Neuroprotection offered by mesenchymal stem cells in perinatal brain injury: Role of mitochondria, inflammation, and reactive oxygen species.

Preclinical studies have shown that mesenchymal stem cells have a positive effect in perinatal brain injury models. The mechanisms that cause these neurotherapeutic effects are not entirely intelligible. Mitochondrial damage, inflammation, and reactive oxygen species are considered to be critically involved in the development of injury. Mesenchymal stem cells have immunomodulatory action and exert mitoprotective effects which attenuate production of reactive oxygen species and promote restoration of tissue function and metabolism after perinatal insults. This review summarizes the present state, the underlying causes, challenges and possibilities for effective clinical translation of mesenchymal stem cell therapy.

Cyclophilin D-dependent oligodendrocyte mitochondrial ion leak contributes to neonatal white matter injury.

Postnatal failure of oligodendrocyte maturation has been proposed as a cellular mechanism of diffuse white matter injury (WMI) in premature infants. However, the molecular mechanisms for oligodendrocyte maturational failure remain unclear. In neonatal mice and cultured differentiating oligodendrocytes, sublethal intermittent hypoxic (IH) stress activated cyclophilin D-dependent mitochondrial proton leak and uncoupled mitochondrial respiration, leading to transient bioenergetic stress. This was associated with development of diffuse WMI: poor oligodendrocyte maturation, diffuse axonal hypomyelination, and permanent sensorimotor deficit. In normoxic mice and oligodendrocytes, exposure to a mitochondrial uncoupler recapitulated the phenotype of WMI, supporting the detrimental role of mitochondrial uncoupling in the pathogenesis of WMI. Compared with WT mice, cyclophilin D-knockout littermates did not develop bioenergetic stress in response to IH challenge and fully preserved oligodendrocyte maturation, axonal myelination, and neurofunction. Our study identified the cyclophilin D-dependent mitochondrial proton leak and uncoupling as a potentially novel subcellular mechanism for the maturational failure of oligodendrocytes and offers a potential therapeutic target for prevention of diffuse WMI in premature infants experiencing chronic IH stress.

Hand Preference Develops Across Childhood and Adolescence in Extremely Preterm Children: The EPICure Study.

AIM: We attempted to determine how handedness changes with age and its relation to brain injury and cognition following birth before 26 weeks of gestation. METHODS: We used data from the EPICure study of health and development following birth in the British Isles in 1995. Handedness was determined by direct observation during standardized testing at age 2.5, six, and 11 years and by self-report using the Edinburgh Handedness Inventory at 19 years. Control data from term births were included at six, 11, and 19 years. RESULTS: In extremely preterm children left handedness increased from 9% to 27% between 2.5 and 19 years, with a progressive reduction in mixed handedness from 59% to 13%. Although individual handedness scores varied over childhood, the between-group effects were consistent through 19 years, with greatest differences in females. In extremely preterm participants, neonatal brain injury was associated with lower right handedness scores at each age and left-handed participants had lower cognitive scores at 19 years after controlling for confounders, but not at other ages. CONCLUSION: Increasing hand lateralization is seen over childhood in extremely preterm survivors, but consistently more individuals have non-right preferences at each age than control individuals.

Incidence of Cardiac Dysfunction After Brain Injury.

INTRODUCTION: Cardiovascular complications in patients with subarachnoid hemorrhage are considered to be a neurally mediated process rather than a manifestation of coronary artery disease. AIM: The aim of study is to show the incidence and type cardiac complications after traumatic and spontaneous SAH. PATIENTS AND METHODS: The study had prospective character in which included 104 patients, with diagnosed subarachnoid hemorrhage (SAH), in the period from 2014 to 2017. Two groups of patients were formed. Group I: patients with SAH caused by the rupture of a brain aneurysm. Group II: patients with SAH after traumatic brain injury. RESULTS: Electrocardiogram (ECG) abnormalities was predominant after traumatic brain injury 74 %, with statistically significant difference atrial fibrillation 42.5 % (p = 0.043) and sinus bradycardia 31.4 % (p = 0.05). Hypertension are predominant in patients with spontaneous SAH with statistically significant difference (15 (27.7%) vs 36 (72%) p=0.034) and hypotension in group II (10 (18.5%) vs 2 (4%) p = 0.021 ) with traumatic SAH patients. The time in Intensive Care Unit (ICU) for traumatic SAH group was 6.1 ± 5.2 days and 3.9 ± 1.16 for spontaneous SAH group with statistical significance (p = 0.046). Respiratory support time was longer in traumatic SAH group (39.4 ± 23.44 vs. 15.66 ± 22.78) with p = 0.043. CONCLUSION: Cardiac dysfunction in patients with subarachnoid hemorrhage are considered to be a neurally mediated process rather than a manifestation of coronary artery disease. Early treatment of cerebral injury could be reduce incidence of cardiac complications after traumatic brain injury. Cardiac dysfunction in patients with SAH is still very high, despite substantial qualitative progress in their treatment.

