measured. Automatic segmentation was used for volumetric analysis. RESULTS: The total Kidokoro score of the infants in the low-threshold group (n = 44) was lower than in the high-threshold group (n = 44; median, 8 [IQR, 5-12] vs median 12 [IQR, 9-17], respectively; P < .001). More infants in the low-threshold group had a normal or mildly increased score vs more infants in the high-threshold group with a moderately or severely increased score (46% vs 11% and 89% vs 54%, respectively; P = .002). The frontal and occipital horn ratio was lower in the low-threshold group (median, 0.42 [IQR, 0.34-0.63]) than the high-threshold group (median 0.48 [IQR, 0.37-0.68], respectively; P = .001). Ventricular cerebrospinal fluid volumes could be calculated in 47 infants and were smaller in the low-threshold group (P = .03). CONCLUSIONS: More brain injury and larger ventricular volumes were demonstrated in the high vs the low-threshold group. These results support the positive effects of early intervention for posthemorrhagic ventricular dilatation. TRIAL REGISTRATION: ISRCTN43171322.

Congenital Amegakaryocytic Thrombocytopenia Type II Presenting with Multiple Central Nervous System Anomalies.

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare autosomal recessive bone marrow failure, caused by MPL gene mutations. The combination of CAMT and central nervous system abnormalities is uncommon. We describe a case with a homozygous missense MPL gene mutation and polymicrogyria, underdevelopment of the cerebellum, and multiple intracranial hemorrhages.

Prognostic value of gradient echo T2* sequences for brain MR imaging in preterm infants.

BACKGROUND: Gradient echo T2*-W sequences are more sensitive than T2-W spin-echo sequences for detecting hemorrhages in the brain. OBJECTIVE: The aim of this study is to correlate presence of hemosiderin deposits in the brain of very preterm infants (gestational age <32 weeks) detected by T2*-W gradient echo MRI to white matter injury and neurodevelopmental outcome at 2 years. MATERIALS AND METHODS: In 101 preterm infants, presence and location of hemosiderin were assessed on T2*-W gradient echo MRI performed around term-equivalent age (range: 40-60 weeks). White matter injury was defined as the presence of >6 non-hemorrhagic punctate white matter lesions (PWML), cysts and/or ventricular dilatation. Six infants with post-hemorrhagic ventricular dilatation detected by US in the neonatal period were excluded. Infants were seen for follow-up at 2 years. Univariate and regression analysis assessed the relation between presence and location of hemosiderin, white matter injury and neurodevelopmental outcome. RESULTS: In 38/95 (40%) of the infants, hemosiderin was detected. Twenty percent (19/95) of the infants were lost to follow-up. There was a correlation between hemosiderin in the ventricular wall with >6 PWML (P < 0.001) and cysts (P < 0.001) at term-equivalent age, and with a lower psychomotor development index (PDI) (P=0.02) at 2 years. After correcting for known confounders (gestational age, gender, intrauterine growth retardation and white matter injury), the correlation with PDI was no longer significant. CONCLUSION: The clinical importance of detecting small hemosiderin deposits is limited as there is no independent association with neurodevelopmental outcome.

Feasibility study to unveil the potential: considerations of constrained spherical deconvolution tractography with unsedated neonatal diffusion brain MRI data.

Purpose: The study aimed to (1) assess the feasibility constrained spherical deconvolution (CSD) tractography to reconstruct crossing fiber bundles with unsedated neonatal diffusion MRI (dMRI), and (2) demonstrate the impact of spatial and angular resolution and processing settings on tractography and derived quantitative measures. Methods: For the purpose of this study, the term-equivalent dMRIs (single-shell b800, and b2000, both 5 b0, and 45 gradient directions) of two moderate-late preterm infants (with and without motion artifacts) from a local cohort [Brain Imaging in Moderate-late Preterm infants (BIMP) study; Calgary, Canada] and one infant from the developing human connectome project with high-quality dMRI (using the b2600 shell, comprising 20 b0 and 128 gradient directions, from the multi-shell dataset) were selected. Diffusion tensor imaging (DTI) and CSD tractography were compared on b800 and b2000 dMRI. Varying image resolution modifications, (pre-)processing and tractography settings were tested to assess their impact on tractography. Each experiment involved visualizing local modeling and tractography for the corpus callosum and corticospinal tracts, and assessment of morphological and diffusion measures. Results: Contrary to DTI, CSD enabled reconstruction of crossing fibers. Tractography was susceptible to image resolution, (pre-) processing and tractography settings. In addition to visual variations, settings were found to affect streamline count, length, and diffusion measures (fractional anisotropy and mean diffusivity). Diffusion measures exhibited variations of up to 23%. Conclusion: Reconstruction of crossing fiber bundles using CSD tractography with unsedated neonatal dMRI data is feasible. Tractography settings affected streamline reconstruction, warranting careful documentation of methods for reproducibility and comparison of cohorts.

