Time is brain — Competence is brain

Zusammenfassung Das angelsächsische Stroke-Unit-Konzept entwickelte sich zunächst als eine rehabilitative Einrichtung mit akutmedizinischer Versorgung, während in Deutschland beim Aufbau der Stroke Units das multimodale Monitoring des Schlaganfallpatienten als neurovaskulärer Notfall und die zunehmende Anwendung der Lysetherapie konzeptionell bestimmend waren. In den angelsächsischen Stroke Units wurde die eindrucksvolle Prognoseverbesserung der Schlaganfallpatienten durch die Stroke-Unit-Behandlung evidenzbasiert bewiesen. Dem therapeutischen Erfolg liegen zwei wesentliche Prinzipien zugrunde, (1) die ausschließliche Behandlung von Schlaganfallpatienten in dieser Einheit und (2) der Team-Approach, d. h. die multiprofessionelle Expertengruppe als Therapeuten. Beide Prinzipien wurden in den deutschen Stroke Units konsequent umgesetzt. Zwei Entwicklungen in Richtung einer Komplettierung und Vereinheitlichung der Stroke-Unit-Behandlung zeichnen sich inzwischen in Europa ab: In England und Skandinavien wird in den Stroke Units zunehmend akzeptiert, dass das multimodale apparative Monitoring notwendig ist und die Prognose zusätzlich verbessert. In den deutschen Stroke Units wird die Schnittstelle zwischen der 3- bis 4-tägigen Stroke-Unit-Behandlung und der nachbehandelnden Allgemeinstation durch Einbeziehung der bereits vorhandenen Ressourcen in eine erweiterte Stroke Unit überwunden. Diese erweiterte Stroke Unit kommt dem britischen Konzept der Comprehensive Stroke Unit, d. h. der Akutbehandlung mit früh einsetzenden Rehabilitationstherapie aus einer Hand, sehr nahe. Die übrigen Mitglieder der Stroke Unit Kommission sind:Peter Berlit, Essen; Christoph Diener, Essen; Karl-Heinz Grotemeyer, Saarbrücken; Roman L. Haberl, München; Werner Hacke, Heidelberg; Lutz Harms, Berlin; Manfred Kaps, Gießen; Christoph Kessler, Greifswald und Klaus Lowitzsch, Heidelberg     

Chronic alterations in rat brain α-adrenoceptors following traumatic brain injury

Norepinephrine (NE) has been implicated in cerebral plasticity and recovery of function after brain injury. To examine the status of noradrenergic mechanisms in the brain following traumatic brain injury (TBI), male Sprague-Dawley rats underwent right sensorimotor cortex contusions and were observed for the next 30 days for recovery of motor function by measurement of the time taken to perform a modified beam walking task! At 30 days, their brains were assayed by receptor autoradiography for αr- and α2-adrenoceptor binding with 1 nM [3H]prazosin and 1 nM [3H]paraminoclonidine, respectively. One day after contusion, TBI rats took 60% longer to run the beam than sham-lesioned controls. Run times were directly proportional (r = 0.784; P = 0.012) to lesion volume determined at 30 days. The motor deficit persisted for 8 days, after which TBI and control rats had similar run times, largely due to increased run times in sham rats. At 30 days, TBI rats had a generalized, bilateral decrease in [3H]prazosin binding across all brain areas read (F[l,13] = 9.23; P = 0.009) with specific 12%-21% decreases in the cortex contralateral to the lesion and bilaterally in the dorsomedial hypothalamic and three thalamic nuclei. On the other hand, [3H]paraminoclonidine binding did not differ from sham lesion controls in any brain area of TBI rats. Thus, unilateral TBI is followed by widespread, bilateral changes in α1-adrenoceptor binding which would leave the animal vulnerable to any factors which reduced the access of NE to its postsynaptic adrenoceptors. This is compatible with the observation that α1-antagonists and α2-agonists can transiently reinstate the motor deficit after recovery has occurred.     

Impact of drug size on brain tumor and brain parenchyma delivery after a blood–brain barrier disruption

Drug delivery to the brain is influenced by the blood–brain barrier (BBB) and blood–tumor barrier (BTB) to an extent that is still debated in neuro-oncology. In this paper, we studied the delivery across the BTB and the BBB of compounds with different molecular sizes in normal and glioma-bearing rats. Studies were performed at baseline as well as after an osmotic BBB disruption (BBBD) using dynamic contrast-enhanced magnetic resonance imaging and two T₁ contrast agents (CAs), Magnevist (743 Da) and Gadomer (17,000 Da). More specifically, we determined the time window for the BBB permeability, the distribution and we calculated the brain exposure to the CAs. A different pattern of accumulation and distribution at baseline as well as after a BBBD procedure was observed for both agents, which is consistent with their different molecular size and weight. Baseline tumor exposure was threefold higher for Magnevist compared with Gadomer, whereas postBBBD tumor exposure was twofold higher for Magnevist. Our study clearly showed that the time window and the extent of delivery across the intact, as well as permeabilized BTB and BBB are influenced by drug size.     

