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1.  Potential for treatment of severe autism in tuberous sclerosis complex 
The Food and Drug Administration (FDA) has approved two mechanism-based treatments for tuberous sclerosis complex (TSC)-everolimus and vigabatrin. However, these treatments have not been systematically studied in individuals with TSC and severe autism. The aim of this review is to identify the clinical features of severe autism in TSC, applicable preclinical models, and potential barriers that may warrant strategic planning in the design phase of clinical trial development. A comprehensive search strategy was formed and searched across PubMed, Embase and SCOPUS from their inception to 2/21/12, 3/16/12, and 3/12/12 respectively. After the final search date, relevant, updated articles were selected from PubMed abstracts generated electronically and emailed daily from PubMed. The references of selected articles were searched, and relevant articles were selected. A search of clinicaltrials.gov was completed using the search term “TSC” and “tuberous sclerosis complex”. Autism has been reported in as many as 60% of individuals with TSC; however, review of the literature revealed few data to support clear classification of the severity of autism in TSC. Variability was identified in the diagnostic approach, assessment of cognition, and functional outcome among the reviewed studies and case reports. Objective outcome measures were not used in many early studies; however, diffusion tensor imaging of white matter, neurophysiologic variability in infantile spasms, and cortical tuber subcategories were examined in recent studies and may be useful for objective classification of TSC in future studies. Mechanism-based treatments for TSC are currently available. However, this literature review revealed two potential barriers to successful design and implementation of clinical trials in individuals with severe autism-an unclear definition of the population and lack of validated outcome measures. Recent studies of objective outcome measures in TSC and further study of applicable preclinical models present an opportunity to overcome these barriers.
doi:10.5409/wjcp.v2.i3.16
PMCID: PMC4145642  PMID: 25254170
Autism; Self-injury; Aggression; Tuberous sclerosis complex; Intellectual disability
2.  Early Neurodevelopmental Screening in TSC: A Potential Window of Opportunity 
Pediatric neurology  2014;51(3):398-402.
BACKGROUND
Infants born with tuberous sclerosis complex (TSC), a genetic condition resulting from a mutation in TSC1 or TSC2, are at increased risk for intellectual disability and/or autism. Features of epilepsy, neuropathology, genetics as well as timing and type of mechanism-based medications have been proposed as risk factors. Neurodevelopmental outcomes have been reported among these studies; however, few include data about the individuals’ early neurodevelopmental profile, a factor that may contribute significantly to these outcomes. Further, there is no clinical standard for the neurodevelopmental assessment of these infants. The paucity of data regarding the natural history of neurodevelopment in infants with TSC and the lack of a gold standard for neurodevelopmental evaluation presents a significant challenge for clinicians and researchers.
METHOD
During the first year of life, we tracked the onset of infantile spasms, the type and timing of antiepileptic treatments and the associated response of 2 age-matched infants with TSC. We also employed Capute Scales as a part of a structured neurodevelopmental evaluation to characterize and compare their neurodevelopmental profiles.
RESULTS
Infant 1 developed infantile spasms as confirmed by hypsarrhythmia at 4 months. Treatment with vigabatrin was initiated within 24 hours with near immediate cessation of seizures and no further seizures to date. Expressive language delay was detected at 12 months and treated with speech/language therapy. Infant 2 developed complex partial seizures at 1 month. Treatment included levetiracetam, oxcarbazepine and the ketogenic diet. Vigabatrin was initiated upon detection of hypsarrhythmia after 4 months. Intractable epilepsy persists to date. Global developmental delay was evident by 8 months and treated with physical, occupational and speech/language therapy.
CONCLUSION
Many risk factors have been associated with intellectual disability and/or autism in individuals with TSC; however, few data are available regarding practical clinical tools for early identification. In our case series, inclusion of the Capute Scales as a part of routine medical care led to the identification of developmental delays in the first 12 months of life and selection of targeted neurodevelopmental interventions. Development of a risk-based assessment using this approach will be the focus of future studies as it may provide a potential window of opportunity for both research and clinical purposes. In research, it may serve as an objective outcome measure. Clinically, this type of assessment has potential for informing clinical treatment decisions and serving as a prognostic indicator of long term cognitive and psychiatric outcomes.
doi:10.1016/j.pediatrneurol.2014.04.028
PMCID: PMC4196722  PMID: 25160545
development; tuberous sclerosis; vigabatrin; everolimus; sirolimus; cognition; Capute scales
3.  Murine model: maternal administration of stem cells for prevention of prematurity 
OBJECTIVE
Using a mouse model of intrauterine inflammation, we have demonstrated that exposure to inflammation induces preterm birth and perinatal brain injury. Mesenchymal stem cells (MSCs) have been shown to exhibit immunomodulatory effects in many inflammatory conditions. We hypothesized that treatment with human adipose tissue-derived MSCs may decrease the rate of preterm birth and perinatal brain injury through changes in antiinflammatory and regulatory milieu.
STUDY DESIGN
A mouse model of intrauterine inflammation was used with the following groups: (1) control; (2) intrauterine inflammation (lipopolysaccharide); and (3) intrauterine lipopolysaccharide + intraperitoneal (MSCs). Preterm birth was investigated. Luminex multiplex enzyme-linked immunosorbent assays were performed for protein levels of cytokines in maternal and fetal compartments. Immunofluorescent staining was used to identify and localize MSCs and to examine microglial morphologic condition and neurotoxicity in perinatal brain. Behavioral testing was performed at postnatal day 5.
