Francis Odeh

Pontine Maps Linking Somatosensory and Cerebellar Cortices Are in Register with Climbing Fiber Somatotopy

The cerebropontocerebellar mossy fiber system is a major CNS sensorimotor pathway. We used a double-retrograde axonal tracing technique (red and green beads) to chart in rats the pontocerebellar projection to different electrophysiologically defined climbing fiber zones in the posterior lobe (face-receiving A2 zone and forelimb- and hindlimb-receiving parts of the C1 zone in the paramedian lobule and copula pyramidis, respectively). Individual cortical injection sites were verified as located in a given zone by mapping the pattern of cell labeling in the inferior olive, whereas labeled cells in the pontine nuclei were mapped using computer-aided three-dimensional reconstruction techniques. A number of topographical differences were found for the pontine projection to the individual zones. Projections to the A2 zone were bilateral, whereas to both parts of the C1 zone, the inputs were mainly contralateral. Furthermore, the A2 (face), C1 (forelimb), and C1 (hindlimb) zone projections were centered in progressively more caudal parts of the pontine nuclei with little or no overlap between them. The areas occupied by cell labeling for each zone corresponded closely to territories in the pontine nuclei shown previously to receive projections from somatotopically equivalent regions of the somatosensory cortex. This precise cerebropontocerebellar topography, defined by climbing fiber somatotopy, is a new principle of organization for linking somatosensory and cerebellar cortices. The convergence of direct and indirect sensory projections is likely to have important implications for cerebellar cortical processing.

Prophylaxis of migraine with melatonin A randomized controlled trial

Background: A previous open-label study of melatonin, a key substance in the circadian system, has shown effects on migraine that warrant a placebo-controlled study. Method: A randomized, double-blind, placebo-controlled crossover study was carried out in 2 centers. Men and women, aged 18–65 years, with migraine but otherwise healthy, experiencing 2–7 attacks per month, were recruited from the general population. After a 4-week run-in phase, 48 subjects were randomized to receive either placebo or extended-release melatonin (Circadin®, Neurim Pharmaceuticals Ltd., Tel Aviv, Israel) at a dose of 2 mg 1 hour before bedtime for 8 weeks. After a 6-week washout treatment was switched. The primary outcome was migraine attack frequency (AF). A secondary endpoint was sleep quality assessed by the Pittsburgh Sleep Quality Index (PSQI). Results: Forty-six subjects completed the study (96%). During the run-in phase, the average AF was 4.2 (±1.2) per month and during melatonin treatment the AF was 2.8 (±1.6). However, the reduction in AF during placebo was almost equal (p = 0.497). Absolute risk reduction was 3% (95% confidence interval −15 to 21, number needed to treat = 33). A highly significant time effect was found. The mean global PSQI score did not improve during treatment (p = 0.09). Conclusion: This study provides Class I evidence that prolonged-release melatonin (2 mg 1 hour before bedtime) does not provide any significant effect over placebo as migraine prophylaxis. Classification of evidence: This study provides Class I evidence that 2 mg of prolonged release melatonin given 1 hour before bedtime for a duration of 8 weeks did not result in a reduction in migraine frequency compared with placebo (p = 0.497).

Expression mapping of tetracycline-responsive prion protein promoter: digital atlasing for generating cell-specific disease models.

We present a digital atlas system that allows mapping of molecular expression patterns at cellular resolution through large series of histological sections. Using this system, we have mapped the distribution of a distinct marker, encoded by the LacZ reporter gene driven by the tetracycline-responsive prion protein promoter in double transgenic mice. The purpose is to evaluate the suitability of this promoter mouse line for targeting genes of interest to specific brain regions, essential for construction of inducible transgenic disease models. Following processing to visualize the promoter expression, sections were counterstained to simultaneously display cytoarchitectonics. High-resolution mosaic images covering entire coronal sections were collected through the mouse brain at intervals of 200 microm. A web-based application provides access to a customized virtual microscopy tool for viewing and navigation within and across the section images. For each section image, the nearest section in a standard atlas is defined, and annotations of key structures and regions inserted. Putative categorization of labeled cells was performed with use of distribution patterns, followed by cell size and shape, as parameters that were compared to legacy data. Among the ensuing results were expression of this promoter in putative glial cells in the cerebellum (and not in Purkinje cells), in putative glial cells in the substantia nigra, in pallidal glial cells or interneurons, and in distinct cell layers and regions of the hippocampus. The study serves as a precursor for a database resource allowing evaluation of the suitability of different promoter mouse lines for generating disease models.

Database and tools for analysis of topographic organization and map transformations in major projection systems of the brain.

Integration of dispersed and complicated information collected from the brain is needed to build new knowledge. But integration may be hampered by rigid presentation formats, diversity of data formats among laboratories, and lack of access to lower level data. We have addressed some of the fundamental issues related to this challenge at the level of anatomical data, by producing a coordinate based digital atlas and database application for a major projection system in the rat brain: the cerebro-ponto-cerebellar system. This application, Functional Anatomy of the Cerebro-Cerebellar System in rat (FACCS), is available via the Rodent Brain WorkBench (http://www.rbwb.org). The data included are x,y,z-coordinate lists describing exact distributions of tissue elements (axonal terminal fields of axons, or cell bodies) that are labeled with axonal tracing techniques. All data are translated to a common local coordinate system to facilitate across animal comparison. A search capability allows queries based on, e.g. location of tracer injection sites, tracer category, size of the injection sites, and contributing author. A graphic search tool allows the user to move a volume cursor inside a coordinate system to detect particular injection sites having connections to a specific tissue volume at chosen density levels. Tools for visualization and analysis of selected data are included, as well as an option to download individual data sets for further analysis. With this application, data and metadata from different experiments are mapped into the same information structure and made available for re-use and re-analysis in novel combinations. The application is prepared for future handling of data from other projection systems as well as other data categories.

