Programming Hippocampal Neural Stem/Progenitor Cells into Oligodendrocytes Enhances Remyelination in the Adult Brain after Injury.

Demyelinating diseases are characterized by a loss of oligodendrocytes leading to axonal degeneration and impaired brain function. Current strategies used for the treatment of demyelinating disease such as multiple sclerosis largely rely on modulation of the immune system. Only limited treatment options are available for treating the later stages of the disease, and these treatments require regenerative therapies to ameliorate the consequences of oligodendrocyte loss and axonal impairment. Directed differentiation of adult hippocampal neural stem/progenitor cells (NSPCs) into oligodendrocytes may represent an endogenous source of glial cells for cell-replacement strategies aiming to treat demyelinating disease. Here, we show that Ascl1-mediated conversion of hippocampal NSPCs into mature oligodendrocytes enhances remyelination in a diphtheria-toxin (DT)-inducible, genetic model for demyelination. These findings highlight the potential of targeting hippocampal NSPCs for the treatment of demyelinated lesions in the adult brain.

Neuroenergetic Response to Prolonged Cerebral Glucose Depletion after Severe Brain Injury and the Role of Lactate.

Lactate may represent a supplemental fuel for the brain. We examined cerebral lactate metabolism during prolonged brain glucose depletion (GD) in acute brain injury (ABI) patients monitored with cerebral microdialysis (CMD). Sixty episodes of GD (defined as spontaneous decreases of CMD glucose from normal to low [<1.0 mmol/L] for at least 2 h) were identified among 26 patients. During GD, we found a significant increase of CMD lactate (from 4±2.3 to 5.4±2.9 mmol/L), pyruvate (126.9±65.1 to 172.3±74.1 μmol/L), and lactate/pyruvate ratio (LPR; 27±6 to 35±9; all, p<0.005), while brain oxygen and blood lactate remained normal. Dynamics of lactate and glucose supply during GD were further studied by analyzing the relationships between blood and CMD samples. There was a strong correlation between blood and brain lactate when LPR was normal (r=0.56; p<0.0001), while an inverse correlation (r=-0.11; p=0.04) was observed at elevated LPR >25. The correlation between blood and brain glucose also decreased from r=0.62 to r=0.45. These findings in ABI patients suggest increased cerebral lactate delivery in the absence of brain hypoxia when glucose availability is limited and support the concept that lactate acts as alternative fuel.

How to monitor the brain in septic patients?

Brain injury is frequently observed after sepsis and may be primarily related to the direct effects of the septic insult on the brain (e.g., brain edema, ischemia, seizures) or to secondary/indirect injuries (e.g., hypotension, hypoxemia, hypocapnia, hyperglycemia). Management of brain injury in septic patients is first focused to exclude structural intracranial complications (e.g., ischemic/hemorrhagic stroke) and possible confounders (e.g., electrolyte alterations or metabolic disorders, such as dysglycemia). Sepsis-associated brain dysfunction is frequently a heterogeneous syndrome. Despite increasing understanding of main pathophysiologic determinants, therapy is essentially limited to protect the brain against further cerebral damage, by way of "simple" therapeutic manipulations of cerebral perfusion and oxygenation and by avoiding over-sedation. Non-invasive monitoring of cerebral perfusion and oxygenation with transcranial Doppler (TCD) and near-infrared spectroscopy (NIRS) is feasible in septic patients. Electroencephalography (EEG) allows detection of sepsis-related seizures and holds promise also as sedation monitoring. Brain CT-scan detects intra-cerebral structural lesions, while magnetic resonance imaging (MRI) provides important insights into primary mechanisms of sepsis-related direct brain injury, (e.g., cytotoxic vs. vasogenic edema) and the development of posterior reversible encephalopathy. Together with EEG and evoked potentials (EP), MRI is also important for coma prognostication. Emerging clinical evidence suggests monitoring of the brain in septic patients can be implemented in the ICU. The objective of this review was to summarize recent clinical data about the role of brain monitoring - including TCD, NIRS, EEG, EP, CT, and MRI - in patients with sepsis and to illustrate its potential utility for the diagnosis, management and prognostication.