RESULTS
Pretreatment with MSCs significantly decreased the rate of preterm birth by 21% compared with the lipopolysaccharide group (P < .01). Pretreatment was associated with increased interleukin-10 in maternal serum, increased interleukin-4 in placenta, decreased interleukin-6 in fetal brain (P < .05), decreased microglial activation (P < .05), and decreased fetal neurotoxicity (P < .05). These findings were associated with improved neurobehavioral testing at postnatal day 5 (P < .05). Injected MSCs were localized to placenta.
CONCLUSION
Maternally administered MSCs appear to modulate maternal and fetal immune response to intrauterine inflammation in the model and decrease preterm birth, perinatal brain injury, and motor deficits in offspring mice.
doi:10.1016/j.ajog.2014.12.032
PMCID: PMC4817275  PMID: 25555657
intrauterine inflammation; mesenchymal stem cell; perinatal brain injury; preterm birth
4.  Transplanted Glial Restricted Precursor Cells Improve Neurobehavioral and Neuropathological Outcomes in a Mouse Model of Neonatal White Matter Injury Despite Limited Cell Survival 
Glia  2014;63(3):452-465.
Objective
Neonatal White Matter Injury (NWMI) is the leading cause of cerebral palsy and other neurocognitive deficits in prematurely-born children, and no restorative therapies exist. Our objective was to determine the fate and effect of glial restricted precursor cell (GRP) transplantation in an ischemic mouse model of NWMI.
Methods
Neonatal CD-1 mice underwent unilateral carotid artery ligation on postnatal-day 5 (P5). At P22, intracallosal injections of either eGFP+ GRPs or saline were performed in control and ligated mice. Neurobehavioral and postmortem studies were performed at four and eight weeks post-transplantation.
Results
GRP survival was comparable at one month but significantly lower at two months post-transplantation in NWMI mice compared to unligated controls. Surviving cells showed better migration capability in controls; however, the differentiation capacity of transplanted cells was similar in control and NWMI. Saline-treated NWMI mice showed significantly altered response in startle amplitude and pre-pulse inhibition paradigms compared to unligated controls, while these behavioral tests were completely normal in GRP-transplanted animals. Similarly, there was significant increase in hemispheric myelin basic protein density, along with significant decrease in pathologic axonal staining in cell-treated NWMI mice compared to saline-treated NWMI animals.
Interpretation
The Reduced long-term survival and migration of transplanted GRPs in an ischemia-induced NWMI model suggests that neonatal ischemia leads to long-lasting detrimental effects on oligodendroglia even months after the initial insult. Despite limited GRP-survival, behavioral and neuropathological outcomes were improved after GRP-transplantation. Our results suggest that exogenous GRPs improve myelination through trophic effects in addition to differentiation into mature oligodendrocytes.
doi:10.1002/glia.22764
PMCID: PMC4293328  PMID: 25377280
Cell Therapy; Cerebral Palsy; Ischemia; Myelination
5.  A Diagnostic Approach for Cerebral Palsy in the Genomic Era 
Neuromolecular medicine  2014;16(4):821-844.
An ongoing challenge in children presenting with motor delay/impairment early in life is to identify neurogenetic disorders with a clinical phenotype which can be misdiagnosed as cerebral palsy (CP). To help distinguish patients in these two groups, conventional magnetic resonance imaging (MRI) of the brain has been of great benefit in “unmasking” many of these genetic etiologies and has provided important clues to differential diagnosis in others. Recent advances in molecular genetics such as chromosomal microarray and next generation sequencing have further revolutionized the understanding of etiology by more precisely classifying these disorders with a molecular cause. In this paper, we present a review of neurogenetic disorders masquerading as cerebral palsy evaluated at one institution. We have included representative case examples children presenting with dyskinetic, spastic and ataxic phenotypes, with the intent to highlight the time honored approach of using clinical tools of history and examination to focus the subsequent etiologic search with advanced neuroimaging modalities and molecular genetic tools. A precise diagnosis of these masqueraders and their differentiation from CP is important in terms of therapy, prognosis, and family counseling. In summary, this review serves as a continued call to remain vigilant for current and other to-be-discovered neurogenetic masqueraders of cerebral palsy, thereby optimizing care for patients and their families.
doi:10.1007/s12017-014-8331-9
PMCID: PMC4229412  PMID: 25280894
Cerebral palsy; masqueraders; spastic; dyskinetic and ataxic phenotypes; neurogenetic
6.  Brain Injury in Canine Models of Cardiac Surgery 
Neuropathology and neurologic impairment were characterized in a clinically relevant canine model of hypothermic (18°C) circulatory arrest (HCA) and cardiopulmonary bypass (CPB). Adult dogs underwent 2 hours of HCA (n = 39), 1 hour of HCA (n = 20), or standard CPB (n = 22) and survived 2 hours, 8 hours, 24 hours or 72 hours. Neurologic impairment and neuropathology were much more severe after 2-hour HCA than after 1-hour HCA or CPB; histopathology and neurologic deficit scores were significantly correlated. Apoptosis developed as early as 2 hours after injury and was most severe in the granule cells of hippocampal dentate gyrus. Necrosis evolved more slowly and was most severe in amygdala and pyramidal neurons in CA hippocampus. Neuronal injury was minimal up to 24 hours post-1-hour HCA, but 1 dog that survived to 72 hours showed substantial necrosis in the hippocampus, suggesting that with longer survival time the injury was worse. Although neuronal injury was minimal after CPB, we observed rare apoptotic and necrotic neurons in hippocampi and caudate nuclei. These results have important implications for CPB in humans and may help explain the subtle cognitive changes experienced by patients after CPB.
doi:10.1097/NEN.0000000000000134
PMCID: PMC4232977  PMID: 25383634
Cardiopulmonary bypass; Circulatory arrest; Histopathology; Hypothermia; Hypoxia; Ischemia; Neurologic deficit score
7.  Cerebral reorganization after hemispherectomy: A DTI study 
Epilepsy research  2013;104(3):253-263.
