Rafael Ceschin

The use of adaptive statistical iterative reconstruction in pediatric head CT: a feasibility study.

BACKGROUND AND PURPOSE: Iterative reconstruction techniques facilitate CT dose reduction; though to our knowledge, no group has explored using iterative reconstruction with pediatric head CT. Our purpose was to perform a feasibility study to assess the use of ASIR in a small group of pediatric patients undergoing head CT. MATERIALS AND METHODS: An Alderson-Rando head phantom was scanned at decreasing 10% mA intervals relative to our standard protocol, and each study was then reconstructed at 10% ASIR intervals. An intracranial region of interest was consistently placed to estimate noise. Our ventriculoperitoneal shunt CT protocol was subsequently modified, and patients were scanned at 20% ASIR with approximately 20% mA reductions. ASIR studies were anonymously compared with older non-ASIR studies from the same patients by 2 attending pediatric neuroradiologists for diagnostic utility, sharpness, noise, and artifacts. RESULTS: The phantom study demonstrated similar noise at 100% mA/0% ASIR (3.9) and 80% mA/20% ASIR (3.7). Twelve pediatric patients were scanned at reduced dose at 20% ASIR. The average CTDIvol and DLP values of the 20% ASIR studies were 22.4 mGy and 338.4 mGy-cm, and for the non-ASIR studies, they were 28.8 mGy and 444.5 mGy-cm, representing statistically significant decreases in the CTDIvol (22.1%, P = .00007) and DLP (23.9%, P = .0005) values. There were no significant differences between the ASIR studies and non-ASIR studies with respect to diagnostic acceptability, sharpness, noise, or artifacts. CONCLUSIONS: Our findings suggest that 20% ASIR can provide approximately 22% dose reduction in pediatric head CT without affecting image quality.

A Multivariate Surface-Based Analysis of the Putamen in Premature Newborns: Regional Differences within the Ventral Striatum

Many children born preterm exhibit frontal executive dysfunction, behavioral problems including attentional deficit/hyperactivity disorder and attention related learning disabilities. Anomalies in regional specificity of cortico-striato-thalamo-cortical circuits may underlie deficits in these disorders. Nonspecific volumetric deficits of striatal structures have been documented in these subjects, but little is known about surface deformation in these structures. For the first time, here we found regional surface morphological differences in the preterm neonatal ventral striatum. We performed regional group comparisons of the surface anatomy of the striatum (putamen and globus pallidus) between 17 preterm and 19 term-born neonates at term-equivalent age. We reconstructed striatal surfaces from manually segmented brain magnetic resonance images and analyzed them using our in-house conformal mapping program. All surfaces were registered to a template with a new surface fluid registration method. Vertex-based statistical comparisons between the two groups were performed via four methods: univariate and multivariate tensor-based morphometry, the commonly used medial axis distance, and a combination of the last two statistics. We found statistically significant differences in regional morphology between the two groups that are consistent across statistics, but more extensive for multivariate measures. Differences were localized to the ventral aspect of the striatum. In particular, we found abnormalities in the preterm anterior/inferior putamen, which is interconnected with the medial orbital/prefrontal cortex and the midline thalamic nuclei including the medial dorsal nucleus and pulvinar. These findings support the hypothesis that the ventral striatum is vulnerable, within the cortico-stiato-thalamo-cortical neural circuitry, which may underlie the risk for long-term development of frontal executive dysfunction, attention deficit hyperactivity disorder and attention-related learning disabilities in preterm neonates.

Abnormal Cerebral Microstructure in Premature Neonates with Congenital Heart Disease

BACKGROUND AND PURPOSE: Abnormal cerebral microstructure has been documented in term neonates with congenital heart disease, portending risk for injury and poor neurodevelopmental outcome. Our hypothesis was that preterm neonates with congenital heart disease would demonstrate diffuse cerebral microstructural abnormalities when compared with critically ill neonates without congenital heart disease. A secondary aim was to identify any association between microstructural abnormalities, white matter injury (eg, punctate white matter lesions), and other clinical variables, including heart lesions. MATERIALS AND METHODS: With the use of tract-based spatial statistics, an unbiased, voxelwise method for analyzing diffusion tensor imaging data, we compared 21 preterm neonates with congenital heart disease with 2 cohorts of neonates without congenital heart disease: 28 term and 27 preterm neonates, identified from the same neonatal intensive care unit. RESULTS: Compared with term neonates without congenital heart disease, preterm neonates with congenital heart disease had microstructural abnormalities in widespread regions of the central white matter. However, 42% of the preterm neonates with congenital heart disease had punctate white matter lesions. When neonates with punctate white matter lesions were excluded, microstructural abnormalities remained only in the splenium. Preterm neonates with congenital heart disease had similar microstructure to preterm neonates without congenital heart disease. CONCLUSIONS: Diffuse microstructural abnormalities were observed in preterm neonates with congenital heart disease, strongly associated with punctate white matter lesions. Independently, regional vulnerability of the splenium, a structure associated with visual spatial function, was observed in all preterm neonates with congenital heart disease.

