Gray Matter Injury Research Articles

The Origin of the Cerebral Palsies: Contribution of Population-Based Neuroimaging Data

Surveillance of cerebral palsy in Europe (SCPE) presents the first population-based results on neuroimaging findings in children with cerebral palsy (CP) using a magnetic resonance imaging classification system (MRICS). MRIs of children with CP born between 1999 and 2009 from 18 European countries were analyzed. MRICS identifies patterns of brain pathology according to timing during brain development which was analyzed with respect to CP subtypes and gestational age. MRIs or written reports from 3,818 children were available. The main clinical characteristics were similar to the 5,415 without such data. Most frequent was predominant white matter injury (49%), followed by predominant gray matter injury (21%). Maldevelopments were found in 11% of cases. Miscellaneous findings were present in 8.5% and normal findings in 10.6%. MRI patterns of children with unilateral spastic, bilateral spastic, and dyskinetic CP were mainly lesional (77, 71, and 59%, respectively), whereas children with ataxic CP had more maldevelopments, miscellaneous, and normal findings (25, 21, and 32%, respectively). In children born preterm, predominant white matter injury was most prevalent (80% in children born <32 weeks of gestation). Analysis of MRI in the European CP database identified CP as a mainly lesional condition on a large population basis, maldevelopments were relatively uncommon. An exception was ataxic CP. Children born preterm mostly presented with a lesion typical for their gestational age (GA) at birth. The decreasing prevalence of CP in this group suggests that progress in perinatal and neonatal medicine may lead to a reduction of these lesions.

Transforming Growth Factor Beta-Activated Kinase 1-Dependent Microglial and Macrophage Responses Aggravate Long-Term Outcomes After Ischemic Stroke.

Background and Purpose- Microglia/macrophages (Mi/MΦ) can profoundly influence stroke outcomes by acquiring functionally dominant phenotypes (proinflammatory or anti-inflammatory; deleterious or salutary). Identification of the molecular mechanisms that dictate the functional status of Mi/MΦ after brain ischemia/reperfusion may reveal novel therapeutic targets for stroke. We hypothesized that activation of TAK1 (transforming growth factor beta-activated kinase 1), a key MAP3K upstream of multiple inflammation-regulating pathways, drives Mi/MΦ toward a proinflammatory phenotype and potentiates ischemia/reperfusion brain injury. Methods- Young adult mice were subjected to 1 hour of middle cerebral artery occlusion (MCAO) followed by reperfusion. TAK1 was targeted by tamoxifen-induced Mi/MΦ-specific knockout or administration of a selective inhibitor 5Z-7-Oxozeaenol after MCAO. Neurobehavioral deficits and long-term gray matter and white matter injury were assessed up to 35 days after MCAO. Mi/MΦ functional status and brain inflammatory profiles were assessed 3 days after MCAO by RNA-seq, flow cytometry, and immunohistochemistry. Results- TAK1 Mi/MΦ-specific knockout markedly ameliorated neurological deficits in the rotarod and cylinder tests for at least 35 days after MCAO. Mechanistically, RNA-seq of purified brain Mi/MΦ demonstrated that proinflammatory genes and their predicted biological functions were downregulated or inhibited in microglia and macrophages from TAK1 Mi/MΦ-specific knockout mice versus WT mice 3 days after MCAO. Consistent with the anti-inflammatory phenotype of Mi/MΦ-specific knockout, oxozeaenol treatment mitigated neuroinflammation 3 days after MCAO, manifested by less Iba1+/CD16+ proinflammatory Mi/MΦ and suppressed brain invasion of various peripheral immune cells. Oxozeaenol treatment beginning 2 hours after MCAO improved long-term sensorimotor and cognitive functions in the foot fault, rotarod, and water maze tests. Furthermore, Oxozeaenol promoted both gray matter and white matter integrity 35 days after MCAO. Conclusions- TAK1 promotes ischemia/reperfusion-induced inflammation, brain injury, and maladaptive behavior by enhancing proinflammatory and deleterious Mi/MΦ responses. Therefore, TAK1 inhibition is a promising therapy to improve long-term stroke outcomes.