Background and Purpose
To characterize changes in DTI scalars in WM tracts of the remaining hemisphere in children after hemispherectomy, assess the associations between WM DTI scalars and age at surgery and time since surgery, and evaluate the changes in GM fractional anisotropy (FA) values in patients compared to controls.
Materials and Methods
Patients with congenital or acquired neurological diseases who required hemispherectomy and high-quality postsurgical DTI data were included into this study. Atlas- and voxel-based analysis of DTI raw data of the remaining hemisphere was performed. FA, mean (MD), axial (AD) and radial (RD) diffusivity values were calculated for WM and GM regions. A linear regression model was used for correlation between DTI scalars and age at and time since surgery.
Results
19 patients after hemispherectomy and 21 controls were included. In patients, a decrease in FA and AD values and an increase in MD and RD values of WM regions were observed compared to controls (p<0.05, corrected for multiple comparisons). In patients with acquired pathologies, time since surgery had a significant positive correlation with white matter FA values. In all patients, an increase in cortical GM FA values was found compared to controls. (p<0.05)
Conclusions
Changes in DTI metrics likely reflect Wallerian and/or transneuronal degeneration of the WM tracts within the remaining hemisphere. In patients with acquired pathologies, postsurgical FA values correlated positively with elapsed time since surgery suggesting a higher ability to recovery compared to patients with congenital pathologies leading to hemispherectomy.
doi:10.1016/j.eplepsyres.2012.10.015
PMCID: PMC4653737  PMID: 23340329
Hemispherectomy; Children; DTI; Neuroimaging; Neuroplasticity
8.  A pilot cohort study of cerebral autoregulation and 2-year neurodevelopmental outcomes in neonates with hypoxic-ischemic encephalopathy who received therapeutic hypothermia 
BMC Neurology  2015;15:209.
Background
Neurodevelopmental disabilities persist in survivors of neonatal hypoxic-ischemic encephalopathy (HIE) despite treatment with therapeutic hypothermia. Cerebrovascular autoregulation, the mechanism that maintains cerebral perfusion during changes in blood pressure, may influence outcomes. Our objective was to describe the relationship between acute autoregulatory vasoreactivity during treatment and neurodevelopmental outcomes at 2 years of age.
Methods
In a pilot study of 28 neonates with HIE, we measured cerebral autoregulatory vasoreactivity with the hemoglobin volume index (HVx) during therapeutic hypothermia, rewarming, and the first 6 h of normothermia. The HVx, which is derived from near-infrared spectroscopy, was used to identify the individual optimal mean arterial blood pressure (MAPOPT) at which autoregulatory vasoreactivity is greatest. Cognitive and motor neurodevelopmental evaluations were completed in 19 children at 21–32 months of age. MAPOPT, blood pressure in relation to MAPOPT, blood pressure below gestational age + 5 (ga + 5), and regional cerebral oximetry (rSO2) were compared to the neurodevelopmental outcomes.
Results
Nineteen children who had HIE and were treated with therapeutic hypothermia performed in the average range on cognitive and motor evaluations at 21–32 months of age, although the mean performance was lower than that of published normative samples. Children with impairments at the 2-year evaluation had higher MAPOPT values, spent more time with blood pressure below MAPOPT, and had greater blood pressure deviation below MAPOPT during rewarming in the neonatal period than those without impairments. Greater blood pressure deviation above MAPOPT during rewarming was associated with less disability and higher cognitive scores. No association was observed between rSO2 or blood pressure below ga + 5 and neurodevelopmental outcomes.
Conclusion
In this pilot cohort, motor and cognitive impairments at 21–32 months of age were associated with greater blood pressure deviation below MAPOPT during rewarming following therapeutic hypothermia, but not with rSO2 or blood pressure below ga + 5. This suggests that identifying individual neonates’ MAPOPT is superior to using hemodynamic goals based on gestational age or rSO2 in the acute management of neonatal HIE.
Electronic supplementary material
The online version of this article (doi:10.1186/s12883-015-0464-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12883-015-0464-4
PMCID: PMC4618147  PMID: 26486728
Autoregulation; NIRS; Hypoxic-Ischemic Encephalopathy; Therapeutic Hypothermia; Neurodevelopmental Outcomes
9.  Heightened Delta Power during Slow-Wave-Sleep in Patients with Rett Syndrome Associated with Poor Sleep Efficiency 
PLoS ONE  2015;10(10):e0138113.