Bilateral deep brain stimulation : the placement of the second electrode is not necessarily less accurate than that of the first one

Introduction La stimulation cérébrale profonde est reconnue comme étant un traitement efficace des pathologies du mouvement. Nous avons récemment modifié notre technique chirurgicale, en limitant le nombre de pénétrations intracérébrales à trois par hémisphère. Objectif Le premier objectif de cette étude est d'évaluer la précision de l'électrode implantée des deux côtés de la chirurgie, depuis l'implémentation de cette technique chirurgicale. Le deuxième objectif est d'étudier si l'emplacement de l'électrode implantée était amélioré grâce à l'électrophysiologie. Matériel et méthode Il s'agit d'une étude rétrospective reprenant les protocoles opératoires et imageries à résonnance magnétique (IRM) cérébrales de 30 patients ayant subi une stimulation cérébrale profonde bilatérale. Pour l'électrophysiologie, nous avons utilisé trois canules parallèles du « Ben Gun », centrées sur la cible planifiée grâce à l'IRM. Les IRM pré- et post-opératoires ont été fusionnées. La distance entre la cible planifiée et le centre de l'artéfact de l'électrode implantée a été mesurée. Résultats Il n'y a pas eu de différence significative concernant la précision du ciblage des deux côtés (hémisphères) de la chirurgie. Il y a eu plus d'ajustements peropératoires du deuxième côté de la chirurgie, basé sur l'électrophysiologie, ce qui a permis d'approcher de manière significative la cible planifiée grâce à l'IRM, sur l'axe médio- latéral. Conclusion Il y a plus d'ajustements nécessaires de la position de la deuxième électrode, possiblement en lien avec le « brain shift ». Nous suggérons de ce fait d'utiliser une trajectoire d'électrode centrale accompagnée par de l'électrophysiologie, associé à une évaluation clinique. En cas de résultat clinique sub-optimal, nous proposons d'effectuer une exploration multidirectionnelle.

Gamma Knife Surgery versus Linac for Brain Metastasis: Which Technique for Which Patient? Analysis of an Historical Cohort of 63 Consecutive Patients Harboring 130 Lesions

Objectives: We present the retrospective analysis of a single-institution experience for radiosurgery (RS) in brain metastasis (BM) with Gamma Knife (GK) and Linac. Methods: From July 2010 to July 2012, 28 patients (with 83 lesions) had RS with GK and 35 patients (with 47 lesions) with Linac. The primary outcome was the local progression-free survival (LPFS). The secondary outcome was the overall survival (OS). Apart a standard statistical analysis, we included a Cox regression model with shared frailty, to modulate the within-patient correlation (preliminary evaluation showed a significant frailty effect, meaning that the correlation within patient could be ignored). Results: The mean follow-up period was 11.7 months (median 7.9, 1.7-22.7) for GK and 18.1 (median 17, 7.5-28.7) for Linac. The median number of lesions per patient was 2.5 (1-9) in GK compared with 1 (1-3) in Linac. There were more radioresistant lesions (melanoma) and more lesions located in functional areas for the GK group. The median dose was 24 Gy (GK) compared with 20 Gy (Linac). The LPFS actuarial rate was as follows: for GK at 3, 6, 9, 12, and 17 months: 96.96, 96.96, 96.96, 88.1, and 81.5%, and remained stable till 32 months; for Linac at 3, 6, 12, 17, 24, and 33 months, it was 91.5, 91.5, 91.5, 79.9, 55.5, and 17.1%, respectively (p = 0.03, chi-square test). After the Cox regression analysis with shared frailty, the p-value was not statistically significant between groups. The median overall survival was 9.7 months for GK and 23.6 months for Linac group. Uni- and multivariate analysis showed a lower GPA score and noncontrolled systemic status were associated with lower OS. Cox regression analysis adjusting for these two parameters showed comparable OS rate. Conclusions: In this comparative report between GK and Linac, preliminary analysis showed that more difficult cases are treated by GK, with patients harboring more lesions, radioresistant tumors, and highly functional located. The groups look, in this sense, very heterogeneous at baseline. After a Cox frailty model, the LPFS rates seemed very similar (p < 0.05). The OS was similar, after adjusting for systemic status and GPA score (p < 0.05). The technical reasons for choosing GK instead of Linac were the anatomical location related to highly functional areas, histology, technical limitations of Linac movements, especially lower posterior fossa locations, or closeness of multiple lesions to highly functional areas optimal dosimetry with Linac