AB031. Neurohabilitation, a procedure to decrease neurologic and cognitive sequelae in newborns with perinatal brain injury

: Neurohabilitation is a therapeutic treatment procedure described by Ferenc Katona, that is characterized by the “elementary neuromotor patterns”. These early integrated complex movements are chains of processes in which the neck, trunk and extremities perform complex and continual movements in certain repetitive patterns. These movements are controlled by the developing subcortical structures and can be activated by determined positions of the head and the body that triggers the activation of the vestibular nuclei and their projections to the spinal cord, the reticular formation, thalamus, cerebellum, basal ganglia and motor cortex. A therapeutic program consists of training of a series of neuromotor patterns each day for a certain time. The generation of these movements repeated several times produce brain engrams that improve motor development. A sample of 282 infants with perinatal brain injury and with different weeks of gestation were studied. All infants had several prenatal and perinatal risk factors for brain damage. In all cases MRI was acquired at the beginning of treatment and 85% of the patients showed white and gray matter injury. Psychomotor development was evaluated with Bayley II tests up to 3 years old and WIPPSI and WISC were used according to the age of the child. Abnormal outcomes according gestational age were observed in 17% of extreme preterm infants, 18% of very preterm infants, 11% of moderate preterm infants, 16% of late preterm infants and 5% of term infants. These results led us to the conclusion that the application of this therapy to infants of two to three months of age during a period of 36 months has been shown to be very beneficial. Acknowledgements: This work was partially supported by Project 4971 of CONACyT and IN200917 of PAPIIT DGAPA UNAM. Authors want to express their gratitude to engineers Héctor Belmont-Tamayo, Paulina Alvarez García, Saulo Hernández Sánchez and Carlos Sair Flores-Bautista, PhD Yuria Cruz-Alanis, PhD ME Mónica Carlier, PhD Lourdes Cubero-Rego, Nurse Alejandra Arenas Tecuapetla, psychologist Lourdes Lara Ayala, Ms Elsa Olivia Ruiz Martínez and Ms Teresa Alvarez Vázquez for their contribution to this work.

A prospective observational study to describe magnetic resonance imaging findings in perinatal asphyxia in terms of severity, outcome and neurological sequel in term and preterm babies

Background: Perinatal asphyxia is a significant cause of neonatal mortality and morbidity. MRI is useful for assessing the severity and pattern of brain injuries. There is less data of MRI findings of perinatal asphyxia from India and the subcontinents. This prospective observational study was done to describe MRI brain findings in neonates with perinatal asphyxia with respect to various determinants.Methods: Initial MRI brain was done when babies were stable after fulfilling inclusion criteria. Immediate outcome was assessed at the end of hospital stay. They were followed up for presence of any sequel up to 1 year. Repeat MRI brain was done in few selected babies. Data was collected and statistically analyzed.Results: Total 55 babies were included in the study (term 27, preterm 28). There were 9 babies in stage 1, 17 babies in stage II and 22 babies in stage III. MRI brain findings were normal in 8 and abnormal in 47 patients. There were Deep gray matter injury (DG) in 22, Para Sagittal subcortical white matter injury (PS) in 6, Germinal matrix haemorrage (GMH), intraventricular haemorrage (IVH) and Periventricular leucomalacia (PVL) in 12 and Mixed pattern of injury in 7 babies. Findings among 9 expired babies were: 4 (44.4%) DG, 2 (22.2%) GMH+IVH and 3 (33.3%) mixed. There was neurological sequel in 13 babies (48.1%). Babies with normal MRI initially had no sequel.Conclusion: Brain injury due to perinatal asphyxia follows several patterns according to gestational age and severity. Early and accurate recognition of these patterns with the help of MRI brain helps in managing the baby and predicting the prognosis.

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.

Longitudinal assessment of recovery after spinal cord injury with behavioral measures and diffusion, quantitative magnetization transfer and functional magnetic resonance imaging.

