Same old: April 2007

Sunday 29 April 2007

GABA and epileptiform networks

Distinct types of ionic modulation of GABA actions in pyramidal cells and interneurons during electrical induction of hippocampal seizure-like network activity.

Distinct types of ionic modulation of GABA actions in pyramidal cells and interneurons during electrical induction of hippocampal seizure-like network activity.

Eur J Neurosci. 2007 Apr 25;

Authors: Fujiwara-Tsukamoto Y, Isomura Y, Imanishi M, Fukai T, Takada M

It has recently been shown that electrical stimulation in normal extracellular fluid induces seizure-like afterdischarge activity that is always preceded by GABA-dependent slow depolarization. These afterdischarge responses are synchronous among mature hippocampal neurons and driven by excitatory GABAergic input. However, the differences in the mechanisms whereby the GABAergic signals in pyramidal cells and interneurons are transiently converted from hyperpolarizing to depolarizing (and even excitatory) have remained unclear. To clarify the network mechanisms underlying this rapid GABA conversion that induces afterdischarges, we examined the temporal changes in GABAergic responses in pyramidal cells and/or interneurons of the rat hippocampal CA1 area in vitro. The extents of slow depolarization and GABA conversion were much larger in the pyramidal cell group than in any group of interneurons. Besides GABA(A) receptor activation, neuronal excitation by ionotropic glutamate receptors enhanced GABA conversion in the pyramidal cells and consequent induction of afterdischarge. The slow depolarization was confirmed to consist of two distinct phases; an early phase that depended primarily on GABA(A)-mediated postsynaptic Cl(-) accumulation, and a late phase that depended on extracellular K(+) accumulation, both of which were enhanced by glutamatergic neuron excitation. Moreover, extracellular K(+) accumulation augmented each oscillatory response of the afterdischarge, probably by further Cl(-) accumulation through K(+)-coupled Cl(-) transporters. Our findings suggest that the GABA reversal potential may be elevated above their spike threshold predominantly in the pyramidal cells by biphasic Cl(-) intrusion during the slow depolarization in GABA- and glutamate-dependent fashion, leading to the initiation of seizure-like epileptiform activity.

PMID: 17459104 [PubMed - as supplied by publisher]

Levetiracetam

Levetiracetam: the profile of a novel anticonvulsant drug-part I: preclinical data.

Levetiracetam: the profile of a novel anticonvulsant drug-part I: preclinical data.

CNS Drug Rev. 2007;13(1):43-56

Authors: De Smedt T, Raedt R, Vonck K, Boon P

The objective of this article was to review and summarize the available reports on the preclinical profile of the novel anticonvulsant drug levetiracetam (LEV). Therefore, a careful search was conducted in the MEDLINE database and combined with guidelines from regulatory agencies, proceedings of professional scientific meetings, and information provided by the manufacturers. This article provides detailed information on the anticonvulsant effects of LEV in various animal models of epilepsy and on its pharmacology in laboratory animals. The mechanism of action of LEV is reviewed, with special regard to its recently discovered binding site, the synaptic vesicle protein 2A. In general, LEV is shown to be a safe, broad-spectrum anticonvulsant drug with highly beneficial pharmacokinetic properties and a distinct mechanism of action. The clinical studies with LEV will be discussed in the second part of this review article to be published subsequently.

PMID: 17461889 [PubMed - in process]

Roles of brain areas in WM processes

Regional brain differences in the effect of distraction during the delay interval of a working memory task.

Regional brain differences in the effect of distraction during the delay interval of a working memory task.

Brain Res. 2007 Mar 28;

Authors: Dolcos F, Miller B, Kragel P, Jha A, McCarthy G

Working memory (WM) comprises operations whose coordinated action contributes to our ability to maintain focus on goal-relevant information in the presence of distraction. The present study investigated the nature of distraction upon the neural correlates of WM maintenance operations by presenting task-irrelevant distracters during the interval between the memoranda and probes of a delayed-response WM task. The study used a region of interest (ROIs) approach to investigate the role of anterior (e.g., lateral and medial prefrontal cortex - PFC) and posterior (e.g., parietal and fusiform cortices) brain regions that have been previously associated with WM operations. Behavioral results showed that distracters that were confusable with the memorandum impaired WM performance, compared to either the presence of non-confusable distracters or to the absence of distracters. These different levels of distraction led to differences in the regional patterns of delay interval activity measured with event-related functional magnetic resonance imaging (fMRI). In the anterior ROIs, dorsolateral PFC activation was associated with WM encoding and maintenance, and in maintaining a preparatory state, and ventrolateral PFC activation was associated with the inhibition of distraction. In the posterior ROIs, activation of the posterior parietal and fusiform cortices was associated with WM and perceptual processing, respectively. These findings provide novel evidence concerning the neural systems mediating the cognitive and behavioral responses during distraction, and places frontal cortex at the top of the hierarchy of the neural systems responsible for cognitive control.

PMID: 17459348 [PubMed - as supplied by publisher]

WM, consciousness etc.

Computational and noncomputational systems in brain and cognition: can one mask the other?

Computational and noncomputational systems in brain and cognition: can one mask the other?

Int J Neurosci. 2007 May;117(5):681-710

Authors: Leisman G, Kaspi M, Koch P

A theory is developed based on the premise that nonneural processes occur in the brain exemplified as spatial working memory, and is the seat of consciousness. Additionally, wave storage of spatial information, a Bose condensate to support the waves, and the location of wave storage are provided as illustrative, "existence proofs" that a coherent theory can be built along these lines in agreement with the data. The theory can be built argues on functional grounds that a nonneural spatial memory may serve a vital biological function. This article demonstrate how this same non-neural memory can bridge the explanatory gap to consciousness, in agreement with the facts. The article proposes a possible mechanism and location for the nonneural component.

PMID: 17464785 [PubMed - in process]

Untitled

The cannabinoid antagonist SR 141716A (Rimonabant) reduces the increase of extra-cellular dopamine release in the rat nucleus accumbens induced by a novel high palatable food.

The cannabinoid antagonist SR 141716A (Rimonabant) reduces the increase of extra-cellular dopamine release in the rat nucleus accumbens induced by a novel high palatable food.

Neurosci Lett. 2007 Apr 8;

Authors: Melis T, Succu S, Sanna F, Boi A, Argiolas A, Melis MR

The assumption of a novel high palatable food (a candied cherry) occurs concomitantly with an increase in the concentration of extra-cellular dopamine and its main metabolite 3,4-dihydroxy-phenylacetic acid (DOPAC) by about 45% in the dialysate obtained by intracerebral microdialysis from the shell of the nucleus accumbens of male rats. Such increase was reversed by SR 141716A (Rimonabant), a selective cannabinoid CB1 receptor antagonist (0.3mg/kg i.p. and 1mg/kg i.p.), which also reduces the assumption of the high palatable food, when given 15min before exposure to the candied cherry. SR 141716A effects on extracellular dopamine and DOPAC were prevented by WIN 55,212-2 (0.3mg/kg i.p.) or HU 210 (0.1mg/kg i.p.) given 15min before SR 141716A. The present results show for the first time that SR 141716A reduces the increase in extra-cellular dopamine induced by a novel high palatable food in the nucleus accumbens. This confirms that cannabinoid CB1 receptors play a key role in food intake and/or appetite and suggests that the mesolimbic dopaminergic system is involved at least in part, in the effects of cannabinoid receptor agonists and antagonists on food intake and/or appetite.

PMID: 17462824 [PubMed - as supplied by publisher]

Thursday 26 April 2007

Carisbamate

Evaluation of carisbamate, a novel antiepileptic drug, in photosensitive patients: An exploratory, placebo-controlled study.

Evaluation of carisbamate, a novel antiepileptic drug, in photosensitive patients: An exploratory, placebo-controlled study.