Early intervention at home in infants with congenital brain lesion with CareToy revised: a RCT protocol.

BACKGROUND: Congenital brain lesions expose infants to be at high-risk for being affected by neurodevelopmental disorders such as cerebral palsy (CP). Early interventions programs can significantly impact and improve their neurodevelopment. Recently, in the framework of the European CareToy (CT) Project ( www.caretoy.eu ), a new medical device has been created to deliver an early, intensive, customized, intervention program, carried out at home by parents but remotely managed by expert and trained clinicians. Reviewing results of previous studies on preterm infants without congenital brain lesion, the CT platform has been revised and a new system created (CT-R). This study describes the protocol of a randomised controlled trial (RCT) aimed to evaluate, in a sample of infants at high-risk for CP, the efficacy of CT-R intervention compared to the Infant Massage (IM) intervention. METHODS/DESIGN: This RCT will be multi-centre, paired and evaluator-blinded. Eligible subjects will be preterm or full-term infants with brain lesions, in first year of age with predefined specific gross motor abilities. Recruited infants will be randomized into CT-R and IM groups at baseline (T0). Based on allocation, infants will perform an 8-week programme of personalized CareToy activities or Infant Massage. The primary outcome measure will be the Infant Motor Profile. On the basis of power calculation, it will require a sample size of 42 infants. Moreover, Peabody Developmental Motor Scales-Second Edition, Teller Acuity Cards, standardized video-recordings of parent-infant interaction and wearable sensors (Actigraphs) will be included as secondary outcome measures. Finally, parents will fill out questionnaires (Bayley Social-Emotional, Parents Stress Index). All outcome measures will be carried out at the beginning (T0) and at end of 8-weeks intervention period, primary endpoint (T1). Primary outcome and some secondary outcomes will be carried out also after 2 months from T1 and at 18 months of age (T2 and T3, respectively). The Bayley Cognitive subscale will be used as additional assessment at T3. DISCUSSION: This study protocol paper is the first study aimed to test CT-R system in infants at high-risk for CP. This paper will present the scientific background and trial methodology. TRIAL REGISTRATION: NCT03211533 and NCT03234959 ( www.clinicaltrials.gov ).

Perinatal Brain Injury: Mechanisms, Prevention, and Outcomes.

Perinatal brain injury may lead to long-term morbidity and neurodevelopmental impairment. Improvements in perinatal care have resulted in the survival of more infants with perinatal brain injury. The effects of hypoxia-ischemia, inflammation, and infection during critical periods of development can lead to a common pathway of perinatal brain injury marked by neuronal excitotoxicity, cellular apoptosis, and microglial activation. Various interventions can prevent or improve the outcomes of different types of perinatal brain injury. The objective of this article is to review the mechanisms of perinatal brain injury, approaches to prevention, and outcomes among children with perinatal brain injury.

Effect of nifedipine and atosiban on perinatal brain injury: secondary analysis of the APOSTEL-III trial.

