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Recent Articles in BMC Neuroscience

R�sseler J, Becker P, Johannes S, M�nte TF
Semantic, syntactic, and phonological processing of written words in adult developmental dyslexic readers: an event-related brain potential study.
BMC Neurosci. 2007;852.
BACKGROUND: The present study used event-related brain potentials to investigate semantic, phonological and syntactic processes in adult German dyslexic and normal readers in a word reading task. Pairs of German words were presented one word at a time. Subjects had to perform a semantic judgment task (house-window; are they semantically related?), a rhyme judgment task (house-mouse; do they rhyme?) and a gender judgment task (das-Haus [the-house]; is the gender correct? [in German, house has a neutral gender: das Haus]). RESULTS: Normal readers responded faster compared to dyslexic readers in all three tasks. Onset latencies of the N400 component were delayed in dyslexic readers in the rhyme judgment and in the gender judgment task, but not in the semantic judgment task. N400 and the anterior negativity peak amplitudes did not differ between the two groups. However, the N400 persisted longer in the dyslexic group in the rhyme judgment and in the semantic judgment tasks. CONCLUSION: These findings indicate that dyslexics are phonologically impaired (delayed N400 in the rhyme judgment task) but that they also have difficulties in other, non-phonological aspects of reading (longer response times, longer persistence of the N400). Specifically, semantic and syntactic integration seem to require more effort for dyslexic readers and take longer irrespective of the reading task that has to be performed. [Abstract/Link to Full Text]

Wierup N, Gunnarsd�ttir A, Ekblad E, Sundler F
Characterisation of CART-containing neurons and cells in the porcine pancreas, gastro-intestinal tract, adrenal and thyroid glands.
BMC Neurosci. 2007;851.
BACKGROUND: The peptide CART is widely expressed in central and peripheral neurons, as well as in endocrine cells. Known peripheral sites of expression include the gastrointestinal (GI) tract, the pancreas, and the adrenal glands. In rodent pancreas CART is expressed both in islet endocrine cells and in nerve fibers, some of which innervate the islets. Recent data show that CART is a regulator of islet hormone secretion, and that CART null mutant mice have islet dysfunction. CART also effects GI motility, mainly via central routes. In addition, CART participates in the regulation of the hypothalamus-pituitary-adrenal-axis. We investigated CART expression in porcine pancreas, GI-tract, adrenal glands, and thyroid gland using immunocytochemistry. RESULTS: CART immunoreactive (IR) nerve cell bodies and fibers were numerous in pancreatic and enteric ganglia. The majority of these were also VIP IR. The finding of intrinsic CART containing neurons indicates that pancreatic and GI CART IR nerve fibers have an intrinsic origin. No CART IR endocrine cells were detected in the pancreas or in the GI tract. The adrenal medulla harboured numerous CART IR endocrine cells, most of which were adrenaline producing. In addition CART IR fibers were frequently seen in the adrenal cortex and capsule. The capsule also contained CART IR nerve cell bodies. The majority of the adrenal CART IR neuronal elements were also VIP IR. CART IR was also seen in a substantial proportion of the C-cells in the thyroid gland. The majority of these cells were also somatostatin IR, and/or 5-HT IR, and/or VIP IR. CONCLUSION: CART is a major neuropeptide in intrinsic neurons of the porcine GI-tract and pancreas, a major constituent of adrenaline producing adrenomedullary cells, and a novel peptide of the thyroid C-cells. CART is suggested to be a regulatory peptide in the porcine pancreas, GI-tract, adrenal gland and thyroid. [Abstract/Link to Full Text]

Xiong F, Xiao S, Yu M, Li W, Zheng H, Shang Y, Peng F, Zhao C, Zhou W, Chen H, Fang L, Chamberlain JS, Zhang C
Enhanced effect of microdystrophin gene transfection by HSV-VP22 mediated intercellular protein transport.
BMC Neurosci. 2007;850.
BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by mutations of dystrophin gene, there is no effective treatment for this disorder at present. Plasmid-mediated gene therapy is a promising therapeutical approach for the treatment of DMD. One of the major issues with plasmid-mediated gene therapy for DMD is poor transfection efficiency and distribution. The herpes simplex virus protein VP22 has the capacity to spread from a primary transduced cell to surrounding cells and improve the outcome of gene transfer. To improve the efficiency of plasmid-mediated gene therapy and investigate the utility of the intercellular trafficking properties of VP22-linked protein for the treatment for DMD, expression vectors for C-terminal versions of VP22-microdystrophin fusion protein was constructed and the VP22-mediated shuttle effect was evaluated both in vitro and in vivo. RESULTS: Our results clearly demonstrate that the VP22-microdystrophin fusion protein could transport into C2C12 cells from 3T3 cells, moreover, the VP22-microdystrophin fusion protein enhanced greatly the amount of microdystrophin that accumulated following microdystrophin gene transfer in both transfected 3T3 cells and in the muscles of dystrophin-deficient (mdx) mice. CONCLUSION: These results highlight the efficiency of the VP22-mediated intercellular protein delivery for potential therapy of DMD and suggested that protein transduction may be a potential and versatile tool to enhance the effects of gene delivery for somatic gene therapy of DMD. [Abstract/Link to Full Text]

Kaske S, Krasteva G, K�nig P, Kummer W, Hofmann T, Gudermann T, Chubanov V
TRPM5, a taste-signaling transient receptor potential ion-channel, is a ubiquitous signaling component in chemosensory cells.
BMC Neurosci. 2007;849.
BACKGROUND: A growing number of TRP channels have been identified as key players in the sensation of smell, temperature, mechanical forces and taste. TRPM5 is known to be abundantly expressed in taste receptor cells where it participates in sweet, amino acid and bitter perception. A role of TRPM5 in other sensory systems, however, has not been studied so far. RESULTS: Here, we systematically investigated the expression of TRPM5 in rat and mouse tissues. Apart from taste buds, where we found TRPM5 to be predominantly localized on the basolateral surface of taste receptor cells, TRPM5 immunoreactivity was seen in other chemosensory organs - the main olfactory epithelium and the vomeronasal organ. Most strikingly, we found solitary TRPM5-enriched epithelial cells in all parts of the respiratory and gastrointestinal tract. Based on their tissue distribution, the low cell density, morphological features and co-immunostaining with different epithelial markers, we identified these cells as brush cells (also known as tuft, fibrillovesicular, multivesicular or caveolated cells). In terms of morphological characteristics, brush cells resemble taste receptor cells, while their origin and biological role are still under intensive debate. CONCLUSION: We consider TRPM5 to be an intrinsic signaling component of mammalian chemosensory organs, and provide evidence for brush cells being an important cellular correlate in the periphery. [Abstract/Link to Full Text]

S�r�s P, Marmurek J, Tam F, Baker N, Staines WR, Graham SJ
Functional MRI of working memory and selective attention in vibrotactile frequency discrimination.
BMC Neurosci. 2007;848.
BACKGROUND: Focal lesions of the frontal, parietal and temporal lobe may interfere with tactile working memory and attention. To characterise the neural correlates of intact vibrotactile working memory and attention, functional MRI was conducted in 12 healthy young adults. Participants performed a forced-choice vibrotactile frequency discrimination task, comparing a cue stimulus of fixed frequency to their right thumb with a probe stimulus of identical or higher frequency. To investigate working memory, the time interval between the 2 stimuli was pseudo-randomized (either 2 or 8 s). To investigate selective attention, a distractor stimulus was occasionally presented contralaterally, simultaneous to the probe. RESULTS: Delayed vibrotactile frequency discrimination, following a probe presented 8 s after the cue in contrast to a probe presented 2 s after the cue, was associated with activation in the bilateral anterior insula and the right inferior parietal cortex. Frequency discrimination under distraction was correlated with activation in the right anterior insula, in the bilateral posterior parietal cortex, and in the right middle temporal gyrus. CONCLUSION: These results support the notion that working memory and attention are organised in partly overlapping neural circuits. In contrast to previous reports in the visual or auditory domain, this study emphasises the involvement of the anterior insula in vibrotactile working memory and selective attention. [Abstract/Link to Full Text]

Sardo P, Ferraro G
Modulatory effects of nitric oxide-active drugs on the anticonvulsant activity of lamotrigine in an experimental model of partial complex epilepsy in the rat.
BMC Neurosci. 2007;847.
BACKGROUND: The effects induced by administering the anticonvulsant lamotrigine, the preferential inhibitor of neuronal nitric oxide synthase 7-nitroindazole and the precursor of NO synthesis L-arginine, alone or in combination, on an experimental model of partial complex seizures (maximal dentate gyrus activation) were studied in urethane anaesthetized rats. The epileptic activity of the dentate gyrus was obtained through the repetitive stimulation of the angular bundle and maximal dentate gyrus activation latency, duration and post-stimulus afterdischarge duration were evaluated. RESULTS: Either Lamotrigine (10 mg kg-1) or 7-nitroindazole (75 mg kg-1) i.p. administration had an anticonvulsant effect, significantly reducing the number of animals responding to angular bundle stimulation. On the contrary, i.p. injection of L-arginine (1 g kg-1) induced an aggravation of the epileptiform phenomena, demonstrated by the significant augmentation of the duration of both maximal dentate activation and afterdischarge. Furthermore, the injection of lamotrigine and 7-nitroindazole in combination significantly increased the anticonvulsant effects induced by the same drugs separately, either reducing the number of responding animals or decreasing both maximal dentate gyrus activation and afterdischarge durations. On the contrary, the combined treatment with L-arginine and lamotrigine did not modify the maximal dentate gyrus activation parameters suggesting an adversative effect of L-arginine-increased nitric oxide levels on the lamotrigine-induced anticonvulsant action. CONCLUSION: The present results indicate that the nitrergic neurotransmission exerts a significant modulatory role in the control of the development of paroxystic phenomena in the maximal dentate gyrus activation model of epilepsy. Finally, our data suggest a functional relationship between the nitric oxide system and the anticonvulsant effect of lamotrigine which could be enhanced by reducing nitric oxide levels and, conversely, dampened by an increased nitrergic activity. [Abstract/Link to Full Text]

Camilleri AA, Willmann R, Sadasivam G, Lin S, R�egg MA, Gesemann M, Fuhrer C
Tyrosine phosphatases such as SHP-2 act in a balance with Src-family kinases in stabilization of postsynaptic clusters of acetylcholine receptors.
BMC Neurosci. 2007;846.
BACKGROUND: Development of neural networks requires that synapses are formed, eliminated and stabilized. At the neuromuscular junction (NMJ), agrin/MuSK signaling, by triggering downstream pathways, causes clustering and phosphorylation of postsynaptic acetylcholine receptors (AChRs). Postnatally, AChR aggregates are stabilized by molecular pathways that are poorly characterized. Gain or loss of function of Src-family kinases (SFKs) disassembles AChR clusters at adult NMJs in vivo, whereas AChR aggregates disperse rapidly upon withdrawal of agrin from cultured src-/-;fyn-/- myotubes. This suggests that a balance between protein tyrosine phosphatases (PTPs) and protein tyrosine kinases (PTKs) such as those of the Src-family may be essential in stabilizing clusters of AChRs. RESULTS: We have analyzed the role of PTPs in maintenance of AChR aggregates, by adding and then withdrawing agrin from cultured myotubes in the presence of PTP or PTK inhibitors and quantitating remaining AChR clusters. In wild-type myotubes, blocking PTPs with pervanadate caused enhanced disassembly of AChR clusters after agrin withdrawal. When added at the time of agrin withdrawal, SFK inhibitors destabilized AChR aggregates but concomitant addition of pervanadate rescued cluster stability. Likewise in src-/-;fyn-/- myotubes, in which agrin-induced AChR clusters form normally but rapidly disintegrate after agrin withdrawal, pervanadate addition stabilized AChR clusters. The PTP SHP-2, known to be enriched at the NMJ, associated and colocalized with MuSK, and agrin increased this interaction. Specific SHP-2 knockdown by RNA interference reduced the stability of AChR clusters in wild-type myotubes. Similarly, knockdown of SHP-2 in adult mouse soleus muscle by electroporation of RNA interference constructs caused disassembly of pretzel-shaped AChR-rich areas in vivo. Finally, we found that src-/-;fyn-/- myotubes contained elevated levels of SHP-2 protein. CONCLUSION: Our data are the first to show that the fine balance between PTPs and SFKs is a key aspect in stabilization of postsynaptic AChR clusters. One phosphatase that acts in this equilibrium is SHP-2. Thus, PTPs such as SHP-2 stabilize AChR clusters under normal circumstances, but when these PTPs are not balanced by SFKs, they render clusters unstable. [Abstract/Link to Full Text]

Langguth B, Kleinjung T, Marienhagen J, Binder H, Sand PG, Hajak G, Eichhammer P
Transcranial magnetic stimulation for the treatment of tinnitus: effects on cortical excitability.
BMC Neurosci. 2007;845.
BACKGROUND: Low frequency repetitive transcranial magnetic stimulation (rTMS) has been proposed as an innovative treatment for chronic tinnitus. The aim of the present study was to elucidate the underlying mechanism and to evaluate the relationship between clinical outcome and changes in cortical excitability. We investigated ten patients with chronic tinnitus who participated in a sham-controlled crossover treatment trial. Magnetic-resonance-imaging and positron-emission-tomography guided 1 Hz rTMS were performed over the auditory cortex on 5 consecutive days. Active and sham treatments were separated by one week. Parameters of cortical excitability (motor thresholds, intracortical inhibition, intracortical facilitation, cortical silent period) were measured serially before and after rTMS treatment by using single- and paired-pulse transcranial magnetic stimulation. Clinical improvement was assessed with a standardized tinnitus-questionnaire. RESULTS: We noted a significant interaction between treatment response and changes in motor cortex excitability during active rTMS. Specifically, clinical improvement was associated with an increase in intracortical inhibition, intracortical facilitation and a prolongation of the cortical silent period. These results indicate that intraindividual changes in cortical excitability may serve as a correlate of response to rTMS treatment. CONCLUSION: The observed alterations of cortical excitability suggest that low frequency rTMS may evoke long-term-depression like effects resulting in an improvement of subcortical inhibitory function. [Abstract/Link to Full Text]

Vogelezang M, Forster UB, Han J, Ginsberg MH, ffrench-Constant C
Neurite outgrowth on a fibronectin isoform expressed during peripheral nerve regeneration is mediated by the interaction of paxillin with alpha4beta1 integrins.
BMC Neurosci. 2007;844.
BACKGROUND: The regeneration of peripheral nerve is associated with a change in the alternative splicing of the fibronectin primary gene transcript to re-express embryonic isoforms containing a binding site for alpha4beta1 integrins that promote neurite outgrowth. Here we use PC12 cells to examine the role of the interaction between paxillin and the alpha4 integrin cytoplasmic domain in neurite outgrowth. RESULTS: Expression of alpha4 with mutations in the paxillin-binding domain reduced neurite outgrowth on recombinant embryonic fibronectin fragments relative to wild type alpha4. Over-expression of paxillin promoted neurite outgrowth while a mutant isoform lacking the LD4 domain implicated in the regulation of ARF and Rac GTPases was less effective. Optimal alpha4-mediated migration in leucocytes requires spatial regulation of alpha4 phosphorylation at Ser988, a post-translational modification that blocks paxillin binding to the integrin cytoplasmic domain. In keeping with this alpha4(S988D), which mimics phosphorylated alpha4, did not promote neurite outgrowth. However, alpha4 was not phosphorylated in the PC12 cells, and a non-phosphorylatable alpha4(S988A) mutant promoted neurite outgrowth indistinguishably from the wild type integrin. CONCLUSION: We establish the importance of the alpha4 integrin-paxillin interaction in a model of axonal regeneration and highlight differing dependence on phosphorylation of alpha4 for extension of neuronal growth cones and migration of non-neural cells. [Abstract/Link to Full Text]