Epilepsy Res. 2007 Apr 18;

Authors: Trenité DG, French JA, Hirsch E, Macher JP, Meyer BU, Grosse PA, Abou-Khalil BW, Rosenfeld WE, van Gerven J, Novak GP, Parmeggiani L, Schmidt B, Gibson D, Guerrini R

PURPOSE: Carisbamate, a novel neuromodulatory agent with antiepileptic properties, was evaluated in patients with photoparoxysmal responses to intermittent photic stimulation (IPS) in this multicenter, non-randomized, single-blind, placebo-controlled, proof-of-concept study. METHODS: Eighteen Caucasian patients (14 females, 4 males) with a mean age of 30 years (range: 16-51 years) underwent standardized IPS under three eye conditions (during eye closure, eyes closed and eyes open) at hourly intervals for up to 8h after receiving placebo (Day 1), carisbamate (Day 2) and placebo (Day 3). Carisbamate was given at single doses of 250-1000mg. All patients received one or two concomitant antiepileptic drugs, most commonly valproate. RESULTS: Carisbamate produced a dose-dependent reduction in photosensitivity in the 13 evaluable patients, with abolishment of photoparoxysmal responses in 3 patients and clinically significant suppression of such responses in 7 additional patients. Photosensitivity was abolished or reduced in all five patients in the 1000-mg dose group. The onset of carisbamate occurred rapidly, with clinically significant suppression achieved before or near the time peak plasma drug levels were reached. The duration of action was dose-related and long-lasting, with clinically significant reductions of photosensitivity observed for up to 32h after doses of 750 or 1000mg. Carisbamate was generally well tolerated, with dizziness and nausea reported more frequently after active drug than placebo. CONCLUSION: This study shows that carisbamate exhibits dose-related antiepileptic effects in the photosensitivity model. Randomized, controlled studies of carisbamate in epilepsy patients inadequately controlled by their existing AED therapy are warranted.

PMID: 17448639 [PubMed - as supplied by publisher]

WM and academic achievement

Relationship of working memory and EEG to academic performance: a study among high school students.

Relationship of working memory and EEG to academic performance: a study among high school students.

Int J Neurosci. 2007 Jun;117(6):869-82

Authors: Aguirre-Pérez DM, Otero-Ojeda GA, Pliego-Rivero FB, Ferreira-Martínez AA

Some biological and behavioral elements which could explain differences between high and low academic attainment (HA/LA) students were identified. The qEEG of subjects under the 10-20 derivation system was recorded at rest and while completing a 3-back working memory (WM) task. While completing the task LA students showed more theta and total absolute potency at rest, and HA individuals showed more energy in delta and theta frequencies in frontal regions; LA students made a higher number of mistakes while executing the WM task with no differences in reaction time between groups. We conclude that a diminished WM capacity is present in LA students.

PMID: 17454248 [PubMed - in process]

WM and arithmetic

The role of working memory in the carry operation of mental arithmetic: Number and value of the carry.

The role of working memory in the carry operation of mental arithmetic: Number and value of the carry.

Q J Exp Psychol (Colchester). 2007 May;60(5):708-31

Authors: Imbo I, Vandierendonck A, De Rammelaere S

Two experiments were conducted to investigate the role of phonological and executive working-memory components in the carry operation in mental arithmetic. We manipulated the number of carry operations, as previous research had done, but also the value that had to be carried. Results of these experiments show that in addition to the number of carry operations, the value of the carry is also an important variable determining the difficulty of arithmetical sums. Furthermore, both variables (number and value) interacted with each other in such a way that the combination of multiple carries and values of carries larger than one resulted in more difficult problems irrespective of the presence of a working-memory load. The findings with respect to working-memory load suggest that mainly the central executive is important in handling the number of carry operations as well as the value that has to be carried. The implications of the present findings for our views on mental arithmetic and its reliance on working memory are discussed.

PMID: 17455078 [PubMed - in process]

NMDAR ligands

In vitro and in vivo characterization of [(3)H]CNS-5161-A use-dependent ligand for the N-methyl-d-aspartate receptor in rat brain.

In vitro and in vivo characterization of [(3)H]CNS-5161-A use-dependent ligand for the N-methyl-d-aspartate receptor in rat brain.

Synapse. 2007 Apr 23;61(8):577-586

Authors: Biegon A, Gibbs A, Alvarado M, Ono M, Taylor S

Glutamate is the major excitatory neurotransmitter in the brain. Glutamate activation of the N-methyl-d-aspartate (NMDA) receptor subtype is thought to mediate important physiological and pathological processes, including memory formation and excitotoxicity. The goal of the present work was to characterize and validate a candidate agent for noninvasive positron emission tomography (PET) imaging of this receptor. [(3)H]-labeled N-[3-(3)H]-methyl-3-(thiomethylphenyl)cyanamide (CNS-5161) was incubated with rat brain homogenates at increasing concentrations, temperatures, and times to establish the binding kinetics and affinity of the ligand in vitro. Nonspecific binding was measured with 100 muM MK-801. The compound was also injected i.v. in rats pretreated with saline, NMDA, MK801, or a combination, and organ and brain regional uptake was assessed at various times after injection by autoradiography or dissection. Blood and brain samples were assayed for metabolites by high-performance liquid chromatography. CNS-5161 binds brain membranes with high affinity (K(d) < 4 nM) and fast association and dissociation kinetics. Specific binding increased in the presence of glutamate and glycine. Intravenous administration in control rats resulted in a heterogeneous brain distribution with hippocampus and cortex >> thalamus >> striatum >> cerebellum, and a cortex/cerebellum ratio of 1.4. Pretreatment with NMDA increased the hippocampus-to-cerebellum ratio to 1.6-1.9 while MK801 abolished this increase, resulting in ratios close to 1. Thus, CNS-5161 binds preferentially to the activated state of the NMDA receptor channel in vitro and in vivo. The high affinity and fast kinetics make it compatible with PET imaging of a carbon-11 labeled CNS-5161. Synapse 61:577-586, 2007. Published 2007 Wiley-Liss, Inc.

PMID: 17455246 [PubMed - as supplied by publisher]

A1 and piriform cortex

Presynaptic adenosine A1 receptors modulate excitatory synaptic transmission in the posterior piriform cortex in ratsIn Press, Accepted Manuscript, Available online 24 April 2007, Su-Ching Yang, Tsai-Hsien Chiu, Hsiu-Wen Yang and Ming-Yuan MinPDF (412 K)

ScienceDirect - Brain Research, Articles in Press

Olfaction and WM

The influence of olfactory-induced negative emotion on verbal working memory: Individual differences in neurobehavioral findings.

The influence of olfactory-induced negative emotion on verbal working memory: Individual differences in neurobehavioral findings.

Brain Res. 2007 Mar 23;

Authors: Habel U, Koch K, Pauly K, Kellermann T, Reske M, Backes V, Seiferth NY, Stöcker T, Kircher T, Amunts K, Jon Shah N, Schneider F

The influence of emotion on cognition plays an important role in people's everyday life as well as in psychiatric and neurological disorders. The present study used fMRI to examine the neural correlates of cognitive-emotional interactions and its inter-individual differences. Twenty-one healthy males performed a 0-back/2-back task while negative or neutral emotion was induced by negative/neutral olfactory stimulation. Subjects revealed a differential effect of emotion on cognition; in 9 subjects, negative odor had a deteriorating influence on verbal working memory ("affected group", AG) while in 12 subjects, performance was not affected in a negative way ("unaffected group", UAG). Although no brain activation differences emerged during the working memory task, the interaction of working memory and emotion yielded significant differences between the AG and the UAG. The latter showed greater activation in the fronto-parieto-cerebellar working memory (WM) network including the precuneus while the AG demonstrated stronger activation in more "emotional" areas (mainly the temporal and medial frontal cortex) as well as compensatory activations in prefrontal regions known to be essential for the cognitive down-regulation of emotions. Hence, the UAG may have been better able to counteract the detrimental influence of negative stimulation during the 2-back task and to effectively sustain or even increase activation in the task-relevant WM network. Correlation analyses for the whole group supported this interpretation; reduced working memory performance during negative stimulation was accompanied by higher activation in the inferior frontal gyrus whereas less performance impairment was related to higher activation in the precuneus. Results confirm the importance of incorporating individual differences in emotion processing and its interaction with cognitive functions in neuroimaging.

PMID: 17448450 [PubMed - as supplied by publisher]

MEA and drug delivery

Poly-HEMA as a drug delivery device for in vitro neural networks on micro-electrode arrays.

Poly-HEMA as a drug delivery device for in vitro neural networks on micro-electrode arrays.

