Periventricular White Matter Injury Research Articles

A second dimension of somatosensory system injury? Thalamic volume loss and neuropathic pain in adults with cerebral palsy and periventricular white matter injury.

Lemniscal (motor-related) and spinothalamic (neuropathic pain-related) somatosensory abnormalities affect different subsets of adults with cerebral palsy (CP). Lemniscal/motor abnormalities are associated with posterior thalamic radiation white matter disruption in individuals with CP and white matter injury. We tested the hypothesis that neuropathic pain symptoms in this population are rather associated with injury of the somatosensory (posterior group nuclei) thalamus. In this cross-sectional study, communicative adults with CP and bilateral white matter injury and neurotypical control participants volunteered to self-report pain symptoms and undergo research MRI. Posterior group thalamic nuclei volume was computed and correlated against neuropathic pain scores. Participants with CP (n=6) had, on average, 24% smaller posterior group thalamic volumes (95% CI [10-39%]; corrected p=0.01) than control participants. More severe volume loss was correlated with more severe neuropathic pain scores (ρ=-0.87 [-0.99,-0.20]; p=0.02). Association with thalamic volume loss suggests that neuropathic pain in adults with CP may frequently be central neuropathic pain. Complementing assessments of white matter microstructure, regional brain volumes hold promise as diagnostic biomarkers for central neuropathic pain in individuals with structural brain disorders.

Structure of brain grey and white matter in infants with spastic cerebral palsy and periventricular white matter injury.

To investigate the possible covariation of grey matter volume (GMV) and white matter fractional anisotropy in infants with spastic cerebral palsy (CP) and periventricular white matter injury. Thirty-nine infants with spastic CP and 25 typically developing controls underwent structural magnetic resonance imaging and diffusion tensor imaging. Multimodal canonical correlation analysis with joint independent component analysis were used to capture differences in GMV and fractional anisotropy between groups. Correlation analysis was performed between imaging findings and clinical features. Infants with spastic CP showed one joint group-discriminating component (i.e. GMV-fractional anisotropy) associated with regions in the cortico-basal ganglia-thalamo-cortical loop and in the corpus callosum compared to typically developing controls and one modality-specific group-discriminating component (i.e. GMV). Significant negative correlations were found between loadings in certain regions and the motor function score in spastic CP. In infants with spastic CP, covarying GMV-fractional anisotropy and altered GMV in specific regions were implicated in motor dysfunction, which confirmed that simultaneous GMV and fractional anisotropy changes underly motor deficits, but might also extend to sensory, cognitive, or visual dysfunction. These findings also suggest that multimodal fusion analysis allows for a more comprehensive understanding of the relevance between grey and white matter structures and its crucial role in the neuropathological mechanisms of spastic CP.

Pharmacological blockade of the interleukin-1 receptor suppressed Escherichia coli lipopolysaccharide-induced neuroinflammation in preterm fetal sheep