Magnusson KR, Scruggs B, Zhao X, Hammersmark R
Age-related declines in a two-day reference memory task are associated with changes in NMDA receptor subunits in mice.
BMC Neurosci. 2007;843.
BACKGROUND: C57BL/6 mice show a relationship during aging between NMDA receptor expression and spatial reference memory performance in a 12-day task. The present study was designed to determine if age-related deficits could be detected with a shorter testing protocol and whether these deficits showed a relationship with NMDA receptors. Mice were trained in a reference memory task for two days in a Morris water maze. Cued testing was performed either after or prior to reference memory testing. Crude synaptosomes were prepared from prefrontal/frontal cortex and hippocampus of the mice that underwent reference memory testing first. NMDA receptor subunit and syntaxin proteins were analyzed with Western blotting. RESULTS: Young mice showed significant improvement in probe and place learning when reference memory testing was done prior to cued testing. A significant decrease in performance was seen between 3 and 26 months of age with the two-day reference task, regardless of whether cued testing was performed before or after reference memory testing. There was a significant decline in the protein expression of the epsilon2 and zeta1 subunits of the NMDA receptor and syntaxin in prefrontal/frontal cortex. The subunit changes showed a significant correlation with both place and probe trial performance. CONCLUSION: The presence of an age-related decline in performance of the reference memory task regardless of when the cued trials were performed suggests that the deficits were due to factors that were unique to the spatial reference memory task. These results also suggest that declines in specific NMDA receptor subunits in the synaptic pool of prefrontal/frontal brain regions contributed to these age-related problems with performing a spatial reference memory task. [Abstract/Link to Full Text]

Tilley MR, Cagniard B, Zhuang X, Han DD, Tiao N, Gu HH
Cocaine reward and locomotion stimulation in mice with reduced dopamine transporter expression.
BMC Neurosci. 2007;842.
BACKGROUND: The dopamine transporter (DAT) plays a critical role in regulating dopamine neurotransmission. Variations in DAT or changes in basal dopaminergic tone have been shown to alter behavior and drug responses. DAT is one of the three known high affinity targets for cocaine, a powerful psychostimulant that produces reward and stimulates locomotor activity in humans and animals. We have shown that cocaine no longer produces reward in knock-in mice with a cocaine insensitive mutant DAT (DAT-CI), suggesting that cocaine inhibition of DAT is critical for its rewarding effect. However, in DAT-CI mice, the mutant DAT has significantly reduced uptake activity resulting in elevated basal dopaminergic tone, which might cause adaptive changes that alter responses to cocaine. Therefore, the objective of this study is to determine how elevated dopaminergic tone affects how mice respond to cocaine. RESULTS: We examined the cocaine induced behavior of DAT knockdown mice that have DAT expression reduced by 90% when compared to the wild type mice. Despite a dramatic reduction of DAT expression and marked elevation in basal dopamine tone, cocaine produced reward, as measured by conditioned place preference, and stimulated locomotor activity in these mice. CONCLUSION: A reduction in DAT expression and elevation of dopaminergic tone do not lead to adaptive changes that abolish the rewarding and stimulating effects of cocaine. Therefore, the lack of reward to cocaine observed in DAT-CI mice is unlikely to have resulted from the reduced DAT activity but instead is likely due to the inability of cocaine to block the mutated DAT and increase extracellular dopamine. This study supports the conclusion that the blockade of DAT is required for cocaine reward and locomotor stimulation. [Abstract/Link to Full Text]

Tom� AR, Castro E, Santos RM, Ros�rio LM
Selective stimulation of catecholamine release from bovine adrenal chromaffin cells by an ionotropic purinergic receptor sensitive to 2-methylthio ATP.
BMC Neurosci. 2007;841.
BACKGROUND: 2-Methylthioadenosine 5'-triphosphate (2-MeSATP), formerly regarded as a specific P2Y (metabotropic) purinergic receptor agonist, stimulates Ca2+ influx and evokes catecholamine release from adrenal chromaffin cells. These cells express P2Y and P2X (ionotropic) purinoceptors, with the latter providing an important Ca2+ influx pathway. Using single cell calcium imaging techniques, we have determined whether 2-MeSATP might be a specific P2X receptor agonist in bovine chromaffin cells and assessed the relative role of P2X and P2Y receptors on catecholamine secretion from these cells. RESULTS: ATP raised the [Ca2+]i in ~50% of the cells. Removing extracellular Ca2+ suppressed the [Ca2+]i-raising ability of 2-MeSATP, observed in ~40% of the ATP-sensitive cells. This indicates that 2-MeSATP behaves as a specific ionotropic purinoceptor agonist in bovine chromaffin cells. The 2-MeSATP-induced [Ca2+]i-rises were suppressed by PPADS. UTP raised the [Ca2+]i in ~40% of the ATP-sensitive cells, indicating that these expressed Ca2+-mobilizing P2Y receptors. UTP-sensitive receptors may not be the only P2Y receptors present, as suggested by the observation that ~20% of the ATP-sensitive pool did not respond to either 2-MeSATP or UTP. The average sizes of the ATP- and 2-MeSATP-evoked [Ca2+]i responses were identical in UTP-insensitive cells. 2-MeSATP stimulated Ca2+ influx and evoked catecholamine release, whereas UTP elicited Ca2+ release from intracellular stores but did not evoke secretion. 2-MeSATP-induced secretion was strongly inhibited by Cd2+ and suppressed by extracellular Ca2+ or Na+ removal. TTX inhibited 2-MeSATP-evoked secretion by ~20%. CONCLUSION: 2-MeSATP is a specific P2X purinoceptor agonist and a potent secretagogue in bovine chromaffin cells. Activation of 2-MeSATP-sensitive receptors stimulates Ca2+ influx mainly via voltage-sensitive Ca2+ channels. For the most part, these are activated by the depolarization brought about by Na+ influx across P2X receptor pores. [Abstract/Link to Full Text]

Stockx EM, Anderson CR, Murphy SM, Cooke IR, Berger PJ
The development of descending projections from the brainstem to the spinal cord in the fetal sheep.
BMC Neurosci. 2007;840.
BACKGROUND: Although the fetal sheep is a favoured model for studying the ontogeny of physiological control systems, there are no descriptions of the timing of arrival of the projections of supraspinal origin that regulate somatic and visceral function. In the early development of birds and mammals, spontaneous motor activity is generated within spinal circuits, but as development proceeds, a distinct change occurs in spontaneous motor patterns that is dependent on the presence of intact, descending inputs to the spinal cord. In the fetal sheep, this change occurs at approximately 65 days gestation (G65), so we therefore hypothesised that spinally-projecting axons from the neurons responsible for transforming fetal behaviour must arrive at the spinal cord level shortly before G65. Accordingly we aimed to identify the brainstem neurons that send projections to the spinal cord in the mature sheep fetus at G140 (term = G147) with retrograde tracing, and thus to establish whether any projections from the brainstem were absent from the spinal cord at G55, an age prior to the marked change in fetal motor activity has occurred. RESULTS: At G140, CTB labelled cells were found within and around nuclei in the reticular formation of the medulla and pons, within the vestibular nucleus, raphe complex, red nucleus, and the nucleus of the solitary tract. This pattern of labelling is similar to that previously reported in other species. The distribution of CTB labelled neurons in the G55 fetus was similar to that of the G140 fetus. CONCLUSION: The brainstem nuclei that contain neurons which project axons to the spinal cord in the fetal sheep are the same as in other mammalian species. All projections present in the mature fetus at G140 have already arrived at the spinal cord by approximately one third of the way through gestation. The demonstration that the neurons responsible for transforming fetal behaviour in early ontogeny have already reached the spinal cord by G55, an age well before the change in motor behaviour occurs, suggests that the projections do not become fully functional until well after their arrival at the spinal cord. [Abstract/Link to Full Text]

Tom� AR, Castro E, Santos RM, Ros�rio LM
Functional distribution of Ca2+-coupled P2 purinergic receptors among adrenergic and noradrenergic bovine adrenal chromaffin cells.
BMC Neurosci. 2007;839.
BACKGROUND: Adrenal chromaffin cells mediate acute responses to stress through the release of epinephrine. Chromaffin cell function is regulated by several receptors, present both in adrenergic (AD) and noradrenergic (NA) cells. Extracellular ATP exerts excitatory and inhibitory actions on chromaffin cells via ionotropic (P2X) and metabotropic (P2Y) receptors. We have taken advantage of the actions of the purinergic agonists ATP and UTP on cytosolic free Ca2+ concentration ([Ca2+]i) to determine whether P2X and P2Y receptors might be asymmetrically distributed among AD and NA chromaffin cells. RESULTS: The [Ca2+]i and the [Na+]i were recorded from immunolabeled bovine chromaffin cells by single-cell fluorescence imaging. Among the ATP-sensitive cells ~40% did not yield [Ca2+]i responses to ATP in the absence of extracellular Ca2+ (Ca2+o), indicating that they expressed P2X receptors and did not express Ca2+- mobilizing P2Y receptors; the remainder expressed Ca2+-mobilizing P2Y receptors. Relative to AD-cells approximately twice as many NA-cells expressed P2X receptors while not expressing Ca2+- mobilizing P2Y receptors, as indicated by the proportion of cells lacking [Ca2+]i responses and exhibiting [Na+]i responses to ATP in the absence and presence of Ca2+o, respectively. The density of P2X receptors in NA-cells appeared to be 30-50% larger, as suggested by comparing the average size of the [Na+]i and [Ca2+]i responses to ATP. Conversely, approximately twice as many AD-cells expressed Ca2+-mobilizing P2Y receptors, and they appeared to exhibit a higher (~20%) receptor density. UTP raised the [Ca2+]i in a fraction of the cells and did not raise the [Na+]i in any of the cells tested, confirming its specificity as a P2Y agonist. The cell density of UTP-sensitive P2Y receptors did not appear to vary among AD- and NA-cells. CONCLUSION: Although neither of the major purinoceptor types can be ascribed to a particular cell phenotype, P2X and Ca2+-mobilizing P2Y receptors are preferentially located to noradrenergic and adrenergic chromaffin cells, respectively. ATP might, in addition to an UTP-sensitive P2Y receptor, activate an UTP-insensitive P2Y receptor subtype. A model for a short-loop feedback interaction is presented whereby locally released ATP acts upon P2Y receptors in adrenergic cells, inhibiting Ca2+ influx and contributing to terminate evoked epinephrine secretion. [Abstract/Link to Full Text]

Teichert T, Wachtler T, Michler F, Gail A, Eckhorn R
Scale-invariance of receptive field properties in primary visual cortex.
BMC Neurosci. 2007;838.
BACKGROUND: Our visual system enables us to recognize visual objects across a wide range of spatial scales. The neural mechanisms underlying these abilities are still poorly understood. Size- or scale-independent representation of visual objects might be supported by processing in primary visual cortex (V1). Neurons in V1 are selective for spatial frequency and thus represent visual information in specific spatial wavebands. We tested whether different receptive field properties of neurons in V1 scale with preferred spatial wavelength. Specifically, we investigated the size of the area that enhances responses, i.e., the grating summation field, the size of the inhibitory surround, and the distance dependence of signal coupling, i.e., the linking field. RESULTS: We found that the sizes of both grating summation field and inhibitory surround increase with preferred spatial wavelength. For the summation field this increase, however, is not strictly linear. No evidence was found that size of the linking field depends on preferred spatial wavelength. CONCLUSION: Our data show that some receptive field properties are related to preferred spatial wavelength. This speaks in favor of the hypothesis that processing in V1 supports scale-invariant aspects of visual performance. However, not all properties of receptive fields in V1 scale with preferred spatial wavelength. Spatial-wavelength independence of the linking field implies a constant spatial range of signal coupling between neurons with different preferred spatial wavelengths. This might be important for encoding extended broad-band visual features such as edges. [Abstract/Link to Full Text]

Tsuneyoshi Y, Tomonaga S, Asechi M, Morishita K, Denbow DM, Furuse M
Central administration of dipeptides, beta-alanyl-BCAAs, induces hyperactivity in chicks.
BMC Neurosci. 2007;837.
BACKGROUND: Carnosine (beta-alanyl-L-histidine) is a putative neurotransmitter and has a possible role in neuron-glia cell interactions. Previously, we reported that carnosine induced hyperactivity in chicks when intracerebroventricularly (i.c.v.) administered. In the present study, we focused on other beta-alanyl dipeptides to determine if they have novel functions. RESULTS: In Experiment 1, i.c.v. injection of beta-alanyl-L-leucine, but not beta-alanyl-glycine, induced hyperactivity behavior as observed with carnosine. Both carnosine and beta-alanyl-L-leucine stimulated corticosterone release. Thus, dipeptides of beta-alanyl-branched chain amino acids were compared in Experiment 2. The i.c.v. injection of beta-alanyl-L-isoleucine caused a similar response as beta-alanyl-L-leucine, but beta-alanyl-L-valine was somewhat less effective than the other two dipeptides. beta-Alanyl-L-leucine strongly stimulated, and the other two dipeptides tended to stimulate, corticosterone release. CONCLUSION: These results suggest that central beta-alanyl-branched chain amino acid stimulates activity in chicks through the hypothalamus-pituitary-adrenal axis. We named beta-alanyl-L-leucine, beta-alanyl-L-isoleucine and beta-alanyl-L-valine as Excitin-1, Excitin-2 and Excitin-3, respectively. [Abstract/Link to Full Text]

Donato R, Miljan EA, Hines SJ, Aouabdi S, Pollock K, Patel S, Edwards FA, Sinden JD
Differential development of neuronal physiological responsiveness in two human neural stem cell lines.
BMC Neurosci. 2007;836.
BACKGROUND: Neural stem cells (NSCs) are powerful research tools for the design and discovery of new approaches to neurodegenerative disease. Overexpression of the myc family transcription factors in human primary cells from developing cortex and mesencephalon has produced two stable multipotential NSC lines (ReNcell VM and CX) that can be continuously expanded in monolayer culture. RESULTS: In the undifferentiated state, both ReNcell VM and CX are nestin positive and have resting membrane potentials of around -60 mV but do not display any voltage-activated conductances. As initially hypothesized, using standard methods (stdD) for differentiation, both cell lines can form neurons, astrocytes and oligodendrocytes according to immunohistological characteristics. However it became clear that this was not true for electrophysiological features which designate neurons, such as the firing of action potentials. We have thus developed a new differentiation protocol, designated 'pre-aggregation differentiation' (preD) which appears to favor development of electrophysiologically functional neurons and to lead to an increase in dopaminergic neurons in the ReNcell VM line. In contrast, the protocol used had little effect on the differentiation of ReNcell CX in which dopaminergic differentiation was not observed. Moreover, after a week of differentiation with the preD protocol, 100% of ReNcell VM featured TTX-sensitive Na+-channels and fired action potentials, compared to 25% after stdD. Currents via other voltage-gated channels did not appear to depend on the differentiation protocol. ReNcell CX did not display the same electrophysiological properties as the VM line, generating voltage-dependant K+ currents but no Na+ currents or action potentials under either stdD or preD differentiation. CONCLUSION: These data demonstrate that overexpression of myc in NSCs can be used to generate electrophysiologically active neurons in culture. Development of a functional neuronal phenotype may be dependent on parameters of isolation and differentiation of the cell lines, indicating that not all human NSCs are functionally equivalent. [Abstract/Link to Full Text]

Laughton JD, Bittar P, Charnay Y, Pellerin L, Kovari E, Magistretti PJ, Bouras C
Metabolic compartmentalization in the human cortex and hippocampus: evidence for a cell- and region-specific localization of lactate dehydrogenase 5 and pyruvate dehydrogenase.
BMC Neurosci. 2007;835.
BACKGROUND: For a long time now, glucose has been thought to be the main, if not the sole substrate for brain energy metabolism. Recent data nevertheless suggest that other molecules, such as monocarboxylates (lactate and pyruvate mainly) could be suitable substrates. Although monocarboxylates poorly cross the blood brain barrier (BBB), such substrates could replace glucose if produced locally.The two key enzymatiques systems required for the production of these monocarboxylates are lactate dehydrogenase (LDH; EC1.1.1.27) that catalyses the interconversion of lactate and pyruvate and the pyruvate dehydrogenase complex that irreversibly funnels pyruvate towards the mitochondrial TCA and oxydative phosphorylation. RESULTS: In this article, we show, with monoclonal antibodies applied to post-mortem human brain tissues, that the typically glycolytic isoenzyme of lactate dehydrogenase (LDH-5; also called LDHA or LDHM) is selectively present in astrocytes, and not in neurons, whereas pyruvate dehydrogenase (PDH) is mainly detected in neurons and barely in astrocytes. At the regional level, the distribution of the LDH-5 immunoreactive astrocytes is laminar and corresponds to regions of maximal 2-deoxyglucose uptake in the occipital cortex and hippocampus. In hippocampus, we observed that the distribution of the oxidative enzyme PDH was enriched in the neurons of the stratum pyramidale and stratum granulosum of CA1 through CA4, whereas the glycolytic enzyme LDH-5 was enriched in astrocytes of the stratum moleculare, the alveus and the white matter, revealing not only cellular, but also regional, selective distributions. The fact that LDH-5 immunoreactivity was high in astrocytes and occurred in regions where the highest uptake of 2-deoxyglucose was observed suggests that glucose uptake followed by lactate production may principally occur in these regions. CONCLUSION: These observations reveal a metabolic segregation, not only at the cellular but also at the regional level, that support the notion of metabolic compartmentalization between astrocytes and neurons, whereby lactate produced by astrocytes could be oxidized by neurons. [Abstract/Link to Full Text]