J Neural Eng. 2005 Dec;2(4):114-22

Authors: Cadotte AJ, DeMarse TB

Delivery of pharmacological agents in vitro can often be a difficult, time consuming and costly process. In this paper, we describe an economical method for in vitro delivery using a hydrogel of poly hydroxyethyl methacrylate (PHEMA) that can absorb up to 50% of its weight of any water-solubilized pharmacological agent. This agent will then passively diffuse into surrounding media upon application in vitro. An in vitro test of PHEMA as a drug delivery device was conducted using dissociated rat-cortical neurons cultured on micro-electrode arrays. These micro-electrode arrays permit the real-time measurement of neural activity at 60 different sites across a network of neurons. Neural activity was compared during the application of PHEMA saturated with cell culture media and PHEMA saturated with bicuculline, a widely used pharmacological agent with stereotypical effects on neural activity patterns. Application of PHEMA saturated with bicuculline produced a gradual increase in concentration in vitro. When the minimum effective concentration of bicuculline was reached, which was found to be 0.59 microM using the diffusion properties of PHEMA, it produced the rapid almost periodic synchronized bursting characteristically associated with this agent. In contrast, the application of PHEMA saturated in culture media alone had no effect on neural activity reinforcing its inherent inert properties. Since PHEMA is nontoxic, can be molded into a variety of shapes, quickly manufactured in any laboratory and is inexpensive to produce, the material represents a promising alternative to drug delivery systems on the market today.

PMID: 16317235 [PubMed - indexed for MEDLINE]

Cannabinoid therapeutics

Implication of cannabinoids in neurological diseases.

Implication of cannabinoids in neurological diseases.

Cell Mol Neurobiol. 2006 Jul-Aug;26(4-6):579-91

Authors: Alsasua del Valle A

1. Preparations from Cannabis sativa (marijuana) have been used for many centuries both medicinally and recreationally. 2. Recent advances in the knowledge of its pharmacological and chemical properties in the organism, mainly due to Delta(9)-tetrahydrocannabinol, and the physiological roles played by the endocannabinoids have opened up new strategies in the treatment of neurological and psychiatric diseases. 3. Potential therapeutic uses of cannabinoid receptor agonists include the management of spasticity and tremor in multiple sclerosis/spinal cord injury, pain, inflammatory disorders, glaucoma, bronchial asthma, cancer, and vasodilation that accompanies advanced cirrhosis. CB(1) receptor antagonists have therapeutic potential in Parkinson's disease. 4. Dr. Julius Axelrod also contributed in studies on the neuroprotective actions of cannabinoids.

PMID: 16699878 [PubMed - indexed for MEDLINE]

NAcc and 2AG

Molecular architecture of the cannabinoid signaling system in the core of the nucleus accumbens.

Molecular architecture of the cannabinoid signaling system in the core of the nucleus accumbens.

Ideggyogy Sz. 2007 Mar 30;60(3-4):187-91

Authors: Mátyás F, Watanabe M, Mackie K, Katona I, Freund TF

Several abused drugs are known to alter glutamatergic signaling in reward pathways of the brain, and these plastic changes may contribute to the establishment of addiction-related behaviour. Glutamatergic synapses of the prefrontal cortical projections to the nucleus accumbens (nAcb)--which are suggested to be under endocannabinoid (eCB) control - play a central role in the addiction process. The most abundant eCB in the brain is 2-arachi-donoyl-glycerol (2-AG). It is synthesized by diacylglycerol lipase alpha (DGL-alpha), and exerts its action via type 1 cannabinoid receptors (CB1). However, the precise localization of DGL-alpha and CB1 - i.e. the sites of synthesis and action of 2AG - is still unknown. At the light microscopic level, immunocytochemistry revealed a granular pattern of DGL-alpha distribution in the core of the nAcb. Electron microscopic analysis confirmed that these granules corresponded to the heads of dendritic spines. On the other hand, presynaptic axon terminals forming excitatory synapses on these spineheads were found to express CB1 receptors. Our results demonstrate that the molecular constituents for a retrograde endocannabinoid control of glutamatergic transmission are available in the core of the nAcb, and their relative subcellular location is consistent with a role of 2-AG in addiction-related plasticity of cortical excitatory synapses in this reward area.

PMID: 17451066 [PubMed - in process]

Wednesday 25 April 2007

PC and NMDA

NMDA inhibitors cause apoptosis of pyramidal neurons in mature piriform cortex: Evidence for a nitric oxide-mediated effect involving inhibitory interneurons.

NMDA inhibitors cause apoptosis of pyramidal neurons in mature piriform cortex: Evidence for a nitric oxide-mediated effect involving inhibitory interneurons.

Neuropharmacology. 2007 Mar 14;

Authors: Zhou L, Welsh AM, Chen D, Koliatsos VE

Pyramidal relay neurons in limbic cortex are vulnerable to denervation lesions, i.e. pyramidal neurons in layer IIalpha of piriform cortex undergo transsynaptic apoptosis after lesions that interrupt their inputs from the olfactory bulb. We have previously established the role of inhibitory interneurons in elaborating signals that lead to the apoptosis of projection neurons in these lesion models, i.e. the upregulation of neuronal NOS and release of nitric oxide. Thus, we have proposed that cortical interneurons play an essential role in transducing injury to degenerative effects for nearby pyramidal neurons. In the present study, we extend the previous findings to a toxic model of degeneration of pyramidal neurons in the adult paralimbic cortex, i.e. after exposure to the NMDA channel blocker MK801. Our findings indicate that treatment of adult rats with MK801 in doses previously found to cause alterations in pyramidal neurons of the retrosplenial cortex (5mg/kg) results in an active caspase 3 (+), ultrastructurally apoptotic type of cell death involving the same projection neurons of layer IIalpha that are also vulnerable to bulbotomy lesions. Interneurons of layer I are induced by MK801 treatment to higher levels of nNOS expression and the selective nNOS inhibitor BRNI ameliorates pyramidal cell apoptosis caused by MK801. Our results indicate that certain pyramidal neurons in piriform cortex are very sensitive to NMDA blockade as they are to disconnection from modality-specific afferents and that inhibitory interneurons play significant roles in mediating various types of pro-apoptotic insults to cortical projection neurons via nNOS/NO signaling.

PMID: 17449067 [PubMed - as supplied by publisher]

Monday 23 April 2007

Neural connectivity

A method for determining neural connectivity and inferring the underlying networknext term dynamics using extracellular spike recordingsValeri A. Makarova, Corresponding Author Contact Information, E-mail The Corresponding Author, Fivos Panetsosa and Oscar de FeobaNeuroscience Laboratory, Department of Applied Mathematics, School of Optics, Universidad Complutense de Madrid, Avda. Arcos de Jalon s/n, 28037 Madrid, SpainbLaboratory of Nonlinear Systems, Swiss Federal Institute of Technology Lausanne; EPFL-IC-LANOS, CH-1015 Lausanne, SwitzerlandReceived 11 October 2004; revised 10 November 2004; accepted 12 November 2004. Available online 21 December 2004.AbstractIn the present paper we propose a novel method for the identification and modeling of neural previous termnetworksnext term using extracellular spike recordings. We create a deterministic model of the effective previous termnetwork,next term whose dynamic behavior fits experimental data. The previous termnetworknext term obtained by our method includes explicit mathematical models of each of the spiking neurons and a description of the effective connectivity between them. Such a model allows us to study the properties of the neuron ensemble independently from the original data. It also permits to infer properties of the ensemble that cannot be directly obtained from the observed spike trains. The performance of the method is tested with spike trains artificially generated by a number of different neural previous termnetworks.next termKeywords: Neural circuits; Spike trains; Connectivity identification; previous termNetworknext term modeling

ScienceDirect - Journal of Neuroscience Methods : A method for determining neural connectivity and inferring the underlying network dynamics using extracellular spike recordings

MEANOVA

Applications of multi-variate analysis of variance (MANOVA) to multi-electrode array electrophysiology dataP.M. Hortona, Corresponding Author Contact Information, E-mail The Corresponding Author, L. Bonnya, A.U. Nicolb, K.M. Kendrickb and J.F.Fengc, d, Corresponding Author Contact Information, E-mail The Corresponding AuthoraDepartment of Informatics, Sussex University, Falmer, Brighton BN1 9QH, UKbLaboratory of Cognitive and Behavioural Neuroscience, The Babraham Institute, Cambridge CB2 4AT, UKcDepartment of Mathematics, Hunan Normal University, 410081, Changsha, PR ChinadDepartment of Computer Science, Warwick University, Coventry CV4 7AL, UKReceived 11 August 2004; revised 22 November 2004; accepted 13 January 2005. Available online 9 March 2005.AbstractWe have developed an adaptation of multi-variate analysis of variance (MANOVA) to analyze statistically both local and global patterns of multi-electrode array (MEA) electrophysiology data where the activities of many (typically ¿100) neurons have been recorded simultaneously. Whereas simple application of standard MANOVA techniques prohibits extraction of useful information in this kind of data, our new approach, MEANOVA (=MEA+MANOVA), allows a more useful and powerful approach to analyze such complex neurophysiological data. The MEANOVA test enables the detection of the “hot-spots” in the MEA data and has been validated using recordings from the rat olfactory bulb. To further validate the power of this approach, we have also applied the MEANOVA test to data obtained from a simple computational networknext term model. This MEANOVA software and other useful statistical methods for MEA data can be downloaded from http://www.sussex.ac.uk/Users/pmh20.Keywords: Multi-electrode array; Multi-variate statistical analysis; Olfactory bulb; Odour; Olfactory bulb modelling