Creatine deficiency syndomes : a new model of partial GAMT deficiency affecting brain cell development

Les syndromes de déficiences cérébrales en créatine (CCDS) sont dus à des mutations dans les gènes GATM et G AMT (codant pour les enzymes AGAT et G AMT de la voie de synthèse de créatine) ainsi que SLC6A8 (transporteur de créatine), et génèrent une absence ou une très forte baisse de créatine (Cr) dans le cerveau, mesurée par spectroscopic de résonance magnétique. Les patients CCDS développent des handicaps neurologiques sévères. Les patients AGAT et GAMT peuvent être traités avec des doses importantes de Cr, mais gardent dans la plupart des cas des séquelles neurologiques irréversibles. Aucun traitement efficace n'existe à ce jour pour la déficience en SLC6A8. Bien que de nombreux modèles aient été développés pour comprendre la Cr cérébrale en conditions physiologiques, les pathomécanismes des CCDS ne sont pas encore compris. Des souris transgéniques pour les gènes Gatm, Gamt et Slc6a8 ont été générées, mais elles ne miment que partiellement la pathologie humaine. Parmi les CCDS, la déficience en GAMT est la plus sévère, en raison de l'accumulation cérébrale de l'intermédiaire guanidinoacétate (GAA). Alors que la toxicité cérébrale du GAA a été étudiée par exposition directe au GAA d'animaux adultes sains, les mécanismes de la toxicité du GAA en condition de déficience en GAMT dans le cerveau en développement sont encore inconnus. Le but de ce projet était donc de développer un modèle de déficience en GAMT dans des cultures 3D primaires de cellules nerveuses de rat en agrégats par knock-down du gène GAMT, en utilisant un virus adéno-associé (AAV) induisant le mécanisme d'interférence à l'ARN (RNAi). Le virus scAAV2, à la multiplicité d'infection de 1000, s'est révélé le plus efficace pour transduire tous les types de cellules nerveuses des cultures (neurones, astrocytes, oligodendrocytes), et générer un knock-down maximal de la protéine GAMT de 85% (jour in vitro 18). Cette déficience partielle en GAMT s'est révélée insuffisante pour générer une déficience en Cr, mais a causé l'accumulation attendue de GAA, à des doses comparables aux niveaux observés dans le LCR des patients GAMT. Le GAA a induit une croissance axonale anarchique accompagnée d'une baisse de l'apoptose naturelle, suivis par une induction tardive de mort cellulaire non-apoptotique. Le co-traitement par la Cr a prévenu tous les effets toxiques du GAA. Ce travail montre que l'accumulation de GAA en absence de déficience en Cr est suffisante pour affecter le développement du tissu nerveux, et suggère que des formes de déficiences en GAMT supplémentaires, ne présentant pas de déficiences en Cr, pourraient être découvertes par mesure du GAA, en particulier à travers les programmes récemment proposés de dépistage néonatal de la déficience en GAMT. -- Cerebral creatine deficiency syndromes (CCDS) are caused by mutations in the genes GATM and GAMT (respectively coding for the two enzymes of the creatine synthetic pathway, AGAT and GAMT) as well as SLC6A8 (creatine transporter), and lead to the absence or very strong decrease of creatine (Cr) in the brain when measured by magnetic resonance spectroscopy. Affected patients show severe neurological impairments. While AGAT and GAMT deficient patients can be treated with high dosages of Cr, most remain with irreversible brain sequelae. No treatment has been successful so far for SLC6A8 deficiency. While many models have helped understanding the cerebral Cr pathways in physiological conditions, the pathomechanisms underlying CCDS are yet to be elucidated. Transgenic mice carrying mutations in the Gatm, Gamt and Slc6a8 genes have been developed, but only partially mimic the human pathology. Among CCDS, GAMT deficiency is the most severe, due to the CNS accumulation of the guanidinoacetate (GAA) intermediate. While brain toxicity of GAA has been explored through direct GAA exposure of adult healthy animals, the mechanisms underlying GAA toxicity in GAMT deficiency conditions on the developing CNS are yet unknown. The aim of this project was thus to develop and characterize a GAMT deficiency model in developing brain cells by gene knockdown, by adeno-associated virus (AAV)-driven RNA interference (RNAi) in rat 3D organotypic primary brain cell cultures in aggregates. scAAV2 with a multiplicity of infection of 1000 was shown as the most efficient serotype, was able to transduce all brain cell types (neurons, astrocytes, oligodendrocytes) and to induce a maximal GAMT protein knockdown of 85% (day in vitro 18). Metabolite analysis showed that partial GAMT knockdown was insufficient to induce Cr deficiency but generated the awaited GAA accumulation at concentrations comparable to the levels observed in cerebrospinal fluid of GAMT-deficient patients. Accumulated GAA induced axonal hypersprouting paralleled with inhibition of natural apoptosis, followed by a later induction in non-apoptotic cell death. Cr supplementation led to the prevention of all GAA-induced toxic effects. This work shows that GAA accumulation without Cr deficiency is sufficient to affect CNS development, and suggests that additional partial GAMT deficiencies, which may not show the classical brain Cr deficiency, may be discovered through GAA measurement including by recently proposed neonatal screening programs for GAMT deficiency.