Spinal cord injuries (SCIs) are a leading cause of disability and can severely impact the quality of life. However, to date, the processes of spontaneous repair of damaged spinal cord remain incompletely understood, partly due to a lack of appropriate longitudinal tracking methods. Noninvasive, multiparametric magnetic resonance imaging (MRI) provides potential biomarkers for the comprehensive evaluation of spontaneous repair after SCI. In this study in rats, a clinically relevant contusion injury was introduced at the lumbar level that impairs both hindlimb motor and sensory functions. Quantitative MRI measurements were acquired at baseline and serially post-SCI for up to 2 wk. The progressions of injury and spontaneous recovery in both white and gray matter were tracked longitudinally using pool-size ratio (PSR) measurements derived from quantitative magnetization transfer (qMT) methods, measurements of water diffusion parameters using diffusion tensor imaging (DTI) and intrasegment functional connectivity derived from resting state functional MRI. Changes in these quantitative imaging measurements were correlated with behavioral readouts. We found (a) a progressive decrease in PSR values within 2 wk post-SCI, indicating a progressive demyelination at the center of the injury that was validated with histological staining, (b) PSR correlated closely with fractional anisotropy and transverse relaxation of free water, but did not show significant correlations with behavioral recovery, and (c) preliminary evidence that SCI induced a decrease in functional connectivity between dorsal horns below the injury site at 24 h. Findings from this study not only confirm the value of qMT and DTI methods for assessing the myelination state of injured spinal cord but indicate that they may also have further implications on whether therapies targeted towards remyelination may be appropriate. Additionally, a better understanding of changes after SCI provides valuable information to guide and assess interventions.

Prognostic value of cranial ultrasonography in comparison with magnetic resonance imaging in children with cerebral palsy: a population-based study.

SUMMARYThe aim of this population-based study was to evaluate the characteristics of cerebral palsy (CP) in relation to the predominant pattern of the Magnetic Resonance Imaging Classification System (MRICS) that was analogously applied to the neonatal/early infant cranial ultrasound (CUS). The study included children born during the 2004-2007 period from the Croatian part (C28 RCP-HR) of the Surveillance of Cerebral Palsy in Europe (SCPE) CP register. Motor functions, accompanying impairments and brain MRI were evaluated in 227 children, 185 of which also had CUS. Concerning CP types, 56% of children had bilateral spastic, 34% unilateral spastic, 9% dyskinetic and 1% ataxic CP type. Gross Motor Function Classification System (GMFCS) revealed that 62.05% had mild (GMFCS I-III) and 37.85% had severe motor impairment (GMFCS IV-V). CUS showed white matter injury in 60%, gray matter injury in 12%, maldevelopments in 8%, miscellaneous changes in 14%, while 6% were normal; MRI showed significant agreement (κ=0.675, p<0.001). Neuroimaging findings of maldevelopments and predominant gray matter injury were associated with more severe CP, but 7% of children with CP had normal MRI. As we found very good agreement between CUS and MRI findings, CUS is recommended in children at an increased risk of CP if MRI is not available.

Active cooling temperature required to achieve therapeutic hypothermia correlates with short-term outcome in neonatal hypoxic-ischaemic encephalopathy.