Lindberg J, Saetre P, Nishino S, Mignot E, Jazin E
Reduced expression of TAC1, PENK and SOCS2 in Hcrtr-2 mutated narcoleptic dog brain.
BMC Neurosci. 2007;834.
BACKGROUND: Narcolepsy causes dramatic behavioral alterations in both humans and dogs, with excessive sleepiness and cataplexy triggered by emotional stimuli. Deficiencies in the hypocretin system are well established as the origin of the condition; both from studies in humans who lack the hypocretin ligand (HCRT) and in dogs with a mutation in hypocretin receptor 2 (HCRTR2). However, little is known about molecular alterations downstream of the hypocretin signals. RESULTS: By using microarray technology we have screened the expression of 29760 genes in the brains of Doberman dogs with a heritable form of narcolepsy (homozygous for the canarc-1 [HCRTR-2-2] mutation), and their unaffected heterozygous siblings. We identified two neuropeptide precursor molecules, Tachykinin precursor 1 (TAC1) and Proenkephalin (PENK), that together with Suppressor of cytokine signaling 2 (SOCS2), showed reduced expression in narcoleptic brains. The difference was particularly pronounced in the amygdala, where mRNA levels of PENK were 6.2 fold lower in narcoleptic dogs than in heterozygous siblings, and TAC1 and SOCS2 showed 4.4 fold and 2.8 fold decrease in expression, respectively. The results obtained from microarray experiments were confirmed by real-time RT-PCR. Interestingly, it was previously shown that a single dose of amphetamine-like stimulants able to increase wakefulness in the dogs, also produce an increase in the expression of both TAC1 and PENK in mice. CONCLUSION: These results suggest that TAC1, PENK and SOCS2 might be intimately connected with the excessive daytime sleepiness not only in dogs, but also in other species, possibly including humans. [Abstract/Link to Full Text]

Okamoto H, Kakigi R, Gunji A, Pantev C
Asymmetric lateral inhibitory neural activity in the auditory system: a magnetoencephalographic study.
BMC Neurosci. 2007;833.
BACKGROUND: Decrements of auditory evoked responses elicited by repeatedly presented sounds with similar frequencies have been well investigated by means of electroencephalography and magnetoencephalography (MEG). However the possible inhibitory interactions between different neuronal populations remains poorly understood. In the present study, we investigated the effect of proceeding notch-filtered noises (NFNs) with different frequency spectra on a following test tone using MEG. RESULTS: Three-second exposure to the NFNs resulted in significantly different N1m responses to a 1000 Hz test tone presented 500 ms after the offset of the NFNs. The NFN with a lower spectral edge closest to the test tone mostly decreased the N1m amplitude. CONCLUSION: The decrement of the N1m component after exposure to the NFNs could be explained partly in terms of lateral inhibition. The results demonstrated that the amplitude of the N1m was more effectively influenced by inhibitory lateral connections originating from neurons corresponding to lower rather than higher frequencies. We interpret this effect of asymmetric lateral inhibition in the auditory system as an important contribution to reduce the asymmetric neural activity profiles originating from the cochlea. [Abstract/Link to Full Text]

Sandstrom MI, Rebec GV
Extracellular ascorbate modulates glutamate dynamics: role of behavioral activation.
BMC Neurosci. 2007;832.
BACKGROUND: A physiological increase in extracellular ascorbate (AA), an antioxidant vitamin found throughout the striatum, elevates extracellular glutamate (GLU). To determine the role of behavioral arousal in this interaction, microdialysis was used to measure striatal GLU efflux in rats tested in either a lights-off or lights-on condition while reverse dialysis either maintained the concentration of AA at 250 microM or increased it to 1000 microM to approximate endogenous changes. RESULTS: When lights were off, both locomotion and GLU increased regardless of AA dose. In contrast, animals in the lights-on condition were behaviorally inactive, and infusion of 1000, but not 250, microM AA significantly increased extracellular GLU. Interestingly, when ambient light returned to the lights-off group, 1000 microM prolonged the GLU increase relative to the 250 microM group. CONCLUSION: Our results not only support evidence that elevated striatal AA increases extracellular GLU but also indicate that this effect depends on behavioral state and the corresponding level of endogenous GLU release. [Abstract/Link to Full Text]

Li J, Bentsman G, Potash MJ, Volsky DJ
Human immunodeficiency virus type 1 efficiently binds to human fetal astrocytes and induces neuroinflammatory responses independent of infection.
BMC Neurosci. 2007;831.
BACKGROUND: HIV-1 infects human astrocytes in vitro and in vivo but the frequency of infected cells is low and its biological significance is unknown. In studies in vitro, recombinant gp120 alone can induce profound effects on astrocyte biology, suggesting that HIV-1 interaction with astrocytes and its functional consequences extend beyond the limited levels of infection in these cells. Here we determined the relative efficiencies of HIV-1 binding and infection in human fetal astrocytes (HFA), mainly at the single cell level, using HIV-1 tagged with green fluorescence protein (GFP)-Vpr fusion proteins, termed HIV-GFP, to detect virus binding and HIV-1 expressing Rev and NefGFP fusion proteins to detect productive infection. RESULTS: Essentially all HFA in a population bound HIV-GFP specifically and independently of CCR5 and CXCR4. The dynamics of this binding at 37 degrees C resembled binding of an HIV fusion mutant to CD4-positive cells, indicating that most of HIV-GFP arrested infection of HFA at the stage of virus-cell fusion. Despite extensive binding, only about 1% of HFA were detectably infected by HIV-RevGFP or HIV-NefGFP, but this proportion increased to the majority of HFA when the viruses were pseudotyped with vesicular stomatitis virus envelope glycoprotein G, confirming that HFA impose a restriction upon HIV-1 entry. Exposure of HFA to HIV-1 through its native proteins rapidly induced synthesis of interleukin-6 and interleukin-8 with increased mRNA detected within 3 h and increased protein detected within 18 h of exposure. CONCLUSION: Our results indicate that HIV-1 binding to human astrocytes, although extensive, is not generally followed by virus entry and replication. Astrocytes respond to HIV-1 binding by rapidly increased cytokine production suggesting a role of this virus-brain cell interaction in HIV-1 neuropathogenesis. [Abstract/Link to Full Text]

Caudle RM, Mannes AJ, Keller J, Perez FM, Suckow SK, Neubert JK
Sensitization of spinal cord nociceptive neurons with a conjugate of substance P and cholera toxin.
BMC Neurosci. 2007;830.
BACKGROUND: Several investigators have coupled toxins to neuropeptides for the purpose of lesioning specific neurons in the central nervous system. By producing deficits in function these toxin conjugates have yielded valuable information about the role of these cells. In an effort to specifically stimulate cells rather than kill them we have conjugated the neuropeptide substance P to the catalytic subunit of cholera toxin (SP-CTA). This conjugate should be taken up selectively by neurokinin receptor expressing neurons resulting in enhanced adenylate cyclase activity and neuronal firing. RESULTS: The conjugate SP-CTA stimulates adenylate cyclase in cultured cells that are transfected with either the NK1 or NK2 receptor, but not the NK3 receptor. We further demonstrate that intrathecal injection of SP-CTA in rats induces the phosphorylation of the transcription factor cyclic AMP response element binding protein (CREB) and also enhances the expression of the immediate early gene c-Fos. Behaviorally, low doses of SP-CTA (1 microg) injected intrathecally produce thermal hyperalgesia. At higher doses (10 microg) peripheral sensitivity is suppressed suggesting that descending inhibitory pathways may be activated by the SP-CTA induced sensitization of spinal cord neurons. CONCLUSION: The finding that stimulation of adenylate cyclase in neurokinin receptor expressing neurons in the spinal cord produces thermal hyperalgesia is consistent with the known actions of these neurons. These data demonstrate that cholera toxin can be targeted to specific cell types by coupling the catalytic subunit to a peptide agonist for a g-protein coupled receptor. Furthermore, these results demonstrate that SP-CTA can be used as a tool to study sensitization of central neurons in vivo in the absence of an injury. [Abstract/Link to Full Text]

Bateman DA, McLaurin J, Chakrabartty A
Requirement of aggregation propensity of Alzheimer amyloid peptides for neuronal cell surface binding.
BMC Neurosci. 2007;829.
BACKGROUND: Aggregation of the amyloid peptides, Abeta40 and Abeta42, is known to be involved in the pathology of Alzheimer's disease (AD). Here we investigate the relationship between peptide aggregation and cell surface binding of three forms of Abeta (Abeta40, Abeta42, and an Abeta mutant). RESULTS: Using confocal microscopy and flow cytometry with fluorescently labelled Abeta, we demonstrate a correlation between the aggregation propensity of the Alzheimer amyloid peptides and their neuronal cell surface association. We find that the highly aggregation prone Abeta42 associates with the surface of neuronal cells within one hour, while the less aggregation prone Abeta40 associates over 24 hours. We show that a double mutation in Abeta42 that reduces its aggregation propensity also reduces its association with the cell surface. Furthermore, we find that a cell line that is resistant to Abeta cytotoxicity, the non-neuronal human lymphoma cell line U937, does not bind either Abeta40 or Abeta42. CONCLUSION: Taken together, our findings reveal that amyloid peptide aggregation propensity is an essential determinant of neuronal cell surface association. We anticipate that our approach, involving Abeta imaging in live cells, will be highly useful for evaluating the efficacy of therapeutic drugs that prevent toxic Abeta association with neuronal cells. [Abstract/Link to Full Text]

Tagnaouti N, Loebrich S, Heisler F, Pechmann Y, Fehr S, De Arcangelis A, Georges-Labouesse E, Adams JC, Kneussel M
Neuronal expression of muskelin in the rodent central nervous system.
BMC Neurosci. 2007;828.
BACKGROUND: The kelch repeat protein muskelin mediates cytoskeletal responses to the extracellular matrix protein thrombospondin 1, (TSP1), that is known to promote synaptogenesis in the central nervous system (CNS). Muskelin displays intracellular localization and affects cytoskeletal organization in adherent cells. Muskelin is expressed in adult brain and has been reported to bind the Cdk5 activator p39, which also facilitates the formation of functional synapses. Since little is known about muskelin in neuronal tissues, we here analysed the tissue distribution of muskelin in rodent brain and analysed its subcellular localization using cultured neurons from multiple life stages. RESULTS: Our data show that muskelin transcripts and polypeptides are expressed throughout the central nervous system with significantly high levels in hippocampus and cerebellum, a finding that resembles the tissue distribution of p39. At the subcellular level, muskelin is found in the soma, in neurite projections and the nucleus with a punctate distribution in both axons and dendrites. Immunostaining and synaptosome preparations identify partial localization of muskelin at synaptic sites. Differential centrifugation further reveals muskelin in membrane-enriched, rather than cytosolic fractions. CONCLUSION: Our results suggest that muskelin represents a multifunctional protein associated with membranes and/or large protein complexes in most neurons of the central nervous system. These data are in conclusion with distinct roles of muskelin's functional interaction partners. [Abstract/Link to Full Text]

Fr�nd I, Busch NA, Schadow J, K�rner U, Herrmann CS
From perception to action: phase-locked gamma oscillations correlate with reaction times in a speeded response task.
BMC Neurosci. 2007;827.
BACKGROUND: Phase-locked gamma oscillations have so far mainly been described in relation to perceptual processes such as sensation, attention or memory matching. Due to its very short latency ( approximately 90 ms) such oscillations are a plausible candidate for very rapid integration of sensory and motor processes. RESULTS: We measured EEG in 13 healthy participants in a speeded reaction task. Participants had to press a button as fast as possible whenever a visual stimulus was presented. The stimulus was always identical and did not have to be discriminated from other possible stimuli. In trials in which the participants showed a fast response, a slow negative potential over central electrodes starting approximately 800 ms before the response and highly phase-locked gamma oscillations over central and posterior electrodes between 90 and 140 ms after the stimulus were observed. In trials in which the participants showed a slow response, no slow negative potential was observed and phase-locked gamma oscillations were significantly reduced. Furthermore, for slow response trials the phase-locked gamma oscillations were significantly delayed with respect to fast response trials. CONCLUSION: These results indicate the relevance of phase-locked gamma oscillations for very fast (not necessarily detailed) integration processes. [Abstract/Link to Full Text]

Annual Meeting of the Study Group Neurochemistry. International Conference of the Gesellschaft f�r Biochemie und Molekularbiologie 2006 (GBM 2006): molecular pathways in health and disease of the nervous system. Witten, Germany. September 28-30, 2006. Abstracts.
BMC Neurosci. 2007;8 Suppl 1P1-37. [Abstract/Link to Full Text]

M�nkk�nen KS, Hakum�ki JM, Hirst RA, Miettinen RA, O'Callaghan C, M�nnist� PT, Laitinen JT
Intracerebroventricular antisense knockdown of G alpha i2 results in ciliary stasis and ventricular dilatation in the rat.
BMC Neurosci. 2007;826.
BACKGROUND: In the CNS, the heterotrimeric G protein Galphai2 is a minor Galpha subunit with restricted localization in the ventricular regions including the ependymal cilia. The localization of Galphai2 is conserved in cilia of different tissues, suggesting a particular role in ciliary function. Although studies with Galphai2-knockout mice have provided information on the role of this Galpha subunit in peripheral tissues, its role in the CNS is largely unknown. We used intracerebroventricular (icv) antisense administration to clarify the physiological role of Galphai2 in the ventricular system. RESULTS: High resolution MRI studies revealed that continuous icv-infusion of Galphai2-specific antisense oligonucleotide caused unilateral ventricular dilatation that was restricted to the antisense-receiving ventricle. Microscopic analysis demonstrated ependymal cell damage and loss of ependymal cilia. Attenuation of Galphai2 in ependymal cells was confirmed by immunohistochemistry. Ciliary beat frequency measurements on cultured ependymal cells indicated that antisense administration resulted in ciliary stasis. CONCLUSION: Our results establish that Galphai2 has an essential regulatory role in ciliary function and CSF homeostasis. [Abstract/Link to Full Text]

Sadakata T, Washida M, Furuichi T
Alternative splicing variations in mouse CAPS2: differential expression and functional properties of splicing variants.
BMC Neurosci. 2007;825.
BACKGROUND: Ca2+-dependent activator protein 2 (CAPS2/CADPS2) is a secretory vesicle-associated protein involved in the release of neurotrophin. We recently reported that an aberrant, alternatively spliced CAPS2 mRNA that lacks exon 3 (CAPS2Deltaexon3) is detected in some patients with autism. Splicing variations in mouse CAPS2 and their expression and functions remain unclear. RESULTS: In this study, we defined 31 exons in the mouse CAPS2 gene and identified six alternative splicing variants, CAPS2a-f. CAPS2a is an isoform lacking exons 22 and 25, which encode part of the Munc13-1-homologous domain (MHD). CAPS2b lacks exon 25. CAPS2c lacks exons 11 and 22. CAPS2d, 2e, and 2f have C-terminal deletions from exon 14, exon 12, and exon 5, respectively. On the other hand, a mouse counterpart of CAPS2Deltaexon3 was not detected in the mouse tissues tested. CAPS2b was expressed exclusively in the brain, and the other isoforms were highly expressed in the brain, but also in some non-neural tissues. In the brain, all isoforms showed predominant expression patterns in the cerebellum. In the developing cerebellum, CAPS2b showed an up-regulated expression pattern, whereas the other isoforms exhibited transiently peaked expression patterns. CAPS2 proteins were mostly recovered in soluble fractions, but some were present in membrane fractions, except for CAPS2c and 2f, both of which lack the PH domain, suggesting that the PH domain is important for membrane association. In contrast to CAPS2a and 2b, CAPS2c showed slightly decreased BDNF-releasing activity, which is likely due to the C-terminal truncation of the PH domain in CAPS2c. CONCLUSION: This study indicates that, in mouse, there are six splicing variants of CAPS2 (CAPS2a-f), and that these are subdivided into two groups: a long form containing the C-terminal MHD and a short form lacking the C-terminal MHD. These results demonstrate that the splicing variations correlate with their expression patterns and intracellular distribution, and affect BDNF release; however, whether or not the short forms possess activities other than BDNF release, for example as natural dominant-negative isoforms, remains to be determined. [Abstract/Link to Full Text]