OBJECTIVE: Brain injury in neonates born prematurely is associated strongly with poor neurodevelopmental outcome. The aim of this study was to evaluate whether tocolysis with nifedipine or atosiban in women with threatened preterm birth can reduce the incidence of overall brain injury in neonates born prematurely. METHODS: This was a secondary analysis of the APOSTEL-III trial (Dutch Clinical Trial Registry, no. NTR2947), a randomized clinical trial in which women with threatened preterm labor between 25 and 34 weeks of gestation were allocated to treatment with nifedipine or atosiban. In this secondary analysis, women delivered at ≤ 32 weeks of gestational age in the two main contributing centers were included. Primary outcome was the presence of neonatal brain injury, which was defined as presence of abnormalities on ultrasound investigation and classified into mild and severe. To evaluate type and severity of brain injury, all neonatal ultrasounds performed during neonatal intensive and medium care admission were analyzed. To test the robustness of our results, a sensitivity analysis was performed assessing differences in baseline or known risk factors for brain injury. RESULTS: A total of 117 neonates (from 102 women) were studied, of which 51 had been exposed to nifedipine and 66 to atosiban. Brain injury was observed in 22 (43.1%) neonates in the nifedipine group compared with 37 (56.1%) in the atosiban group (OR, 0.60; 95% CI, 0.29-1.24). Presence of mild brain injury was comparable between the nifedipine (33.3%) and atosiban (48.5%) groups (OR, 0.53; 95% CI, 0.25-1.13). Severe brain injury was also comparable between the groups, observed in 9.8% of neonates in the nifedipine vs 7.6% of those in the atosiban group (OR, 1.33; 95% CI, 0.36-4.85). Intraventricular hemorrhage (≥ Grade I) was the most frequently seen ultrasound abnormality, observed in 18 (35.3%) neonates in the nifedipine group vs 25 (37.9%) in the atosiban group (OR, 0.90; 95% CI, 0.42-1.91). The sensitivity analysis, with adjustment for maternal age and gestational age at randomization, showed no statistical difference between the groups for presence of brain injury (OR, 0.58; 95% CI, 0.27-1.27). CONCLUSION: In children born before 32 weeks of gestation after the use of tocolytics, the prevalence of brain injury was high. No significant differences were found with respect to overall brain injury between neonates exposed to nifedipine and those exposed to atosiban. However, as this study was a secondary analysis of the APOSTEL III trial, it was underpowered for brain injury. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Prenatal Factors Associated with Postnatal Brain Injury in Infants with Congenital Diaphragmatic Hernia.

BACKGROUND AND PURPOSE: Approximately 60% of infants with congenital diaphragmatic hernia have evidence of brain injury on postnatal MR imaging. It is unclear whether any brain injury is present before birth. In this study, we evaluated fetal MR imaging findings of brain injury and the association of congenital diaphragmatic hernia severity with postnatal brain injury. MATERIALS AND METHODS: Fetal MR imaging and postnatal brain MR imaging were retrospectively evaluated in 36 cases of congenital diaphragmatic hernia (from 2009 to 2014) by 2 pediatric neuroradiologists. Brain injury on postnatal MR imaging and brain injury and congenital diaphragmatic hernia severity on fetal MR imaging were recorded. Correlations between brain abnormalities on fetal and postnatal brain MR imaging were analyzed. Postnatal brain injury findings correlating with the severity of congenital diaphragmatic hernia were also assessed. RESULTS: On fetal MR imaging, enlarged extra-axial spaces (61%), venous sinus distention (21%), and ventriculomegaly (6%) were identified. No maturational delay, intracranial hemorrhage, or brain parenchymal injury was identified on fetal MR imaging. On postnatal MR imaging, 67% of infants had evidence of abnormality, commonly, enlarged extra-axial spaces (44%). Right-sided congenital diaphragmatic hernia was associated with a greater postnatal brain injury score (P = .05). Low observed-to-expected lung volume was associated with postnatal white matter injury (P = .005) and a greater postnatal brain injury score (P = .008). Lack of liver herniation was associated with normal postnatal brain MR imaging findings (P = .03). CONCLUSIONS: Fetal lung hypoplasia is associated with postnatal brain injury in congenital diaphragmatic hernia, suggesting that the severity of lung disease and associated treatments affect brain health as well. We found no evidence of prenatal brain parenchymal injury or maturational delay.

Increase of neuronal injury markers Tau and neurofilament light proteins in umbilical blood after intrapartum asphyxia.

AIM: Compare the levels of the brain injury biomarkers Tau and neurofilament light protein (NFL) in cases of asphyxia with those in controls. MATERIALS AND METHODS: We analyzed the neuronal proteins Tau and NFL in umbilical blood of 10 cases of severe-moderate intrapartum asphyxia and in 18 control cases. RESULTS: The levels of both Tau and neurofilament were significantly higher after asphyxia and it appeared to be a correlation between the levels of the biomarkers and the severity of the insult. DISCUSSION: Future studies are warranted to support or refute the value of Tau/NFLin clinical practice. CONCLUSION: Fetal asphyxia remains a clinical problem resulting in life-long neurological disabilities. We urgently need more accurate early predictive markers to direct the clinician when to provide neuroprotective therapy.