Small cerebellar hemorrhage in preterm infants: perinatal and postnatal factors and outcome.

The objective of the study is to determine perinatal and postnatal factors that may affect the occurrence of small cerebellar hemorrhage (CBH) and to evaluate the effect of small CBH on neurodevelopmental outcome in very preterm infants. This prospective study in an unselected cohort of very preterm infants was approved by the medical ethics committee, and informed parental consent was obtained. Presence of small CBH (<4 mm) was assessed with magnetic resonance imaging around term equivalent age in 108 preterm infants (<32 weeks gestation). We compared infants with and without small CBH for perinatal and postnatal factors, supratentorial brain injury, and for neurodevelopmental outcome at 2 years corrected age. Follow-up consisted of a neurological examination, mental and developmental assessment (Bayley Scales of Infant Development), and behavior checklist. Univariate and multivariate logistic regression analyses were performed to examine the relationships between variables. Small CBH was diagnosed in 16/108 very preterm infants. Univariate analyses identified gestational age, high-frequency oscillation (HFO) ventilation, and grade 3-4 intraventricular hemorrhage (IVH) as factors associated with small CBH. HFO ventilation and severe IVH were independent predictors of small CBH. We found no association between small CBH and neurodevelopmental outcome at 2 years of age. Small CBH is a frequent finding in preterm infants. These hemorrhages are independently associated with HFO ventilation and severe supratentorial hemorrhage and seem to have a favorable short-term prognosis.

Tractography of white-matter tracts in very preterm infants: a 2-year follow-up study.

AIM: The aim of this study was to determine whether tractography of white-matter tracts can independently predict neurodevelopmental outcome in very preterm infants. METHOD: Out of 84 very preterm infants admitted to a neonatal intensive care unit, 64 (41 males, 23 females; median gestational age 29.1 weeks [range 25.6-31.9]; birthweight 1163 g [range 585-1960]) underwent follow-up at 2 years. Diffusion tensor imaging (DTI) values obtained around term were associated with a neurological examination and mental and psychomotor developmental index scores at 2 years based on the Bayley Scales of Infant Development (version 3). Univariate and logistic regression analyses tested for associations between DTI values and follow-up parameters. Cut-off values predicting motor delay and cerebral palsy (CP) were determined for fractional anisotropy, apparent diffusion coefficient (ADC), and fibre lengths. RESULTS: Infants with psychomotor delay and CP had significantly lower fractional anisotropy values (p=0.002, p=0.04 respectively) and shorter fibre lengths (p=0.02, p=0.02 respectively) of the posterior limb of the internal capsule. Infants with psychomotor delay also had significantly higher ADC values (p=0.03) and shorter fibre lengths (p=0.002) of the callosal splenium. Fractional anisotropy values of the posterior limb of the internal capsule independently predicted motor delay and CP, with sensitivity between 80 and 100% and specificity between 66 and 69%. ADC values of the splenium independently predicted motor delay with sensitivity of 100% and specificity of 65%. INTERPRETATION: Diffusion tensor imaging tractography at term-equivalent age independently predicts psychomotor delay at 2 years of age in preterm infants.

The Association of Dexamethasone and Hydrocortisone with Cerebellar Growth in Premature Infants.

