Cerebral Palsy

MyD88 KO (knockout) mice are exquisitely sensitive to CNS (central nervous system) infection with Staphylococcus aureus, a common aetiological agent of brain abscess, exhibiting global defects in innate immunity and exacerbated tissue damage. However, since brain abscesses are typified by the involvement of both activated CNS-resident and infiltrating immune cells, in our previous studies it has been impossible to determine the relative contribution of MyD88-dependent signalling in the CNS compared with the peripheral immune cell compartments. In the present study we addressed this by examining the course of S. aureus infection in MyD88 bone marrow chimaera mice. Interestingly, chimaeras where MyD88 was present in the CNS, but not bone marrow-derived cells, mounted pro-inflammatory mediator expression profiles and neutrophil recruitment equivalent to or exceeding that detected in WT (wild-type) mice. These results implicate CNS MyD88 as essential in eliciting the initial wave of inflammation during the acute response to parenchymal infection. Microarray analysis of infected MyD88 KO compared with WT mice revealed a preponderance of differentially regulated genes involved in apoptotic pathways, suggesting that the extensive tissue damage characteristic of brain abscesses from MyD88 KO mice could result from dysregulated apoptosis. Collectively, the findings of the present study highlight a novel mechanism for CNS-resident cells in initiating a protective innate immune response in the infected brain and, in the absence of MyD88 in this compartment, immunity is compromised.

There is an increase in the numbers of neural precursors in the SVZ (subventricular zone) after moderate ischaemic injuries, but the extent of stem cell expansion and the resultant cell regeneration is modest. Therefore our studies have focused on understanding the signals that regulate these processes towards achieving a more robust amplification of the stem/progenitor cell pool. The goal of the present study was to evaluate the role of the EGFR [EGF (epidermal growth factor) receptor] in the regenerative response of the neonatal SVZ to hypoxic/ischaemic injury. We show that injury recruits quiescent cells in the SVZ to proliferate, that they divide more rapidly and that there is increased EGFR expression on both putative stem cells and progenitors. With the amplification of the precursors in the SVZ after injury there is enhanced sensitivity to EGF, but not to FGF (fibroblast growth factor)-2. EGF-dependent SVZ precursor expansion, as measured using the neurosphere assay, is lost when the EGFR is pharmacologically inhibited, and forced expression of a constitutively active EGFR is sufficient to recapitulate the exaggerated proliferation of the neural stem/progenitors that is induced by hypoxic/ischaemic brain injury. Cumulatively, our results reveal that increased EGFR signalling precedes that increase in the abundance of the putative neural stem cells and our studies implicate the EGFR as a key regulator of the expansion of SVZ precursors in response to brain injury. Thus modulating EGFR signalling represents a potential target for therapies to enhance brain repair from endogenous neural precursors following hypoxic/ischaemic and other brain injuries.

Object Progressive hydrocephalus may lead to edema of the periventricular white matter and to damage of the brain parenchyma because of compression, stretching, and ischemia. The aim of the present study was to investigate whether cerebral edema can be quantified using diffusion-weighted imaging in infants with hydrocephalus and whether CSF diversion could decrease cerebral edema. Methods Diffusion-weighted MR imaging was performed in 24 infants with progressive hydrocephalus before and after CSF diversion. Parametric images of the trace apparent diffusion coefficients (ADCs) were obtained. The ADCs of 5 different cortical and subcortical regions of interest were calculated pre- and postoperatively in each patient. The ADC values were compared with age-related normal values. Mean arterial blood pressure and anterior fontanel pressure were measured immediately after each MR imaging study. Results After CSF diversion, the mean ADC decreased from a preoperative value of 1209 +/- 116 x 10(-6) mm(2)/second to a postoperative value of 928 +/- 64 x 10(-6) mm(2)/second (p < 0.005). Differences between pre- and postoperative ADC values were most prominent in the periventricular white matter, supporting the existence of preoperative periventricular edema. Compared with age-related normal values, the preoperative ADC values were higher and the postoperative ADC values were lower, although within normal range. The decrease in ADC after CSF drainage was more rapid than the more gradual physiological decrease that is related to age. The preoperative ICP was elevated in all patients. After CSF diversion the ICP decreased significantly to within the normal range. A linear correlation between ADC values and ICP was found (correlation coefficient 0.496, p < 0.001). In all patients the mean arterial blood pressure was within physiological limits both pre- and postoperatively. Conclusions This study shows a rapid and more extensive decrease in ADC values after CSF diversion than is to be expected from physiological ADC decrease solely due to increasing patient age. The preoperative ADC increase can be explained by interstitial edema caused by transependymal CSF leakage or by vasogenic edema caused by capillary compression and stretching of the brain parenchyma. This study population of infants with (early recognized) hydrocephalus did not suffer from cytotoxic edema. These findings may help to detect patients at risk for cerebral damage by differentiating between progressive and compensated hydrocephalus.