Validation of an MRI Brain Injury and Growth Scoring System in Very Preterm Infants Scanned at 29- to 35-Week Postmenstrual Age.

BACKGROUND AND PURPOSE: The diagnostic and prognostic potential of brain MR imaging before term-equivalent age is limited until valid MR imaging scoring systems are available. This study aimed to validate an MR imaging scoring system of brain injury and impaired growth for use at 29 to 35 weeks postmenstrual age in infants born at <31 weeks gestational age. MATERIALS AND METHODS: Eighty-three infants in a prospective cohort study underwent early 3T MR imaging between 29 and 35 weeks' postmenstrual age (mean, 32+2 ± 1+3 weeks; 49 males, born at median gestation of 28+4 weeks; range, 23+6-30+6 weeks; mean birthweight, 1068 ± 312 g). Seventy-seven infants had a second MR scan at term-equivalent age (mean, 40+6 ± 1+3 weeks). Structural images were scored using a modified scoring system which generated WM, cortical gray matter, deep gray matter, cerebellar, and global scores. Outcome at 12-months corrected age (mean, 12 months 4 days ± 1+2 weeks) consisted of the Bayley Scales of Infant and Toddler Development, 3rd ed. (Bayley III), and the Neuro-Sensory Motor Developmental Assessment. RESULTS: Early MR imaging global, WM, and deep gray matter scores were negatively associated with Bayley III motor (regression coefficient for global score ß = -1.31; 95% CI, -2.39 to -0.23; P = .02), cognitive (ß = -1.52; 95% CI, -2.39 to -0.65; P < .01) and the Neuro-Sensory Motor Developmental Assessment outcomes (ß = -1.73; 95% CI, -3.19 to -0.28; P = .02). Early MR imaging cerebellar scores were negatively associated with the Neuro-Sensory Motor Developmental Assessment (ß = -5.99; 95% CI, -11.82 to -0.16; P = .04). Results were reconfirmed at term-equivalent-age MR imaging. CONCLUSIONS: This clinically accessible MR imaging scoring system is valid for use at 29 to 35 weeks postmenstrual age in infants born very preterm. It enables identification of infants at risk of adverse outcomes before the current standard of term-equivalent age.

Lesion characteristics driving right-hemispheric language reorganization in congenital left-hemispheric brain damage.

Pre- or perinatally acquired ("congenital") left-hemispheric brain lesions can be compensated for by reorganizing language into homotopic brain regions in the right hemisphere. Language comprehension may be hemispherically dissociated from language production. We investigated the lesion characteristics driving inter-hemispheric reorganization of language comprehension and language production in 19 patients (7-32years; eight females) with congenital left-hemispheric brain lesions (periventricular lesions [n=11] and middle cerebral artery infarctions [n=8]) by fMRI. 16/17 patients demonstrated reorganized language production, while 7/19 patients had reorganized language comprehension. Lesions to the insular cortex and the temporo-parietal junction (predominantly supramarginal gyrus) were significantly more common in patients in whom both, language production and comprehension were reorganized. These areas belong to the dorsal stream of the language network, participating in the auditory-motor integration of language. Our data suggest that the integrity of this stream might be crucial for a normal left-lateralized language development.

High-mobility group box-1 and receptor for advanced glycation end products in preterm infants with brain injury.