Sleep problems are commonly reported in Rett syndrome (RTT); however the electroencephalographic (EEG) biomarkers underlying sleep dysfunction are poorly understood. The aim of this study was to analyze the temporal evolution of quantitative EEG (qEEG) biomarkers in overnight EEGs recorded from girls (2–9 yrs. old) diagnosed with RTT using a non-traditional automated protocol. In this study, EEG spectral analysis identified high delta power cycles representing slow wave sleep (SWS) in 8–9h overnight sleep EEGs from the frontal, central and occipital leads (AP axis), comparing age-matched girls with and without RTT. Automated algorithms quantitated the area under the curve (AUC) within identified SWS cycles for each spectral frequency wave form. Both age-matched RTT and control EEGs showed similar increasing trends for recorded delta wave power in the EEG leads along the antero-posterior (AP). RTT EEGs had significantly fewer numbers of SWS sleep cycles; therefore, the overall time spent in SWS was also significantly lower in RTT. In contrast, the AUC for delta power within each SWS cycle was significantly heightened in RTT and remained heightened over consecutive cycles unlike control EEGs that showed an overnight decrement of delta power in consecutive cycles. Gamma wave power associated with these SWS cycles was similar to controls. However, the negative correlation of gamma power with age (r = -.59; p<0.01) detected in controls (2–5 yrs. vs. 6–9 yrs.) was lost in RTT. Poor % SWS (i.e., time spent in SWS overnight) in RTT was also driven by the younger age-group. Incidence of seizures in RTT was associated with significantly lower number of SWS cycles. Therefore, qEEG biomarkers of SWS in RTT evolved temporally and correlated significantly with clinical severity.
doi:10.1371/journal.pone.0138113
PMCID: PMC4596813  PMID: 26444000
10.  Circadian cycle dependent EEG biomarkers of pathogenicity in adult mice following prenatal exposure to in utero inflammation 
Neuroscience  2014;275:305-313.
Intrauterine infection or inflammation in preterm neonates is a known risk for adverse neurological outcomes, including cognitive, motor and behavioral disabilities. Our previous data suggest that there is acute fetal brain inflammation in a mouse model of intrauterine exposure to lipopolysaccharides (LPS). We hypothesized that the in utero inflammation induced by LPS produces long-term EEG biomarkers of neurodegeneration in the exposed mice that could be determined by using continuous quantitative video-EEG-EMG analyses. A single LPS injection at E17 was performed in pregnant CD1 dams. Control dams were injected with same volumes of saline (LPS n=10, Control n=8). At postnatal age of P90-100, 24h synchronous video/EEG/EMG recordings were done using a tethered recording system and implanted subdural electrodes. Behavioral state scoring was performed blind to treatment group, on each 10 second EEG epochs using synchronous video, EMG and EEG trace signatures to generate individual hypnograms. Automated EEG power spectrums were analyzed for delta and theta-beta power ratios during wake vs. sleep cycles. Both control and LPS hypnograms showed an ultradian wake/sleep cycling. Since rodents are nocturnal animals, control mice showed the expected diurnal variation with significantly longer time spent in wake states during the dark cycle phase. In contrast, the LPS treated mice lost this circadian rhythm. Sleep microstructure also showed significant alteration in the LPS mice specifically during the dark cycle, caused by significantly longer average NREM cycle durations. No significance was found between treatment groups for the delta power data; however, significant activity dependent changes in theta-beta power ratios seen in controls were absent in the LPS-exposed mice. In conclusion, exposure to in utero inflammation in CD1 mice resulted in significantly altered sleep architecture as adults that were circadian cycle and activity state dependent.
doi:10.1016/j.neuroscience.2014.06.022
PMCID: PMC4228951  PMID: 24954445
LPS - Lipopolysaccharide; qEEG - quantitative electroencephalogram; EMG- electromyogram; prenatal maternal infection; circadian; TBR - theta beta ratio
11.  Perinatal biomarkers in prematurity: Early identification of neurologic injury 
Over the past few decades, biomarkers have become increasingly utilized as non-invasive tools in the early diagnosis and management of various clinical conditions. In perinatal medicine, the improved survival of extremely premature infants who are at high risk for adverse neurologic outcomes has increased the demand for the discovery of biomarkers in detecting and predicting the prognosis of infants with neonatal brain injury. By enabling the clinician to recognize potential brain damage early, biomarkers could allow clinicians to intervene at the early stages of disease, and to monitor the efficacy of those interventions. This review will first examine the potential perinatal biomarkers for neurologic complications of prematurity, specifically, intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL) and posthemorrhagic hydrocephalus (PHH). It will also evaluate knowledge gained from animal models regarding the pathogenesis of perinatal brain injury in prematurity.
doi:10.1016/j.ijdevneu.2014.04.002
PMCID: PMC4101019  PMID: 24768951
biomarkers; intraventricular hemorrhage; periventricular leukomalacia; brain injury; prematurity
12.  Serum Biomarkers of MRI Brain Injury in Neonatal Hypoxic Ischemic Encephalopathy Treated With Whole-Body Hypothermia: A Pilot Study 
Objectives
To determine if candidate biomarkers, ubiquitin carboxyl-terminal esterase L1 and glial fibrillary acidic protein, are elevated in neonates with hypoxic ischemic encephalopathy who die or have severe MRI injury compared with surviving infants with minimal or no injury on brain MRI.
Design
Prospective observational study.
Setting
Level IIIC outborn neonatal ICU in a free-standing children's hospital.