Proverbio AM, Del Zotto M, Zani A
The emergence of semantic categorization in early visual processing: ERP indices of animal vs. artifact recognition.
BMC Neurosci. 2007;824.
BACKGROUND: Neuroimaging and neuropsychological literature show functional dissociations in brain activity during processing of stimuli belonging to different semantic categories (e.g., animals, tools, faces, places), but little information is available about the time course of object perceptual categorization. The aim of the study was to provide information about the timing of processing stimuli from different semantic domains, without using verbal or naming paradigms, in order to observe the emergence of non-linguistic conceptual knowledge in the ventral stream visual pathway. Event related potentials (ERPs) were recorded in 18 healthy right-handed individuals as they performed a perceptual categorization task on 672 pairs of images of animals and man-made objects (i.e., artifacts). RESULTS: Behavioral responses to animal stimuli were ~50 ms faster and more accurate than those to artifacts. At early processing stages (120-180 ms) the right occipital-temporal cortex was more activated in response to animals than to artifacts as indexed by posterior N1 response, while frontal/central N1 (130-160) showed the opposite pattern. In the next processing stage (200-260) the response was stronger to artifacts and usable items at anterior temporal sites. The P300 component was smaller, and the central/parietal N400 component was larger to artifacts than to animals. CONCLUSION: The effect of animal and artifact categorization emerged at ~150 ms over the right occipital-temporal area as a stronger response of the ventral stream to animate, homomorphic, entities with faces and legs. The larger frontal/central N1 and the subsequent temporal activation for inanimate objects might reflect the prevalence of a functional rather than perceptual representation of manipulable tools compared to animals. Late ERP effects might reflect semantic integration and cognitive updating processes. Overall, the data are compatible with a modality-specific semantic memory account, in which sensory and action-related semantic features are represented in modality-specific brain areas. [Abstract/Link to Full Text]

Recent Articles in BMC Neurology

Meinzer M, Flaisch T, Obleser J, Assadollahi R, Djundja D, Barthel G, Rockstroh B
Brain regions essential for improved lexical access in an aged aphasic patient: a case report.
BMC Neurol. 2006;628.
BACKGROUND: The relationship between functional recovery after brain injury and concomitant neuroplastic changes is emphasized in recent research. In the present study we aimed to delineate brain regions essential for language performance in aphasia using functional magnetic resonance imaging and acquisition in a temporal sparse sampling procedure, which allows monitoring of overt verbal responses during scanning. CASE PRESENTATION: An 80-year old patient with chronic aphasia (2 years post-onset) was investigated before and after intensive language training using an overt picture naming task. Differential brain activation in the right inferior frontal gyrus for correct word retrieval and errors was found. Improved language performance following therapy was mirrored by increased fronto-thalamic activation while stability in more general measures of attention/concentration and working memory was assured. Three healthy age-matched control subjects did not show behavioral changes or increased activation when tested repeatedly within the same 2-week time interval. CONCLUSION: The results bear significance in that the changes in brain activation reported can unequivocally be attributed to the short-term training program and a language domain-specific plasticity process. Moreover, it further challenges the claim of a limited recovery potential in chronic aphasia, even at very old age. Delineation of brain regions essential for performance on a single case basis might have major implications for treatment using transcranial magnetic stimulation. [Abstract/Link to Full Text]

Kos D, Nagels G, D'Hooghe MB, Duportail M, Kerckhofs E
A rapid screening tool for fatigue impact in multiple sclerosis.
BMC Neurol. 2006;627.
BACKGROUND: Fatigue is a common complaint in multiple sclerosis (MS) and often interferes with daily functioning. Both clinicians and researchers may need to detect high levels of fatigue impact using a time and effort efficient tool. This study evaluates the psychometric properties of a rapid screening instrument for fatigue impact in multiple sclerosis. METHODS: Three visual analogue scales (VAS) for assessing the impact of fatigue were developed. Sixty two subjects with definite MS (mean age 52 +/- 10.5 years; 29 women) and 24 healthy controls (mean age 52 +/- 14 years; 13 women) completed all VAS scales (range 0-100), the Fatigue Severity Scale (FSS) (range 7-63), the Modified Fatigue Impact Scale (MFIS) (range 0-84) and the Guy's Neurological Disability Scale (GNDS) (range 0-5). All tests were repeated with an interval of maximum three days.To evaluate the reproducibility, intraclass correlations (ICC) were calculated, based on one-way analysis of variance for repeated measurements. Validity was considered by means of correlation coefficients. ROC analysis was used to determine the accuracy of the VAS scales. RESULTS: The ICC of the VAS scales ranged from 0.68 to 0.69. VAS scales showed low to moderate correlation with FSS, MFIS and GNDS (Kendall's tau 0.23-0.45) and were not related with physical or cognitive performance, or with depression. All VAS scales were able to discriminate between subjects with MS and controls. Twenty five subjects with MS had a Fatigue Severity Scale score of 36 or more and were classified into the "fatigue" group. ROC analysis showed that VAS_1 is most useful to classify subjects in the "fatigue" group. A cut-off value of VAS_1 of 59 displayed 76% sensitivity and 72% specificity. When using the MFIS score of 40 or more to classify the groups, VAS_1 remained the strongest tool, with 81% sensitivity and 77% specificity at a cut-off value of 59. CONCLUSION: The VAS for the impact of fatigue on daily life (VAS_1) is a moderately reliable, though valid and useful tool to screen rapidly for fatigue impact in multiple sclerosis. A cut-off value of 59 satisfactorily classifies individuals having severe fatigue with a high impact on daily life. In clinical practice, a more comprehensive assessment of fatigue and the impact on daily life is recommended. [Abstract/Link to Full Text]

Swarztrauber K, Graf E, Cheng E
The quality of care delivered to Parkinson's disease patients in the U.S. Pacific Northwest Veterans Health System.
BMC Neurol. 2006;626.
BACKGROUND: Parkinson's disease (PD) is the second most common chronic neurological disorder of the elderly. Despite the fact that a comprehensive review of general health care in the United States showed that the quality of care delivered to patients usually falls below professional standards, there is limited data on the quality of care for patients with PD. METHODS: Using the administrative database, the Pacific Northwest Veterans Health Administration (VHA) Data Warehouse, a population of PD patients with encounters from 10/1/98-12/31/04 were identified. A random sample of 350 patient charts underwent further review for diagnostic evaluation. All patients whose records revealed a physician diagnosis of definite or possible Idiopathic Parkinson's (IPD) disease (n = 150) were included in a medical chart review to evaluate adherence to five evidence-based quality of care indicators. RESULTS: For those care indicators with good inter-rater reliability, 16.6% of care received by PD patients was adherent for annual depression screening, 23.4% of care was adherent for annual fall screening and, 67.3% of care was adherent for management of urinary incontinence. Patients receiving specialty care were more likely to be adherent with fall screening than those not receiving specialty care OR = 2.3, 95%CI = 1.2-4.2, but less likely to be adherent with management of urinary incontinence, OR = 0.3, 95%CI = 0.1-0.8. Patients receiving care outside the VA system were more likely to be adherent with depression screening OR = 2.4, 95%CI = >1.0-5.5 and fall screening OR = 2.2, 95%CI = 1.1-4.4. CONCLUSION: We found very low rates of adherence for annual screening for depression and falls for PD patients but reasonable adherence rates for management of urinary incontinence. Interestingly, receiving concurrent specialty care did not necessarily result in higher adherence for all care indicators suggesting some coordination and role responsibility confusion. The increased adherence in PD patients receiving care outside the VA system suggests that patients with outside care may demand better care within the VA system. [Abstract/Link to Full Text]

Cuadrado-Corrales N, Jim�nez-Huete A, Albo C, Hortig�ela R, Vega L, Cerrato L, Sierra-Moros M, R�bano A, de Pedro-Cuesta J, Calero M
Impact of the clinical context on the 14-3-3 test for the diagnosis of sporadic CJD.
BMC Neurol. 2006;625.
BACKGROUND: The 14-3-3 test appears to be a valuable aid for the clinical diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) in selected populations. However, its usefulness in routine practice has been challenged. In this study, the influence of the clinical context on the performance of the 14-3-3 test for the diagnosis of sCJD is investigated through the analysis of a large prospective clinical series. METHODS: Six hundred seventy-two Spanish patients with clinically suspected sCJD were analyzed. Clinical classification at sample reception according to the World Health Organization's (WHO) criteria (excluding the 14-3-3 test result) was used to explore the influence of the clinical context on the pre-test probabilities, and positive (PPV) and negative (NPV) predictive values of the 14-3-3 test. RESULTS: Predictive values of the test varied greatly according to the initial clinical classification: PPV of 98.8%, 96.5% and 45.0%, and NPV of 26.1%, 66.6% and 100% for probable sCJDi (n = 115), possible sCJDi (n = 73) and non-sCJDi (n = 484) cases, respectively. According to multivariate and Bayesian analyses, these values represent an improvement of diagnostic certainty compared to clinical data alone. CONCLUSION: In three different contexts of sCJD suspicion, the 14-3-3 assay provides useful information complementary to clinical and electroencephalographic (EEG) data. The test is most useful supporting a clinical impression, whilst it may show deceptive when it is not in agreement with clinical data. [Abstract/Link to Full Text]

Guerreiro RJ, Bras JM, Santana I, Januario C, Santiago B, Morgadinho AS, Ribeiro MH, Hardy J, Singleton A, Oliveira C
Association of HFE common mutations with Parkinson's disease, Alzheimer's disease and mild cognitive impairment in a Portuguese cohort.
BMC Neurol. 2006;624.
BACKGROUND: Pathological brain iron deposition has been implicated as a source of neurotoxic reactive oxygen species in Alzheimer (AD) and Parkinson diseases (PD). Iron metabolism is associated with the gene hemochromatosis (HFE Human genome nomenclature committee ID:4886), and mutations in HFE are a cause of the iron mismetabolism disease, hemochromatosis. Several reports have tested the association of HFE variants with neurodegenerative diseases, such as AD and PD with conflicting results. METHODS: Genotypes were analysed for the two most common variants of HFE in a series of 130 AD, 55 Mild Cognitive Impairment (MCI) and 132 PD patients. Additionally, a series of 115 healthy age-matched controls was also screened. RESULTS: A statistically significant association was found in the PD group when compared to controls, showing that the presence of the C282Y variant allele may confer higher risk for developing the disease. CONCLUSION: Taken together these results suggest that the common variants in HFE may be a risk factor for PD, but not for AD in the Portuguese population. [Abstract/Link to Full Text]

Fruhmann Berger M, Pross RD, Ilg UJ, Karnath HO
Deviation of eyes and head in acute cerebral stroke.
BMC Neurol. 2006;623.
BACKGROUND: It is a well-known phenomenon that some patients with acute left or right hemisphere stroke show a deviation of the eyes (Pr�vost's sign) and head to one side. Here we investigated whether both right- and left-sided brain lesions may cause this deviation. Moreover, we studied the relationship between this phenomenon and spatial neglect. In contrast to previous studies, we determined not only the discrete presence or absence of eye deviation with the naked eye through clinical inspection, but actually measured the extent of horizontal eye-in-head and head-on-trunk deviation. In further contrast, measurements were performed early after stroke onset (1.5 days on average). METHODS: Eye-in-head and head-on-trunk positions were measured at the bedside in 33 patients with acute unilateral left or right cerebral stroke consecutively admitted to our stroke unit. RESULTS: Each single patient with spatial neglect and right hemisphere lesion showed a marked deviation of the eyes and the head to the ipsilesional, right side. The average spontaneous gaze position in this group was 46 degrees right, while it was close to the saggital body midline (0 degrees ) in the groups with acute left- or right-sided stroke but no spatial neglect as well as in healthy subjects. CONCLUSION: A marked horizontal eye and head deviation observed approximately 1.5 days post-stroke is not a symptom associated with acute cerebral lesions per se, nor is a general symptom of right hemisphere lesions, but rather is specific for stroke patients with spatial neglect. The evaluation of the patient's horizontal eye and head position thus could serve as a brief and easy way helping to diagnose spatial neglect, in addition to the traditional paper-and-pencil tests. [Abstract/Link to Full Text]

Eftekhar B, Dadmehr M, Ansari S, Ghodsi M, Nazparvar B, Ketabchi E
Are the distributions of variations of circle of Willis different in different populations? - Results of an anatomical study and review of literature.
BMC Neurol. 2006;622.
BACKGROUND: Previous studies have proposed correlation between variants of the cerebral arterial circle (also known as circle of Willis) and some cerebrovascular diseases. Differences in the incidence of these diseases in different populations have also been investigated. The study of variations in the anatomy of the cerebral arterial circle may partially explain differences in the incidence of some of the cerebrovascular diseases in different ethnic or racial groups.While many studies have investigated the variations in the anatomy of each segment of the cerebral arterial circle, few have addressed the variants of the cerebral arterial circle as a whole. Similarly, the frequency of occurrence of such variants in different ethnic or racial groups has not been compared. METHODS: 102 brains of recently deceased Iranian males were dissected, in order to observe variations in the anatomy of the cerebral arterial circle. The dissection process was recorded on film and digitized. One resized picture from each dissection, showing complete circle has been made available online. The variations of the circle as whole and segmental variations were compared with previous studies. RESULTS: On the whole, the frequencies of the different variants of the entire cerebral arterial circle and segmental variations were comparable with previous studies.More specifically variants with uni- and bilateral hypoplasia of posterior communicating arteries were the most common in our study, similar to the previous works. No hypoplasia of the precommunicating part of the left anterior cerebral artery (A1), aplasia of A1 or the precommunicating part of the posterior cerebral artery (P1) was seen. In 3% both right and left posterior communcating arteries were absent. CONCLUSION: The anatomical variations found in the cerebral arterial circle of the Iranian males in the current study were not significantly different to those of more diverse populations reported in the literature. While taking into account potential confounding factors, the authors conclude that based on available studies, there is no evidence suggesting that the distributions of the variations of cerebral arterial circle differ in different populations. [Abstract/Link to Full Text]

Fecteau S, Lassonde M, Th�oret H
Intrahemispheric dysfunction in primary motor cortex without corpus callosum: a transcranial magnetic stimulation study.
BMC Neurol. 2006;621.
BACKGROUND: The two human cerebral hemispheres are continuously interacting, through excitatory and inhibitory influences and one critical structure subserving this interhemispheric balance is the corpus callosum. Interhemispheric neurophysiological abnormalities and intrahemispheric behavioral impairments have been reported in individuals lacking the corpus callosum. The aim of this study was to examine intrahemispheric neurophysiological function in primary motor cortex devoid of callosal projections. METHODS: Intracortical excitatory and inhibitory systems were tested in three individuals with complete agenesis of the corpus callosum and sixteen healthy individuals. These systems were assessed using transcranial magnetic stimulation (TMS) protocols: motor threshold at rest, paired-pulse curve, and cortical silent period. RESULTS: TMS revealed no difference between the patient and control groups on the motor threshold measure, as well as intracortical facilitation and intracortical inhibition systems as tested by paired stimulation. However, intrahemispheric inhibitory function was found to be abnormal in participants without callosal projections, as the cortical silent period duration was significantly increased in the patient group. CONCLUSION: These data suggest that in addition to previously reported impaired interhemispheric function, patients lacking the entire corpus callosum also display abnormal intrahemispheric excitability of the primary motor cortex. [Abstract/Link to Full Text]

Hills NK, Johnston SC
Duration of hospital participation in a nationwide stroke registry is associated with improved quality of care.
BMC Neurol. 2006;620.
BACKGROUND: There are several proven therapies for patients with ischemic stroke or transient ischemic attack (TIA), including prophylaxis of deep venous thrombosis (DVT) and initiation of antithrombotic medications within 48 h and at discharge. Stroke registries have been promoted as a means of increasing use of such interventions, which are currently underutilized. METHODS: From 1999 through 2003, 86 U.S. hospitals participated in Ethos, a voluntary web-based acute stroke treatment registry. Detailed data were collected on all patients admitted with a diagnosis of TIA or ischemic stroke. Rates of optimal treatment (defined as either receipt or a valid contraindication) were examined within each hospital as a function of its length of time in registry. Generalized estimating equations were used to adjust for patient and hospital characteristics. RESULTS: A total of 16,301 patients were discharged with a diagnosis of stroke or TIA from 50 hospitals that participated for more than 1 year. Rates of optimal treatment during the first 3 months of participation were as follows: 92.5% for antithrombotic medication within 48 h, 84.6% for antithrombotic medications at discharge, and 77.1% for DVT prophylaxis. Rates for all treatments improved with duration of participation in the registry (p < 0.05), with the most dramatic improvements in the first year. CONCLUSION: In a large cohort of patients with stroke or TIA, three targeted quality-improvement measures improved among hospitals participating in a disease-specific registry. Although the changes could be attributed to interventions other than the registry, these findings demonstrate the potential for hospital-level interventions to improve care for patients with stroke and TIA. [Abstract/Link to Full Text]