Intraamniotic inflammation is associated with preterm birth, especially in cases occurring before 32 weeks' gestation, and is causally linked with an increased risk for neonatal mortality and morbidity. Targeted anti-inflammatory interventions may assist in improving the outcomes for pregnancies impacted by intrauterine inflammation. Interleukin-1 is a central upstream mediator of inflammation. Accordingly, interleukin-1 is a promising candidate target for intervention therapies and has been targeted previously using the interleukin-1 receptor antagonist, anakinra. Recent studies have shown that the novel, noncompetitive, allosteric interleukin-1 receptor inhibitor, rytvela, partially resolved inflammation associated with preterm birth and fetal injury. In this study, we used a preterm sheep model of chorioamnionitis to investigate the anti-inflammatory efficacy of rytvela and anakinra, administered in the amniotic fluid in the setting of intraamniotic Escherichia coli lipopolysaccharide exposure. We hypothesized that both rytvela and anakinra would reduce lipopolysaccharide-induced intrauterine inflammation and protect the fetal brain. Ewes with a singleton fetus at 105 days of gestation (term is ∼150 days) were randomized to one of the following groups: (1) intraamniotic injections of 2 mL saline at time=0 and time=24 hours as a negative control group (saline group, n=12); (2) intraamniotic injection of 10 mg Escherichia coli lipopolysaccharide in 2 mL saline and intraamniotic injections of 2 mL saline at time=0 hours and time=24 hours as an inflammation positive control group (lipopolysaccharide group, n=11); (3) intraamniotic injection of Escherichia coli lipopolysaccharide in 2 mL saline and intraamniotic injections of 2.5 mg rytvela at time=0 hours and time=24 hours to test the anti-inflammatory efficacy of rytvela (lipopolysaccharide + rytvela group, n=10); or (4) intraamniotic injection of Escherichia coli lipopolysaccharide in 2 mL saline and intraamniotic injections of 100 mg anakinra at time=0 hours and time=24 hours to test the anti-inflammatory efficacy of anakinra (lipopolysaccharide + anakinra group, n=12). Amniotic fluid was sampled at time 0, 24, and 48 hours (ie, at each intervention and at delivery). Fetal umbilical cord blood was collected at delivery for differential blood counts and chemical studies. Inflammation was characterized by the analysis of fetal tissue cytokine and chemokine levels using quantitative polymerase chain reaction, enzyme-linked inmmunosorbent assay, and histology. The primary study outcome of interest was the assessment of anakinra and rytvela brain-protective effects in the setting of Escherichia coli lipopolysaccharide-induced intrauterine inflammation. Secondary outcomes of interest were to assess protection from fetal and intrauterine (ie, amniotic fluid, chorioamnion) inflammation. Intraamniotic administration of lipopolysaccharide caused inflammation of the fetal lung, brain, and chorioamnionitis in preterm fetal sheep. Relative to treatment with saline only in the setting of lipopolysaccharide exposure, intraamniotic administration of both rytvela and anakinra both significantly prevented periventricular white matter injury, microglial activation, and histologic chorioamnionitis. Anakinra showed additional efficacy in inhibiting fetal lung myeloperoxidase activity, but its use was associated with metabolic acidaemia and reduced fetal plasma insulin-like growth factor-1 levels at delivery. Intraamniotic administration of rytvela or anakinra significantly inhibited fetal brain inflammation and chorioamnionitis in preterm fetal sheep exposed to intraamniotic lipopolysaccharide. In addition, anakinra treatment was associated with potential negative impacts on the developing fetus.

Kaempferol improves periventricular white matter injury in premature infants by inhibiting microglial activation

This study mainly explored the mechanism by which kaempferol inhibits the activation of microglia, thereby improving periventricular white matter injury (WMI) in premature infants. Firstly, WMI model of premature rats was herein established and assigned into WMI model group, kaempferol group, hypoxia-inducible factor 1 (HIF-1) group and kaempferol group+HIF-1 group. Four pups were taken from each group for swimming test and open field test to detect the behavioral function. hematoxylin-eosin staining (HE) staining assessed lateral ventricles along with expressions of HIF-1α gene and protein related to myelination and activation of microglial cells. Kaempferol promoted the recovery of early motor function after WMI around the pups through the HIF-1 pathway. Compared with WMI model group, kaempferol group, HIF-1 group, and kaempferol group+HIF-1 group rats had significantly reduced lateral ventricle area after drug intervention, especially in the kaempferol group+HIF-1 group, where it was decreased most significantly (all P <0.05). Moreover, Kaempferol reduced the expression of HIF-1α and had an effect on mRNA expression of myelin-related genes [Myelin basic protein (MBP) Multiepitope antigenic gene (MAG), myelin oligodendrocyte glycoprotein (MOG) and Recombinant Early Growth Response Protein 1 (EGR1) in the brain tissue of offspring rats. The number of activated microglial cells in the cingulate gyrus and corpus callosum of WMI model group were significantly increased and reduced after drug intervention, especially in the kaempferol group+HIF-1 group (P <0.05). Kaempferol reduced HIF-1α expression by inhibiting HIF-1 pathway, so as to inhibit microglial cell activation, which is related to its significant anti-inflammatory and anti-oxidative pharmacological mechanism with promising brain protection effect, which provides a new direction for drug treatment of WMI.

Perspectives : Understanding the Pathophysiology of Intraventricular Hemorrhage in Preterm Infants and Considering of the Future Direction for Treatment.