ScienceDirect - Journal of Neuroscience Methods : Applications of multi-variate analysis of variance (MANOVA) to multi-electrode array electrophysiology data

Neuronal correlates from extracellular data

Decomposing rhythmic hippocampal data to obtain neuronal correlatesJ.A. Gillisa, b, Corresponding Author Contact Information, E-mail The Corresponding Author, W.P. Luka, d, 1, L. Zhanga, c, d, 1 and F.K. Skinnera, b, c, e, 2aThe Toronto Western Research Institute, UHN, Toronto, Ont., Canada M5T 2S8bDepartment of Physiology, University of Toronto, Toronto, Ont., Canada M5S 1A8cFaculty of Medicine (Neurology), University of Toronto, Toronto, Ont., Canada M5B 1W8dInstitute of Medical Science, University of Toronto, Toronto, Ont., Canada M5S 1A8eIBBME, University of Toronto, Toronto, Ont., Canada M5S 3G9Received 28 May 2004; revised 3 February 2005; accepted 25 March 2005. Available online 10 May 2005.AbstractCharacterizing hippocampal electrical rhythmic activities requires a broadly applicable methodology that lends itself to physiological interpretation. In the intact hippocampal preparation, spontaneous rhythmic field potentials are exhibited in the 3–4 Hz range which evidence suggests is due to discharges in the inhibitory interneuron population. Because field rhythms arise as a networknext term effect and models must be built from the neuron up, we focus on developing a methodology to deconstruct the non-stationary rhythms into its important constituents. This study uses 50 CA1/CA3 local field potentials to determine the important constituents, and an additional field recording and two intracellular recordings are examined subsequently. We determine the suitability of several time–frequency techniques. Distinct regions in the time–frequency domain which account for the signal behaviour are then characterized in terms of duration and frequency. These characteristics are interpreted as arising from a statistical mixture distribution. The decomposition of the 50 recordings yields three components whose patterns of activity match those of the intracellular recordings. We suggest that the statistical variability of the local field data can be linked to the variability of neuronal activities seen in intracellular data.Keywords: Time–frequency; EEG; Cluster; Intracellular; Deconstruction; Mixture distributions; Oscillations

ScienceDirect - Journal of Neuroscience Methods : Decomposing rhythmic hippocampal data to obtain neuronal correlates

MEAs and restrictive growth

An automated microdrop delivery system for neuronal networknext term patterning on microelectrode arraysElisabetta Macisa, Mariateresa Tedescoa, Paolo Massobrioa, Roberto Raiteria and Sergio MartinoiaCorresponding Author Contact Information, a, E-mail The Corresponding Author, E-mail The Corresponding AuthoraNeuroengineering and Bio-Nanotechnology Group (NBT Group), Department of Biophysical and Electronic Engineering (DIBE), University of Genova, Via Opera Pia 11a, 16145 Genova, ItalyReceived 31 July 2006; revised 12 October 2006; accepted 13 October 2006. Available online 1 December 2006.AbstractThe aim of this work is to present a new technique for defining interconnected sub-populations of cultured neurons on microelectrode arrays (MEAs). An automated microdrop delivery technique allows to design and realize spatially distributed neuronal ensembles by depositing sub-nanoliter volumes of adhesion molecules in which neurons grow and develop. Electrophysiological tests demonstrate that functionally interconnected clusters are obtained and experimental results (both spontaneous and stimulus evoked activity recordings) attesting the feasibility of the proposed approach are presented. By means of the automated system, different and specific architectures can be easily designed and functionally studied. In the presented system the speed of drop deposition is about 30 drops/min; the mean diameter is 147 μm; typical cell survival time is 4–5 weeks. By changing drop size and spacing, investigations about how the previous termnetworknext term dynamics is related to the previous termnetworknext term structure can be systematically carried out.Keywords: Neuronal patterning; Cultured cortical neurons; Microdrop deposition; Ink-jet deposition; Microelectrode array (MEA); Neuronal electrophysiological activity

ScienceDirect - Journal of Neuroscience Methods : An automated microdrop delivery system for neuronal network patterning on microelectrode arrays

Alzheimer's and EEG

Application and comparison of classification algorithms for recognition of Alzheimer's disease in electrical brain activity (EEG)Christoph Lehmanna, Corresponding Author Contact Information, E-mail The Corresponding Author, E-mail The Corresponding Author, Thomas Koeniga, Vesna Jelicb, Leslie Prichepc, d, Roy E. Johnc, d, Lars-Olof Wahlundb, Yadolah Dodgee and Thomas DierksaaUniversity Hospital of Clinical Psychiatry, Department of Psychiatric Neurophysiology, University of Berne, Bolligenstrasse 111, CH-3000 Bern 60, SwitzerlandbKarolinska Institute, Department of Neurotec., Division of Geriatric Medicine, Karolinska University Hospital, Huddinge, Stockholm, SwedencBrain Research Laboratories, New York University School of Medicine, USAdNathan S. Kline Institute for Psychiatric Research, USAeGroup of Statistics, University of Neuchatel, SwitzerlandReceived 13 September 2006; revised 26 October 2006; accepted 27 October 2006. Available online 6 December 2006.AbstractThe early detection of subjects with probable Alzheimer's disease (AD) is crucial for effective appliance of treatment strategies. Here we explored the ability of a multitude of linear and non-linear classification algorithms to discriminate between the electroencephalograms (EEGs) of patients with varying degree of AD and their age-matched control subjects. Absolute and relative spectral power, distribution of spectral power, and measures of spatial synchronization were calculated from recordings of resting eyes-closed continuous EEGs of 45 healthy controls, 116 patients with mild AD and 81 patients with moderate AD, recruited in two different centers (Stockholm, New York). The applied classification algorithms were: principal component linear discriminant analysis (PC LDA), partial least squares LDA (PLS LDA), principal component logistic regression (PC LR), partial least squares logistic regression (PLS LR), bagging, random forest, support vector machines (SVM) and feed-forward neural network.next term Based on 10-fold cross-validation runs it could be demonstrated that even tough modern computer-intensive classification algorithms such as random forests, SVM and neural previous termnetworksnext term show a slight superiority, more classical classification algorithms performed nearly equally well. Using random forests classification a considerable sensitivity of up to 85% and a specificity of 78%, respectively for the test of even only mild AD patients has been reached, whereas for the comparison of moderate AD vs. controls, using SVM and neural previous termnetworks,next term values of 89% and 88% for sensitivity and specificity were achieved. Such a remarkable performance proves the value of these classification algorithms for clinical diagnostics.Keywords: EEG; Alzheimer's disease; Multivariate statistics; Classification

ScienceDirect - Journal of Neuroscience Methods : Application and comparison of classification algorithms for recognition of Alzheimer's disease in electrical brain activity (EEG)

Causal entropies

Causal entropies—A measure for determining changes in the temporal organization of neural systemsJack Waddella, Rhonda Dzakpasua, Victoria Boothb, c, Brett Rileyb, Jonathan Reasord, Gina Poeb, e and Michal Zochowskia, f, Corresponding Author Contact Information, E-mail The Corresponding AuthoraDepartment of Physics, University of Michigan, Ann Arbor, MI 48109-1040, USAbDepartment of Anesthesiology, University of Michigan, Ann Arbor, MI 48109-0615, USAcDepartment of Mathematics, University of Michigan, Ann Arbor, MI 48109, USAdDepartment of Neurology, University of Michigan, Ann Arbor, MI 48109, USAeDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109-0615, USAfBiophysics Research Division, University of Michigan, 450 Church St., Ann Arbor, MI 48109, USAReceived 12 April 2006; revised 4 November 2006; accepted 14 December 2006. Available online 22 December 2006.AbstractWe propose a novel measure to detect temporal ordering in the activity of individual neurons in a local network,next term which is thought to be a hallmark of activity-dependent synaptic modifications during learning. The measure, called causal entropy, is based on the time-adaptive detection of asymmetries in the relative temporal patterning between neuronal pairs. We characterize properties of the measure on both simulated data and experimental multiunit recordings of hippocampal neurons from the awake, behaving rat, and show that the metric can more readily detect those asymmetries than standard cross correlation-based techniques, especially since the temporal sensitivity of causal entropy can detect such changes rapidly and dynamically.Keywords: Temporal pattern formation; Multiunit recording; Hippocampal CA1; Long term potentiation; Asymmetric correlation

ScienceDirect - Journal of Neuroscience Methods : Causal entropies—A measure for determining changes in the temporal organization of neural systems

Language and epilepsy

Language localization, the developing brain and childhood epilepsy: Back to the future.