OBJECT: The availability of sophisticated neural probes is a key prerequisite in the development of future brain-machine interfaces (BMIs). In this study, the authors developed and validated a neural probe design capable of simultaneous drug delivery and electrophysiology recordings in vivo. Focal drug delivery promises to extend dramatically the recording lives of neural probes, a limiting factor to clinical adoption of BMI technology. METHODS: To form the multifunctional neural probe, the authors affixed a 16-channel microfabricated silicon electrode array to a fused silica catheter. Three experiments were conducted in rats to characterize the performance of the device. Experiment 1 examined cellular damage from probe insertion and the drug distribution in tissue. Experiment 2 measured the effects of saline infusions delivered through the probe on concurrent electrophysiological measurements. Experiment 3 demonstrated that a physiologically relevant amount of drug can be delivered in a controlled fashion. For these experiments, Hoechst and propidium iodide stains were used to assess insertion trauma and the tissue distribution of the infusate. Artificial CSF (aCSF) and tetrodotoxin (TTX) were injected to determine the efficacy of drug delivery. RESULTS: The newly developed multifunctional neural probes were successfully inserted into rat cortex and were able to deliver fluids and drugs that resulted in the expected electrophysiological and histological responses. The damage from insertion of the device into brain tissue was substantially less than the volume of drug dispersion in tissue. Electrophysiological activity, including both individual spikes as well as local field potentials, was successfully recorded with this device during real-time drug delivery. No significant changes were seen in response to delivery of aCSF as a control experiment, whereas delivery of TTX produced the expected result of suppressing all spiking activity in the vicinity of the catheter outlet. CONCLUSIONS: Multifunctional neural probes such as the ones developed and validated within this study have great potential to help further understand the design space and criteria for the next generation of neural probe technology. By incorporating integrated drug delivery functionality into the probes, new treatment options for neurological disorders and regenerative neural interfaces using localized and feedback-controlled delivery of drugs can be realized in the near future.

Electrocorticography (ECoG) offers a powerful and versatile platform for developing brain-computer interfaces; it avoids the risks of brain-invasive methods such as intracortical implants while providing significantly higher signal-to-noise ratio than noninvasive techniques such as electroencephalography. The authors demonstrate that both contra- and ipsilateral finger movements can be discriminated from ECoG signals recorded from a single brain hemisphere. The ECoG activation patterns over sensorimotor areas for contra- and ipsilateral movements were found to overlap to a large degree in the recorded hemisphere. Ipsilateral movements, however, produced less pronounced activity compared with contralateral movements. The authors also found that single-trial classification of movements could be improved by selecting patient-specific frequency components in high-frequency bands (> 50 Hz). Their discovery that ipsilateral hand movements can be discriminated from ECoG signals from a single hemisphere has important implications for neurorehabilitation, suggesting in particular the possibility of regaining ipsilateral movement control using signals from an intact hemisphere after damage to the other hemisphere.

One of the most completely validated processes involved in secondary tissue damage following acute brain or spinal cord injury and in many chronic neurodegenerative diseases has to do with the pathological formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). These are generated by multiple mechanisms and give rise to highly reactive oxygen radicals that can damage neuronal, glial, and microvascular elements. Particular interest has centered upon oxygen radical-induced, iron-catalyzed lipid peroxidation (LP) as the principal mechanism of neuronal injury associated with oxygen radicals. Thus, there has been a growing interest in monitoring increased oxygen radical levels as an index of oxidative stress, as well as measuring markers of LP-associated oxidative injury in in vitro and in vivo model systems and neurological patient samples. Accordingly, the purpose of this unit is to provide a variety of methods for the measurement of hydroxyl radical formation and/or LP in nervous tissue or biofluids.Curr. Protoc. Neurosci. 48:7.17.1-7.17.51. (c) 2009 by John Wiley & Sons, Inc.

AIM. To provide a summary of the different experimental models of traumatic brain injury (TBI) designed under both in vivo and in vitro conditions. A comprehensible review of the specific types of brain lesions induced, as well as the technical details to reproduce each model at the laboratory is given. DEVELOPMENT. Outcome of patients suffering from a TBI has significantly improved with the rapid application of vital supporting measures in addition to a strict control of blood and intracranial pressure at the intensive care units. However no specific treatment for post-traumatic brain lesions has proven as efficacious in the clinical settings. A deeper knowledge of the physiopathological events associated with TBI is necessary for the development of new specific therapies. Due to the heterogeneity of the human TBI, each experimental model has been designed to reproduce a different type of brain lesion. Experimental TBI models allow the study of the dynamic evolution of brain injuries under controlled conditions. Usefulness of experimental models is limited by their reliability and reproducibility among different researchers. Small rodents have been the preferred animals to reproduce TBI injuries, mainly due to the similar cerebral physiology shared by these animals and the human beings. CONCLUSION. The use of experimental models of TBI is the most appropriate tool to study the mechanisms underlying this type of injury. However their simplicity precludes an exact reproduction of the heterogeneous cerebral damage observed in clinical settings. This could be the main reason for the discrepancies observed in the therapeutic effects of treatments between experimental and clinical studies.