Then Bergh F, K�mpfel T, Schumann E, Held U, Schwan M, Blazevic M, Wism�ller A, Holsboer F, Yassouridis A, Uhr M, Weber F, Daumer M, Trenkwalder C, Auer DP
Monthly intravenous methylprednisolone in relapsing-remitting multiple sclerosis - reduction of enhancing lesions, T2 lesion volume and plasma prolactin concentrations.
BMC Neurol. 2006;619.
BACKGROUND: Intravenous methylprednisolone (IV-MP) is an established treatment for multiple sclerosis (MS) relapses, accompanied by rapid, though transient reduction of gadolinium enhancing (Gd+) lesions on brain MRI. Intermittent IV-MP, alone or with immunomodulators, has been suggested but insufficiently studied as a strategy to prevent relapses. METHODS: In an open, single-cross-over study, nine patients with relapsing-remitting MS (RR-MS) underwent cranial Gd-MRI once monthly for twelve months. From month six on, they received a single i.v.-infusion of 500 mg methylprednisolone (and oral tapering for three days) after the MRI. Primary outcome measure was the mean number of Gd+ lesions during treatment vs. baseline periods; T2 lesion volume and monthly plasma concentrations of cortisol, ACTH and prolactin were secondary outcome measures. Safety was assessed clinically, by routine laboratory and bone mineral density measurements. Soluble immune parameters (sTNF-RI, sTNF-RII, IL1-ra and sVCAM-1) and neuroendocrine tests (ACTH test, combined dexamethasone/CRH test) were additionally analyzed. RESULTS: Comparing treatment to baseline periods, the number of Gd+ lesions/scan was reduced in eight of the nine patients, by a median of 43.8% (p = 0.013, Wilcoxon). In comparison, a pooled dataset of 83 untreated RR-MS patients from several studies, selected by the same clinical and MRI criteria, showed a non-significant decrease by a median of 14% (p = 0.32). T2 lesion volume decreased by 21% during treatment (p = 0.001). Monthly plasma prolactin showed a parallel decline (p = 0.027), with significant cross-correlation with the number of Gd+ lesions. Other hormones and immune system variables were unchanged, as were ACTH test and dexamethasone-CRH test. Treatment was well tolerated; routine laboratory and bone mineral density were unchanged. CONCLUSION: Monthly IV-MP reduces inflammatory activity and T2 lesion volume in RR-MS. [Abstract/Link to Full Text]

Satoh J, Nanri Y, Tabunoki H, Yamamura T
Microarray analysis identifies a set of CXCR3 and CCR2 ligand chemokines as early IFNbeta-responsive genes in peripheral blood lymphocytes in vitro: an implication for IFNbeta-related adverse effects in multiple sclerosis.
BMC Neurol. 2006;618.
BACKGROUND: A substantial proportion of multiple sclerosis (MS) patients discontinue interferon-beta (IFNbeta) treatment due to various adverse effects, most of which emerge at the early phase after initiation of the treatment and then diminish with time. At present, the molecular mechanism underlying IFNbeta-related adverse effects remains largely unknown. The aim of this study is to identify a comprehensive list of early IFNbeta-responsive genes (IRGs) in peripheral blood mononuclear cells (PBMC) that may play a key role in induction of adverse effects. METHODS: Total RNA of PBMC exposed to 50 ng/ml recombinant human IFNbeta for 3 to 24 hours in vitro was processed for cDNA microarray analysis, followed by quantitative real-time RT-PCR analysis. RESULTS: Among 1,258 genes on the array, IFNbeta elevated the expression of 107 and 87 genes, while it reduced the expression of 22 and 23 genes at 3 and 24 hours, respectively. Upregulated IRGs were categorized into conventional IFN-response markers, components of IFN-signaling pathways, chemokines, cytokines, growth factors, and their receptors, regulators of apoptosis, DNA damage, and cell cycle, heat shock proteins, and costimulatory and adhesion molecules. IFNbeta markedly upregulated CXCR3 ligand chemokines (SCYB11, SCYB10 and SCYB9) chiefly active on effector T helper type 1 (Th1) T cells, and CCR2 ligand chemokines (SCYA8 and SCYA2) effective on monocytes, whereas it downregulated CXCR2 ligand chemokines (SCYB2, SCYB1 and IL8) primarily active on neutrophils. CONCLUSION: IFNbeta immediately induces a burst of gene expression of proinflammatory chemokines in vitro that have potential relevance to IFNbeta-related early adverse effects in MS patients in vivo. [Abstract/Link to Full Text]

Grosskreutz J, Kaufmann J, Fr�drich J, Dengler R, Heinze HJ, Peschel T
Widespread sensorimotor and frontal cortical atrophy in Amyotrophic Lateral Sclerosis.
BMC Neurol. 2006;617.
BACKGROUND: Widespread cortical atrophy in Amyotrophic Lateral Sclerosis (ALS) has been described in neuropathological studies. The presence of cortical atrophy in conventional and scientific neuroimaging has been a matter of debate. In studies using computertomography, positron emission tomography, proton magnetic resonance spectroscopy and conventional T2-weighted and proton-weighted images, results have been variable. Recent morphometric studies by magnetic resonance imaging have produced conflicting results regarding the extent of grey and white matter involvement in ALS patients. METHODS: The authors used optimized voxel-based morphometry as an unbiased whole brain approach to detect differences between regional grey and white matter volumes. Seventeen patients with a diagnosis of ALS according to El-Escorial criteria and seventeen age-matched controls received a high resolution anatomical T1 scan. RESULTS: In ALS patients regional grey matter volume (GMV) reductions were found in the pre- and postcentral gyrus bilaterally which extended to premotor, parietal and frontal regions bilaterally compared with controls (p < 0.05, corrected for the entire volume). The revised ALS functional rating scale showed a positive correlation with GMV reduction of the right medial frontal gyrus corresponding to the dorsolateral prefrontal cortex. No significant differences were found for white matter volumes or when grey and white matter density images were investigated. There were no further correlations with clinical variables found. CONCLUSION: In ALS patients, primary sensorimotor cortex atrophy can be regarded as a prominent feature of the disease. Supporting the concept of ALS being a multisystem disorder, our study provides further evidence for extramotor involvement which is widespread. The lack of correlation with common clinical variables probably reflects the fact that heterogeneous disease processes underlie ALS. The discrepancy within all published morphometric studies in ALS so far may be related to differences in patient cohorts and several methodological factors of the data analysis process. Longitudinal studies are required to further clarify the time course and distribution of grey and white matter pathology during the course of ALS. [Abstract/Link to Full Text]

Robertson WC, Given CA
Spontaneous intracranial arterial dissection in the young: diagnosis by CT angiography.
BMC Neurol. 2006;616.
BACKGROUND: Spontaneous carotid artery dissections have been rarely reported in children. Diagnosis has traditionally been confirmed by catheter arteriography. More recently diagnosis has been made by magnetic resonance imaging and magnetic resonance angiography; however the sensitivity of these techniques has yet to be determined. The authors are unaware of reports of carotid dissection confirmed by dynamic computed tomography (computerized tomographic arteriography) in the young. CASE PRESENTATION: We recently evaluated a fourteen year-old male following the development of transient neurologic symptoms. There was no antecedent illness or trauma. Dynamic computed tomography revealed an intracranial dissection involving the supraclinoid segment of the left internal carotid artery (confirmed by catheter arteriography). Studies for vasculitis, pro-thrombotic states, and defects of collagen were negative. CONCLUSION: Spontaneous carotid artery dissection is a potential cause of transient neurological symptoms and ischemic stroke in the pediatric population. Dynamic computed tomography appears to be a reliable diagnostic tool which can lead to early diagnosis. [Abstract/Link to Full Text]

Carnero-Pardo C, Gurpegui M, Sanchez-Cantalejo E, Frank A, Mola S, Barquero MS, Montoro-Rios MT
Diagnostic accuracy of the Eurotest for dementia: a naturalistic, multicenter phase II study.
BMC Neurol. 2006;615.
BACKGROUND: Available screening tests for dementia are of limited usefulness because they are influenced by the patient's culture and educational level. The Eurotest, an instrument based on the knowledge and handling of money, was designed to overcome these limitations. The objective of this study was to evaluate the diagnostic accuracy of the Eurotest in identifying dementia in customary clinical practice. METHODS: A cross-sectional, multi-center, naturalistic phase II study was conducted. The Eurotest was administered to consecutive patients, older than 60 years, in general neurology clinics. The patients' condition was classified as dementia or no dementia according to DSM-IV diagnostic criteria. We calculated sensitivity (Sn), specificity (Sp) and area under the ROC curves (aROC) with 95% confidence intervals. The influence of social and educational factors on scores was evaluated with multiple linear regression analysis, and the influence of these factors on diagnostic accuracy was evaluated with logistic regression. RESULTS: Sixteen neurologists recruited a total of 516 participants: 101 with dementia, 380 without dementia, and 35 who were excluded. Of the 481 participants who took the Eurotest, 38.7% were totally or functionally illiterate and 45.5% had received no formal education. Mean time needed to administer the test was 8.2+/-2.0 minutes. The best cut-off point was 20/21, with Sn = 0.91 (0.84-0.96), Sp = 0.82 (0.77-0.85), and aROC = 0.93 (0.91-0.95). Neither the scores on the Eurotest nor its diagnostic accuracy were influenced by social or educational factors. CONCLUSION: This naturalistic and pragmatic study shows that the Eurotest is a rapid, simple and useful screening instrument, which is free from educational influences, and has appropriate internal and external validity. [Abstract/Link to Full Text]

Chakarov V, Hummel S, Losch F, Schulte-M�nting J, Kristeva R
Handwriting performance in the absence of visual control in writer's cramp patients: initial observations.
BMC Neurol. 2006;614.
BACKGROUND: The present study was aimed at investigating the writing parameters of writer's cramp patients and control subjects during handwriting of a test sentence in the absence of visual control. METHODS: Eight right-handed patients with writer's cramp and eight healthy volunteers as age-matched control subjects participated in the study. The experimental task consisted in writing a test sentence repeatedly for fifty times on a pressure-sensitive digital board. The subject did not have visual control on his handwriting. The writing performance was stored on a PC and analyzed off-line. RESULTS: During handwriting all patients developed a typical dystonic limb posture and reported an increase in muscular tension along the experimental session. The patients were significantly slower than the controls, with lower mean vertical pressure of the pen tip on the paper and they could not reach the endmost letter of the sentence in the given time window. No other handwriting parameter differences were found between the two groups. CONCLUSION: Our findings indicate that during writing in the absence of visual feedback writer's cramp patients are slower and could not reach the endmost letter of the test sentence, but their level of automatization is not impaired and writer's cramp handwriting parameters are similar to those of the controls except for even lower vertical pressure of the pen tip on the paper, which is probably due to a changed strategy in such experimental conditions. [Abstract/Link to Full Text]

Emsley HC, Young CA, White RP
Circle of Willis variation in a complex stroke presentation: a case report.
BMC Neurol. 2006;613.
BACKGROUND: The impact of circle of Willis anatomical variation upon the presentation of stroke is probably underrecognized. CASE PRESENTATION: A 63-year-old right-handed woman developed a left hemiparesis and right leg weakness sequentially following a road traffic accident (RTA). Despite initial concern about the possibility of cervical spinal cord injury, the final diagnosis was bilateral artery-to-artery embolic cerebral infarction with dominant right internal carotid artery. CONCLUSION: The case illustrates the complex presentation of stroke as a pseudo-cervical cord lesion and the impact of circle of Willis anatomical variation upon the expression of large vessel cerebrovascular disease. [Abstract/Link to Full Text]

Yiangou Y, Facer P, Durrenberger P, Chessell IP, Naylor A, Bountra C, Banati RR, Anand P
COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord.
BMC Neurol. 2006;612.
BACKGROUND: While multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) are primarily inflammatory and degenerative disorders respectively, there is increasing evidence for shared cellular mechanisms that may affect disease progression, particularly glial responses. Cyclooxygenase 2 (COX-2) inhibition prolongs survival and cannabinoids ameliorate progression of clinical disease in animal models of ALS and MS respectively, but the mechanism is uncertain. Therefore, three key molecules known to be expressed in activated microglial cells/macrophages, COX-2, CB2 and P2X7, which plays a role in inflammatory cascades, were studied in MS and ALS post-mortem human spinal cord. METHODS: Frozen human post mortem spinal cord specimens, controls (n = 12), ALS (n = 9) and MS (n = 19), were available for study by immunocytochemistry and Western blotting, using specific antibodies to COX-2, CB2 and P2X7, and markers of microglial cells/macrophages (CD 68, ferritin). In addition, autoradiography for peripheral benzodiazepine binding sites was performed on some spinal cord sections using [3H] (R)-PK11195, a marker of activated microglial cells/macrophages. Results of immunostaining and Western blotting were quantified by computerized image and optical density analysis respectively. RESULTS: In control spinal cord, few small microglial cells/macrophages-like COX-2-immunoreactive cells, mostly bipolar with short processes, were scattered throughout the tissue, whilst MS and ALS specimens had significantly greater density of such cells with longer processes in affected regions, by image analysis. Inflammatory cell marker CD68-immunoreactivity, [3H] (R)-PK11195 autoradiography, and double-staining against ferritin confirmed increased production of COX-2 by activated microglial cells/macrophages. An expected 70-kDa band was seen by Western blotting which was significantly increased in MS spinal cord. There was good correlation between the COX-2 immunostaining and optical density of the COX-2 70-kDa band in the MS group (r = 0.89, P = 0.0011, n = 10). MS and ALS specimens also had significantly greater density of P2X7 and CB2-immunoreactive microglial cells/macrophages in affected regions. CONCLUSION: It is hypothesized that the known increase of lesion-associated extracellular ATP contributes via P2X7 activation to release IL-1 beta which in turn induces COX-2 and downstream pathogenic mediators. Selective CNS-penetrant COX-2 and P2X7 inhibitors and CB2 specific agonists deserve evaluation in the progression of MS and ALS. [Abstract/Link to Full Text]

Saft C, Lauter T, Kraus PH, Przuntek H, Andrich JE
Dose-dependent improvement of myoclonic hyperkinesia due to Valproic acid in eight Huntington's Disease patients: a case series.
BMC Neurol. 2006;611.
BACKGROUND: Chorea in Huntington's Disease (HD) is usually treated with antidopaminergic neuroleptics like haloperidol, olanzapine and tiaprid or dopamine depleting drugs like tetrabenazine. Some patients with hyperkinesia, however, react to treatment with antidopaminergic drugs by developing extrapyramidal side effects. In earlier studies valproic acid showed no beneficial effect on involuntary choreatic movements. Myoclonus is rare in HD and is often overseen or misdiagnosed as chorea. METHODS: In this report, we present eight patients whose main symptom is myoclonic hyperkinesia. All patients were treated with valproic acid and scored by using the Unified Huntington's Disease Rating Scale (UHDRS) motor score before and after treatment. In addition to this, two patients agreed to be videotaped. RESULTS: In seven patients myoclonus and, therefore the UHDRS motor score improved in a dose dependent manner. In three of these patients antidopaminergic medication could be reduced. CONCLUSION: In the rare subgroup of HD patients suffering from myoclonic hyperkinesia, valproic acid is a possible alternative treatment. [Abstract/Link to Full Text]