BACKGROUND: High-mobility group box-1 (HMGB1) protein acts as an important pro-infl ammatory mediator, which is capable of activating inflammation and tissue repair. HMGB1 can bind to its receptor such as advanced glycation end products (RAGE). RAGE, in turn, can promote the production of pro-inflammatory cytokines. Soluble RAGE (sRAGE) is a truncated form of the receptor comprising the extracellular domain of RAGE and can inhibit RAGE-activation. The objective of this study was to investigate whether HMGB1 and RAGE are involved in the development of brain injury in preterm infants. METHODS: In total, 108 infants ≤34 weeks gestation at birth were divided into 3 groups according to cranial altrasound scan: mild brain damage (n=33), severe brain damage (n=8) and no brain damage (n=67). All the placentas were submitted for pathologic evaluation. Histological chorioamnionitis (HCA) was defined as neutrophil infi ltration of amniotic membranes, umbilical cord or chorionic plate. Expressions of HMGB1 and RAGE proteins were assessed by immunohistochemical analysis. The concentration of HMGB1 and sRAGE in umbilical cord blood were measured by enzyme-linked immunosorbent assay. RESULTS: The frequency of HCA was 30.12%. HCA was associated with elevated concentrations of HMGB1 and decreased sRAGE in umbilical cord blood. The severe brain injury group demonstrated higher cord blood HMGB1 concentrations (P<0.001) and lower sRAGE concentrations (P<0.001) than both other groups. Brain injury in the premature infants was linked to intense staining for HMGB1/RAGE, particularly in infl ammatory cells. CONCLUSIONS: Changes of cord blood HMGB1 and sRAGE of premature infants had direct relationship with the degree of infl ammation and severity of brain damage. Monitoring sRAGE and HMGB1 levels may be helpful to predict intrauterine infection and brain injury in premature infants.

Processing verbal morphology in patients with congenital left-hemispheric brain lesions.

The goal of this study was to test whether children, teenagers and adults with congenital left-hemispheric brain lesions master the regularities of German verbal inflectional morphology. Thirteen patients and 35 controls without brain damage participated in three experiments. A grammaticality judgment task, a participle inflection task and a nonce-verb inflection task revealed significant differences between patients and controls. In addition, a main effect of verb type could be observed as patients and controls made more mistakes with irregular than with regular verbs. The findings indicate that the congenitally damaged brain not only has difficulties with complex syntactic structures during language development, as reported by earlier studies, but also has persistent deficits on the morphological level. These observations suggest that the plasticity of the developing brain cannot fully compensate for congenital brain damage which affects regions associated with language functions.

Microarray expression profile analysis of long noncoding RNAs in premature brain injury: A novel point of view.

Long noncoding RNAs (lncRNAs) are abundant in the central nervous system and have a key role in brain function as well as many neurological disorders. However, the regulatory function of lncRNAs in the premature brain has not been well studied. This study described the expression profile of lncRNAs in premature mice using microarray technology. 1999 differentially expressed lncRNAs and 955 differentially expressed mRNAs were identified. Gene Ontology (GO) and pathway analysis showed that these lncRNAs were involved in multiple biological processes, including the nervous system development and inflammatory response. Additionally, the lncRNA-mRNA-network and TF-gene-lncRNA-network were constructed to identify core regulatory lncRNAs and transcription factors. The sex-determining region of Y chromosome (SRY) gene may be a key transcription factor that regulates premature brain development and injury. This study for the first time represents an expression profile of differentially expressed lncRNAs in the premature brain and may provide a novel point of view into the mechanisms of premature brain injury.

Metabolic Alterations in Developing Brain After Injury: Knowns and Unknowns.

Brain development is a highly orchestrated complex process. The developing brain utilizes many substrates including glucose, ketone bodies, lactate, fatty acids and amino acids for energy, cell division and the biosynthesis of nucleotides, proteins and lipids. Metabolism is crucial to provide energy for all cellular processes required for brain development and function including ATP formation, synaptogenesis, synthesis, release and uptake of neurotransmitters, maintaining ionic gradients and redox status, and myelination. The rapidly growing population of infants and children with neurodevelopmental and cognitive impairments and life-long disability resulting from developmental brain injury is a significant public health concern. Brain injury in infants and children can have devastating effects because the injury is superimposed on the high metabolic demands of the developing brain. Acute injury in the pediatric brain can derail, halt or lead to dysregulation of the complex and highly regulated normal developmental processes. This paper provides a brief review of metabolism in developing brain and alterations found clinically and in animal models of developmental brain injury. The metabolic changes observed in three major categories of injury that can result in life-long cognitive and neurological disabilities, including neonatal hypoxia-ischemia, pediatric traumatic brain injury, and brain injury secondary to prematurity are reviewed.

Postural complexity influences development in infants born preterm with brain injury: relating perception-action theory to 3 cases.