Early Metabolic Development of Posteromedial Cortex and Thalamus in Humans Analyzed Via In Vivo Quantitative Magnetic Resonance Spectroscopy

The posteromedial cortex (PMC) including the posterior cingulate, retrosplenial cortex, and medial parietal cortex/precuneus is an epicenter of cortical interactions in a wide spectrum of neural activity. Anatomic connections between PMC and thalamic components have been established in animal studies, but similar studies do not exist for the fetal and neonatal period. Magnetic resonance spectroscopy (MRS) allows for noninvasive measurement of metabolites in early development. Using single‐voxel 3‐T MRS, healthy term neonates (n = 31, mean postconception age 41.5 weeks ± 3.8 weeks) were compared with control children (n = 23, mean age 9.4 years ± 5.1 years) and young adults (n = 10, mean age 24.1 years ± 2.6 years). LCModel‐based calculations compared metabolites within medial parietal gray matter (colocalizing to the PMC), posterior thalamus, and parietal white matter voxels. Common metabolic changes existed for neuronal−axonal maturation and structural markers in the PMC, thalamus, and parietal white matter with increasing NAA and glutamate and decreasing myoinositol and choline with age. Key differences in creatine and glucose metabolism were noted in the PMC, in contrast to the thalamic and parietal white matter locations, suggesting a unique role of energy metabolism. Significant parallel metabolite developmental changes of multiple other metabolites including aspartate, glutamine, and glutathione with age were present between PMC and parietal white matter but not between PMC and thalamus. These findings offer insight into the metabolic architecture of the interface between structural and functional topology of brain networks. Further investigation unifying metabolic changes with functional and anatomic pathways may further enhance the understanding of the PMC in posterior default mode network development. J. Comp. Neurol. 522:3717–3732, 2014.

Alterations of resting state networks and structural connectivity in relation to the prefrontal and anterior cingulate cortices in late prematurity.

Late preterm birth is increasingly recognized as a risk factor for cognitive and social deficits. The prefrontal cortex is particularly vulnerable to injury in late prematurity because of its protracted development and extensive cortical connections. Our study examined children born late preterm without access to advanced postnatal care to assess structural and functional connectivity related to the prefrontal cortex. Thirty-eight preadolescents [19 born late preterm (34–36 6/7 weeks gestational age) and 19 at term] were recruited from a developing community in Brazil. Participants underwent neuropsychological testing. Individuals underwent three-dimensional T1-weighted, diffusion-weighted, and resting state functional MRI. Probabilistic tractography and functional connectivity analyses were carried out using unilateral seeds combining the medial prefrontal cortex and the anterior cingulate cortex. Late preterm children showed increased functional connectivity within regions of the default mode, salience, and central-executive networks from both right and left frontal cortex seeds. Decreased functional connectivity was observed within the right parahippocampal region from left frontal seeding. Probabilistic tractography showed a pattern of decreased streamlines in frontal white matter pathways and the corpus callosum, but also increased streamlines in the left orbitofrontal white matter and the right frontal white matter when seeded from the right. Late preterm children and term control children scored similarly on neuropsychological testing. Prefrontal cortical connectivity is altered in late prematurity, with hyperconnectivity observed in key resting state networks in the absence of neuropsychological deficits. Abnormal structural connectivity indicated by probabilistic tractography suggests subtle changes in white matter development, implying disruption of normal maturation during the late gestational period.