Remarkable advances in neonatal care have significantly improved the survival of extremely low birth weight infants in recent years. However, intraventricular hemorrhage (IVH) continues to be a major complication in preterm infants, leading to a high incidence of cerebral palsy and cognitive impairment. IVH is primarily caused by disruption of the fragile vascular network of the subependymal germinal matrix, and subsequent ventricular dilatation adversely affects the developing infant brain. Based on recent research, periventricular white matter injury is caused not only by ischemia and morphological distortion due to ventricular dilatation but also by free iron and inflammatory cytokines derived from hematoma and its lysates. The current guidelines for the treatment of posthemorrhagic hydrocephalus (PHH) in preterm infants do not provide strong recommendations, but initiating treatment intervention based on ultrasound measurement values before the appearance of clinical symptoms of PHH has been proposed. Moreover, in the past decade, therapeutic interventions that actively remove hematomas and lysates have been introduced. The era is moving beyond cerebrospinal fluid shunt toward therapeutic goals aimed at improving neurodevelopmental outcomes.

Relationship between gross motor function and magnetic resonance imaging findings in children with cerebral palsy

This cross-sectional study was carried out at the department of Pediatric Neurology, Institute of Pediatric Neurodisorder and Autism, Bangabandhu Sheikh Mujib Medical University, Dhaka with the aim to assess the relationship between gross motor function and MRI findings in children with cerebral palsy. The duration of the study was 12 months. All the cerebral palsy cases who met the selection criteria were enrolled. Detailed history taking and physical examination was done. The gross motor function of all cases was evaluated according to Gross Motor Function Classification System- Expanded and Revised (GMECS-E and R). Magnetic resonance imaging of brain was done in all enrolled patients and reports were evaluated. MRI findings were classified as maldevelopment, cortical and subcortical gray matter lesion, periventricular white matter injury, basal ganglia lesion, normal and other findings. A total of 45 children with cerebral palsy aged between 2 to 12 years were included in this study. Mean age of the children was 4.73 (+3.17) years. Male were 31 and female were 14 in number. Functionally majority patients were in GMFCS level IV (26.7%) and level V (20%). MRI findings were abnormal in 35 (77.78%) cases. Most common abnormal MRI finding was cortical and subcortical grey matter lesions 22 (48.9%). This study revealed that cortical and subcortical gray matter lesions were significantly associated with higher level of GMFCS (IV-V) (P=0.038) and maldevelopment of brain were also significantly associated with higher level of GMFCS (P=0.01). Normal MRI findings had significant association with mild to moderate GMFCS level (I-III) (P=0.012). From this study significant relationship was found between gross motor function and MRI of brain findings in children with cerebral palsy. Bangabandhu Sheikh Mujib Medical University Journal 2022;15(4):8-15

Risk Factors for Term-Born Periventricular White Matter Injury in Children With Cerebral Palsy: A Case-Control Study.

The aim of this study was to identify possible risk factors associated with term-born children with cerebral palsy (CP) and periventricular white matter injury (PVWMI) on imaging. This is a case-controlled study restricted to term-born children with CP with the cases extracted from the Canadian Cerebral Palsy Registry and controls from Alberta Pregnancy Outcomes and Nutrition (APrON) study. A diagnosis of PVWMI was performed based on expert categorization of MRI reports. Risk factor variables were selected a priori; these included pregnancy complications, antenatal toxin exposure, perinatal infection, sex, small for gestational age, and perinatal adversity (i.e., neonatal encephalopathy presumably on the basis of intrapartum hypoxia-ischemia). We used multivariable analyses to calculate odds ratios (ORs) and their 95% CIs. A total of 160 cases (7.06% of the registry sample) were compared with 1,950 controls. Of the term-born PVWMI participants, 59.4% were male and 13.5% were born to mothers of extreme maternal age. Multivariable analysis of each risk factor controlled for weight showed PVWMI is associated with pregnancy complications (OR = 3.35; 95% CI = 2.23-4.94), antenatal toxin exposure (OR = 2.45; 95% CI = 1.67-3.55), perinatal infection (OR = 3.61; 95% CI = 1.96-6.29), and perinatal adversity (OR = 2.03; 95% CI = 1.42-2.94). Term-born male participants were not more likely to experience PVWMI compared with female participants (OR = 1.37; 95% CI = 0.98-1.93). Multiple regression analyses suggested independent associations between PVWMI and pregnancy complications (OR = 3.75; 95% CI 2.46-5.62), antenatal toxin exposure (OR = 2.80; 95% CI 1.88-4.12), perinatal infection (OR = 4.62; 95% CI 2.46-8.42), and perinatal adversity (OR = 2.49; 95% CI = 1.71-3.69). Risk factors such as pregnancy complications, antenatal toxin exposure, perinatal infection, and perinatal adversity are associated with PVWMI in term-born children, suggesting perhaps variable interactions between antenatal and perinatal factors to yield this under-recognized CP phenotype.