Patients
Term newborns with moderate-to-severe hypoxic ischemic encephalopathy referred for therapeutic hypothermia
Interventions
Serum specimens were collected at 0, 12, 24, and 72 hours of cooling. MRI was performed in surviving infants at target 7–10 days of life and was scored by a pediatric neuroradiologist masked to biomarker and clinical data.
Measurements and Main Results
Serial biomarker levels were determined in 20 hypoxic ischemic encephalopathy patients. Ubiquitin carboxyl-terminal esterase L1 was higher at initiation and 72 hours of cooling, while glial fibrillary acidic protein was higher at 24 and 72 hours in babies with adverse outcome compared with those with favorable outcome.
Conclusions
This preliminary data support further studies to evaluate ubiquitin carboxyl-terminal esterase L1 and glial fibrillary acidic protein as immediate biomarkers of cerebral injury severity in newborns with hypoxic ischemic encephalopathy.
doi:10.1097/PCC.0b013e3182720642
PMCID: PMC4420174  PMID: 23392373
asphyxia; biomarker; hypoxic ischemic encephalopathy; neonate; therapeutic hypothermia
13.  IL-1 Receptor Blockade Prevents Fetal Cortical Brain Injury But Not Preterm Birth in a Mouse Model of Inflammation-Induced Preterm Birth and Perinatal Brain Injury 
Problem
Exposure to intrauterine inflammation, associated with preterm birth, has been linked to a devastating spectrum of neurobehavioral disorders. Mechanisms of this injury are unknown. Using a mouse model of intrauterine inflammation, we have observed a disruption of fetal neuronal morphology along with a marked elevation of Interleukin (IL)-1β in the fetal brain and placenta. In the current study, we hypothesized that IL-1 plays a key role in perinatal brain injury.
Method of Study
Utilizing a mouse model of inflammation-induced preterm birth, we investigated the role of IL-1 in fetal cortical injury as well as preterm birth. In these studies, dams received systemic treatment with IL-1 receptor antagonist prior to administration of intrauterine inflammation.
Results
Systemic maternal antagonism of IL-1 improved fetal cortical neuronal injury associated with the exposure to intrauterine inflammation, without affecting the phenotype of preterm birth. IL-1 receptor antagonist blocked activation of neuronal nitric oxide synthase in perinatal cortex, a key enzyme implicated in neurotoxicity.
Conclusion
Our data suggest that fetal cortical brain injury and preterm birth may occur by divergent mechanisms. Furthermore, our studies indicate maternal administration of IL-1 receptor antagonist (IL-1RA) blocked neuronal nitric oxide synthase activation observed in the brain cortex and, we speculate, that this alteration in activation leads to demonstrated decreased neurotoxicity.
doi:10.1111/aji.12216
PMCID: PMC3989434  PMID: 24592965
Intrauterine inflammation; mouse model; IL-1 receptor antagonist
14.  MOUSE MODEL OF INTRAUTERINE INFLAMMATION: SEX-SPECIFIC DIFFERENCES IN LONG-TERM NEUROLOGIC AND IMMUNE SEQUELAE 
Preterm infants, especially those that are exposed to prenatal intrauterine infection or inflammation, are at a major risk for adverse neurological outcomes, including cognitive, motor and behavioral disabilities. We have previously shown in a mouse model that there is an acute fetal brain insult associated with intrauterine inflammation. The objectives of this study were: 1) to elucidate long-term (into adolescence and adulthood) neurological outcomes by assessing neurobehavioral development, MRI, immunohistochemistry and flow cytometry of cells of immune origin and 2) to determine whether there are any sex-specific differences in brain development associated with intrauterine inflammation. Our results have shown that prenatal exposure appeared to lead to changes in MRI and behavior patterns throughout the neonatal period and during adulthood. Furthermore, we observed chronic brain inflammation in the offspring, with persistence of microglial activation and increased numbers of macrophages in the brain, ultimately resulting in neuronal loss. Moreover, our study highlights the sex-specific differences in long-term sequelae. This study, while extending the growing literature of adverse neurologic outcomes following exposure to inflammation during early development, presents novel findings in the context of intrauterine inflammation.
doi:10.1016/j.bbi.2014.01.014
PMCID: PMC3989501  PMID: 24486323
intrauterine inflammation; preterm birth; mouse model; lipopolysaccharide; brain damage; MRI and behavior
15.  Treatment advances in neonatal neuroprotection and neurointensive care 
Lancet neurology  2011;10(4):372-382.
Knowledge of the nature, prognosis, and ways to treat brain lesions in neonatal infants has increased remarkably. Neonatal hypoxic-ischaemic encephalopathy (HIE) in term infants, mirrors a progressive cascade of excito-oxidative events that unfold in the brain after an asphyxial insult. In the laboratory, this cascade can be blocked to protect brain tissue through the process of neuroprotection. However, proof of a clinical effect was lacking until the publication of three positive randomised controlled trials of moderate hypothermia for term infants with HIE. These results have greatly improved treatment prospects for babies with asphyxia and altered understanding of the theory of neuroprotection. The studies show that moderate hypothermia within 6 h of asphyxia improves survival without cerebral palsy or other disability by about 40% and reduces death or neurological disability by nearly 30%. The search is on to discover adjuvant treatments that can further enhance the effects of hypothermia.
doi:10.1016/S1474-4422(11)70016-3
PMCID: PMC3757153  PMID: 21435600
16.  Injury to the Preterm Brain and Cerebral Palsy: Clinical Aspects, Molecular Mechanisms, Unanswered Questions, and Future Research Directions 
Journal of child neurology  2009;24(9):1064-1084.