Abnormal Error Monitoring in Math-Anxious Individuals: Evidence from Error-Related Brain Potentials.

This study used event-related brain potentials to investigate whether math anxiety is related to abnormal error monitoring processing. Seventeen high math-anxious (HMA) and seventeen low math-anxious (LMA) individuals were presented with a numerical and a classical Stroop task. Groups did not differ in terms of trait or state anxiety. We found enhanced error-related negativity (ERN) in the HMA group when subjects committed an error on the numerical Stroop task, but not on the classical Stroop task. Groups did not differ in terms of the correct-related negativity component (CRN), the error positivity component (Pe), classical behavioral measures or post-error measures. The amplitude of the ERN was negatively related to participants" math anxiety scores, showing a more negative amplitude as the score increased. Moreover, using standardized low resolution electromagnetic tomography (sLORETA) we found greater activation of the insula in errors on a numerical task as compared to errors in a nonnumerical task only for the HMA group. The results were interpreted according to the motivational significance theory of the ERN.

Drug abuse, brain calcification and glutamate-induced neurodegeneration

Positive and negative reinforcing systems are part of the mechanism of drug dependence. Drugs with abuse potential may change the manner of response to negative emotional stimuli, activate positive emotional reactions and possess primary reinforcing properties. Catecholaminergic and peptidergic processes are of importance in these mechanisms. Current research needs to understand the types of adaptations that underlie the particularly long-lived aspects of addiction. Presently, glutamate is candidate to play a role in the enduring effects of drugs of abuse. For example, it participates in the chronic pathological changes of corticostriatal terminals produced by methamphetamine. At the synaptic level, a link between over-activation of glutamate receptors, [C(a2+)](i) increase and neuronal damage has been clearly established leading to neurodegeneration. Thus, neurodegeneration can start after an acute over-stimulation whose immediate effects depend on a diversity of calcium-activated mechanisms. If sufficient, the initial insult results in calcification and activation of a chronic on-going process with a progressive loss of neurons. At present, long-term effects of drug dependence underlie an excitotoxicity process linked to a polysynaptic pathway that dynamically regulates synaptic glutamate. Retaliatory mechanisms include energy capability of the neurons, inhibitory systems and cytoplasmic calcium precipitation as part of the neuron-glia interactions. This paper presents an integrated view of these molecular and cellular mechanisms to help understand their relationship and interdependence in a chronic pathological process that suggest new targets for therapeutic intervention.

Pattern of injury with a graded excitotoxic insult and ensuing chronic medial septal damage in the rat brain

Brain damage caused by an acute injury depends on the initial severity of the injury and the time elapsed after the injury. To determine whether these two variables activate common mechanisms, we compared the response of the rat medial septum to insult with a graded series of concentrations of a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) with the time-course effects of a low dose of AMPA. For this purpose we conducted a dose-response study at concentrations of AMPA between 0.27 and 10.8 nmol to measure atrophy of the septal area, losses of cholinergic and GABAergic neurons, astroglial and microglial reactions, and calcification. Cholinergic neurons, whose loss paralleled the degree of septal atrophy produced by AMPA, are more sensitive than GABAergic neurons to the injury produced by AMPA. At doses of AMPA above 2.7 nmol, calcification and the degree of microglial reaction increased only in the GABAergic region of the septal area, whereas atrophy and neuronal loss reached a plateau. We chose the 2.7-nmol dose of AMPA to determine how these parameters were modified between 4 days and 6 months after injection. We found that atrophy and neuronal loss increased progressively through the 6-month study period, whereas astrogliosis ceased to be observed after 1 month, and calcium precipitates were never detected. We conclude that septal damage does not increase with the intensity of an excitotoxic insult. Rather, it progresses continuously after the insult. Because these two situations involve different mechanisms, short-term paradigms are inappropriate for interpreting the pathogenic mechanisms responsible for long-term neurodegenerative processes.