Hypoxic-ischaemic encephalopathy (HIE) affects 2-4/1000 live term births. Treatment with therapeutic hypothermia (TH) improves the long-term neurodevelopmental outcome of neonates with moderate to severe HIE. However, early prediction of outcome still remains challenging, and no reliable and easily obtainable biomarker has been identified to date. Neonates with HIE display impaired thermoregulation, resulting in spontaneous hypothermia. The degree of cooling required to achieve TH may therefore act as a biomarker of injury severity. The present study demonstrates a correlation between servo-controlled mattress temperature during TH and short-term outcome. Neonates with an unfavourable outcome require less cooling to maintain a core temperature between 33 and 34°C during TH compared to neonates with a favourable outcome. The degree of impaired temperature regulation was strongly associated with a high magnetic resonance imaging injury score and death. Cooling device output temperature is a potential and easily obtainable early physiological biomarker of outcome in infants with HIE undergoing TH. Neonatal hypoxic-ischaemic encephalopathy (HIE) is a leading cause of death and disability in children. Therapeutic hypothermia (TH) at 33.5°C for 72h is the only therapy to date shown to improve outcome in moderate to severe HIE; however, assessment of severity and prediction of outcome remains challenging. Infants with HIE display significant physiological perturbations, including spontaneous hypothermia. We hypothesized that neonates with more severe brain injury on magnetic resonance imaging (MRI) would exhibit a greater degree of spontaneous hypothermia, and thus require less active cooling to attain TH. Twenty-eight neonates with moderate or severe HIE treated with TH were included in the present study. MRI images obtained on day of life 4-7 were scored according to standardized injury criteria. Unfavourable outcome was defined as death or significant grey matter injury on MRI according to a previously validated scoring system. A significantly higher cooling device output temperature was seen in infants with an unfavourable outcome. All neonates who required the mattress to provide a temperature≥32°C to maintain their core body temperature at 33.5°C had a high likelihood of unfavourable outcome (likelihood ratio=14.4).By contrast, infants who never required a device output temperature ≥32°C had a low likelihood of an unfavourable outcome (likelihood ratio=0.07, P<0.001). Infants with significant grey matter injury on MRI require less active cooling to maintain target temperature during TH. The cooling device output temperature has the potential to be an easily accessible physiological biomarker and predictor of injury and mortality in neonates with moderate or severe HIE.

Increased severity of the CHIMERA model induces acute vascular injury, sub-acute deficits in memory recall, and chronic white matter gliosis

Traumatic brain injury (TBI) is a leading cause of death and disability in modern societies. Diffuse axonal and vascular injury are nearly universal consequences of mechanical energy impacting the head and contribute to disability throughout the injury severity spectrum. CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration) is a non-surgical, impact-acceleration model of rodent TBI that reliably produces diffuse axonal injury characterized by white matter gliosis and axonal damage. At impact energies up to 0.7 joules, which result in mild TBI in mice, CHIMERA does not produce detectable vascular or grey matter injury. This study was designed to expand CHIMERA's capacity to induce more severe injuries, including vascular damage and grey matter gliosis. This was made possible by designing a physical interface positioned between the piston and animal's head to allow higher impact energies to be transmitted to the head without causing skull fracture. Here, we assessed interface-assisted single CHIMERA TBI at 2.5 joules in wild-type mice using a study design that spanned 6 h–60 d time points. Injured animals displayed robust acute neurological deficits, elevated plasma total tau and neurofilament-light levels, transiently increased proinflammatory cytokines in brain tissue, blood-brain barrier (BBB) leakage and microstructural vascular abnormalities, and grey matter microgliosis. Memory deficits were evident at 30 d and resolved by 60 d. Intriguingly, white matter injury was not remarkable at acute time points but evolved over time, with white matter gliosis being most extensive at 60 d. Interface-assisted CHIMERA thus enables experimental modeling of distinct endophenotypes of TBI that include acute vascular and grey matter injury in addition to chronic evolution of white matter damage, similar to the natural history of human TBI.

Magnetic Resonance Imaging Atlas-Based Volumetric Mapping of the Cervical Cord Gray Matter in Cervical Canal Stenosis

White matter volume loss may be an anatomic driver in the development of clinical symptoms in cervical spondylotic myelopathy (CSM). Considerably less attention has been devoted to gray matter (GM) injury. Newly developed atlas-based mapping techniques may allow evaluation of GM cord volume alterations in CSM. There were 29 subjects evaluated: 15 patients with CSM (61.1 ± 8.7 years old) and 14 age-matched control subjects (56.1 ± 5.3 years old). All subjects underwent 3T magnetic resonance imaging of the cervical spine. Post-processing with the Spinal Cord Toolbox (v3.0) provided GM volumetric analysis. Clinical scores collected included modified Japanese Orthopaedic Association, neck and arm numeric rating scales, Nurick Scale, and Neck Disability Index. All volumes were normalized to account for anatomic variability. Normalized mean ventral GM volume in the compression region was significantly lower in patients compared with control subjects (1.103 ± 0.21 vs. 1.35 ± 0.32, P= 0.027). Normalized mean dorsal volume in the compression region was decreased in patients compared with control subjects (0.90 ± 0.17 vs. 1.04 ± 0.15, P=0.049). GM volumes were associated with clinical scores, including Neck Disability Index, arm numeric rating scale, modified Japanese Orthopaedic Association, and Nurick Scale scores (P= 0.022, P= 0.004, P= 0.027, and P= 0.016). GM volume loss may be evaluated through atlas-based post-processing techniques and may correlate with clinical symptoms in CSM.