The predictive brain state: timing deficiency in traumatic brain injury?

Attention and memory deficits observed in traumatic brain injury (TBI) are postulated to result from the shearing of white matter connections between the prefrontal cortex, parietal lobe, and cerebellum that are critical in the generation, maintenance, and precise timing of anticipatory neural activity. These fiber tracts are part of a neural network that generates predictions of future states and events, processes that are required for optimal performance on attention and working memory tasks. The authors discuss the role of this anticipatory neural system for understanding the varied symptoms and potential rehabilitation interventions for TBI. Preparatory neural activity normally allows the efficient integration of sensory information with goal-based representations. It is postulated that an impairment in the generation of this activity in traumatic brain injury (TBI) leads to performance variability as the brain shifts from a predictive to reactive mode. This dysfunction may constitute a fundamental defect in TBI as well as other attention disorders, causing working memory deficits, distractibility, a loss of goal-oriented behavior, and decreased awareness.     

Primate adult brain cell autotransplantation, a new tool for brain repair?

If successful, autologous brain cell transplantation is an attractive approach to repair lesions and restore function of the central nervous system. We demonstrate that monkey adult brain cells obtained from cortical biopsy and kept in culture for 4 weeks exhibit neural progenitor characteristics. After reimplantation into a lesion area of the donor cerebral cortex, these cells can successfully survive and acquire neuronal characteristics over time. These results open new perspectives in the field of brain repair and may lead to future clinical applications.     

Why the maternal brain?

In the rat, the change from a virgin/nulliparous female to the maternal animal takes place at many levels. A subtle developmental wave washes over the female nervous system and transforms her from largely self-centred to offspring-directed, from personal care and protection to care of genetically-related offspring, from indifference to ardour. Such change is preceded by substantial and apparently permanent neural alterations, the depth of which results in the maternal brain, and is the basis of the present review. The neuroplasticity of pregnancy, inherent to the female brain and, we believe, representative of the full expression of the female nervous system's capacity, is a result of significant hormonal and other neurochemical actions. It results in the striking brain changes that are associated with, and necessary for, successful reproduction. We discuss some of these changes and their ramifications. Collectively, they represent the culmination of mammalian evolution and have led to the development of the social brain characteristic of higher orders of mammal, including the human. We also examine different facets of the maternal brain, beginning with a review of the genes involved in maternal behaviour, and in the subsequent 'expression' of the maternal brain. We next discuss olfaction and the manner in which this major sense draws from the rich sensory milieu of the mother to regulate and support maternal behaviour. Last, we discuss the 'whys' of maternal behaviour, a theoretical foray into the reasons for such substantial maternal brain alterations. We focus on the male's potential role as the raison d'etre for the manifest alterations in his mate's brain. In the end, it is clear that the female brain undergoes a significant reorganisation en route to motherhood, the results of which are deep and enduring.     

What is the brain?

From a structural perspective, there are ten basic parts of the vertebrate CNS that are almost universally agreed upon. These parts have been grouped in at least five different ways corresponding to five different theories about its basic plan or architecture. Two classical models that remain popular today are derived from (1) comparative anatomy and the body's segmental organization, and (2) comparative embryology and the neural tube's transverse and longitudinal organization. A new approach is concerned with deciphering the genetic program that assembles the nervous system during embryogenesis; how it will correspond to the other models remains to be determined. The simplest current model to explain the organization of the mammalian nervous system involves a segmental trunk that mediates reflex sensory-motor functions, and suprasegmental cerebral hemispheres and cerebellum.     

The gut or the brain?—gastrointestinal misdiagnoses of infantile brain tumors

Purpose

Central nervous system tumors account for the largest number of cancer deaths in childhood. Brain tumors in infants less than 3 years of age are rare; symptoms and signs are often non-specific. Patent anterior fontanelles/unfused cranial sutures in infants can accommodate rising intracranial pressure without acutely compromising the neurological status. We hypothesize that vomiting as the initial symptom, in infants with brain tumors, can possibly lead to extensive gastrointestinal evaluation, delaying the diagnosis of intracranial pathology.