Language localization, the developing brain and childhood epilepsy: Back to the future.

J Int Neuropsychol Soc. 2007 May;13(3):501-4

Authors: Duchowny M

The defining role of language for communicating and forming social bonds has captured the imagination of scientists and scholars throughout the ages, and scientific inquiry into the neural correlates of language is now centuries old. Theories of linguistic structure and function occupy center stage in fields as diverse as neuroscience, embryology, anthropology and evolution. This should come as no surprise as the neural basis of linguistic function holds promise for understanding how the mind works and what makes us uniquely human.

PMID: 17445299 [PubMed - in process]

Bursting in cell culture

Activity deprivation leads to seizures in hippocampal slice cultures: is epilepsy the consequence of homeostatic plasticity?

Activity deprivation leads to seizures in hippocampal slice cultures: is epilepsy the consequence of homeostatic plasticity?

J Clin Neurophysiol. 2007 Apr;24(2):154-64

Authors: Trasande CA, Ramirez JM

SUMMARY:: Neural networks operate robustly despite destabilizing factors, ranging from gene product turnover to circuit refinement, throughout life. Maintaining functional robustness of neuronal networks critically depends upon forms of homeostatic plasticity including synaptic scaling. Synaptic strength and intrinsic excitability have been shown to "scale" (up or down) in response to altered ambient activity levels, and this has led to the general idea that homeostatic plasticity operates along a continuum. After 48 hours of activity deprivation, cultured hippocampal networks exhibited a homeostatic-type reconfiguration that was discrete: a switch from spontaneous spiking to oscillatory bursting. Blockade of fast glutamatergic and GABAergic transmission abolished spontaneous network bursting, but the majority of neurons exhibited intrinsic bursting in response to current injection, which was not the case in control tissue. This de novo intrinsic bursting could be blocked by cadmium chloride, suggesting that this bursting involves calcium mechanisms. Immunohistochemistry confirmed that activity-deprived slice cultures exhibited a widespread upregulation of voltage-dependent calcium channels compared with controls. Calcium imaging studies from activity-deprived slices demonstrated that spontaneous bursting was not a local behavior, but rather a global, synchronous phenomenon, reminiscent of seizure activity. These data suggest that the input/output transformation of individual neurons undergoing homeostatic remodeling is more complex than simple scaling. Network consequences of this transformation include network destabilization of epileptic proportions. Spontaneous activity plays a critical role in actively maintaining homeostatic balance in networks, which is lost after activity deprivation.

PMID: 17414971 [PubMed - in process]

Vitamin C as a neuroprotectant in epilepsy

The Effects of Ascorbic Acid on Penicillin-induced Epileptiform Activity in Rats.

The Effects of Ascorbic Acid on Penicillin-induced Epileptiform Activity in Rats.

Epilepsia. 2007 Apr 13;

Authors: Ayyildiz M, Coskun S, Yildirim M, Agar E

Purpose: Epileptic seizure results from excessive discharge in a population of hyperexcitable neurons. A number of studies help to document the effects of active oxygen free radical scavengers such as alpha-tocopherol or ascorbic acid (vitamin C). In the present study, we examined the effects of ascorbic acid, at the six different doses, on penicillin-induced epileptiform activity. Methods: A single microinjection of penicillin (2.5 mul, 500 units, intracortically) into the left sensorimotor cortex induced epileptiform activity within 2-5 min, progressing to full seizure activity lasting approximately 3-5 h. In the first set of experiments, 30 min after penicillin injection, six different doses of ascorbic acid (25, 50, 100, 200, 400, or 800 mg/kg) were administered intraperitoneally (IP). The other group of animals received the effective dose of ascorbic acid (100 mg/kg, IP) for 7 days. Ascorbic acid administration was stopped 24 h before penicillin treatment. Another group of rats received the effective dose of ascorbic acid (100 mg/kg, IP) 30 min before penicillin treatment. In the second set of experiments, the lipid peroxidation (MDA) and reduced glutathione (GSH) levels of brain were measured in the control, control + ascorbic acid, penicillin, and penicillin + ascorbic acid groups. Results: Ascorbic acid, at the low dose (50, 100 mg/kg, 30 min after penicillin injection), decreased both the frequency and amplitude of penicillin-induced epileptiform activity in rats. Ascorbic acid, at intermediate doses (200, 400 mg/kg, 30 min after penicillin injection), decreased the frequency of epileptiform activity without changing the amplitude. Ascorbic acid, at the lowest dose (25 mg/kg) and highest dose (800 mg/kg) (30 min after penicillin injection), did not change either the frequency or amplitude of epileptiform activity. Ascorbic acid, at the low dose (100 mg/kg) was the most effective dose in changing the frequency and amplitude of penicillin-induced epileptiform activity. Pretreatment with ascorbic acid (100 mg/kg) 30 min before penicillin treatment caused a significant delay in the onset of penicillin-induced epileptiform activity. Pretreatment with ascorbic acid (100 mg/kg) for 7 days did not change the latency of epileptiform activity. The most effective dose of ascorbic acid (100 mg/kg) prevented both the decrease in GSH level and the increase in lipid peroxidation level (MDA) occurring after penicillin-induced epileptiform activity. Conclusions: These data indicate that ascorbic acid has neuroprotective activity against penicillin-induced epileptiform electrocorticogram activity.

PMID: 17433052 [PubMed - as supplied by publisher]

Well I never....

The New Field of Neuroskeletal Biology.

The New Field of Neuroskeletal Biology.

Calcif Tissue Int. 2007 Apr 18;

Authors: Patel MS, Elefteriou F

The fields of neuroscience and bone biology have recently converged following the discovery that bone remodeling is directly regulated by the brain. This work has defined bone remodeling as one of the cardinal physiological functions of the body, subject to homeostatic regulation and integrated with the other major physiological functions by the hypothalamus. Central to this discovery was the definition of the adipocyte-derived hormone leptin as a regulator of both arms of bone remodeling, formation and resorption, through its action on the ventromedial hypothalamus and subsequently via the sympathetic nervous system to osteoblasts. The characterization of the sympathetic nervous system as a regulator of bone remodeling has led to several large clinical studies demonstrating a substantial protective effect of ss-blockers, particularly ss1-blockers, on fracture risk. Studies in model organisms have reinforced the role of the central nervous system in the regulation of bone remodeling in vivo by the identification of several additional genes, namely cocaine and amphetamine regulated transcript (Cart), melanocortin 4 receptor (Mc4R), neuropeptide Y (NPY), Y2 receptor, cannabinoid receptor CB1 (Cnbr1), and the genes of the circadian clock. These genes have several common features, including high levels of expression in the hypothalamus and the ability to regulate other major physiological functions in addition to bone remodeling including energy homeostasis, body weight, and reproduction. We review the major pathways that define the new field of neuroskeletal biology and identify further avenues of inquiry.

PMID: 17440766 [PubMed - as supplied by publisher]

Species different cannabinoid effects

Correlated species differences in the effects of cannabinoid ligands on anxiety and on GABAergic and glutamatergic synaptic transmission.