Cerebral palsy will affect nearly 10% of the 60,000 very-low-birth-weight infants born in the United States in the next year, and an even greater percentage will display some form of permanent neurological impairment resulting from injury to the preterm brain. The 2008 Neurobiology of Disease in Children Symposium, held in conjunction with the 37th annual meeting of the Child Neurology Society, aimed to define current knowledge and to develop specific aims for future clinical, translational, and fundamental science. A complex interplay of both destructive and developmental forces is responsible for injury to the preterm brain. Advances in imaging and histology have implicated a variety of cell types, though pre-oligodendrocyte injury remains the focus. Research into different mechanisms of injury is facilitating new neuroprotective and rehabilitative interventions. A cooperative effort is necessary to translate basic research findings into clinically effective therapies and better care for these children.
doi:10.1177/0883073809338957
PMCID: PMC3695641  PMID: 19745084
cerebral palsy; molecular mechanisms; translational research
17.  Dendrimer Brain Uptake and Targeted Therapy for Brain Injury in a Large Animal Model of Hypothermic Circulatory Arrest 
ACS Nano  2014;8(3):2134-2147.
Treatment of brain injury following circulatory arrest is a challenging health issue with no viable therapeutic options. Based on studies in a clinically relevant large animal (canine) model of hypothermic circulatory arrest (HCA)-induced brain injury, neuroinflammation and excitotoxicity have been identified as key players in mediating the brain injury after HCA. Therapy with large doses of valproic acid (VPA) showed some neuroprotection but was associated with adverse side effects. For the first time in a large animal model, we explored whether systemically administered polyamidoamine (PAMAM) dendrimers could be effective in reaching target cells in the brain and deliver therapeutics. We showed that, upon systemic administration, hydroxyl-terminated PAMAM dendrimers are taken up in the brain of injured animals and selectively localize in the injured neurons and microglia in the brain. The biodistribution in other major organs was similar to that seen in small animal models. We studied systemic dendrimer–drug combination therapy with two clinically approved drugs, N-acetyl cysteine (NAC) (attenuating neuroinflammation) and valproic acid (attenuating excitotoxicity), building on positive outcomes in a rabbit model of perinatal brain injury. We prepared and characterized dendrimer-NAC (D-NAC) and dendrimer-VPA (D-VPA) conjugates in multigram quantities. A glutathione-sensitive linker to enable for fast intracellular release. In preliminary efficacy studies, combination therapy with D-NAC and D-VPA showed promise in this large animal model, producing 24 h neurological deficit score improvements comparable to high dose combination therapy with VPA and NAC, or free VPA, but at one-tenth the dose, while significantly reducing the adverse side effects. Since adverse side effects of drugs are exaggerated in HCA, the reduced side effects with dendrimer conjugates and suggestions of neuroprotection offer promise for these nanoscale drug delivery systems.
doi:10.1021/nn404872e
PMCID: PMC4004292  PMID: 24499315
PAMAM dendrimers; cardiac arrest; canine model; brain injury; biodistribution; combination therapies; neuroinflammation; cytotoxicity; valproic acid; N-acetylcysteine
18.  Age- and sex-dependent susceptibility to phenobarbital-resistant neonatal seizures: role of chloride co-transporters 
Ischemia in the immature brain is an important cause of neonatal seizures. Temporal evolution of acquired neonatal seizures and their response to anticonvulsants are of great interest, given the unreliability of the clinical correlates and poor efficacy of first-line anti-seizure drugs. The expression and function of the electroneutral chloride co-transporters KCC2 and NKCC1 influence the anti-seizure efficacy of GABAA-agonists. To investigate ischemia-induced seizure susceptibility and efficacy of the GABAA-agonist phenobarbital (PB), with NKCC1 antagonist bumetanide (BTN) as an adjunct treatment, we utilized permanent unilateral carotid-ligation to produce acute ischemic-seizures in post-natal day 7, 10, and 12 CD1 mice. Immediate post-ligation video-electroencephalograms (EEGs) quantitatively evaluated baseline and post-treatment seizure burdens. Brains were examined for stroke-injury and western blot analyses to evaluate the expression of KCC2 and NKCC1. Severity of acute ischemic seizures post-ligation was highest at P7. PB was an efficacious anti-seizure agent at P10 and P12, but not at P7. BTN failed as an adjunct, at all ages tested and significantly blunted PB-efficacy at P10. Significant acute post-ischemic downregulation of KCC2 was detected at all ages. At P7, males displayed higher age-dependent seizure susceptibility, associated with a significant developmental lag in their KCC2 expression. This study established a novel neonatal mouse model of PB-resistant seizures that demonstrates age/sex-dependent susceptibility. The age-dependent profile of KCC2 expression and its post-insult downregulation may underlie the PB-resistance reported in this model. Blocking NKCC1 with low-dose BTN following PB treatment failed to improve PB-efficacy.