Regional vulnerability of longitudinal cortical association connectivity: Associated with structural network topology alterations in preterm children with cerebral palsy

Preterm born children with spastic diplegia type of cerebral palsy and white matter injury or periventricular leukomalacia (PVL), are known to have motor, visual and cognitive impairments. Most diffusion tensor imaging (DTI) studies performed in this group have demonstrated widespread abnormalities using averaged deterministic tractography and voxel-based DTI measurements. Little is known about structural network correlates of white matter topography and reorganization in preterm cerebral palsy, despite the availability of new therapies and the need for brain imaging biomarkers. Here, we combined novel post-processing methodology of probabilistic tractography data in this preterm cohort to improve spatial and regional delineation of longitudinal cortical association tract abnormalities using an along-tract approach, and compared these data to structural DTI cortical network topology analysis. DTI images were acquired on 16 preterm children with cerebral palsy (mean age 5.6 ± 4) and 75 healthy controls (mean age 5.7 ± 3.4). Despite mean tract analysis, Tract-Based Spatial Statistics (TBSS) and voxel-based morphometry (VBM) demonstrating diffusely reduced fractional anisotropy (FA) reduction in all white matter tracts, the along-tract analysis improved the detection of regional tract vulnerability. The along-tract map-structural network topology correlates revealed two associations: (1) reduced regional posterior–anterior gradient in FA of the longitudinal visual cortical association tracts (inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, optic radiation, posterior thalamic radiation) correlated with reduced posterior–anterior gradient of intra-regional (nodal efficiency) metrics with relative sparing of frontal and temporal regions; and (2) reduced regional FA within frontal–thalamic–striatal white matter pathways (anterior limb/anterior thalamic radiation, superior longitudinal fasciculus and cortical spinal tract) correlated with alteration in eigenvector centrality, clustering coefficient (inter-regional) and participation co-efficient (inter-modular) alterations of frontal–striatal and fronto-limbic nodes suggesting re-organization of these pathways. Both along tract and structural topology network measurements correlated strongly with motor and visual clinical outcome scores. This study shows the value of combining along-tract analysis and structural network topology in depicting not only selective parietal occipital regional vulnerability but also reorganization of frontal–striatal and frontal–limbic pathways in preterm children with cerebral palsy. These finding also support the concept that widespread, but selective posterior–anterior neural network connectivity alterations in preterm children with cerebral palsy likely contribute to the pathogenesis of neurosensory and cognitive impairment in this group.

Brain Dysplasia Associated with Ciliary Dysfunction in Infants with Congenital Heart Disease

OBJECTIVE To test for associations between abnormal respiratory ciliary motion (CM) and brain abnormalities in infants with congenital heart disease (CHD) STUDY DESIGN: We recruited 35 infants with CHD preoperatively and performed nasal tissue biopsy to assess respiratory CM by videomicroscopy. Cranial ultrasound scan and brain magnetic resonance imaging were obtained pre- and/or postoperatively and systematically reviewed for brain abnormalities. Segmentation was used to quantitate cerebrospinal fluid and regional brain volumes. Perinatal and perioperative clinical variables were collected. RESULTS A total of 10 (28.5%) patients with CHD had abnormal CM. Abnormal CM was not associated with brain injury but was correlated with increased extraaxial cerebrospinal fluid volume (P < .001), delayed brain maturation (P < .05), and a spectrum of subtle dysplasia including the hippocampus (P < .0078) and olfactory bulb (P < .034). Abnormal CM was associated with higher composite dysplasia score (P < .001), and both were correlated with elevated preoperative serum lactate (P < .001). CONCLUSIONS Abnormal respiratory CM in infants with CHD is associated with a spectrum of brain dysplasia. These findings suggest that ciliary defects may play a role in brain dysplasia in patients with CHD and have the potential to prognosticate neurodevelopmental risks.

Altered Structural and Functional Connectivity in Late Preterm Preadolescence: An Anatomic Seed-Based Study of Resting State Networks Related to the Posteromedial and Lateral Parietal Cortex