Eur J Neurosci. 2007 Apr;25(8):2445-56

Authors: Haller J, Mátyás F, Soproni K, Varga B, Barsy B, Németh B, Mikics E, Freund TF, Hájos N

Cannabinoid ligands show therapeutic potential in a variety of disorders including anxiety. However, the anxiety-related effects of cannabinoids remain controversial as agonists show opposite effects in mice and rats. Here we compared the effects of the cannabinoid agonist WIN-55,212 and the CB1 antagonist AM-251 in CD1 mice and Wistar rats. Special attention was paid to antagonist-agonist interactions, which had not yet been studied in rats. In mice, WIN-55,212 decreased whereas AM-251 increased anxiety. The antagonist abolished the effects of the agonist. In contrast, WIN-55,212 increased anxiety in rats. Surprisingly, the antagonist potentiated this effect. Cannabinoids affect both GABAergic and glutamatergic functions, which play opposite roles in anxiety. We hypothesized that discrepant findings resulted from species differences in the relative responsiveness of the two transmitter systems to cannabinoids. We investigated this hypothesis by studying the effects of WIN-55,212 on evoked hippocampal inhibitory and excitatory postsynaptic currents (IPSCs and EPSCs). IPSCs were one order of magnitude more sensitive to WIN-55,212 in mice than in rats. In mice, IPSCs were more sensitive than EPSCs to WIN-55,212. This is the first study showing that the relative cannabinoid sensitivity of GABA and glutamate neurotransmission is species-dependent. Based on behavioural and electrophysiological findings, we hypothesize that WIN-55,212 reduced anxiety in mice by affecting GABA neurotransmission whereas it increased anxiety in rats via glutamatergic mechanisms. In rats, AM-251 potentiated this anxiogenic effect by inhibiting the anxiolytic GABAergic mechanism. We suggest that the anxiety-related effects of cannabinoids depend on the relative cannabinoid responsiveness of GABAergic and glutamatergic neurotransmission.

PMID: 17445240 [PubMed - in process]

Thursday 19 April 2007

Cortex and striatum

Novel and Distinct Operational Principles of Intralaminar Thalamic Neurons and Their Striatal Projections

Neurons of the intralaminar thalamus, including central lateral (CL) and parafascicular (Pf) nuclei, innervate the cortex and striatum and are important for cognitive, sensory, and motor processes. We tested the hypothesis that CL and Pf neurons provide functionally distinct inputs to the striatum. We performed recordings of single CL and Pf neurons in anesthetized rats and, after juxtacellularly labeling the neurons, their somatodendritic features and synaptic connections were characterized.

All CL neurons (n = 31) discharged classic low-threshold Ca²⁺ spike bursts during cortical slow-wave activity in vivo. In contrast, Pf neurons (n = 52) rarely fired such bursts, but instead discharged groups of spikes at relatively low frequencies. The activity of CL and Pf neurons was often temporally coupled to cortical slow oscillations. Identified CL neurons possessed archetypal "bushy" dendrites and preferentially established synapses with dendritic spines (91% of synapses) of striatal projection neurons. Pf neurons possessed "reticular-like" dendrites, and, on average, preferentially established synapses with dendritic shafts (63%) in striatum, although connectivity was markedly heterogeneous across neurons. Two of the six Pf neurons studied exclusively targeted dendritic shafts, whereas another neuron almost exclusively (97%) targeted spines. The remaining three neurons preferentially targeted dendritic shafts (53–70%).

Thus, the fundamental properties of CL and Pf neurons differ (the latter do not express the typical operational principles of thalamic relay neurons), and they provide different temporally patterned inputs to distinct striatal targets. This mechanistic diversity likely underpins the transmission of specific and discrete information from intralaminar thalamic nuclei to striatal and cortical targets.

Delay and anticipation

How Do Primates Anticipate Uncertain Future Events?

The timing of an upcoming event depends on two factors: its temporal position, proximal or distal with respect to the present moment, and the unavoidable stochastic variability around this temporal position. We searched for a general mechanism that could describe how these two factors influence the anticipation of an upcoming event in an oculomotor task. Monkeys were trained to pursue a moving target with their eyes. During a delay period inserted before target motion onset, anticipatory pursuit responses were frequently observed. We found that anticipatory movements were altered by the temporal position of the target. Increasing the timing uncertainty associated with the stimulus resulted in an increase in the width of the latency distribution of anticipatory pursuit. These results show that monkeys relied on an estimation of the changing probability of target motion onset as time elapsed during the delay to decide when to initiate an anticipatory smooth eye movement.

Persistent Activity

Thalamocortical Up States: Differential Effects of Intrinsic and Extrinsic Cortical Inputs on Persistent Activity

During behavioral quiescence, the neocortex generates spontaneous slow oscillations that consist of Up and Down states. Up states are short epochs of persistent activity that resemble the activated neocortex during arousal and cognition. Although Up states are generated within the cortex, the impact of extrinsic (thalamocortical) and intrinsic (intracortical) inputs on the persistent activity is not known. Using thalamocortical slices, we found that the persistent cortical activity during spontaneous Up states effectively drives thalamocortical relay cells through corticothalamic connections. However, thalamic activity can also precede the onset of cortical Up states, which suggests a role of thalamic activity in triggering cortical Up states through thalamocortical connections. In support of this hypothesis, we found that cutting the connections between thalamus and cortex reduced the incidence of spontaneous Up states in the cortex. Consistent with a facilitating role of thalamic activity on Up states, electrical or chemical stimulation of the thalamus triggered cortical Up states very effectively and enhanced those occurring spontaneously. In contrast, stimulation of the cortex triggered Up states only at very low intensities but otherwise had a suppressive effect on Up states. Moreover, cortical stimulation suppressed the facilitating effect of thalamic stimulation on Up states. In conclusion, thalamocortical inputs facilitate and intracortical inputs suppress cortical Up states. Thus, extrinsic and intrinsic cortical inputs differentially regulate persistent activity, which may serve to adjust the processing state of thalamocortical networks during behavior.

Wednesday 18 April 2007

LEV

Levetiracetam Monotherapy in Children With Epilepsy.

Levetiracetam Monotherapy in Children With Epilepsy.

Pediatr Neurol. 2007 Apr;36(4):227-230

Authors: Khurana DS, Kothare SV, Valencia I, Melvin JJ, Legido A

Although levetiracetam has shown efficacy in children with epilepsy, when used as adjunctive therapy, limited data are available regarding its use as monotherapy. The objective of this study is to evaluate the efficacy and tolerability of levetiracetam monotherapy in a cohort of pediatric patients with epilepsy. A retrospective analysis of pediatric epilepsy patients receiving levetiracetam at a single institution was performed over a 3-year period. Eighty-one patients were identified, 18 of whom received levetiracetam as monotherapy (mean age, 9.6 years). Epilepsy types were partial in 14 and generalized in 4. Conversion to levetiracetam monotherapy occurred in 16 patients due to lack of efficacy or adverse events, and 2 patients were initially started on monotherapy. Dose range of levetiracetam was 14-60 mg/kg, and duration of therapy ranged from 2-24 months. Eleven patients became seizure free on levetiracetam, one had at least 50% reduction in seizures, and six others had no change in seizure frequency. Adverse events included worsening of behavior, irritability, and possible cognitive changes, seen in 4 patients. Levetiracetam was discontinued in seven patients overall. Levetiracetam monotherapy appeared to be effective and well tolerated in this group of children with epilepsy and warrants further investigation in a well-controlled, prospective study.

PMID: 17437904 [PubMed - as supplied by publisher]

NMDA and dev. seizures

Alterations of NR2B and PSD-95 expression after early-life epileptiform discharges in developing neurons.

Alterations of NR2B and PSD-95 expression after early-life epileptiform discharges in developing neurons.

Int J Dev Neurosci. 2007 Feb 21;

Authors: Jiang Q, Wang J, Wu X, Jiang Y

As an extreme form of abnormally synchronized activity, epilepsy may modify patterns of organization in the nervous system. It is clear that enhanced glutamatergic excitatory synaptic transmission with alterations in the expression of ionotropic glutamate receptors is a mechanism critical for seizure susceptibility and excitotoxicity. However, the exact quomodo and the roles of regulated N-methyl-d-aspartate receptor (NMDAR) composition and expression of a major postsynaptic density (PSD) scaffolding molecule, PSD-95, are as yet unclear. To study protein expression changes after epileptiform discharges in cultured immature rat cortical neurons, we divided cells into three groups which were transiently exposed to regular Neurobasal/B27 (control group), physiological solution (PS group) and magnesium-free physiological solution (MGF group) at cultured day 6. Neurons at three different culture ages (DIV7, DIV12 and DIV17) were collected for immunoblotting analysis. We found a decrease in expression of NR2B NMDAR subunit and PSD-95 (P<0.05) shortly after insult (within 24h), which may show that brief magnesium-free media treatment of primary cultured rat cortical neurons, an in vitro model of seizure brain injury, has a major influence on the expression of NR2B subunit and PSD-95.