Subthalamic (STN) Deep Brain Stimulation (DBS) in Parkinson's Disease (PD): Correlation Between the Location of the Stimulated Contacts and the Clinical Effects in 14 Patients

Objectives: To correlate the chronic stimulated electrode position on postoperative MRI with the clinical response obtained in PD patients. Material and Method: We retrospectively reviewed 14 consecutive parkinsonian patients who were selected for STN-DBS surgery. Coordinates were determined on an IR T2 MRI coronal section per pendicular to AC-PC plane 3 mm posterior to midcommissural point (MCP) and 12 mm lateral to the midline the inferior aspect of subthalamic region. A CRW stereotactic frame was used for the surgical procedure. A 3D IR T2 MRI was performed postoperatively to determine the location of the stimulated contact in each patient. The clinical results were assessed independently by the neurological team. Results: All but 2 patients had monopolar stimulation. The mean coordinates of the stimulated contacts were: AP ^ ÿ4:23G1:4, Lat ^ 1:12G0:15, Vert ^ ÿ4:1 G2:7 to the MCP. With a mean follow-up of 8 months, all stimulated patients had a significant clinical improvement (preop/postop «ON» UPDRS: 25:8G7:0= 23:3 G8:6; preop/postop «OFF» UPDRS: 50:2G11:4=26:0 G7:8), 60% of them without any antiparkinsonian drug. Conclusion: According to the stereotactic atlas of Schaltenbrand and Warren and the 3D shape of the STN, our results show that our targetting is accurate and almost all the stimulated contacts are comprised in the STN volume. This indicates that MRI is a safe, precise and reproducible procedure for targetting the STN. The location of the stimulated contact within the STN volume is a good predictor of the clinical results.

Tangential migration of neuronal precursors of glutamatergic neurons in the adult mammalian brain.

In a classic model of mammalian brain formation, precursors of principal glutamatergic neurons migrate radially along radial glia fibers whereas GABAergic interneuron precursors migrate tangentially. These migration modes have significant implications for brain function. Here we used clonal lineage tracing of active radial glia-like neural stem cells in the adult mouse dentate gyrus and made the surprising discovery that proliferating neuronal precursors of glutamatergic granule neurons exhibit significant tangential migration along blood vessels, followed by limited radial migration. Genetic birthdating and morphological and molecular analyses pinpointed the neuroblast stage as the main developmental window when tangential migration occurs. We also developed a partial "whole-mount" dentate gyrus preparation and observed a dense plexus of capillaries, with which only neuroblasts, among the entire population of progenitors, are directly associated. Together, these results provide insight into neuronal migration in the adult mammalian nervous system.

Visual performance in preterm infants with brain injuries compared with low-risk preterm infants

Background: Neonatal brain injuries are the main cause of visual deficit produced by damage to posterior visual pathways.While there are several studies of visual function in low-risk preterm infants or older children with brain injuries, research in children of early age is lacking. Aim: To assess several aspects of visual function in preterm infants with brain injuries and to compare them with another group of low-risk preterm infants of the same age. Study design and subjects: Forty-eight preterm infants with brain injuries and 56 low-risk preterm infants. Outcome measures: The ML Leonhardt Battery of Optotypes was used to assess visual functions. This test was previously validated at a post-menstrual age of 40 weeks in newborns and at 30-plus weeks in preterm infants. Results: The group of preterminfants with brain lesions showed a delayed pattern of visual functions in alertness, fixation, visual attention and tracking behavior compared to infants in the healthy preterm group. The differences between both groups, in the visual behaviors analyzed were around 30%. These visual functions could be identified from the first weeks of life. Conclusion: Our results confirm the importance of using a straightforward screening test with preterminfants in order to assess altered visual function, especially in infants with brain injuries. The findings also highlight the need to provide visual stimulation very early on in life.