P.086 Risk factors for term born periventricular white matter injury in children with cerebral palsy: a case control study

Background: The aim of this study was to identify possible risk factors associated with term-born newborns with cerebral palsy and PWMI on imaging. Methods: This is a case-controlled study with cases from the Canadian Cerebral Palsy Registry and controls from Alberta Pregnancy Outcomes and Nutrition Study. PWMI was diagnosed based on MRI reports and 160 cases were compared to 1950 controls. Risk factor were selected a priori; including pregnancy complications, toxin exposure, perinatal infection, sex, small for gestational age, and perinatal adversity. Multivariate regression binomial model was used to calculate odds ratios(OR) and 95% confidence intervals(CI). Results: Multivariable analyses suggested PWMI was associated with pregnancy complications(OR=3.35; 95% CI=2.23-4.94), antenatal toxin exposure(OR=2.45; 95% CI=1.67-3.55), perinatal infection(OR=3.61; 95% CI=1.96-6.29) and perinatal adversity(OR=2.03; 95% CI=1.42-2.94). Term born males were not more likely to have PWMI compared to females(OR=1.37; 95% CI=0.98-1.93). Multiple regression analyses suggested independent associations between PWMI and pregnancy complications(OR=3.63; 95% CI 2.40-5.40), antenatal toxin exposure(OR=2.62; 95% CI 1.77-3.84), perinatal infection(OR=3.42; 95% CI 1.83-6.05) and perinatal adversity(OR=2.49; 95% CI= 1.71-3.69). Conclusions: Risk factors such as pregnancy complications, toxin exposure, perinatal infection and perinatal adversity are associated with PWMI in term-borns, suggesting a ‘two-hit’ model that could involve an interaction among both antenatal and perinatal variables.

Spotlight on the January 25 Issue

#### Notable in Neurology This Week This issue features an article that investigates the roles of cerebrovascular collaterals in children with stroke; another explores how physical activity affects the association of air pollution with brain volume. A featured Special Article examines ethical considerations for the use of aducanumab to treat Alzheimer disease. ### Microstructural Periventricular White Matter Injury in Post-hemorrhagic Ventricular Dilation ![Graphic][1]</img> In a cohort of very preterm infants, diffusion basis spectrum imaging (DBSI) showed that infants with post-hemorrhagic hydrocephalus (PHH) had more severe white matter … [1]: /embed/inline-graphic-1.gif

Microstructural Periventricular White Matter Injury in Post-hemorrhagic Ventricular Dilatation.