Objective Late preterm birth confers increased risk of developmental delay, academic difficulties and social deficits. The late third trimester may represent a critical period of development of neural networks including the default mode network (DMN), which is essential to normal cognition. Our objective is to identify functional and structural connectivity differences in the posteromedial cortex related to late preterm birth. Methods Thirty-eight preadolescents (ages 9–13; 19 born in the late preterm period (≥32 weeks gestational age) and 19 at term) without access to advanced neonatal care were recruited from a low socioeconomic status community in Brazil. Participants underwent neurocognitive testing, 3-dimensional T1-weighted imaging, diffusion-weighted imaging and resting state functional MRI (RS-fMRI). Seed-based probabilistic diffusion tractography and RS-fMRI analyses were performed using unilateral seeds within the posterior DMN (posterior cingulate cortex, precuneus) and lateral parietal DMN (superior marginal and angular gyri). Results Late preterm children demonstrated increased functional connectivity within the posterior default mode networks and increased anti-correlation with the central-executive network when seeded from the posteromedial cortex (PMC). Key differences were demonstrated between PMC components with increased anti-correlation with the salience network seen only with posterior cingulate cortex seeding but not with precuneus seeding. Probabilistic tractography showed increased streamlines within the right inferior longitudinal fasciculus and inferior fronto-occipital fasciculus within late preterm children while decreased intrahemispheric streamlines were also observed. No significant differences in neurocognitive testing were demonstrated between groups. Conclusion Late preterm preadolescence is associated with altered functional connectivity from the PMC and lateral parietal cortex to known distributed functional cortical networks despite no significant executive neurocognitive differences. Selective increased structural connectivity was observed in the setting of decreased posterior interhemispheric connections. Future work is needed to determine if these findings represent a compensatory adaptation employing alternate neural circuitry or could reflect subtle pathology resulting in emotional processing deficits not seen with neurocognitive testing.

Parametric Response Mapping of Apparent Diffusion Coefficient as an Imaging Biomarker to Distinguish Pseudoprogression from True Tumor Progression in Peptide-Based Vaccine Therapy for Pediatric Diffuse Intrinsic Pontine Glioma

BACKGROUND AND PURPOSE: Immune response to cancer therapy may result in pseudoprogression, which can only be identified retrospectively and may disrupt an effective therapy. This study assesses whether serial parametric response mapping (a voxel-by-voxel method of image analysis also known as functional diffusion mapping) analysis of ADC measurements following peptide-based vaccination may help prospectively distinguish progression from pseudoprogression in pediatric patients with diffuse intrinsic pontine gliomas. MATERIALS AND METHODS: From 2009 to 2012, 21 children, 4–18 years of age, with diffuse intrinsic pontine gliomas were enrolled in a serial peptide-based vaccination protocol following radiation therapy. DWI was acquired before immunotherapy and at 6-week intervals during vaccine treatment. Pseudoprogression was identified retrospectively on the basis of clinical and radiographic findings, excluding DWI. Parametric response mapping was used to analyze 96 scans, comparing ADC measures at multiple time points (from the first vaccine to up to 12 weeks after the vaccine was halted) with prevaccine baseline values. Log-transformed fractional increased ADC, fractional decreased ADC, and parametric response mapping ratio (fractional increased ADC/fractional decreased ADC) were compared between patients with and without pseudoprogression, by using generalized estimating equations with inverse weighting by cluster size. RESULTS: Median survival was 13.1 months from diagnosis (range, 6.4–24.9 months). Four of 21 children (19%) were assessed as experiencing pseudoprogression. Patients with pseudoprogression had higher fitted average log-transformed parametric response mapping ratios (P = .01) and fractional decreased ADCs (P = .0004), compared with patients without pseudoprogression. CONCLUSIONS: Serial parametric response mapping of ADC, performed at multiple time points of therapy, may distinguish pseudoprogression from true progression in patients with diffuse intrinsic pontine gliomas treated with peptide-based vaccination.

Developmental synergy between thalamic structure and interhemispheric connectivity in the visual system of preterm infants

Thalamic structural co-variation with cortical regions has been demonstrated in preterm infants, but its relationship to cortical function and severity of non-cystic white matter injury (non-cystic WMI) is unclear. The relationship between thalamic morphology and both cortical network synchronization and cortical structural connectivity has not been established. We tested the hypothesis that in preterm neonates, thalamic volume would correlate with primary cortical visual function and microstructural integrity of cortico-cortical visual association pathways. A total of 80 term-equivalent preterm and 44 term-born infants underwent high-resolution structural imaging coupled with visual functional magnetic resonance imaging or diffusion tensor imaging. There was a strong correlation between thalamic volume and primary visual cortical activation in preterms with non-cystic WMI (r = 0.81, p-value = 0.001). Thalamic volume also correlated strongly with interhemispheric cortico-cortical connectivity (splenium) in preterm neonates with a relatively higher severity of non-cystic WMI (p-value < 0.001). In contrast, there was lower correlation between thalamic volume and intrahemispheric cortico-cortical connectivity, including the inferior longitudinal fasciculus and inferior frontal orbital fasciculus. This study shows distinct temporal overlap in the disruption of thalamo-cortical and interhemispheric cortico-cortical connectivity in preterm infants suggesting developmental synergy between thalamic morphology and the emergence of cortical networks in the last trimester.