Neonatal hypoxic encephalopathy: Correlation between post-cooling brain MRI findings and 2 years neurodevelopmental outcome.

Objective:This study aims to evaluate the magnetic resonance imaging (MRI) brain patterns among hypoxic-ischemic encephalopathy (HIE) babies who underwent post-cooling MRI brain as well as to correlate the post-cooling brain scoring with patient's neurodevelopmental outcome at 2 years.Subjects and Methods:It was a retrospective cross sectional study carried out at a tertiary university hospital. Record of patients diagnosed with neonatal HIE from 2007 until 2016 who completed 72 h of cooling therapy and had MRI brain within 2 weeks of life were included in this study. A new scoring system by Trivedi et al. that emphasizes on subcortical deep gray matter and posterior limb internal capsule injury were utilized upon MRI assessment, using TW, T2W, and diffusion-weighted imaging (DWI) sequences. Cumulative MRI brain score was obtained and graded as none, mild, moderate, and severe brain injury. The MRI brain scoring was then correlated with patient's 2 years neurodevelopmental outcome using Fisher's Exact Test.Results:A total of 23 patients were eligible of which 19 term neonates were included. 13% of these neonates (n = 3) had mild MRI brain injury grading with 52.2% (n = 12) moderate and 34.8% (n = 8) severe. There was no significant correlation seen between MRI brain grading and developmental outcome at 2 years old (P > 0.05).Conclusion:There was no significant correlation between neonatal MRI brain injury grading and 2 years neurodevelopmental outcome. Nevertheless, the new MRI brain scoring by Trivedi et al. is reproducible and comprehensive as it involves various important brain structures, assessed from different MRI sequences.

Thalamic and thalamic projection abnormalities on DTI and NODDI analysis following acute concussion

ObjectiveTo compare preseason and post-concussive MRI in a cohort of collegiate football players utilizing Diffusion Tensor Imaging (DTI) and Neurite Orientation Dispersion and Density Imaging (NODDI) post processing.BackgroundAcute post-concussive symptoms can vary in clinical characteristics and severity. However, vestibular and ocular dysfunction in particular, has been associated with poor clinical outcomes. The vestibular system comprises a complex network of projections from peripheral vestibular organs to thalamic relay systems and numerous cortical regions. The visual/oculomotor system is also complex, involving brainstem, subcortical-cortical and thalamo-cortical connections. Oculomotor deficits are thought to involve the midbrain and the visual and parietal association cortices, both of which have thalamic projections.Design/MethodsWe gathered pre-season MR diffusion weighted imaging on a cohort of 30 collegiate football players. We performed repeat imaging within 36 hours of any diagnosed concussion in the same subject cohort. DTI metrics: mean diffusivity (MD), axial diffusivity (AD), fractional anisotropy (FA), and radial diffusivity (RD) along with NODDI metric: orientation dispersion index (ODI), were analyzed for statistical comparisons between groups.Results4 subjects with pre-season MRI underwent repeat MRI within 36 hours of concussive injury. A paired t-test between these two groups using DTI and NODDI metrics showed significant (p &lt; 0.05) decreases in: AD and MD in the left posterior thalamic radiations, FA in the column and body of the fornix, and MD in the right anterior corona radiata and superior fronto-occipital fasciculus, and a significant decrease in ODI in the anterior thalamus.ConclusionsDisruptions in the thalamus and its white matter projections may play a role in the vestibular/ocular dysfunction associated with acute concussive injury. While our numbers are small, the findings suggest that DTI and NODDI processing techniques have the capability to locate and measure grey and white matter injury patterns after concussive injury.