Methods

We conducted a retrospective chart review of infants less than 3 years of age diagnosed with brain tumors over the period of 4.7 years from February 2008 to October 2012 at Inova Children’s Hospital, Virginia.

Results

We identified three of 21 patients (14.3 %) who presented with vomiting and underwent initial or extensive abdominal imaging investigations. All patients were relatively young (median age, 5.4 months). Working diagnoses were pyloric stenosis, viral gastritis, or gastroesophageal reflux. All patients eventually had computed tomography of the head to rule out increased intracranial pressure and were found to have large brain tumors with obstructive hydrocephalus. Tumor locations were cerebral hemispheres (2/3) and posterior fossa (1/3). All patients had biologically aggressive high-grade tumors (glioblastoma multiforme, atypical teratoid rhabdoid tumor, and anaplastic/large cell medulloblastoma) and died within weeks of diagnosis.

Conclusions

Our study highlights a clinical challenge of persistent vomiting in infants, which in the absence of convincing gastrointestinal pathology after evaluation should raise the physician’s suspicion of an underlying intracranial pathology even if neurological features are absent.     

Approaches to transport therapeutic drugs across the blood–brain barrier to treat brain diseases

The central nervous system is protected by barriers which control the entry of compounds into the brain, thereby regulating brain homeostasis. The blood–brain barrier, formed by the endothelial cells of the brain capillaries, restricts access to brain cells of blood–borne compounds and facilitates nutrients essential for normal metabolism to reach brain cells. This very tight regulation of the brain homeostasis results in the inability of some small and large therapeutic compounds to cross the blood–brain barrier (BBB). Therefore, various strategies are being developed to enhance the amount and concentration of therapeutic compounds in the brain. In this review, we will address the different approaches used to increase the transport of therapeutics from blood into the brain parenchyma. We will mainly concentrate on the physiologic approach which takes advantage of specific receptors already expressed on the capillary endothelial cells forming the BBB and necessary for the survival of brain cells.Among all the approaches used for increasing brain delivery of therapeutics, the most accepted method is the use of the physiological approach which takes advantage of the transcytosis capacity of specific receptors expressed at the BBB. The low density lipoprotein receptor related protein (LRP) is the most adapted for such use with the engineered peptide compound (EPiC) platform incorporating the Angiopep peptide in new therapeutics the most advanced with promising data in the clinic.     

Nicotine-induced changes of brain β-endorphin

A consensus has emerged that endogenous opioid peptides and their receptors play an important role in the psychoactive properties of nicotine. Although behavioral studies have shown that β-endorphin contributes to the rewarding and emotional effects of nicotine, whether the drug alters the function of brain endorphinergic neurons is not fully explored. These studies investigated the effect of acute, 1mg/kg, sc, and chronic, daily injection of 1mg/kg, sc, for 14 days, administration of free base nicotine on brain β-endorphin and its precursor proopiomelanocortin (POMC). Acute and chronic treatment with nicotine decreased β-endorphin content in hypothalamus, the principal site of β-endorphin producing neurons in the brain, and in the endorphinergic terminal fields in striatum and hippocampus. The acute effect of nicotine on β-endorphin was reversed by the nicotinic antagonist mecamylamine and the dopamine antagonist haloperidol, indicating pharmacological specificity and involvement of dopamine D2-like receptors. Similar observations were made in prefrontal cortex. POMC mRNA in hypothalamus and prefrontal cortex was unchanged following acute nicotine, but it decreased moderately with chronic treatment. The nicotine treatments had no effect on pituitary and plasma β-endorphin. Taken together, these results could be interpreted to indicate that nicotine alters the synthesis and release of β-endorphin in the limbic brain in vivo. Altered endorphinergic function may contribute to the behavioral effects of acute and chronic nicotine treatment and play a role in nicotine addiction.     

Does stress damage the brain?

Studies in animals showed that stress results in damage to the hippocampus, a brain area involved in learning and memory, with associated memory deficits. The mechanism involves glucocorticoids and possibly serotonin acting through excitatory amino acids to mediate hippocampal atrophy. Patients with posttraumatic stress disorder (PTSD) from Vietnam combat and childhood abuse had deficits on neuropsychological measures that have been validated as probes of hippocampal function. In addition, magnetic resonance imaging (MRI) showed reduction in volume of the hippocampus in both combat veterans and victims of childhood abuse. In combat veterans, hippocampal volume reduction was correlated with deficits in verbal memory on neuropsychological testing. These studies introduce the possibility that experiences in the form of traumatic stressors can have long-term effects on the structure and function of the brain.