Jepsen JR, Laursen LH, Hagert CG, Kreiner S, Larsen AI
Diagnostic accuracy of the neurological upper limb examination II: relation to symptoms of patterns of findings.
BMC Neurol. 2006;610.
BACKGROUND: In a sample of patients in clinical occupational medicine we have demonstrated that an upper limb neurological examination can reliably identify patterns of findings suggesting upper limb focal neuropathies. This further study aimed at approaching the diagnostic accuracy of the examination. METHODS: 82 limbs were semi-quantitatively assessed by two blinded examiners (strength in 14 individual muscles, sensibility in 7 homonymous territories, and mechanosensitivity at 10 locations along nerves). Based on the topography of nerves and their muscular and sensory innervation we defined 10 neurological patterns each suggesting a localized nerve affliction. Information on complaints (pain, weakness and/or numbness/tingling) collected by others served as a reference for comparison. The relation between the presence of pattern(s) and complaints was assessed by kappa-statistics. Sensitivity, specificity, and positive/negative predictive values were calculated, and pre-test odds were compared to post-test probability. RESULTS : The two examiners identified pattern(s) suggesting focal neuropathy in 34/36 out of 38 symptomatic limbs, respectively (kappa = 0.70/0.75), with agreement in 28 limbs. Out of 44 non-symptomatic limbs the examiners agreed on absence of any pattern in 38 limbs. With concordance between the examiners with regard to the presence or absence of any pattern, the sensitivity, specificity, positive and negative predictive values were 0.73, 0.86, 0.93 and 0.90, respectively. While the pre-test odds for a limb to be symptomatic amounted to 0.46 the post-test probability was 0.81. For each examiner the post-test probability was 0.87 and 0.88, respectively. CONCLUSION: The improved diagnostic confidence is an indication of one aspect of construct validity of the physical examination. For determination of clinical feasibility of the examination further studies are required, most importantly 1) studies of validity by means of comparison with additional references and 2) studies of the potential benefit that can be attained from its use. [Abstract/Link to Full Text]

Tanaka M, Sadato N, Okada T, Mizuno K, Sasabe T, Tanabe HC, Saito DN, Onoe H, Kuratsune H, Watanabe Y
Reduced responsiveness is an essential feature of chronic fatigue syndrome: a fMRI study.
BMC Neurol. 2006;69.
BACKGROUND: Although the neural mechanism of chronic fatigue syndrome has been investigated by a number of researchers, it remains poorly understood. METHODS: Using functional magnetic resonance imaging, we studied brain responsiveness in 6 male chronic fatigue syndrome patients and in 7 age-matched male healthy volunteers. Responsiveness of auditory cortices to transient, short-lived, noise reduction was measured while subjects performed a fatigue-inducing continual visual search task. RESULTS: Responsiveness of the task-dependent brain regions was decreased after the fatigue-inducing task in the normal and chronic fatigue syndrome subjects and the decrement of the responsiveness was equivalent between the 2 groups. In contrast, during the fatigue-inducing period, although responsiveness of auditory cortices remained constant in the normal subjects, it was attenuated in the chronic fatigue syndrome patients. In addition, the rate of this attenuation was positively correlated with the subjective sensation of fatigue as measured using a fatigue visual analogue scale, immediately before the magnetic resonance imaging session. CONCLUSION: Chronic fatigue syndrome may be characterised by attenuation of the responsiveness to stimuli not directly related to the fatigue-inducing task. [Abstract/Link to Full Text]

Jepsen JR, Laursen LH, Hagert CG, Kreiner S, Larsen AI
Diagnostic accuracy of the neurological upper limb examination I: inter-rater reproducibility of selected findings and patterns.
BMC Neurol. 2006;68.
BACKGROUND: We have previously assessed the reproducibility of manual testing of the strength in 14 individual upper limb muscles in patients with or without upper limb complaints. This investigation aimed at additionally studying sensory disturbances, the mechanosensitivity of nerve trunks, and the occurrence of physical findings in patterns which may potentially reflect a peripheral neuropathy. The reproducibility of this part of the neurological examination has never been reported. METHODS: Two blinded examiners performed a semi-quantitative assessment of 82 upper limbs (strength in 14 individual muscles, sensibility in 7 homonymous territories, and mechanosensitivity of nerves at 10 locations). Based on the topography of nerves and their muscular and cutaneous innervation we defined 10 neurological patterns each suggesting a focal neuropathy. The individual findings and patterns identified by the two examiners were compared. RESULTS: Strength, sensibility to touch, pain and vibration, and mechanosensitivity were predominantly assessed with moderate to very good reproducibility (median kappa-values 0.54, 0.69, 0.48, 0.58, and 0.53, respectively). The reproducibility of the defined patterns was fair to excellent (median correlation coefficient = 0.75) and the overall identification of limbs with/without pattern(s) was good (kappa = 0.75). CONCLUSION: This first part of a study on diagnostic accuracy of a selective neurological examination has demonstrated a promising inter-rater reproducibility of individual neurological items and patterns. Generalization and clinical feasibility require further documentation: 1) Reproducibility in cohorts of other composition, 2) validity with comparison to currently applied standards, and 3) potential benefits that can be attained by the examination. [Abstract/Link to Full Text]

Sterr A, Herron K, Hayward C, Montaldi D
Are mild head injuries as mild as we think? Neurobehavioral concomitants of chronic post-concussion syndrome.
BMC Neurol. 2006 Feb 6;6(1):7.
ABSTRACT: BACKGROUND: Mild traumatic brain injury (MTBI) can sometimes lead to persistent postconcussion symptoms. One well accepted hypothesis claims that chronic PCS has a neural origin, and is related to neurobehavioral deficits. But the evidence is not conclusive. In the attempt to characterise chronic MTBI consequences, the present experiment used a group comparison design, which contrasted persons (a) with MTBI and PCS, (b) MTBI without PCS, and (c) matched controls. We predicted that participants who have experienced MTBI but show no signs of PCS would perform similar to controls. At the same time, a subgroup of MTBI participants would show PCS symptoms and only these volunteers would have poorer cognitive performance. Thereby, the performance deficits should be most noticeable in participants with highest PCS severity. METHOD: 38 patients with a single MTBI that had occurred at least 12 month prior to testing, and 38 matched controls, participated in the experiment. A combination of questionnaires and neuropsychological test batteries were used to assess the extent of PCS and related deficits in neurobehavioral performance. RESULTS: 11 out of 38 MTBI participants (29%) were found to suffer from PCS. This subgroup of MTBI patients performed poorly on neuropsychological test batteries. Thereby, a correlation was found between PCS symptom severity and test performance suggesting that participants with more pronounced PCS symptoms performed worse in cognitive tasks. In contrast, MTBI patients with no PCS showed performed similar to matched control. We further found that loss of consciousness, a key criterion for PCS diagnosis, was not predictive of sustained PCS. CONCLUSION: The results support the idea that MTBI can have sustained consequences, and that the subjectively experienced symptoms and difficulties in everyday situations are related to objectively measurable parameters in neurocognitive function. [Abstract/Link to Full Text]

Kolb SJ, Gubitz AK, Olszewski RF, Ottinger E, Sumner CJ, Fischbeck KH, Dreyfuss G
A novel cell immunoassay to measure survival of motor neurons protein in blood cells.
BMC Neurol. 2006;66.
BACKGROUND: The motor neuron degenerative disease spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality and is caused by mutations in the survival of motor neurons (SMN) gene that reduce the expression levels of the SMN protein. A major goal of current therapeutic approaches is to increase SMN levels in SMA patients. The purpose of this study was to develop a reliable assay to measure SMN protein levels from peripheral blood samples. METHODS: We developed a novel cell immunoassay to quantitatively measure SMN levels from peripheral blood mononuclear cells (PBMCs) using a single anti-SMN antibody. RESULTS: SMN levels determined by the cell immunoassay are comparable to levels determined by Western blot, but in contrast, the immunoassay does not involve cell lysis, requires a small amount of patient material, and can be done on a large number of samples simultaneously. SMN levels from PBMCs are not influenced by cell type heterogeneity. CONCLUSION: SMN levels measured from total PBMCs provide an important snapshot of SMN protein expression, which should be a useful aid in SMA diagnosis, and a surrogate marker of efficacy of treatment in SMA clinical trials. [Abstract/Link to Full Text]

Ali S, Khan MA, Khealani B
Limb-shaking Transient Ischemic Attacks: case report and review of literature.
BMC Neurol. 2006;65.
BACKGROUND: Limb shaking Transient Ischemic Attack is a rare manifestation of carotid-occlusive disease. The symptoms usually point towards a seizure like activity and misdiagnosed as focal seizures. On careful history the rhythmic seizure like activity reveals no Jacksonian march mainly precipitated by maneuvers which lead to carotid compression. We here present a case of an elderly gentleman who was initially worked up as suffering from epileptic discharge and then later on found to have carotid occlusion. CASE PRESENTATION: Elderly gentleman presented with symptoms of rhythmic jerky movements of the left arm and both the lower limbs. Clinical suspicion of focal epilepsy was made and EEG, MRI-Brain with MRA were done. EEG and MRI-Brain revealed normal findings but the MRA revealed complete occlusion of right internal carotid artery. On a follow-up visit jerky movements of the left arm were precipitated by hyperextension and a tremor of 3-4 Hz was revealed. Based on this the diagnosis of low flow TIA was made the patient was treated conservatively with adjustment of his anti-hypertensive and anti-platelet medications. CONCLUSION: Diagnosis of limb-shaking TIA is important and should be differentiated from other disorders presenting as tremors. Timely diagnosis is important as these patients are shown to benefit from reperfusion procedures either surgical or radiological reducing their risk of stroke. [Abstract/Link to Full Text]

Grunsfeld AA, Login IS
Abulia following penetrating brain injury during endoscopic sinus surgery with disruption of the anterior cingulate circuit: case report.
BMC Neurol. 2006;64.
BACKGROUND: It is common knowledge that the frontal lobes mediate complex human behavior and that damage to these regions can cause executive dysfunction, apathy, disinhibition and personality changes. However, it is less well known that subcortical structures such as the caudate and thalamus are part of functionally segregated fronto-subcortical circuits, that can also alter behavior after injury. CASE PRESENTATION We present a 57 year old woman who suffered penetrating brain injury during endoscopic sinus surgery causing right basal ganglia injury which resulted in an abulic syndrome. CONCLUSION: Abulia does not result solely from cortical injury but can occur after disruption anywhere in the anterior cingulate circuit--in the case of our patient, most prominently at the right caudate. [Abstract/Link to Full Text]

Thakore NJ, Pioro EP, Rucker JC, Leigh RJ
Motor neuronopathy with dropped hands and downbeat nystagmus: a distinctive disorder? A case report.
BMC Neurol. 2006;63.
BACKGROUND: Eye movements are clinically normal in most patients with motor neuron disorders until late in the disease course. Rare patients are reported to show slow vertical saccades, impaired smooth pursuit, and gaze-evoked nystagmus. We report clinical and oculomotor findings in three patients with motor neuronopathy and downbeat nystagmus, a classic sign of vestibulocerebellar disease. CASE PRESENTATION: All patients had clinical and electrodiagnostic features of anterior horn cell disease. Involvement of finger and wrist extensors predominated, causing finger and wrist drop. Bulbar or respiratory dysfunction did not occur. All three had clinically evident downbeat nystagmus worse on lateral and downgaze, confirmed on eye movement recordings using the magnetic search coil technique in two patients. Additional oculomotor findings included alternating skew deviation and intermittent horizontal saccadic oscillations, in one patient each. One patient had mild cerebellar atrophy, while the other two had no cerebellar or brainstem abnormality on neuroimaging. The disorder is slowly progressive, with survival up to 30 years from the time of onset. CONCLUSION: The combination of motor neuronopathy, characterized by early and prominent wrist and finger extensor weakness, and downbeat nystagmus with or without other cerebellar eye movement abnormalities may represent a novel motor neuron syndrome. [Abstract/Link to Full Text]

Zaccai J, Ince P, Brayne C
Population-based neuropathological studies of dementia: design, methods and areas of investigation--a systematic review.
BMC Neurol. 2006;62.
BACKGROUND: Prospective population-based neuropathological studies have a special place in dementia research which is under emphasised. METHODS: A systematic review of the methods of population-based neuropathological studies of dementia was carried out. These studies were assessed in relation to their representativeness of underlying populations and the clinical, neuropsychological and neuropathological approaches adopted. RESULTS: Six studies were found to be true population-based neuropathological studies of dementia in the older people: the Hisayama study (Japan); Vantaa 85+ study (Finland); CC75C study (Cambridge, UK); CFAS (multicentre, UK); Cache County study (Utah, USA); HAAS (Hawa�, USA). These differ in the core characteristics of their populations. The studies used standardised neuropathological methods which facilitate analyses on: clinicopathological associations and confirmation of diagnosis, assessing the validity of hierarchical models of neuropathological lesion burden; investigating the associations between neuropathological burden and risk factors including genetic factors. Examples of findings are given although there is too little overlap in the areas investigated amongst these studies to form the basis of a systematic review of the results. CONCLUSION: Clinicopathological studies based on true population samples can provide unique insights in dementia. Individually they are limited in power and scope; together they represent a powerful source to translate findings from laboratory to populations. [Abstract/Link to Full Text]

Durrenberger PF, Facer P, Casula MA, Yiangou Y, Gray RA, Chessell IP, Day NC, Collins SD, Bingham S, Wilson AW, Elliot D, Birch R, Anand P
Prostanoid receptor EP1 and Cox-2 in injured human nerves and a rat model of nerve injury: a time-course study.
BMC Neurol. 2006;61.
BACKGROUND: Recent studies show that inflammatory processes may contribute to neuropathic pain. Cyclooxygenase-2 (Cox-2) is an inducible enzyme responsible for production of prostanoids, which may sensitise sensory neurones via the EP1 receptor. We have recently reported that while macrophages infiltrate injured nerves within days of injury, they express increased Cox-2-immunoreactivity (Cox-2-IR) from 2 to 3 weeks after injury. We have now investigated the time course of EP1 and Cox-2 changes in injured human nerves and dorsal root ganglia (DRG), and the chronic constriction nerve injury (CCI) model in the rat. METHODS: Tissue sections were immunostained with specific antibodies to EP1, Cox-2, CD68 (human macrophage marker) or OX42 (rat microglial marker), and neurofilaments (NF), prior to image analysis, from the following: human brachial plexus nerves (21 to 196 days post-injury), painful neuromas (9 days to 12 years post-injury), avulsion injured DRG, control nerves and DRG, and rat CCI model tissues. EP1 and NF-immunoreactive nerve fibres were quantified by image analysis. RESULTS: EP1:NF ratio was significantly increased in human brachial plexus nerve fibres, both proximal and distal to injury, in comparison with uninjured nerves. Sensory neurones in injured human DRG showed a significant acute increase of EP1-IR intensity. While there was a rapid increase in EP1-fibres and CD-68 positive macrophages, Cox-2 increase was apparent later, but was persistent in human painful neuromas for years. A similar time-course of changes was found in the rat CCI model with the above markers, both in the injured nerves and ipsilateral dorsal spinal cord. CONCLUSION: Different stages of infiltration and activation of macrophages may be observed in the peripheral and central nervous system following peripheral nerve injury. EP1 receptor level increase in sensory neurones, and macrophage infiltration, appears to precede increased Cox-2 expression by macrophages. However, other methods for detecting Cox-2 levels and activity are required. EP1 antagonists may show therapeutic effects in acute and chronic neuropathic pain, in addition to inflammatory pain. [Abstract/Link to Full Text]

Booya F, Bandarian F, Larijani B, Pajouhi M, Nooraei M, Lotfi J
Potential risk factors for diabetic neuropathy: a case control study.
BMC Neurol. 2005;524.
BACKGROUND: Diabetes mellitus type II afflicts at least 2 million people in Iran. Neuropathy is one of the most common complications of diabetes and lowers the patient's quality of life. Since neuropathy often leads to ulceration and amputation, we have tried to elucidate the factors that can affect its progression. METHODS: In this case-control study, 110 diabetic patients were selected from the Shariati Hospital diabetes clinic. Michigan Neuropathic Diabetic Scoring (MNDS) was used to differentiate cases from controls. The diagnosis of neuropathy was confirmed by nerve conduction studies (nerve conduction velocity and electromyography). The multiple factors compared between the two groups included consumption of angiotensin converting enzyme inhibitors (ACEI), blood pressure, serum lipid level, sex, smoking, method of diabetes control and its quality. RESULTS: Statistically significant relationships were found between neuropathy and age, gender, quality of diabetes control and duration of disease (P values in the order: 0.04, 0.04, < 0.001 and 0.005). No correlation was found with any atherosclerosis risk factor (high BP, hyperlipidemia, cigarette smoking). CONCLUSION: In this study, hyperglycemia was the only modifiable risk factor for diabetic neuropathy. Glycemic control reduces the incidence of neuropathy, slows its progression and improves the diabetic patient's quality of life. More attention must be paid to elderly male diabetic patients with poor diabetes control with regard to regular foot examinations and more practical education. [Abstract/Link to Full Text]