Interneuron Development Is Disrupted in Preterm Brains With Diffuse White Matter Injury: Observations in Mouse and Human.

Preterm brain injury, occurring in approximately 30% of infants born <32 weeks gestational age, is associated with an increased risk of neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). The mechanism of gray matter injury in preterm born children is unclear and likely to be multifactorial; however, inflammation, a high predictor of poor outcome in preterm infants, has been associated with disrupted interneuron maturation in a number of animal models. Interneurons are important for regulating normal brain development, and disruption in interneuron development, and the downstream effects of this, has been implicated in the etiology of neurodevelopmental disorders. Here, we utilize postmortem tissue from human preterm cases with or without diffuse white matter injury (WMI; PMA range: 23+2 to 28+1 for non-WMI group, 26+6 to 30+0 for WMI group, p = 0.002) and a model of inflammation-induced preterm diffuse white matter injury (i.p. IL-1β, b.d., 10 μg/kg/injection in male CD1 mice from P1–5). Data from human preterm infants show deficits in interneuron numbers in the cortex and delayed growth of neuronal arbors at this early stage of development. In the mouse, significant reduction in the number of parvalbumin-positive interneurons was observed from postnatal day (P) 10. This decrease in parvalbumin neuron number was largely rectified by P40, though there was a significantly smaller number of parvalbumin positive cells associated with perineuronal nets in the upper cortical layers. Together, these data suggest that inflammation in the preterm brain may be a contributor to injury of specific interneuron in the cortical gray matter. This may represent a potential target for postnatal therapy to reduce the incidence and/or severity of neurodevelopmental disorders in preterm infants.

Neuroprotective effects of minocycline and progesterone on white matter injury after focal cerebral ischemia

Stroke induced white matter injury can induce marked neurological deficits even after relatively small infarcts, due to the tightly packed nature of white matter tracts especially in certain areas in the brain. Many drugs which were successful in the pre-clinical trials failed in clinical trials, which was attributed in part to the focus on grey matter injury completely and ignoring their effect on white matter. In this work we selected two known neuroprotective drugs (minocycline and progesterone) and examined their effect on white matter injury after focal cerebral ischemia/reperfusion injury in rats. Focal cerebral ischemia was induced in male Wistar rats (one-hour ischemia followed by reperfusion). Progesterone and minocycline were administered immediately after reperfusion onset. Infarct size, microglial activation and white matter injury were assessed and compared between the treatment and no-treatment groups and Sham operated animals. Our data showed that both progesterone and minocycline reduced infarct size, microglial activation and white matter injury. This work shows a new neuroprotective mechanism of both drugs, via white matter injury reduction, that can be exploited for stroke management. While the utility of either drugs as a sole agent in the management of stroke is questionable, there is a value of using either drugs as an adjuvant therapy to traditional stroke therapy, making use of the white matter protective effect that would improve outcome and facilitate healing after stroke.

Fetal inflammation is associated with persistent systemic and hippocampal inflammation and dysregulation of hippocampal glutamatergic homeostasis.

BACKGROUND:Inflammation is a major cause of preterm birth and often results in a fetal inflammatory response syndrome (FIRS). Preterm infants with FIRS have a higher childhood incidence of neurodevelopmental disability than preterm infants without FIRS. The mechanisms connecting FIRS to neurodevelopmental disability in formerly preterm infants are not fully understood, but the effect on premature gray matter may have an important role.METHODS:Fetal rats were exposed to intra-amniotic (i.a.) LPS two days prior to birth to model FIRS. On postnatal day 7, expression of inflammatory mediators was measured in the liver, lung and brain. Activation of microglia and expression of glutamatergic receptor subunits and transporters were measured in the hippocampus and cortex.RESULTS:LPS caused persistent systemic inflammatory mediators gene expression. In the brain, there was corresponding activation of microglia in the hippocampus and cortex. Expression of inflammatory mediators persisted in the hippocampus, but not the cortex, and was associated with altered glutamatergic receptor subunits and transporters.CONCLUSION:Hippocampal inflammation and dysregulation of glutamate metabolism persisted well into the postnatal period following i.a. LPS. Poor neurodevelopmental outcomes after FIRS in preterm infants may result in part through glutamatergically-driven gray matter injury to the neonatal hippocampus.