AbstractAim:To test the role of the Beclin 1-dependent autophagy pathway in brain damage during cerebral ischemia.Methods:Focal cerebral ischemia was established in rats using a middle cerebral artery occlusion (MCAO) model. A lentiviral vector-associated RNA interference (RNAi) system was stereotaxically injected into the ipsilateral lateral ventricle to reduce Beclin1 expression. We measured the ipsilateral infarct volume, autophagosome formation, neurogenesis and apoptosis, all of which could be modulated by Beclin1 RNAi.Results:On the 14th day after MCAO, Beclin1 downregulation by RNAi increased the population of neural progenitor cells (BrdU(+)-DCX(+)), newborn immature cells (BrdU(+)-Tuj-1(+)) and mature neurons (BrdU(+)-MAP-2(+)), and reduced the apoptosis of immature neurons (caspase-3(+)-DCX(+) and caspase-3(+)-Tuj-1(+)) surrounding the ischemic core of the ipsilateral hemisphere. Furthermore, RNAi-mediated downregulation of Beclin1 decreased infarct volume and inhibited histological injury and neurological deficits.Conclusion:RNAi-mediated downregulation of Beclin1 improves outcomes after transient MCAO.Acta Pharmacologica Sinica (2009) 30: 919-927; doi: 10.1038/aps.2009.79.

The concentration of the protein S100B in serum is used as a brain damage marker in various conditions. We wanted to investigate whether a voluntary, prolonged apnea in trained breath-hold divers resulted in an increase of S100B in serum. Nine trained breath-hold divers performed a protocol mimicking the procedures they use during breath-hold training and competition, including extensive pre-apneic hyperventilation and glossopharyngeal insufflation, in order to perform a maximum-duration apnea, i.e. “static apnea” (average: 335 s, range: 281-403 s). Arterial blood samples were collected and cardiovascular variables recorded. The arterial partial pressures of O2 and CO2 (PaO2 and PaCO2) were 128 Torr and 20 Torr, respectively, at the start of apnea. The degree of asphyxia at the end of apnea was considerable, with PaO2 and PaCO2 reaching 28 Torr and 45 Torr, respectively. The concentration of S100B in serum transiently increased from 0.066 microg*L(-1) at the start of apnea to 0.083 microg*L(-1) after the apnea (P < 0.05). The increase in S100B is attributed to the asphyxia or to other physiological responses to apnea, for example increased blood pressure, and probably indicates a temporary opening of the blood-brain barrier. It is not possible to conclude that the observed increase in S100B levels in serum after a maximal-duration apnea reflects a serious injury to the brain, although the results raise concerns considering negative long-term effects. At least, the results indicate that prolonged, voluntary apnea affects the integrity of the central nervous system, and do not preclude cumulative effects. Key words: hemoglobin, hypoxia, ionized calcium, lactate.

The development of sclerosing cholangitis (SC) is observed in up to 50% of children followed up for autoimmune hepatitis (AIH). In adults, the prevalence is less known, although a recent study found evidence of SC in 10% of AIH patients using magnetic resonance cholangiopancreatography (MRCP). The aim of this study was to assess prospectively the prevalence of SC in adults with AIH. Fifty-nine consecutive patients with AIH diagnosed according to International Autoimmune Hepatitis Group score (women, 71%; mean age, 48 years; cirrhosis, 23%) underwent both MRCP and percutaneous liver biopsy. Twenty-seven patients with cirrhosis of nonbiliary or non-autoimmune etiology served as controls. Fourteen AIH patients (24%) showed mild MRCP abnormalities of intrahepatic bile ducts (IHBDs). None had abnormal common bile duct or convincing evidence of SC on MRCP or biopsy. A diagnosis of overlapping SC was nevertheless retained in one patient with MRCP abnormalities who subsequently developed symptomatic cholestasis despite corticosteroid therapy. Fibrosis score was the only independent parameter associated with bile duct abnormalities on MRCP (odds ratio 2.4; 95% confidence interval 1.4-4.7) and the percentage of patients with IHBD MRCP abnormalities was not different among F3-F4 AIH patients (n = 24) and cirrhotic controls (46% versus 59%; NS). Conclusion: In this cohort of adult patients with AIH, the prevalence of SC was much lower than previously reported (1.7%). Mild MRCP abnormalities of IHBD were seen in a quarter of patients, but these abnormalities resulted from hepatic fibrosis and not SC. In the absence of cholestatic presentation, MRCP screening does not seem justified in adult-onset AIH. (HEPATOLOGY 2009.).