Ward MA, Carlsson CM, Trivedi MA, Sager MA, Johnson SC
The effect of body mass index on global brain volume in middle-aged adults: a cross sectional study.
BMC Neurol. 2005;523.
BACKGROUND: Obesity causes or exacerbates a host of medical conditions, including cardiovascular, pulmonary, and endocrine diseases. Recently obesity in elderly women was associated with greater risk of dementia, white matter ischemic changes, and greater brain atrophy. The purpose of this study was to determine whether body type affects global brain volume, a marker of atrophy, in middle-aged men and women. METHODS: T1-weighted 3D volumetric magnetic resonance imaging was used to assess global brain volume for 114 individuals 40 to 66 years of age (average = 54.2 years; standard deviation = 6.6 years; 43 men and 71 women). Total cerebrospinal fluid and brain volumes were obtained with an automated tissue segmentation algorithm. A regression model was used to determine the effect of age, body mass index (BMI), and other cardiovascular risk factors on brain volume and cognition. RESULTS: Age and BMI were each associated with decreased brain volume. BMI did not predict cognition in this sample; however elevated diastolic blood pressure was associated with poorer episodic learning performance. CONCLUSION: These findings suggest that middle-aged obese adults may already be experiencing differentially greater brain atrophy, and may potentially be at greater risk for future cognitive decline. [Abstract/Link to Full Text]

Recent Articles in Journal of Neuroinflammation

Hensley K, Abdel-Moaty H, Hunter J, Mhatre M, Mou S, Nguyen K, Potapova T, Pye QN, Qi M, Rice H, Stewart C, Stroukoff K, West M
Primary glia expressing the G93A-SOD1 mutation present a neuroinflammatory phenotype and provide a cellular system for studies of glial inflammation.
J Neuroinflammation. 2006;32.
Detailed study of glial inflammation has been hindered by lack of cell culture systems that spontaneously demonstrate the "neuroinflammatory phenotype". Mice expressing a glycine --> alanine substitution in cytosolic Cu, Zn-superoxide dismutase (G93A-SOD1) associated with familial amyotrophic lateral sclerosis (ALS) demonstrate age-dependent neuroinflammation associated with broad-spectrum cytokine, eicosanoid and oxidant production. In order to more precisely study the cellular mechanisms underlying glial activation in the G93A-SOD1 mouse, primary astrocytes were cultured from 7 day mouse neonates. At this age, G93A-SOD1 mice demonstrated no in vivo hallmarks of neuroinflammation. Nonetheless astrocytes cultured from G93A-SOD1 (but not wild-type human SOD1-expressing) transgenic mouse pups demonstrated a significant elevation in either the basal or the tumor necrosis alpha (TNFalpha)-stimulated levels of proinflammatory eicosanoids prostaglandin E2 (PGE2) and leukotriene B4 (LTB4); inducible nitric oxide synthase (iNOS) and *NO (indexed by nitrite release into the culture medium); and protein carbonyl products. Specific cytokine- and TNFalpha death-receptor-associated components were similarly upregulated in cultured G93A-SOD1 cells as assessed by multiprobe ribonuclease protection assays (RPAs) for their mRNA transcripts. Thus, endogenous glial expression of G93A-SOD1 produces a metastable condition in which glia are more prone to enter an activated neuroinflammatory state associated with broad-spectrum increased production of paracrine-acting substances. These findings support a role for active glial involvement in ALS and may provide a useful cell culture tool for the study of glial inflammation. [Abstract/Link to Full Text]

Huber VC, Mondal T, Factor SA, Seegal RF, Lawrence DA
Serum antibodies from Parkinson's disease patients react with neuronal membrane proteins from a mouse dopaminergic cell line and affect its dopamine expression.
J Neuroinflammation. 2006;31.
Evidence exists suggesting that the immune system may contribute to the severity of idiopathic Parkinson's disease (IPD). The data presented here demonstrates that antibodies in the sera of patients with IPD have increased binding affinity to dopaminergic (DA) neuronal (MN9D cell line) membrane antigens in comparison to antibodies in sera from healthy controls. In general, the degree of antibody reactivity to these antigens of the mouse MN9D cell line appears to correlate well with the disease severity of the IPD patients contributing sera, based on the total UPDRS scores. Surprisingly, the sera from IPD patients enhanced the DA content of MN9D cells differentiated with n-butyrate; the n-butyrate-differentiated MN9D cells had a greater concentration of DA (DA/mg total protein) than undifferentiated MN9D cells, especially early in culture. Although the IPD sera did not directly harm MN9D cellular viability or DA production, in the presence of the N9 microglial cell line, the amount of DA present in cultures of untreated or n-butyrate-treated MN9D cells was lowered by the IPD sera. The results suggest the involvement of antibodies in the decline of dopamine production and, thus, the potential of immune system participation in IPD. [Abstract/Link to Full Text]

Ehrhart J, Obregon D, Mori T, Hou H, Sun N, Bai Y, Klein T, Fernandez F, Tan J, Shytle RD
Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation.
J Neuroinflammation. 2005;229.
BACKGROUND: Activated microglial cells have been implicated in a number of neurodegenerative disorders, including Alzheimer's disease (AD), multiple sclerosis (MS), and HIV dementia. It is well known that inflammatory mediators such as nitric oxide (NO), cytokines, and chemokines play an important role in microglial cell-associated neuron cell damage. Our previous studies have shown that CD40 signaling is involved in pathological activation of microglial cells. Many data reveal that cannabinoids mediate suppression of inflammation in vitro and in vivo through stimulation of cannabinoid receptor 2 (CB2). METHODS: In this study, we investigated the effects of a cannabinoid agonist on CD40 expression and function by cultured microglial cells activated by IFN-gamma using RT-PCR, Western immunoblotting, flow cytometry, and anti-CB2 small interfering RNA (siRNA) analyses. Furthermore, we examined if the stimulation of CB2 could modulate the capacity of microglial cells to phagocytise Abeta1-42 peptide using a phagocytosis assay. RESULTS: We found that the selective stimulation of cannabinoid receptor CB2 by JWH-015 suppressed IFN-gamma-induced CD40 expression. In addition, this CB2 agonist markedly inhibited IFN-gamma-induced phosphorylation of JAK/STAT1. Further, this stimulation was also able to suppress microglial TNF-alpha and nitric oxide production induced either by IFN-gamma or Abeta peptide challenge in the presence of CD40 ligation. Finally, we showed that CB2 activation by JWH-015 markedly attenuated CD40-mediated inhibition of microglial phagocytosis of Abeta1-42 peptide. Taken together, these results provide mechanistic insight into beneficial effects provided by cannabinoid receptor CB2 modulation in neurodegenerative diseases, particularly AD. [Abstract/Link to Full Text]

Zhou J, Fonseca MI, Kayed R, Hernandez I, Webster SD, Yazan O, Cribbs DH, Glabe CG, Tenner AJ
Novel Abeta peptide immunogens modulate plaque pathology and inflammation in a murine model of Alzheimer's disease.
J Neuroinflammation. 2005;228.
BACKGROUND: Alzheimer's disease, a common dementia of the elder, is characterized by accumulation of protein amyloid deposits in the brain. Immunization to prevent this accumulation has been proposed as a therapeutic possibility, although adverse inflammatory reactions in human trials indicate the need for novel vaccination strategies. METHOD: Here vaccination with novel amyloid peptide immunogens was assessed in a transgenic mouse model displaying age-related accumulation of fibrillar plaques. RESULTS: Immunization with any conformation of the amyloid peptide initiated at 12 months of age (at which time fibrillar amyloid has just begun to accumulate) showed significant decrease in total and fibrillar amyloid deposits and in glial reactivity relative to control transgenic animals. In contrast, there was no significant decrease in amyloid deposition or glial activation in mice in which vaccination was initiated at 16 months of age, despite the presence of similar levels anti-Abeta antibodies in young and old animals vaccinated with a given immunogen. Interestingly, immunization with an oligomeric conformation of Abeta was equally as effective as other amyloid peptides at reducing plaque accumulation. However, the antibodies generated by immunization with the oligomeric conformation of Abeta have more limited epitope reactivity than those generated by fAbeta, and the microglial response was significantly less robust. CONCLUSION: These results suggest that a more specific immunogen such as oligomeric Abeta can be designed that achieves the goal of depleting amyloid while reducing potential detrimental inflammatory reactions. In addition, the data show that active immunization of older Tg2576 mice with any amyloid conformation is not as efficient at reducing amyloid accumulation and related pathology as immunization of younger mice, and that serum anti-amyloid antibody levels are not quantitatively related to reduced amyloid-associated pathology. [Abstract/Link to Full Text]

Hoozemans JJ, van Haastert ES, Veerhuis R, Arendt T, Scheper W, Eikelenboom P, Rozemuller AJ
Maximal COX-2 and ppRb expression in neurons occurs during early Braak stages prior to the maximal activation of astrocytes and microglia in Alzheimer's disease.
J Neuroinflammation. 2005 Nov 21;227.
Neuronal expression of cyclooxygenase-2 (COX-2) and cell cycle proteins is suggested to contribute to neurodegeneration during Alzheimer's disease (AD). The stimulus that induces COX-2 and cell cycle protein expression in AD is still elusive. Activated glia cells are shown to secrete substances that can induce expression of COX-2 and cell cycle proteins in vitro. Using post mortem brain tissue we have investigated whether activation of microglia and astrocytes in AD brain can be correlated with the expression of COX-2 and phosphorylated retinoblastoma protein (ppRb). The highest levels of neuronal COX-2 and ppRb immunoreactivity are observed in the first stages of AD pathology (Braak 0-II, Braak A). No significant difference in COX-2 or ppRb neuronal immunoreactivity is observed between Braak stage 0 and later Braak stages for neurofibrillary changes or amyloid plaques. The mean number of COX-2 or ppRb immunoreactive neurons is significantly decreased in Braak stage C compared to Braak stage A for amyloid deposits. Immunoreactivity for glial markers KP1, CR3/43 and GFAP appears in the later Braak stages and is significantly increased in Braak stage V-VI compared to Braak stage 0 for neurofibrillary changes. In addition, a significant negative correlation is observed between the presence of KP1, CR3/43 and GFAP immunoreactivity and the presence of neuronal immunoreactivity for COX-2 and ppRb. These data show that maximal COX-2 and ppRb immunoreactivity in neurons occurs during early Braak stages prior to the maximal activation of astrocytes and microglia. In contrast to in vitro studies, post mortem data do not support a causal relation between the activation of microglia and astrocytes and the expression of neuronal COX-2 and ppRb in the pathological cascade of AD. [Abstract/Link to Full Text]

Ruohonen S, Khademi M, Jagodic M, Taskinen HS, Olsson T, R�ytt� M
Cytokine responses during chronic denervation.
J Neuroinflammation. 2005 Nov 18;226.
BACKGROUND: The aim of the present study was to examine inflammatory responses during Wallerian degeneration in rat peripheral nerve when the regrowth of axons was prevented by suturing. METHODS: Transected rat sciatic nerve was sutured and ligated to prevent reinnervation. The samples were collected from the left sciatic nerve distally and proximally from the point of transection. The endoneurium was separated from the surrounding epi- and perineurium to examine the expression of cytokines in both of these compartments. Macrophage invasion into endoneurium was investigated and Schwann cell proliferation was followed as well as the expression of cytokines IL-1beta, IL-10, IFN-gamma and TNF-alpha mRNA. The samples were collected from 1 day up to 5 weeks after the primary operation. RESULTS: At days 1 to 3 after injury in the epi-/perineurium of the proximal and distal stump, a marked expression of the pro-inflammatory cytokines TNF-alpha and IL-1beta and of the anti-inflammatory cytokine IL-10 was observed. Concurrently, numerous macrophages started to gather into the epineurium of both proximal and distal stumps. At day 7 the number of macrophages decreased in the perineurium and increased markedly in the endoneurium of both stumps. At this time point marked expression of TNF-alpha and IFN-gamma mRNA was observed in the endo- and epi-/perineurium of the proximal stump. At day 14 a marked increase in the expression of IL-1beta could be noted in the proximal stump epi-/perineurium and in the distal stump endoneurium. At that time point many macrophages were observed in the longitudinally sectioned epineurium of the proximal 2 area as well as in the cross-section slides from the distal stump. At day 35 TNF-alpha, IL-1beta and IL-10 mRNA appeared abundantly in the proximal epi-/perineurium together with macrophages. CONCLUSION: The present studies show that even during chronic denervation there is a cyclic expression pattern for the studied cytokines. Contrary to the previous findings on reinnervating nerves the studied cytokines show increased expression up to 35 days. The high expressions of pro-inflammatory and anti-inflammatory cytokines in the proximal epi-/perineurial area at day 35 may be involved in the formation of fibrosis due to irreversible nerve injury and thus may have relevance to the formation of traumatic neuroma. [Abstract/Link to Full Text]

Huuskonen J, Suuronen T, Miettinen R, van Groen T, Salminen A
A refined in vitro model to study inflammatory responses in organotypic membrane culture of postnatal rat hippocampal slices.
J Neuroinflammation. 2005 Nov 15;225.
BACKGROUND: Propagated tissue degeneration, especially during aging, has been shown to be enhanced through potentiation of innate immune responses. Neurodegenerative diseases and a wide variety of inflammatory conditions are linked together and several anti-inflammatory compounds considered as having therapeutic potential for example in Alzheimer's disease (AD). In vitro brain slice techniques have been widely used to unravel the complexity of neuroinflammation, but rarely, has the power of the model itself been reported. Our aim was to gain a more detailed insight and understanding of the behaviour of hippocampus tissue slices in serum-free, interface culture per se and after exposure to different pro- and anti-inflammatory compounds. METHODS: The responses of the slices to pro- and anti-inflammatory stimuli were monitored at various time points by measuring the leakage of lactate dehydrogenase (LDH) and the release of cytokines interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-alpha) and nitric oxide (NO) from the culture media. Histological methods were applied to reveal the morphological status after exposure to stimuli and during the time course of the culture period. Statistical power analysis were made with nQuery Advisor, version 5.0, (Statistical Solutions, Saugus, MA) computer program for Wilcoxon (Mann-Whitney) rank-sum test. RESULTS: By using the interface membrane culture technique, the hippocampal slices largely recover from the trauma caused by cutting after 4-5 days in vitro. Furthermore, the cultures remain stable and retain their responsiveness to inflammatory stimuli for at least 3 weeks. During this time period, cultures are susceptible to modification by inflammatory stimuli as assessed by quantitative biochemical assays and morphological characterizations. CONCLUSION: The present report outlines the techniques for studying immune responses using a serum-free slice culture model. Statistically powerful data under controlled culture conditions and with ethically justified use of animals can be obtained as soon as after 4-5 DIV. The model is most probably suitable also for studies of chronic inflammation. [Abstract/Link to Full Text]

Town T, Nikolic V, Tan J
The microglial "activation" continuum: from innate to adaptive responses.
J Neuroinflammation. 2005 Oct 31;224.
Microglia are innate immune cells of myeloid origin that take up residence in the central nervous system (CNS) during embryogenesis. While classically regarded as macrophage-like cells, it is becoming increasingly clear that reactive microglia play more diverse roles in the CNS. Microglial "activation" is often used to refer to a single phenotype; however, in this review we consider that a continuum of microglial activation exists, with phagocytic response (innate activation) at one end and antigen presenting cell function (adaptive activation) at the other. Where activated microglia fall in this spectrum seems to be highly dependent on the type of stimulation provided. We begin by addressing the classical roles of peripheral innate immune cells including macrophages and dendritic cells, which seem to define the edges of this continuum. We then discuss various types of microglial stimulation, including Toll-like receptor engagement by pathogen-associated molecular patterns, microglial challenge with myelin epitopes or Alzheimer's beta-amyloid in the presence or absence of CD40L co-stimulation, and Alzheimer disease "immunotherapy". Based on the wide spectrum of stimulus-specific microglial responses, we interpret these cells as immune cells that demonstrate remarkable plasticity following activation. This interpretation has relevance for neurodegenerative/neuroinflammatory diseases where reactive microglia play an etiological role; in particular viral/bacterial encephalitis, multiple sclerosis and Alzheimer disease. [Abstract/Link to Full Text]