Hypoxic preconditioning improves long-term functional outcomes after neonatal hypoxia-ischemic injury by restoring white matter integrity and brain development.

SummaryAimsNeonatal hypoxia–ischemia (H/I) results in gray and white matter injury, characterized by neuronal loss, failure of neural network formation, retarded myelin formation, and abnormal accumulation of oligodendrocyte progenitor cells (OPCs). These changes lead to severe neurological deficits and mortality. Sublethal hypoxic preconditioning (HPC) can protect the developing brain against H/I. However, limited evidence is available concerning its effect on white matter injury.MethodsIn this study, P6 neonatal Sprague‐Dawley rats were subjected to normoxic (21% O2) or HPC (7.8% O2) for 3 hours followed 24 hours later by H/I brain injury. Neurological deficits were assessed by gait, righting reflex, foot fault, and Morris water maze tests. Compound action potential of the corpus callosum was recorded 35 days after surgery, and the correlation between axon myelination and neurological function was determined.ResultsHypoxic preconditioning significantly attenuated H/I brain injury at 7 days and remarkably improved both sensorimotor and cognitive functional performances up to 35 days after H/I. HPC‐afforded improvement in long‐term neurological outcomes was attributable, at least in part, to restoration of the differentiation and maturation capacity in oligodendrocyte progenitor cells, amelioration of microglia/macrophage activation and neuroinflammation, and continuation of brain development after H/I.ConclusionsHypoxic preconditioning restores white matter repair, development, and functional integrity in developing brain after H/I brain injury.

Effects of Xiaoshuan Enteric-Coated Capsule on White and Gray Matter Injury Evaluated by Diffusion Tensor Imaging in Ischemic Stroke

Xiaoshuan enteric-coated capsule (XSECC) is a drug approved by the Chinese State Food and Drug Administration for the treatment of stroke. This study was to investigate the effects of XSECC on white and gray matter injury in a rat model of ischemic stroke by diffusion tensor imaging (DTI) and histopathological analyses. The ischemia was induced by middle cerebral artery occlusion (MCAO). The cerebral blood flow measured by arterial spin labeling was improved by treatment with XSECC on the 3rd, 7th, 14th and 30th days after MCAO. Spatiotemporal white and gray matter changes in MCAO rats were examined with DTI-derived parameters (fractional anisotropy, FA; apparent diffusion coefficient, ADC; axial diffusivity, λ//; radial diffusivity, λ⊥). The increased FA was found in the XSECC treatment group in the corpus callosum, external capsule and internal capsule, linked with the decreased λ//, λ⊥ and ADC on the 3rd day and reduced ADC on the 30th day in the external capsule, suggesting XSECC reduced the axon and myelin damage in white matter after stroke. The relative FA in the striatum, cortex and thalamus in XSECC treatment group was significantly increased on the 3rd, 7th, 14th and 30th days accompanied by the increased λ// on the 3rd day and reduced relative ADC and λ⊥ on the 30th day, indicating that XSECC attenuated cell swelling and membrane damage in the early stage and tissue liquefaction necrosis in the late stage in gray matter after stroke. Additionally, XSECC-treated rats exhibited increased mean fiber length assessed by diffusion tensor tractography. Moreover, histopathological analyses provided evidence that XSECC relieved nerve cell and myelin damage in white and gray matter after stroke. Our research reveals that XSECC could alleviate white and gray matter injury, especially reducing nerve cell damage and promoting the repair of axon and myelin after ischemic stroke.