OBJECTIVES: Corticosteroids are used to prevent or treat lung disease of prematurity. While neurological side effects have been reported, detailed effects on cerebellar growth are unknown. This study aimed to compare cerebellar growth in premature infants who received dexamethasone or hydrocortisone to premature infants who did not receive postnatal corticosteroids. STUDY DESIGN: Retrospective case-control study in infants born at a gestational age of <29 weeks and admitted to two level 3 neonatal intensive care units. Exclusion criteria were severe congenital anomalies and cerebellar or severe supratentorial lesions. Infants were treated with dexamethasone (unit 1) or hydrocortisone (unit 2) for chronic lung disease. Controls (unit 1) did not receive postnatal corticosteroids. Sequential head circumference (HC) and ultrasound measurements of transcerebellar diameter (TCD), biparietal diameter (BPD), and corpus callosum-fastigium length (CCFL) were performed until 40 weeks' postmenstrual age (PMA). Growth was assessed using linear mixed models correcting for PMA at measurement, sex, HC z-score at birth, and a propensity score indicating illness severity. Group differences before treatment were assessed using linear regression. RESULTS: 346 infants were included (68 dexamethasone, 37 hydrocortisone, 241 controls). Before starting corticosteroids, TCD, BPD, and HC measurements did not differ between patients and controls at a comparable PMA. After starting treatment, both types of corticosteroid had a negative association with TCD growth. BPD, CCFL, and HC growth were not negatively affected. CONCLUSION: Administration of dexamethasone and hydrocortisone are both associated with impaired cerebellar growth in premature infants without evident negative associations with cerebral growth.

Neurological Surveillance in Moderate-Late Preterm Infants-Results from a Dutch-Canadian Survey.

Preterm birth remains an important cause of abnormal neurodevelopment. While the majority of preterm infants are born moderate-late preterm (MLPT; 32-36 weeks), international and national recommendations on neurological surveillance in this population are lacking. We conducted an observational quantitative survey among Dutch and Canadian neonatal level I-III centres (June 2020-August 2021) to gain insight into local clinical practices on neurological surveillance in MLPT infants. All centres caring for MLPT infants designated one paediatrician/neonatologist to complete the survey. A total of 85 out of 174 (49%) qualifying neonatal centres completed the survey (60 level I-II and 25 level III centres). Admission of MLPT infants was based on infant-related criteria in 78/85 (92%) centres. Cranial ultrasonography to screen the infant's brain for abnormalities was routinely performed in 16/85 (19%) centres, while only on indication in 39/85 (46%). In 57/85 (67%) centres, neurological examination was performed at least once during admission. Of 85 centres, 51 (60%) followed the infants' development post-discharge, with follow-up duration ranging from 1-52 months of age. The survey showed a wide variety in neurological surveillance in MLPT infants among Dutch and Canadian neonatal centres. Given the risk for short-term morbidity and long-term neurodevelopmental disabilities, future studies are required to investigate best practices for in-hospital care and follow-up of MLPT infants.

Improved neonatal brain MRI segmentation by interpolation of motion corrupted slices.

BACKGROUND AND PURPOSE: To apply and evaluate an intensity-based interpolation technique, enabling segmentation of motion-affected neonatal brain MRI. METHODS: Moderate-late preterm infants were enrolled in a prospective cohort study (Brain Imaging in Moderate-late Preterm infants "BIMP-study") between August 2017 and November 2019. T2-weighted MRI was performed around term equivalent age on a 3T MRI. Scans without motion (n = 27 [24%], control group) and with moderate-severe motion (n = 33 [29%]) were included. Motion-affected slices were re-estimated using intensity-based shape-preserving cubic spline interpolation, and automatically segmented in eight structures. Quality of interpolation and segmentation was visually assessed for errors after interpolation. Reliability was tested using interpolated control group scans (18/54 axial slices). Structural similarity index (SSIM) was used to compare T2-weighted scans, and Sørensen-Dice was used to compare segmentation before and after interpolation. Finally, volumes of brain structures of the control group were used assessing sensitivity (absolute mean fraction difference) and bias (confidence interval of mean difference). RESULTS: Visually, segmentation of 25 scans (22%) with motion artifacts improved with interpolation, while segmentation of eight scans (7%) with adjacent motion-affected slices did not improve. Average SSIM was .895 and Sørensen-Dice coefficients ranged between .87 and .97. Absolute mean fraction difference was ≤0.17 for less than or equal to five interpolated slices. Confidence intervals revealed a small bias for cortical gray matter (0.14-3.07 cm3 ), cerebrospinal fluid (0.39-1.65 cm3 ), deep gray matter (0.74-1.01 cm3 ), and brainstem volumes (0.07-0.28 cm3 ) and a negative bias in white matter volumes (-4.47 to -1.65 cm3 ). CONCLUSION: According to qualitative and quantitative assessment, intensity-based interpolation reduced the percentage of discarded scans from 29% to 7%.