PMID: 17428633 [PubMed - as supplied by publisher]

Interesting hypothalamic e-phys

Pharmacological and molecular characterization of ATP-sensitive K(+) conductances in CART and NPY/AgRP expressing neurons of the hypothalamic arcuate nucleus.

Pharmacological and molecular characterization of ATP-sensitive K(+) conductances in CART and NPY/AgRP expressing neurons of the hypothalamic arcuate nucleus.

Neuroscience. 2007 Feb 9;144(3):815-24

Authors: van den Top M, Lyons DJ, Lee K, Coderre E, Renaud LP, Spanswick D

The role of hypothalamic ATP-sensitive potassium channels in the maintenance of energy homeostasis has been extensively explored. However, how these channels are incorporated into the neuronal networks of the arcuate nucleus remains unclear. Whole-cell patch-clamp recordings from rat arcuate nucleus neurons in hypothalamic slice preparations revealed widespread expression of functional ATP-sensitive potassium channels within the nucleus. ATP-sensitive potassium channels were expressed in orexigenic neuropeptide Y/agouti-related protein (NPY/AgRP) and ghrelin-sensitive neurons and in anorexigenic cocaine-and-amphetamine regulated transcript (CART) neurons. In 70% of the arcuate nucleus neurons recorded, exposure to glucose-free bathing medium induced inhibition of electrical excitability, the response being characterized by membrane hyperpolarization, a reduction in neuronal input resistance and a reversal potential consistent with opening of potassium channels. These effects were reversible upon re-introduction of glucose to the bathing medium or upon exposure to the ATP-sensitive potassium channel blockers tolbutamide or glibenclamide. The potassium channel opener diazoxide, but not pinacidil, also induced a tolbutamide and glibenclamide-sensitive inhibition of electrical excitability. Single-cell reverse transcription-polymerase chain reaction revealed expression of mRNA for sulfonylurea receptor 1 but not sulfonylurea receptor 2 subunits of ATP-sensitive potassium channels. Thus, rat arcuate nucleus neurons, including those involved in functionally antagonistic orexigenic and anorexigenic pathways express functional ATP-sensitive potassium channels which include sulfonylurea receptor 1 subunits. These data indicate a crucial role for these ion channels in central sensing of metabolic and energy status. However, further studies are needed to clarify the differential roles of these channels, the organization of signaling pathways that regulate them and how they operate in functionally opposing cell types.

PMID: 17137725 [PubMed - indexed for MEDLINE]

Lovely....

Olfactory lateralization in homing pigeons: initial orientation of birds receiving a unilateral olfactory input.

Olfactory lateralization in homing pigeons: initial orientation of birds receiving a unilateral olfactory input.

Eur J Neurosci. 2007 Mar;25(5):1511-6

Authors: Gagliardo A, Pecchia T, Savini M, Odetti F, Ioalè P, Vallortigara G

It has been shown that homing pigeons (Columba livia) rely on olfactory cues to navigate from unfamiliar locations. In fact, the integrity of the olfactory system, from the olfactory mucosa to the piriform cortex, is required for pigeons to navigate over unfamiliar areas. Recently it has been shown that there is a functional asymmetry in the piriform cortex, with the left piriform cortex more involved in the use of the olfactory navigational map than the right piriform cortex. To investigate further the lateralization of the olfactory system in relation to navigational processes in carrier pigeons, we compared their homing performance after either their left or the right nostril was plugged. Contrary to our expectations, we observed an impairment in the initial orientation of the pigeons with their right nostril plugged. However, both groups released with one nostril plugged tended to be poorer than control pigeons in their homing performance. The observed asymmetry in favour of the right nostril might be due to projections from the olfactory bulbs to the contralateral globus pallidum, a structure involved in motor responses.

PMID: 17425577 [PubMed - in process]

CB changes in epilepsy

Status epilepticus causes a long-lasting redistribution of hippocampal cannabinoid type 1 receptor expression and function in the rat pilocarpine model of acquired epilepsy.

Status epilepticus causes a long-lasting redistribution of hippocampal cannabinoid type 1 receptor expression and function in the rat pilocarpine model of acquired epilepsy.

Neuroscience. 2007 Apr 11;

Authors: Falenski KW, Blair RE, Sim-Selley LJ, Martin BR, Delorenzo RJ

Activation of the cannabinoid type 1 (CB1) receptor, a major G-protein-coupled receptor in brain, acts to regulate neuronal excitability and has been shown to mediate the anticonvulsant effects of cannabinoids in several animal models of seizure, including the rat pilocarpine model of acquired epilepsy. However, the long-term effects of status epilepticus on the expression and function of the CB1 receptor have not been described. Therefore, this study was initiated to evaluate the effect of status epilepticus on CB1 receptor expression, binding, and G-protein activation in the rat pilocarpine model of acquired epilepsy. Using immunohistochemistry, we demonstrated that status epilepticus causes a unique "redistribution" of hippocampal CB1 receptors, consisting of specific decreases in CB1 immunoreactivity in the dense pyramidal cell layer neuropil and dentate gyrus inner molecular layer, and increases in staining in the CA1-3 strata oriens and radiatum. In addition, this study demonstrates that the redistribution of CB1 receptor expression results in corresponding functional changes in CB1 receptor binding and G-protein activation using [(3)H] R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl](1-napthalen-yl)methanone mesylate (WIN55,212-2) and agonist-stimulated [(35)S]GTPgammaS autoradiography, respectively. The redistribution of CB1 receptor-mediated [(35)S]GTPgammaS binding was 1) attributed to an altered maximal effect (E(max)) of WIN55,212-2 to stimulate [(35)S]GTPgammaS binding, 2) reversed by the CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A), 3) confirmed by the use of other CB1 receptor agonists, and 4) not reproduced in other G-protein-coupled receptor systems examined. These results demonstrate that status epilepticus causes a unique and selective reorganization of the CB1 receptor system that persists as a permanent hippocampal neuronal plasticity change associated with the development of acquired epilepsy.

PMID: 17433556 [PubMed - as supplied by publisher]

Very interesting....Ca channels, network-level excitability etc.

Density is destiny--on [corrected] the relation between quantity of T-type Ca2+ channels and neuronal electrical behavior.

Density is destiny--on [corrected] the relation between quantity of T-type Ca2+ channels and neuronal electrical behavior.

CNS Neurol Disord Drug Targets. 2006 Dec;5(6):655-62

Authors: Chorev E, Manor Y, Yarom Y

The electroresponsiveness fingerprint of a neuron reflects the types and distributions of the ionic channels that are embedded in the neuronal membrane as well as its morphology. Theoretical analysis shows that subtle changes in the density of channels can contribute substantially to the electroresponsive fingerprints of neurons. We have confirmed these predictions, using the dynamic clamp approach to emulate changes in channels' densities in neurons from the inferior olive. We demonstrate how the density of T-type channels determines the behavioral destiny of neurons. We argue that regulation of channel densities could be an efficient mechanism for controlling the electrical activity of single cells, as well as the output of neuronal networks.

PMID: 17168749 [PubMed - indexed for MEDLINE]

Thursday 12 April 2007

Ictogenesis and non-linear analyses

Epilepsia. 2003;44 Suppl 12:30-43. Links Toward a neurodynamical understanding of ictogenesis. * Le Van Quyen M, * Navarro V, * Martinerie J, * Baulac M, * Varela FJ. LENA (Laboratoire de Neurosciences Cognitives et Imagerie Cerebrale), CNRS UPR 640, Hopital de la Pitie-Salpetriere, 47 Boulevard de l'Hopital, 75651 Paris cedex 13, France. Although considerable information on cellular and network mechanisms of epilepsy exists, it is still not understood why, how, and when the transition from interictal to ictal state takes place. The authors review their work on nonlinear EEG analysis and provide consistent evidences that dynamical changes in the neural activity allows the characterization of a preictal state several minutes before seizure onset. This new neurodynamical approach of ictogenesis opens new perspectives for studying the basic mechanisms in epilepsy as well as for possible therapeutic interventions. PMID: 14641559 [PubMed - indexed for MEDLINE]

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Ictogenesis and models

C R Biol. 2005 Feb;328(2):187-98. Links Anticipating epileptic seizures: from mathematics to clinical applications. * Le Van Quyen M. Laboratoire de Neurosciences Cognitives et Imagerie Cerebrale, LENA, CNRS UPR 640, Hopital de la Pitie-Salpetriere, 47, bd de l'Hopital, 75651 Paris, France. lenalm@ext.jussieu.fr The study of dynamical changes in the neural activity preceding an epileptic seizure allows the characterization of a preictal state several minutes prior to seizure onset. This opens new perspectives for studying the mechanisms of ictogenesis as well as for possible therapeutic interventions that represent a major breakthrough. In this review we present and discuss the results from our group in this domain using nonlinear analysis of brain signals, as well as its limitation and open questions. PMID: 15771005 [PubMed - indexed for MEDLINE]

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Very significant!