Preconditioning with partial caloric restriction confers long-term protection against grey and white matter injury after transient focal ischemia

Caloric restriction (CR) has been extensively examined as a preventative strategy against aging and various diseases, but CR effects on cerebral ischemia are largely unknown. We subjected C57BL6/J mice to ad libitum food access (LF) or a diet restricted to 70% of ad libitum food access (RF) for two to four weeks followed by 60 min of transient focal ischemia (tFCI). RF for four weeks protected against subsequent tFCI-induced infarct. RF improved sensorimotor function after stroke in the foot fault and corner tests, as well as performance in the Morris water maze test. In addition, RF preserved ischemic white matter tract integrity assessed by histology and compound action potential. Sirt1 and Sirt3 were both upregulated in RF ischemic brain, but heterozygous deletion of Sirt1 or knockout of Sirt3 did not alter the protection induced by RF against ischemic injury. RF induced significant release of adiponectin, a hormone related to glucose metabolism. Knockout of adiponectin decreased RF-induced protection after tFCI. These data demonstrate the novel finding that white matter, as well as neurons, benefit from CR prior to cerebral ischemic injury, and that adiponectin may contribute to these protective effects.

Repeated mild shaking of neonates induces transient cerebral microhemorrhages and anxiety-related behavior in adult rats

Growing evidence suggests that neonatal cerebral microhemorrhages (MHs) are implicated in neuropsychiatric diseases in adults. Although animal studies have identified the progression of the underlying mechanisms of MHs, few studies have investigated the histopathology and behavioral outcomes. In this study, we created an experimental rat model of MHs using a new experimental device for repeated mild shaking brain injury (SBI) in the neonatal period and examined temporal changes in MHs using susceptibility weighted imaging (SWI) and iron histochemistry. SWI demonstrated transient MHs in the gray matter of the cerebral cortex and hippocampus in injured rats. Iron histochemical staining demonstrated leakage of iron and iron-positive cells surrounding MHs. This staining pattern lasted for a long time and continued after disappearance of hemorrhagic signals on SWI. These data suggested the presence of iron-associated gray matter injury after MHs. In the open field test, these injured rats showed anxiety-related behavior as adults. This model may be useful for exploring the underlying mechanisms of changes that occur after MHs and the behavioral outcomes of repeated mild SBI in early development.

Effects of Intrauterine Inflammation on Cortical Gray Matter of Near-Term Lambs.

Introduction: Ventilation causes cerebral white matter inflammation and injury, which is exacerbated by intrauterine inflammation. However, the effects on cortical gray matter are not well-known. Our aim was to examine the effect of ventilation on the cerebral cortex of near-term lambs exposed to intrauterine inflammation.Method:Pregnant ewes at 119 ± 1 days gestation received an intra-amniotic injection of saline or lipopolysaccharide (LPS; 10 mg). Seven days later, lambs were randomized to either a high tidal volume injurious ventilation strategy (INJSAL N = 6, INJLPS N = 5) or a protective ventilation strategy (PROTSAL N = 5, PROTLPS N = 6). Respiratory parameters, heart rate and blood gases were monitored during the neonatal period. At post-mortem, the brain was collected and processed for immunohistochemical assessment. Neuronal density (NeuN), apoptotic cell death (caspase 8 and TUNEL), microglial density (Iba-1), astrocytic density (GFAP), and vascular protein extravasation (sheep serum) were assessed within the frontal, parietal, temporal and occipital lobes of the cerebral cortex.Results:A significant reduction in the number of neurons in all cortical layers except 4 was observed in LPS-exposed lambs compared to controls (layer #1: p = 0.041; layers #2 + 3: p = 0.023; layers #5 + 6: p = 0.016). LPS treatment caused a significant increase in gray matter area, indicative of edema. LPS+ventilation did not cause apoptotic cell death in the gray matter. Astrogliosis was not observed following PROT or INJ ventilation, with or without LPS exposure. LPS exposure was associated with vascular protein extravasation.Conclusion:Ventilation had little effect on gray matter inflammation and injury. Intrauterine inflammation reduced neuronal cell density, caused edema of the cortical gray matter, and blood vessel extravasation in the brain of near-term lambs.