The neurologic deficits of neonatal post-hemorrhagic hydrocephalus (PHH) have been linked to periventricular white matter injury. To improve understanding of PHH-related injury, diffusion basis spectrum imaging (DBSI) was applied in neonates, modeling axonal and myelin integrity, fiber density, and extrafiber pathologies. Objectives included characterizing DBSI measures in periventricular tracts, associating measures with ventricular size, and examining MRI findings in the context of postmortem white matter histology from similar cases. A prospective cohort of infants born very preterm underwent term equivalent MRI, including infants with PHH, high-grade intraventricular hemorrhage without hydrocephalus (IVH), and controls (very preterm [VPT]). DBSI metrics extracted from the corpus callosum, corticospinal tracts, and optic radiations included fiber axial diffusivity, fiber radial diffusivity, fiber fractional anisotropy, fiber fraction (fiber density), restricted fractions (cellular infiltration), and nonrestricted fractions (vasogenic edema). Measures were compared across groups and correlated with ventricular size. Corpus callosum postmortem immunohistochemistry in infants with and without PHH assessed intra- and extrafiber pathologies. Ninety-five infants born very preterm were assessed (68 VPT, 15 IVH, 12 PHH). Infants with PHH had the most severe white matter abnormalities and there were no consistent differences in measures between IVH and VPT groups. Key tract-specific white matter injury patterns in PHH included reduced fiber fraction in the setting of axonal or myelin injury, increased cellular infiltration, vasogenic edema, and inflammation. Specifically, measures of axonal injury were highest in the corpus callosum; both axonal and myelin injury were observed in the corticospinal tracts; and axonal and myelin integrity were preserved in the setting of increased extrafiber cellular infiltration and edema in the optic radiations. Increasing ventricular size correlated with worse DBSI metrics across groups. On histology, infants with PHH had high cellularity, variable cytoplasmic vacuolation, and low synaptophysin marker intensity. PHH was associated with diffuse white matter injury, including tract-specific patterns of axonal and myelin injury, fiber loss, cellular infiltration, and inflammation. Larger ventricular size was associated with greater disruption. Postmortem immunohistochemistry confirmed MRI findings. These results demonstrate DBSI provides an innovative approach extending beyond conventional diffusion MRI for investigating neuropathologic effects of PHH on neonatal brain development.

Impact of sex differences on thrombin-induced hydrocephalus and white matter injury: the role of neutrophils

BackgroundThrombin has been implicated in playing a role in hydrocephalus development following intraventricular hemorrhage (IVH). However, the mechanisms underlying the sex differences to the detrimental effects of thrombin post-IVH remain elusive.MethodThree-month old male and female Sprague-Dawley rats underwent unilateral intracerebroventricular (ICV) injections of 3U or 5U thrombin, or saline, to examine differences in thrombin-induced hydrocephalus and white matter injury. Mortality, and lateral ventricle volume and white matter injury were measured on magnetic resonance imaging evaluation at 24 h post-injection. In addition, male rats were pretreated with 17-β estradiol (E2, 5 mg/kg) or vehicle at 24 and 2 h prior to ICV injection of 3U thrombin. All rats were euthanized at 24 h post-injection for histology and immunohistochemistry.ResultsICV injection of 5U thrombin caused 100 and 0% mortality in female and male rats, respectively. 3U of thrombin resulted in significant ventricular dilation and white matter damage at 24 h in both male and female rats, but both were worse in females (p < 0.05). Furthermore, neutrophil infiltration into choroid plexus and periventricular white matter was enhanced in female rats and may play a critical role in the sex difference in brain injury. Pre-treating male rats with E2, increased thrombin (3U)-induced hydrocephalus, periventricular white matter injury and neutrophil infiltration into the choroid plexus and white matter.ConclusionsICV thrombin injection induced more severe ventricular dilation and white matter damage in female rats compared to males. Estrogen appears to contribute to this difference which may involve greater neutrophil infiltration in females. Understanding sex differences in thrombin-induced brain injury may shed light on future interventions for hemorrhagic stroke.

Neuroradiologic Features Associated With Severe Restriction of Functional Mobility in Children With Cerebral Palsy in North India.

Few studies have focused on magnetic resonance imaging (MRI) brain findings associated with functional mobility in cerebral palsy. To determine association between MRI findings and Gross Motor Functional Classification System (GMFCS) levels in cerebral palsy. Prospective-observational study conducted in Pediatric Neurology Clinic at a public teaching hospital, Northern India. First 3 new cases of cerebral palsy were enrolled on particular neuro-clinic day per week for 1 year. Functional mobility was classified according to GMFCS. Association between MRI findings, cerebral palsy type, and GMFCS levels were evaluated using χ2 test. A total of 138 cases (mean age 2.71 [SD = 1.91] years; male [64.5%]) were enrolled. Reported types of cerebral palsy were as follows: spastic quadriplegia (47.8%), spastic diplegia (28.35%), spastic hemiplegia (11.6%), extrapyramidal (6.5%), and ataxic/hypotonic (5.8%). GMFCS were classified into level 1 (13%), level 2 (7.2%), level 3 (4.3%), level 4 (10.9%), and level 5 (64.5%). Spastic quadriplegia and extrapyramidal cerebral palsy were significantly associated with higher (severe) levels (IV and V), whereas spastic diplegia and hemiplegia were significantly associated with lower (mild) levels (I-III) of GMFCS. MRI features of periventricular white matter injury, deep gray matter injury, basal ganglia and thalamic changes, and superficial gray matter injury were significantly associated with severe levels of GMFCS (V and IV). MRI was normal in 8 children (5 = mild category, 3 = severe category). Severe cerebral palsy is most often associated with spastic quadriplegia, extrapyramidal cerebral palsy, superficial gray matter lesions, deep gray matter lesions, and periventricular white matter injury. This information is useful for anticipating and addressing the needs of children with cerebral palsy and for prognostication.