BACKGROUND AND PURPOSE: Perception-action theory suggests a cyclical relationship between movement and perceptual information. In this case series, changes in postural complexity were used to quantify an infant's action and perception during the development of early motor behaviors. CASE DESCRIPTION: Three infants born preterm with periventricular white matter injury were included. OUTCOMES: Longitudinal changes in postural complexity (approximate entropy of the center of pressure), head control, reaching, and global development, measured with the Test of Infant Motor Performance and the Bayley Scales of Infant and Toddler Development, were assessed every 0.5 to 3 months during the first year of life. All 3 infants demonstrated altered postural complexity and developmental delays. However, the timing of the altered postural complexity and the type of delays varied among the infants. For infant 1, reduced postural complexity or limited action while learning to control her head in the midline position may have contributed to her motor delay. However, her ability to adapt her postural complexity eventually may have supported her ability to learn from her environment, as reflected in her relative cognitive strength. For infant 2, limited early postural complexity may have negatively affected his learning through action, resulting in cognitive delay. For infant 3, an increase in postural complexity above typical levels was associated with declining neurological status. DISCUSSION: Postural complexity is proposed as a measure of perception and action in the postural control system during the development of early behaviors. An optimal, intermediate level of postural complexity supports the use of a variety of postural control strategies and enhances the perception-action cycle. Either excessive or reduced postural complexity may contribute to developmental delays in infants born preterm with white matter injury.

Abnormal heart rate characteristics are associated with abnormal neuroimaging and outcomes in extremely low birth weight infants.

OBJECTIVE: Brain injury in preterm infants may lead to an inflammatory response and central nervous system dysfunction reflected by abnormal heart rate characteristics (HRC). We hypothesized that a continuously monitored HRC index reflecting reduced HR variability and decelerations correlates with abnormal neuroimaging and outcomes in extremely low birth weight infants (ELBW). STUDY DESIGN: We analyzed the average HRC index within 28 days after birth (aHRC28) and head ultrasound (HUS) in 384 ELBW infants. In 50 infants with brain magnetic resonance imaging (MRI) and 70 infants with Bayley neurodevelopmental testing at 1 year of age, we analyzed the relationship between aHRC28, MRI abnormalities and low Bayley scores. RESULT: aHRC28 was higher in infants with severe HUS abnormalities (2.65±1.27 for Grade III-IV intraventricular hemorrhage (IVH) or cystic periventricular leukomalacia (cPVL) versus 1.72±0.95 for normal or Grade I-II IVH, P<0.001). Higher aHRC28 was also associated with white matter damage on MRI and death or Bayley motor or mental developmental index <70. Associations persisted after adjusting for gestational age, birth weight and septicemia. For every one point increase in aHRC28, the odds ratio of death or Bayley score <70 was 2.45 (95% CI 1.46, 4.05, P<0.001). CONCLUSION: A continuously monitored HRC index provides an objective, noninvasive measure associated with abnormal brain imaging and adverse neurologic outcomes in ELBW infants.

Intranasal epidermal growth factor treatment rescues neonatal brain injury.

There are no clinically relevant treatments available that improve function in the growing population of very preterm infants (less than 32 weeks' gestation) with neonatal brain injury. Diffuse white matter injury (DWMI) is a common finding in these children and results in chronic neurodevelopmental impairments. As shown recently, failure in oligodendrocyte progenitor cell maturation contributes to DWMI. We demonstrated previously that the epidermal growth factor receptor (EGFR) has an important role in oligodendrocyte development. Here we examine whether enhanced EGFR signalling stimulates the endogenous response of EGFR-expressing progenitor cells during a critical period after brain injury, and promotes cellular and behavioural recovery in the developing brain. Using an established mouse model of very preterm brain injury, we demonstrate that selective overexpression of human EGFR in oligodendrocyte lineage cells or the administration of intranasal heparin-binding EGF immediately after injury decreases oligodendroglia death, enhances generation of new oligodendrocytes from progenitor cells and promotes functional recovery. Furthermore, these interventions diminish ultrastructural abnormalities and alleviate behavioural deficits on white-matter-specific paradigms. Inhibition of EGFR signalling with a molecularly targeted agent used for cancer therapy demonstrates that EGFR activation is an important contributor to oligodendrocyte regeneration and functional recovery after DWMI. Thus, our study provides direct evidence that targeting EGFR in oligodendrocyte progenitor cells at a specific time after injury is clinically feasible and potentially applicable to the treatment of premature children with white matter injury.