doi:10.3389/fncel.2015.00173
PMCID: PMC4429249  PMID: 26029047
neonatal seizures; ischemia; KCC2; NKCC1; phenobarbital; bumetanide
19.  Temporal and regional alterations in NMDA receptor expression in Mecp2-null mice 
Our previous postmortem study of girls with Rett Syndrome (RTT), a development disorder caused by MECP2 mutations, found increases in the density of NMDA receptors in the prefrontal cortex of 2–8 year-old girls, while girls older than 10 years had reductions in NMDA receptors compared to age matched controls (Blue et al., 1999b). Using [3H]-CGP to label NMDA type glutamate receptors in 2 and 7 week old wildtype (WT), Mecp2-null and Mecp2-heterozygous (HET) mice (Bird model), we found that frontal areas of the brain also exhibited a bimodal pattern in NMDA expression, with increased densities of NMDA receptors in Mecp2-null mice at 2 weeks of age, but decreased densities at 7 weeks of age. Visual cortex showed a similar pattern, while other cortical regions only exhibited changes in NMDA receptor densities at 2 weeks (retrosplenial granular) or 7 weeks (somatosensory). In thalamus of null mice, NMDA receptors were increased at 2 and 7 weeks. No significant differences in density were found between HET and WT mice at both ages. Western blots for NMDAR1 expression in frontal brain showed higher levels of expression in Mecp2-null mice at two weeks of age, but not at 1 or 7 weeks of age. Our mouse data support the notion that deficient MeCP2 function is the primary cause of the NMDA receptor changes we observed in RTT. Furthermore, the findings of regional and temporal differences in NMDA expression illustrate the importance of age and brain region in evaluating different genotypes of mice.
doi:10.1002/ar.21380
PMCID: PMC4122218  PMID: 21901842
Rett syndrome; NMDA; Mouse models; Development
20.  Temporal- and Location-Specific Alterations of the GABA Recycling System in Mecp2 KO Mouse Brains 
Rett syndrome (RTT), associated with mutations in methyl-CpG-binding protein 2 (Mecp2), is linked to diverse neurological symptoms such as seizures, motor disabilities, and cognitive impairments. An altered GABAergic system has been proposed as one of many underlying pathologies of progressive neurodegeneration in several RTT studies. This study for the first time investigated the temporal- and location-specific alterations in the expression of γ-amino butyric acid (GABA) transporter 1 (GAT-1), vesicular GABA transporter (vGAT), and glutamic acid decarboxylase 67kD (GAD67) in wild type (WT) and knockout (KO) mice in the Mecp2tm1.1Bird/y mouse model of RTT. Immunohistochemistry (IHC) co-labeling of GAT-1 with vGAT identified GABAergic synapses that were quantitated for mid-sagittal sections in the frontal cortex (FC), hippocampal dentate gyrus (DG), and striatum (Str). An age-dependent increase in the expression of synaptic GABA transporters, GAT-1, and vGAT, was observed in the FC and DG in WT brains. Mecp2 KO mice showed a significant alteration in this temporal profile that was location-specific, only in the FC. GAD67-positive cell densities also showed an age-dependent increase in the FC, but a decrease in the DG in WT mice. However, these densities were not significantly altered in the KO mice in the regions examined in this study. Therefore, the significant location-specific downregulation of synaptic GABA transporters in Mecp2 KO brains with unaltered densities of GAD67-positive interneurons may highlight the location-specific synaptic pathophysiology in this model of RTT.
doi:10.4137/JCNSD.S14012
PMCID: PMC3981570  PMID: 24737935
Rett syndrome; MeCP2 mutation; GABAergic neurons; synapse; lipofuscin; GAT-1
21.  THE POTENTIAL FOR CELL-BASED THERAPY IN PERINATAL BRAIN INJURIES 
Translational stroke research  2013;4(2):137-148.
Perinatal brain injuries are a leading cause of cerebral palsy worldwide. The potential of stem cell therapy to prevent or reduce these impairments has been widely discussed within the medical and scientific communities and an increasing amount of research is being conducted in this field. Animal studies support the idea that a number of stem cells types, including cord blood and mesenchymal stem cells have a neuroprotective effect in neonatal hypoxia-ischemia. Both these cell types are readily available in a clinical setting. The mechanisms of action appear to be diverse, including immunomodulation, activation of endogenous stem cells, release of growth factors, and anti-apoptotic effects. Here, we review the different types of stem cells and progenitor cells that are potential candidates for therapeutic strategies in perinatal brain injuries, and summarize recent preclinical and clinical studies.
doi:10.1007/s12975-013-0254-5
PMCID: PMC3692557  PMID: 23814628
Stem Cell; Cerebral Palsy; neonate; brain injury; hypoxia ischemia
22.  Hypoxic Ischemic Encephalopathy in the Term Infant 
Clinics in perinatology  2009;36(4):835-vii.
Synopsis
Hypoxia-ischemia in the perinatal period is an important cause of cerebral palsy and associated disabilities in children. There has been significant research progress in hypoxic-ischemic encephalopathy over the last two decades and many new molecular mechanisms have been identified. Despite all these advances, therapeutic interventions are still limited. In this review paper, we discuss a number of molecular pathways involved in hypoxia-ischemia, and potential therapeutic targets.
doi:10.1016/j.clp.2009.07.011
PMCID: PMC2849741  PMID: 19944838
Hypoxia ischemia; neonatal encephalopathy; apoptosis; oxidative stress; hypothermia
23.  Ischemia Induced Neuroinflammation is Associated with Disrupted Development of Oligodendrocyte Progenitors in a Model of Periventricular Leukomalacia 
Developmental neuroscience  2013;35(0):182-196.