A review of the literature to inform the development of a practice framework for supporting children with cerebral visual impairment (CVI)

ABSTRACT Cerebral visual impairment (CVI) is now the most common cause of visual impairment affecting children in the developed world. Due to the increased survival rates of preterm infants and other early insult brain conditions, such as cerebral palsy, hydrocephalus and periventricular white matter injury, the numbers of children with CVI will also continue to rise. As such, focus needs to turn to developing effective approaches for supporting the growing number of children with this condition. Currently, many children with CVI are being supported using approaches and strategies that have been developed for children with ocular visual impairments (OVI). This is despite current evidence suggesting that many of these strategies may not be effective for children with CVI and in fact, in some situations, may actually be detrimental for them. This detailed review of relevant medical/scientific, educational and rehabilitation literature outlines a potential practical framework that could be implemented to help support each individual child with CVI. The proposed CVI practice framework has three main components, including: individual CVI profiles that detail the child’s visual, emotional and behavioural needs; individualised habilitation/rehabilitation programmes based on the child’s individual CVI profile; and empowerment of the child with CVI and their family.

Structural network performance for early diagnosis of spastic cerebral palsy in periventricular white matter injury

Periventricular white matter injury (PWMI) is a common cause of spastic cerebral palsy (SCP). Diffusion tensor imaging (DTI) shows high sensitivity but moderate specificity for predicting SCP. The limited specificity may be due to the diverse and extensive brain injuries seen in infants with PWMI. We enrolled 72 infants with corrected age from 6 to 18months in 3 groups: PWMI with SCP (n = 20), non-CP PWMI (n = 19), and control (n = 33) groups. We compared DTI-based brain network properties among the three groups and evaluated the diagnostic performance of brain network properties for SCP in PWMI infants. Our results show abnormal global parameters (reduced global and local efficiency, and increased shortest path length), and local parameters (reduced node efficiency) in the PWMI with SCP group. On logistic regression, the combined node efficiency of the bilateral precentral gyrus and right middle frontal gyrus had a high sensitivity (90%) and specificity (95%) for differentiating PWMI with SCP from non-CP PWMI, and significantly correlated with the Gross Motor Function Classification System scores. This study confirms that DTI-based brain network has great diagnostic performance for SCP in PWMI infants, and the combined node efficiency improves the diagnostic accuracy.

Brain magnetic resonance imaging is a predictor of bimanual performance and executive function in children with unilateral cerebral palsy.

To examine the association between brain magnetic resonance imaging (MRI) characteristics and executive function and bimanual performance in children with unilateral cerebral palsy (CP). Clinical MRI brain scans were classified as: (1) predominant pathological pattern (normal, white matter injury [WMI]; grey matter injury; focal vascular insults [FVI]; malformations; or miscellaneous); and (2) focal lesions (frontal, basal ganglia, and/or thalamus). Assessments included: (1) bimanual performance; (2) unimanual dexterity; and (3) executive function tasks (information processing, attention control, cognitive flexibility, and goal setting) and behavioural ratings (parent). From 131 recruited children, 60 were ineligible for analysis, leaving 71 children (47 males, 24 females) in the final sample (mean age 9y [SD 2y], 6y-12y 8mo). Brain MRIs were WMI (69%) and FVI (31%); and frontal (59%), thalamic (45%), basal ganglia (37%), and basal ganglia plus thalamic (21%). Bimanual performance was lower in FVI versus WMI (p<0.003), and with frontal (p=0.36), basal ganglia (p=0.032), and thalamic/basal ganglia lesions (p=0.013). Other than information processing, executive function tasks were not associated with predominant pattern. Frontal lesions predicted attention control (p=0.049) and cognitive flexibility (p=0.009) but not goal setting, information processing, or behavioural ratings. Clinical brain MRI predicts cognitive and motor outcomes when focal lesions and predominate lesion patterns are considered. What this paper adds Early brain magnetic resonance imaging (MRI) predicts bimanual performance and cognitive outcomes. Brain MRI may identify children requiring targeted interventions. Basal ganglia with/without thalamic lesions predicted bimanual performance. Frontal lesions were associated with attention control and cognitive flexibility. Brain MRI predominant patterns predicted motor, not cognitive outcomes, other than information processing.