Atlas of transgenic Tet-Off Ca2+/calmodulin-dependent protein kinase II and prion protein promoter activity in the mouse brain

Conditional transgenic mouse models are important tools for investigations of neurodegenerative diseases and evaluation of potential therapeutic interventions. A popular conditional transgenic system is the binary tetracycline-responsive gene (Tet-Off) system, in which the expression of the gene of interest depends on a tetracycline-regulatable transactivator (tTA) under the control of a specific promoter construct. The most frequently used Tet-Off promoter mouse lines are the Ca(2+)/calmodulin-dependent protein kinase II (CamKII) and prion protein (PrP) promoter lines, respectively. To target the regulated gene of interest to relevant brain regions, a priori knowledge about the spatial distribution of the regulated gene expression in the brain is important. Such distribution patterns can be investigated using double transgenic mice in which the promoter construct regulates a LacZ reporter gene encoding the marker β-galactosidase which can be histologically detected using its substrate X-gal. We have previously published an atlas showing the brain-wide expression mediated by the Tet-Off PrP promoter mouse line, but the distribution of activity in the Tet-Off CamKII promoter mouse line is less well known. To compare promoter activity distributions in these two Tet-Off mouse lines, we have developed an online digital atlas tailored for side-by-side comparison of histological section images. The atlas provides a comprehensive list of brain regions containing X-gal labeling and an interactive dual image viewer tool for panning and zooming of corresponding section images. Comparison of spatial expression patterns between the two lines show considerable regional and cellular differences, relevant in context of generation and analysis of inducible models based on these two tetracycline responsive promoter mouse lines.

Hodepine etter spinalpunksjon

BACKGROUND Headache is a complication of lumbar puncture that has been known for more than a hundred years. The aim of this paper is to provide an overview of the incidence and symptoms of, the risk factors for and the treatment of this type of headache. METHOD The article is based on a literature search in PubMed for studies on headache after lumbar puncture followed by discretionary selection of publications. RESULTS Post-dural puncture headache (PDPH) is characterised by the occurrence of a headache with a significant orthostatic component within 5 days of a lumbar puncture. The incidence depends on a number of factors. Younger women with a previous history of headaches appear to be at highest risk. The incidence can be significantly reduced by using a thin lumbar puncture needle with an atraumatic tip. The condition is self-limiting and harmless, but leads to significant morbidity. Caffeine alleviates the symptoms and reduces the course of the illness. When bed rest and caffeine prove ineffective, an epidural blood patch works well for the majority, but there is no consensus on when such treatment should be offered. INTERPRETATION Headache frequently occurs after lumbar puncture. There is substantial evidence for recommending the use of a thin, atraumatic needle to reduce the incidence. For practical reasons, a needle thinner than 22 G is not suitable for diagnostic lumbar puncture.

Progressive multifocal leukoencephalopathy in a patient with systemic mastocytosis treated with cladribine

BACKGROUND Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic brain infection caused by the human polyomavirus JC (JCPyV). A particular problem with the drug cladribine seems to be prolonged suppression of the CD4+ T-cells, a well-known risk factor for PML. CASE DESCRIPTION A 67-year-old male presented with a 3-weeks history of unsteady gait, dysarthria and a dysfunctional right arm. Seven years earlier, he had been diagnosed with urticaria pigmentosa, and 2 years later aggressive systemic mastocytosis. Cladribine treatment was initiated and regarded effective, but the course was complicated with bouts of severe anemia and recurrent episodes of salmonella associated gastroenteritis. His lymphocyte count fell to 0.1×109/L at its lowest level, but gradually rose. Despite this, in the 6 month wake of the last dose of cladribine given, the patient experienced herpetic stomatitis, had CMV present in blood, and ultimately developed the neurological symptoms. An MRI scan revealed a lesion in the right cerebellar hemisphere compatible with PML, and PCR analysis of the CSF showed positive for JCPyV DNA with a load of 323 950 copies/ml. No pathological cells were seen on CSF flow cytometry. The CD4/CD8-ratio was 0.45 (160 CD4+ cells/mm3 and 360 CD8+ cells/mm3). The patient passed away 3 weeks later. CONCLUSION PML may be the consequence of prolonged lymphopenia due to the use of cladribine.

Amyotrophic lateral sclerosis in Nordland county, Norway, 2000–2015: prevalence, incidence, and clinical features

Abstract Objective: There are some indications of increasing incidence of amyotrophic lateral sclerosis (ALS). Awareness of cognitive impairment in ALS has increased in recent years. We describe the epidemiology and clinical features of ALS in a county in northern Norway over a period of 15 years. Methods: All patients with motor neuron disease (MND) living in Nordland County in the period 2000–2015 were identified and the medical records were scrutinized. The average annual incidence was calculated for the whole period and for five-year periods. Prevalence point was 1 January 2015. Results: We identified 74 cases with MND. The crude point prevalence was 4.1 per 100,000. The average annual incidence was 2.1 per 100,000 for the whole period, 2.0 in the period 2000–2004, 2.3 in 2005–2009, and 2.0 in 2010–2014. All except one of the 22 patients with other forms of MND developed ALS during the course of the disease. The mean survival time was 38 months, patients with bulbar symptoms at diagnosis had a mean survival time of 29 months and those with solely spinal symptoms had a mean survival time of 50 months. Seven patients were diagnosed with frontotemporal dementia (FTD). Conclusion: The incidence was stable during the study period. Other forms of MND converts to clinical ALS given time. Survival time is almost two years shorter in patients with bulbar symptoms at the first examination, compared to those with solely symptoms from spinal muscles. FTD was found in 9% of the patients.