Muscarinic Control of Long-Range GABAergic Inhibition within the Rhinal Cortices

The perirhinal cortex plays a critical role in memory formation, in part because it forms reciprocal connections with the neocortex and entorhinal cortex and is thus in a position to integrate and transfer higher-order information to and from the hippocampus. However, for reasons that remain unclear, perirhinal transfer of neocortical inputs to the entorhinal cortex occurs with a low probability. Using patch recordings in vitro and tract-tracing combined with GAD-67 immunohistochemistry, we show that the perirhinal cortex contains GABAergic neurons with long-range projections to superficial entorhinal cells. This finding challenges the traditional model of cortical inhibition in which all trans-areal inhibition is thought to be disynaptic because the axons of GABAergic interneurons are assumed to be confined within the area in which their somata are located. Moreover, consistent with recent studies indicating that the formation of perirhinal-dependent memories requires activation of muscarinic receptors, long-range IPSPs were presynaptically inhibited by M₂ receptor activation. Overall, these results suggest that long-range feedforward inhibition regulates perirhinal transfer of neocortical inputs to the entorhinal cortex, but that cholinergic inputs can presynaptically adjust the impact of this control mechanism as a function of environmental contingencies.

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Hypoxia rears its head again....

Hypoxia Suppresses Glutamate Transport in Astrocytes

Glutamate uptake by astrocytes is fundamentally important in the regulation of CNS function. Disruption of uptake can lead to excitotoxicity and is implicated in various neurodegenerative processes as well as a consequence of hypoxic/ischemic events. Here, we investigate the effect of hypoxia on activity and expression of the key glutamate transporters excitatory amino acid transporter 1 (EAAT1) [GLAST (glutamate-aspartate transporter)] and EAAT2 [GLT-1 (glutamate transporter 1)]. Electrogenic, Na⁺-dependent glutamate uptake was monitored via whole-cell patch-clamp recordings from cortical astrocytes. Under hypoxic conditions (2.5 and 1% O₂ exposure for 24 h), glutamate uptake was significantly reduced, and pharmacological separation of uptake transporter subtypes suggested that the EAAT2 subtype was preferentially reduced relative to the EAAT1. This suppression was confirmed at the level of EAAT protein expression (via Western blots) and mRNA levels (via real-time PCR). These effects of hypoxia to inhibit glutamate uptake current and EAAT protein levels were not replicated by desferrioxamine, cobalt, FG0041, or FG4496, agents known to mimic effects of hypoxia mediated via the transcriptional regulator, hypoxia-inducible factor (HIF). Furthermore, the effects of hypoxia were not prevented by topotecan, which prevents HIF accumulation. In stark contrast, inhibition of nuclear factor-B (NF-B) with SN50 fully prevented the effects of hypoxia on glutamate uptake and EAAT expression. Our results indicate that prolonged hypoxia can suppress glutamate uptake in astrocytes and that this effect requires activation of NF-B but not of HIF. Suppression of glutamate uptake via this mechanism may be an important contributory factor in hypoxic/ischemic triggered glutamate excitotoxicity.

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Wednesday 11 April 2007

Feedforward inhibition

Feedforward inhibition contributes to the control of epileptiform propagation speed.

Feedforward inhibition contributes to the control of epileptiform propagation speed.

J Neurosci. 2007 Mar 28;27(13):3383-7

Authors: Trevelyan AJ, Sussillo D, Yuste R

It is still poorly understood how epileptiform events can recruit cortical circuits. Moreover, the speed of propagation of epileptiform discharges in vivo and in vitro can vary over several orders of magnitude (0.1-100 mm/s), a range difficult to explain by a single mechanism. We previously showed how epileptiform spread in neocortical slices is opposed by a powerful feedforward inhibition ahead of the ictal wave. When this feedforward inhibition is intact, epileptiform spreads very slowly (approximately 100 microm/s). We now investigate whether changes in this inhibitory restraint can also explain much faster propagation velocities. We made use of a very characteristic pattern of evolution of ictal activity in the zero magnesium (0 Mg2+) model of epilepsy. With each successive ictal event, the number of preictal inhibitory barrages dropped, and in parallel with this change, the propagation velocity increased. There was a highly significant correlation (p < 0.001) between the two measures over a 1000-fold range of velocities, indicating that feedforward inhibition was the prime determinant of the speed of epileptiform propagation. We propose that the speed of propagation is set by the extent of the recruitment steps, which in turn is set by how successfully the feedforward inhibitory restraint contains the excitatory drive. Thus, a single mechanism could account for the wide range of propagation velocities of epileptiform events observed in vitro and in vivo.

PMID: 17392454 [PubMed - in process]

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Novel thought....

Arq Neuropsiquiatr. 2007 Mar;65(1):1-4. First, do no harm: the risks of overtreating children with epilepsy. * Chuang E, * Guerreiro MM, * Tsuchie SY, * Santucci A, * Guerreiro CA, * Montenegro MA. Department of Neurology, State University of CampinasSP, Brazil. BACKGROUND: Although overtreatment with antiepileptic drugs contributes to the morbidity associated with epilepsy, many children still are overtreated. OBJECTIVE: To evaluate if the withdrawal of at least one antiepileptic drug (AED) in children with refractory epilepsy using polytherapy enable a better seizure control. METHOD: This was a prospective study. Children with refractory epilepsy using at least two AEDs were included. Once the patient, or guardian, agreed to participate in the study, one or more AED were slowly tapered off. The remaining AEDs dosages could be adjusted as needed, but a new AED could not be introduced. RESULTS: Fifteen patients were evaluated, three girls; ages ranging from 3 to 18 (mean=8.7 years). After at least one AED withdrawal, two (13.5%) patients became seizure free, seizures improved >50% in 5 (33.5%) patients, did not change in 5 (33.5%), and seizure frequency became worse in 3 (20%). Adverse events improved in 12 patients (80%). CONCLUSION: The withdrawal of at least one AED is a valuable option in the treatment of selected children with refractory epilepsy. PMID: 17420817 [PubMed - as supplied by publisher]

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From the department of 'Ooh, what a surprise'!

Unilateral low-frequency stimulation of central piriform cortex inhibits amygdaloid-kindled seizures in Sprague-Dawley rats.

Unilateral low-frequency stimulation of central piriform cortex inhibits amygdaloid-kindled seizures in Sprague-Dawley rats.

Neuroscience. 2007 Apr 3;

Authors: Zhu-Ge ZB, Zhu YY, Wu DC, Wang S, Liu LY, Hu WW, Chen Z

The central piriform cortex (cPC) is considered to be critically involved in the generation and propagation of kindled seizures. Our previous study found that low-frequency stimulation (LFS) of the cPC inhibits the development process of amygdala kindling. In this study, we determined whether unilateral LFS of the cPC had an inhibitory effect on amygdaloid-kindled seizures in Sprague-Dawley rats. When fully-kindled seizures were achieved by daily amygdala electrical stimulation (2 s train of 1 ms pulses at 60 Hz and 150-300 muA), LFS (15 min train of 0.1 ms pulses at 1 Hz and 50-150 muA) was applied to the ipsilateral or contralateral cPC 1 s after cessation of kindling stimulation for 10 days. LFS of the ipsilateral cPC significantly decreased the incidence of generalized seizures and seizure stage, and shortened cumulative afterdischarge duration and cumulative generalized seizure duration. LFS of the contralateral cPC also significantly decreased the expression of seizure stage, but had no appreciable effect on the generalized seizure incidence, cumulative afterdischarge duration and cumulative generalized seizure duration. On the other hand, LFS of the ipsilateral cPC significantly increased the afterdischarge threshold and further increased the differences of current intensity between afterdischarge threshold and generalized seizure threshold. Our data suggest that LFS of the cPC may be an effective method of inhibiting kindled seizures by preventing both afterdischarge generation and propagation. It provide further evidence that brain regions like the cPC, other than the seizure focus, can serve as targets for deep brain stimulation treatment of epilepsy.

PMID: 17412517 [PubMed - as supplied by publisher]

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