Anchor-Based Segmentation of Periventricular White Matter for Neonatal HIE

The segmentation and quantitative features of periventricular white matter injury in magnetic resonance imaging are helpful for determining an accurate diagnosis of neonatal hypoxia ischemia encephalopathy (HIE) in clinical practice, but they are tedious tasks. In this paper, we present an interactive segmentation method for clinical magnetic resonance imaging (MRI) using sample estimation at the subvoxel level to establish a quantitative diagnosis. The coarse-grained voxels in clinical MRI are divided into subvoxels, and the intensities of subvoxels are adjusted using gradient adaptive filtering. Because the cerebrospinal fluid is more obvious in grayscale than the white matter and gray matter on T1-weighted images (T1WI), T2-weighted images (T2WI) and fluid-attenuated inversion recovery (FLAIR) images, and its population variance follows a Chi-square distribution, we segment the periventricular region as an anchor by estimating the parameters of the selected data and expand the anchor to obtain periventricular white matter of various widths. After aligning the segmented periventricular white matter in various modalities, we compute the radiomics features of regions of interest for the quantitative diagnosis of HIE. Current clinical practice confirms that our approach is effective and satisfies the clinical diagnostic requirements for neonatal HIE.

Network based statistics reveals trophic and neuroprotective effect of early high dose erythropoetin on brain connectivity in very preterm infants.

Periventricular white matter injury is common in very preterm infants and it is associated with long term neurodevelopmental impairments. While evidence supports the protective effects of erythropoetin (EPO) in preventing injury, we currently lack the complete understanding of how EPO affects the emergence and maturation of anatomical brain connectivity and function. In this case-control study, connectomic analysis based on diffusion MRI tractography was applied to evaluate the effect of early high-dose EPO in preterm infants. A whole brain, network-level analysis revealed a sub-network of anatomical brain connections in which connectivity strengths were significantly stronger in the EPO group. This distributed network comprised connections predominantly in the frontal and temporal lobe bilaterally, and the effect of EPO was focused on peripheral and feeder connections of the core structural connectivity network. EPO resulted in a globally increased clustering coefficient, higher global and average local efficiency, while higher strength and increased clustering was found for regions in the frontal lobe and cingulate gyrus. The connectivity network most affected by the EPO treatment showed a steeper increase graph theoretical measures with age compared to the placebo group. Our results demonstrate a weak but widespread effect of EPO on the structural connectivity network and a possible trophic effect of EPO reflected by increasing network segregation, predominantly in local connections.

Early Diagnosis of Spastic Cerebral Palsy in Infants with Periventricular White Matter Injury Using Diffusion Tensor Imaging.