Microglial activation in crossing white matter tracts is a hallmark of noncystic periventricular leukomalacia (PVL), the leading pathology underlying cerebral palsy in prematurely born infants. Recent studies indicate that neuroinflammation within an early time-window can produce long-lasting defects in oligodendroglial maturation, myelination-deficit, as well as disruption of transcription factors important in oligodendroglial maturation. We recently reported an ischemic mouse model of PVL, induced by unilateral neonatal carotid artery ligation, leading to selective long lasting bilateral myelination deficits, ipsilateral thinning of the corpus callosum, ventriculomegaly, as well as evidence of axonopathy.
Here, we report that permanent unilateral carotid ligation on postnatal day 5 (P5) in CD-1 mice induces an inflammatory response, as defined by microglial activation and recruitment, as well as significant changes in cytokine expression (increased IL-1b, IL-6, TGF-b1, and TNF-a) following ischemia. Transient reduction in counts of oligodendrocyte progenitor cells (OPCs) at 24 and 48 hours post-ischemia, a shift in OPC cell size and morphology towards the more immature form, as well as likely migration of OPCs were found. These OPC changes were topographically associated with areas showing microglial activation, and OPC counts negatively correlated with increased microglial staining.
The presented data shows a striking neuroinflammatory response in an ischemia-induced model of PVL, associated with oligodendroglial injury. Future studies modulating the neuroinflammatory response in this model, may contribute to a better understanding of the interaction between microglia and OPCs in PVL and open opportunities for future therapies.
doi:10.1159/000346682
PMCID: PMC3764456  PMID: 23445614
Infants; inflammation; ischemia; microglia; neonatal; oligodendrocyte progenitor; white matter
24.  Sex differences in mitochondrial biogenesis determine neuronal death and survival in response to oxygen glucose deprivation and reoxygenation 
BMC Neuroscience  2014;15:9.
Background
Mitochondrial dysfunction has been linked to neuronal death and a wide array of neurodegenerative diseases. Previously, we have shown sex differences in mitochondria-mediated cell death pathways following hypoxia-ischemia. However, the role of mitochondrial biogenesis in hypoxic-ischemic brain injury between male vs. female has not been studied yet.
Results
Primary cerebellar granule neurons (CGNs), isolated from P7 male and female mice (CD-1) segregated based on visual inspection of sex, were exposed to 2 h of oxygen glucose deprivation (OGD) followed by 6–24 h of reoxygenation (Reox). Mitochondrial membrane potential (ΔΨm) and cellular ATP levels were reduced significantly in XX CGNs as compared to XY CGNs. Mitochondrial DNA (mtDNA) content was increased (>2-fold) at 2 h OGD in XY CGNs and remained increased up to 24 h of Reox compared to XX neurons and normoxia controls. The expression of mitochondrial transcription factor A (Tfam), the nuclear respiratory factor-1 (NRF-1) and the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, were up-regulated (2-fold, ***p < 0.001) in XY CGNs but slightly reduced or remained unchanged in XX neurons. Similarly, the TFAM and PGC-1α protein levels and the mitochondrial proteins HSP60 and COXIV were increased in XY neurons only. Supportively, a balanced stimulation of fusion (Mfn 1and Mfn 2) and fission (Fis 1 and Drp 1) genes and enhanced formation of donut-shaped mitochondria were observed in XY CGNs vs. XX neurons (**p < 0.01).
Conclusions
Our results demonstrate that OGD/Reox alters mitochondrial biogenesis and morphological changes in a sex-specific way, influencing neuronal injury/survival differently in both sexes.
doi:10.1186/1471-2202-15-9
PMCID: PMC3898007  PMID: 24410996
Hypoxia-ischemia; Mitochondrial DNA; Mitochondrial fusion and fission; Donut mitochondria; Sexual dimorphism
25.  Twenty-four hour quantitative-EEG and in-vivo glutamate biosensor detects activity and circadian rhythm dependent biomarkers of pathogenesis in Mecp2 null mice 
Mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (Mecp2) cause most cases of Rett syndrome (RTT). Currently there is no cure for RTT. Abnormal EEGs are found in 100% of RTT cases and are associated with severe sleep dysfunction, the cause of which is not well understood. Mice deficient in MeCP2 protein have been studied and characterized for their neuropathological and behavioral deficits to better understand RTT. With the goal to study the non-ictal EEG correlates in symptomatic Mecp2 KO mice (Mecp2tm1.1Bird/y), and determine novel EEG biomarkers of their reported progressive neurodegeneration, we used 24 h video-EEG/EMG with synchronous in-vivo cortical glutamate biosensor in the frontal cortex. We scored the EEG for activity states and spectral analysis was performed to evaluate correlations to the synchronous extracellular glutamate fluctuations underlying Mecp2 inactivation as compared to WT. Significant alterations in sleep structure due to dark cycle-specific long wake states and poor quality of slow-wave sleep were associated with a significant increase in glutamate loads per activity cycle. The dynamics of the activity-state-dependent physiological rise and fall of glutamate indicative of glutamate homeostasis were significantly altered in the KO mice. Colorimetric quantitation of absolute glutamate levels in frontal cortex also indicated the presence of significantly higher levels in KO. This study for the first time found evidence of uncompensated sleep deprivation-like EEG biomarkers that were associated with glutamate homeostatic dysfunction in the Mecp2 KO mice.
doi:10.3389/fnsys.2014.00118
PMCID: PMC4072927  PMID: 25018705
Mecp2; sleep structure; glutamate; biomarkers; Rett syndrome

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