Periventricular white matter injury is the common cause of spastic cerebral palsy. However, the early diagnosis of spastic cerebral palsy still remains a challenge. Our aim was to investigate whether infants with periventricular white matter injury with bilateral spastic cerebral palsy have unique lesions different from those in infants without cerebral palsy and to evaluate the efficiency of DTI in the early diagnosis of spastic cerebral palsy. Infants with periventricular white matter injury and controls underwent MR imaging at 6-18 months of age. Fractional anisotropy was calculated from DTI. Cerebral palsy was diagnosed by 24-30 months of age. Subjects were divided into 3 groups: infants with periventricular white matter injury with bilateral spastic cerebral palsy, infants with periventricular white matter injury without cerebral palsy, and controls. Tract-Based Spatial Statistics and Automated Fiber Quantification were used to investigate intergroup differences. Receiver operating characteristic curves were used to assess the diagnostic accuracy of spastic cerebral palsy. Correlations between motor function scores and fractional anisotropy were evaluated along white matter tracts. There were 20, 19, and 33 subjects in periventricular white matter injury with spastic cerebral palsy, periventricular white matter injury without cerebral palsy, and control groups, respectively. Decreased fractional anisotropy in the corticospinal tract was only observed in infants with periventricular white matter injury with spastic cerebral palsy, whereas decreased fractional anisotropy in the posterior thalamic radiation and genu and splenium of the corpus callosum was seen in both periventricular white matter injury subgroups. Fractional anisotropy in the corticospinal tract at the internal capsule level was effective in differentiating infants with periventricular white matter injury with spastic cerebral palsy from those without cerebral palsy by a threshold of 0.53, and it had strong correlations with motor function scores. Corticospinal tract lesions play a crucial role in motor impairment related to spastic cerebral palsy in infants with periventricular white matter injury. Fractional anisotropy in the corticospinal tract at the internal capsule level could aid in the early diagnosis of spastic cerebral palsy with high diagnostic accuracy.

Inhibitory Effect of LPS on the Proliferation of Oligodendrocyte Precursor Cells through the Notch Signaling Pathway in Intrauterine Infection-induced Rats

Periventricular white matter injury (PWMI) is very common in survivors of premature birth, and the final outcomes are a reduction in myelinated neurons leading to white matter hypomyelination. How and (or) why the oligodendrocyte lineage develops abnormally and myelination is reduced is a hot topic in the field. This study focuses on the effect of intrauterine inflammation on the proliferation of oligodendrocyte lineage cells and the underlying mechanisms. Lipopolysaccharide (LPS) (300 μg/kg) was intraperitoneally injected into pregnant Sprague-Dawley rats at embryonic days 19 and 20 to establish a rat model of intrauterine infection-induced white matter injury. Corpus callosum tissues were collected at postnatal day 14 (P14) to quantify the number of oligodendrocytes, the number and proliferation of oligodendrocyte precursor cells (OPCs), and the expression of myelin proteins (MBP and PLP). Furthermore, the expression of Wnt and Notch signaling-related proteins was analyzed. The results showed that the number of oligodendrocytes in the corpus callosum tissues of LPS-treated rats was reduced, and the expression levels of myelinating proteins were down-regulated. Further analysis showed that the Notch signaling pathway was down-regulated in the LPStreated group. These results indicate that intrauterine LPS may inhibit the proliferation of OPCs by down-regulating the Notch rather than the Wnt signaling pathway, leading to hypomyelination of white matter.

Human Umbilical Cord Blood Therapy Protects Cerebral White Matter from Systemic LPS Exposure in Preterm Fetal Sheep

Background: Infants born preterm following exposure to in utero inflammation/chorioamnionitis are at high risk of brain injury and life-long neurological deficits. In this study, we assessed the efficacy of early intervention umbilical cord blood (UCB) cell therapy in a large animal model of preterm brain inflammation and injury. We hypothesised that UCB treatment would be neuroprotective for the preterm brain following subclinical fetal inflammation. Methods: Chronically instrumented fetal sheep at 0.65 gestation were administered lipopolysaccharide (LPS, 150 ng, 055:B5) intravenously over 3 consecutive days, followed by 100 million human UCB mononuclear cells 6 h after the final LPS dose. Controls were administered saline instead of LPS and cells. Ten days after the first LPS dose, the fetal brain and cerebrospinal fluid were collected for analysis of subcortical and periventricular white matter injury and inflammation. Results: LPS administration increased microglial aggregate size, neutrophil recruitment, astrogliosis and cell death compared with controls. LPS also reduced total oligodendrocyte count and decreased mature myelinating oligodendrocytes. UCB cell therapy attenuated cell death and inflammation, and recovered total and mature oligodendrocytes, compared with LPS. Conclusions: UCB cell treatment following inflammation reduces preterm white matter brain injury, likely mediated via anti-inflammatory actions.