Janelsins MC, Mastrangelo MA, Oddo S, LaFerla FM, Federoff HJ, Bowers WJ
Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specifically within the entorhinal cortex of triple transgenic Alzheimer's disease mice.
J Neuroinflammation. 2005 Oct 18;223.
BACKGROUND: Alzheimer's disease is a complex neurodegenerative disorder characterized pathologically by a temporal and spatial progression of beta-amyloid (Abeta) deposition, neurofibrillary tangle formation, and synaptic degeneration. Inflammatory processes have been implicated in initiating and/or propagating AD-associated pathology within the brain, as inflammatory cytokine expression and other markers of inflammation are pronounced in individuals with AD pathology. The current study examines whether inflammatory processes are evident early in the disease process in the 3xTg-AD mouse model and if regional differences in inflammatory profiles exist. METHODS: Coronal brain sections were used to identify Abeta in 2, 3, and 6-month 3xTg-AD and non-transgenic control mice. Quantitative real-time RT-PCR was performed on microdissected entorhinal cortex and hippocampus tissue of 2, 3, and 6-month 3xTg-AD and non-transgenic mice. Microglial/macrophage cell numbers were quantified using unbiased stereology in 3xTg-AD and non-transgenic entorhinal cortex and hippocampus containing sections. RESULTS: We observed human Abeta deposition at 3 months in 3xTg-AD mice which is enhanced by 6 months of age. Interestingly, we observed a 14.8-fold up-regulation of TNF-alpha and 10.8-fold up-regulation of MCP-1 in the entorhinal cortex of 3xTg-AD mice but no change was detected over time in the hippocampus or in either region of non-transgenic mice. Additionally, this increase correlated with a specific increase in F4/80-positive microglia and macrophages in 3xTg-AD entorhinal cortex. CONCLUSION: Our data provide evidence for early induction of inflammatory processes in a model that develops amyloid and neurofibrillary tangle pathology. Additionally, our results link inflammatory processes within the entorhinal cortex, which represents one of the earliest AD-affected brain regions. [Abstract/Link to Full Text]

Heneka MT, Sastre M, Dumitrescu-Ozimek L, Dewachter I, Walter J, Klockgether T, Van Leuven F
Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice.
J Neuroinflammation. 2005 Oct 7;222.
BACKGROUND: Inflammation is suspected to contribute to the progression and severity of neurodegeneration in Alzheimer's disease (AD). Transgenic mice overexpressing the london mutant of amyloid precursor protein, APP [V717I], robustly recapitulate the amyloid pathology of AD. METHODS: Early and late, temporal and spatial characteristics of inflammation were studied in APP [V717I] mice at 3 and 16 month of age. Glial activation and expression of inflammatory markers were determined by immunohistochemistry and RT-PCR. Amyloid deposition was assessed by immunohistochemistry, thioflavine S staining and western blot experiments. BACE1 activity was detected in brain lysates and in situ using the BACE1 activity kit from R&D Systems, Wiesbaden, Germany. RESULTS: Foci of activated micro- and astroglia were already detected at age 3 months, before any amyloid deposition. Inflammation parameters comprised increased mRNA levels coding for interleukin-1beta, interleukin-6, major histocompatibility complex II and macrophage-colony-stimulating-factor-receptor. Foci of CD11b-positive microglia expressed these cytokines and were neighbored by activated astrocytes. Remarkably, beta-secretase (BACE1) mRNA, neuronal BACE1 protein at sites of focal inflammation and total BACE1 enzyme activity were increased in 3 month old APP transgenic mice, relative to age-matched non-transgenic mice. In aged APP transgenic mice, the mRNA of all inflammatory markers analysed was increased, accompanied by astroglial iNOS expression and NO-dependent peroxynitrite release, and with glial activation near almost all diffuse and senile Abeta deposits. CONCLUSION: The early and focal glial activation, in conjunction with upregulated BACE1 mRNA, protein and activity in the presence of its substrate APP, is proposed to represent the earliest sites of amyloid deposition, likely evolving into amyloid plaques. [Abstract/Link to Full Text]

Ayasolla KR, Singh AK, Singh I
5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) attenuates the expression of LPS- and Abeta peptide-induced inflammatory mediators in astroglia.
J Neuroinflammation. 2005 Sep 20;221.
BACKGROUND: Alzheimer's disease (AD) pathology shows characteristic 'plaques' rich in amyloid beta (Abeta) peptide deposits. Inflammatory process-related proteins such as pro-inflammatory cytokines have been detected in AD brain suggesting that an inflammatory immune reaction also plays a role in the pathogenesis of AD. Glial cells in culture respond to LPS and Abeta stimuli by upregulating the expression of cytokines TNF-alpha, IL-1beta, and IL-6, and also the expression of proinflammatory genes iNOS and COX-2. We have earlier reported that LPS/Abeta stimulation-induced ceramide and ROS generation leads to iNOS expression and nitric oxide production in glial cells. The present study was undertaken to investigate the neuroprotective function of AICAR (a potent activator of AMP-activated protein kinase) in blocking the pro-oxidant/proinflammatory responses induced in primary glial cultures treated with LPS and Abeta peptide. METHODS: To test the anti-inflammatory/anti-oxidant functions of AICAR, we tested its inhibitory potential in blocking the expression of pro-inflammatory cytokines and iNOS, expression of COX-2, generation of ROS, and associated signaling following treatment of glial cells with LPS and Abeta peptide. We also investigated the neuroprotective effects of AICAR against the effects of cytokines and inflammatory mediators (released by the glia), in blocking neurite outgrowth inhibition, and in nerve growth factor-(NGF) induced neurite extension by PC-12 cells. RESULTS: AICAR blocked LPS/Abeta-induced inflammatory processes by blocking the expression of proinflammatory cytokine, iNOS, COX-2 and MnSOD genes, and by inhibition of ROS generation and depletion of glutathione in astroglial cells. AICAR also inhibited down-stream signaling leading to the regulation of transcriptional factors such as NFkappaB and C/EBP which are critical for the expression of iNOS, COX-2, MnSOD and cytokines (TNF-alpha/IL-1beta and IL-6). AICAR promoted NGF-induced neurite growth and reduced neurite outgrowth inhibition in PC-12 cells treated with astroglial conditioned medium. CONCLUSION: The observed anti-inflammatory/anti-oxidant and neuroprotective functions of AICAR suggest it as a viable candidate for use in treatment of Alzheimer's disease. [Abstract/Link to Full Text]

Mander P, Brown GC
Activation of microglial NADPH oxidase is synergistic with glial iNOS expression in inducing neuronal death: a dual-key mechanism of inflammatory neurodegeneration.
J Neuroinflammation. 2005 Sep 12;220.
BACKGROUND: Inflammation-activated glia are seen in many CNS pathologies and may kill neurons through the release of cytotoxic mediators, such as nitric oxide from inducible NO synthase (iNOS), and possibly superoxide from NADPH oxidase (NOX). We set out to determine the relative role of these species in inducing neuronal death, and to test the dual-key hypothesis that the production of both species simultaneously is required for significant neuronal death. METHODS: Primary co-cultures of cerebellar granule neurons and glia from rats were used to investigate the effect of NO (from iNOS, following lipopolysaccharide (LPS) and/or cytokine addition) or superoxide/hydrogen peroxide (from NOX, following phorbol 12-myristate 13-acetate (PMA), ATP analogue (BzATP), interleukin-1beta (IL-1beta) or arachidonic acid (AA) addition) on neuronal survival. RESULTS: Induction of glial iNOS caused little neuronal death. Similarly, activation of NOX alone resulted in little or no neuronal death. However, if NOX was activated (by PMA or BzATP) in the presence of iNOS (induced by LPS and interferon-gamma) then substantial delayed neuronal death occurred over 48 hours, which was prevented by inhibitors of iNOS (1400W), NOX (apocynin) or a peroxynitrite decomposer (FeTPPS). Neurons and glia were also found to stain positive for nitrotyrosine (a putative marker of peroxynitrite) only when both iNOS and NOX were simultaneously active. If NOX was activated by weak stimulators (IL-1beta, AA or the fibrillogenic prion peptide PrP106-126) in the presence of iNOS, it caused microglial proliferation and delayed neurodegeneration, which was prevented by iNOS or NOX inhibitors, a peroxynitrite decomposer or a NMDA-receptor antagonist (MK-801). CONCLUSION: These results suggest a dual-key mechanism, whereby glial iNOS or microglial NOX activation alone is relatively benign, but if activated simultaneously are synergistic in killing neurons, through generating peroxynitrite. This mechanism may mediate inflammatory neurodegeneration in response to cytokines, bacteria, ATP, arachidonate and pathological prions, in which case neurons may be protected by iNOS or NOX inhibitors, or scavengers of NO, superoxide or peroxynitrite. [Abstract/Link to Full Text]

Thomas MS, Zhang W, Jordan PM, Saragovi HU, Taglialatela G
Signaling pathways mediating a selective induction of nitric oxide synthase II by tumor necrosis factor alpha in nerve growth factor-responsive cells.
J Neuroinflammation. 2005 Sep 6;219.
BACKGROUND: Inflammation and oxidative stress play a critical role in neurodegeneration associated with acute and chronic insults of the nervous system. Notably, affected neurons are often responsive to and dependent on trophic factors such as nerve growth factor (NGF). We previously showed in NGF-responsive PC12 cells that tumor necrosis factor alpha (TNFalpha) and NGF synergistically induce the expression of the free-radical producing enzyme inducible nitric oxide synthase (iNOS). We proposed that NGF-responsive neurons might be selectively exposed to iNOS-mediated oxidative damage as a consequence of elevated TNFalpha levels. With the aim of identifying possible therapeutic targets, in the present study we investigated the signaling pathways involved in NGF/TNFalpha-promoted iNOS induction. METHODS: Western blotting, RT-PCR, transcription factor-specific reporter gene systems, mutant cells lacking the low affinity p75NTR NGF receptor and transfections of TNFalpha/NGF chimeric receptors were used to investigate signalling events associated with NGF/TNFalpha-promoted iNOS induction in PC12 cells. RESULTS: Our results show that iNOS expression resulting from NGF/TNFalpha combined treatment can be elicited in PC12 cells. Mutant PC12 cells lacking p75NTR did not respond, suggesting that p75NTR is required to mediate iNOS expression. Furthermore, cells transfected with chimeric TNFalpha/NGF receptors demonstrated that the simultaneous presence of both p75NTR and TrkA signaling is necessary to synergize with TNFalpha to mediate iNOS expression. Lastly, our data show that NGF/TNFalpha-promoted iNOS induction requires activation of the transcription factor nuclear factor kappa B (NF-kappaB). CONCLUSION: Collectively, our in vitro model suggests that cells bearing both the high and low affinity NGF receptors may display increased sensitivity to TNFalpha in terms of iNOS expression and therefore be selectively at risk during acute (e.g. neurotrauma) or chronic (e.g. neurodegenerative diseases) conditions where high levels of pro-inflammatory cytokines in the nervous system occur pathologically. Our results also suggest that modulation of NFkappaB-promoted transcription of selective genes could serve as a potential therapeutic target to prevent neuroinflammation-induced neuronal damage. [Abstract/Link to Full Text]

Strohmeyer R, Kovelowski CJ, Mastroeni D, Leonard B, Grover A, Rogers J
Microglial responses to amyloid beta peptide opsonization and indomethacin treatment.
J Neuroinflammation. 2005 Aug 19;218.
BACKGROUND: Recent studies have suggested that passive or active immunization with anti-amyloid beta peptide (Abeta) antibodies may enhance microglial clearance of Abeta deposits from the brain. However, in a human clinical trial, several patients developed secondary inflammatory responses in brain that were sufficient to halt the study. METHODS: We have used an in vitro culture system to model the responses of microglia, derived from rapid autopsies of Alzheimer's disease patients, to Abeta deposits. RESULTS: Opsonization of the deposits with anti-Abeta IgG 6E10 enhanced microglial chemotaxis to and phagocytosis of Abeta, as well as exacerbated microglial secretion of the pro-inflammatory cytokines TNF-alpha and IL-6. Indomethacin, a common nonsteroidal anti-inflammatory drug (NSAID), had no effect on microglial chemotaxis or phagocytosis, but did significantly inhibit the enhanced production of IL-6 after Abeta opsonization. CONCLUSION: These results are consistent with well known, differential NSAID actions on immune cell functions, and suggest that concurrent NSAID administration might serve as a useful adjunct to Abeta immunization, permitting unfettered clearance of Abeta while dampening secondary, inflammation-related adverse events. [Abstract/Link to Full Text]

Sunnemark D, Eltayeb S, Nilsson M, Wallstr�m E, Lassmann H, Olsson T, Berg AL, Ericsson-Dahlstrand A
CX3CL1 (fractalkine) and CX3CR1 expression in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis: kinetics and cellular origin.
J Neuroinflammation. 2005 Jul 29;217.
BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). It is associated with local activation of microglia and astroglia, infiltration of activated macrophages and T cells, active degradation of myelin and damage to axons and neurons. The proposed role for CX3CL1 (fractalkine) in the control of microglia activation and leukocyte infiltration places this chemokine and its receptor CX3CR1 in a potentially strategic position to control key aspects in the pathological events that are associated with development of brain lesions in MS. In this study, we examine this hypothesis by analyzing the distribution, kinetics, regulation and cellular origin of CX3CL1 and CX3CR1 mRNA expression in the CNS of rats with an experimentally induced MS-like disease, myelin oligodendrocyte glycoprotein (MOG)-induced autoimmune encephalomyelitis (EAE). METHODS: The expression of CX3CL1 and its receptor CX3CR1 was studied with in situ hybridization histochemical detection of their mRNA with radio labeled cRNA probes in combination with immunohistochemical staining of phenotypic cell markers. Both healthy rat brains and brains from rats with MOG EAE were analyzed. In defined lesional stages of MOG EAE, the number of CX3CR1 mRNA-expressing cells and the intensity of the in situ hybridization signal were determined by image analysis. Data were statistically evaluated by ANOVA, followed by Tukey\primes multiple comparison test. RESULTS: Expression of CX3CL1 mRNA was present within neuronal-like cells located throughout the neuraxis of the healthy rat. Expression of CX3CL1 remained unaltered in the CNS of rats with MOG-induced EAE, with the exception of an induced expression in astrocytes within inflammatory lesions. Notably, the brain vasculature of healthy and encephalitic animals did not exhibit signs of CX3CL1 mRNA expression. The receptor, CX3CR1, was expressed by microglial cells in all regions of the healthy brain. Induction of MOG-induced EAE was associated with a distinct accumulation of CX3CR1 mRNA expressing cells within the inflammatory brain lesions, the great majority of which stained positive for markers of the microglia-macrophage lineage. Analysis in time-staged brain lesions revealed elevated levels of CX3CR1 mRNA in microglia in the periplaque zone, as well as a dramatically enhanced accumulation of CX3CR1 expressing cells within the early-active, late-active and inactive, demyelinated lesions. CONCLUSION: Our data demonstrate constitutive and regulated expression of the chemokine CX3CL1 and its receptor CX3CR1 by neurons/astrocytes and microglia, respectively, within the normal and inflamed rat brain. Our findings propose a mechanism by which neurons and reactive astrocytes may control migration and function of the surrounding microglia. In addition, the accumulation of CX3CR1 expressing cells other than microglia within the inflammatory brain lesions indicate a possible role for CX3CL1 in controlling invasion of peripheral leucocytes to the brain. [Abstract/Link to Full Text]

Guillemin GJ, Wang L, Brew BJ
Quinolinic acid selectively induces apoptosis of human astrocytes: potential role in AIDS dementia complex.
J Neuroinflammation. 2005 Jul 26;216.
There is evidence that the kynurenine pathway (KP) and particularly one of its end products, quinolinic acid (QUIN) play a role in the pathogenesis of several major neuroinflammatory diseases, and more particularly AIDS dementia complex (ADC). We hypothesized that QUIN may be involved in astrocyte apoptosis because: 1) apoptotic astrocytes have been observed in the brains of ADC patients, 2) ADC patients have elevated cerebrospinal fluid QUIN concentrations, and 3) QUIN can induce astrocyte death. Primary cultures of human fetal astrocytes were treated with three pathophysiological concentrations of QUIN. Numeration of apoptotic cells was assessed using double immunocytochemistry for expression of active caspase 3 and for nucleus condensation. We found that treatment of human astrocytes with QUIN induced morphological (cell body shrinking) and biochemical changes (nucleus condensation and over-expression of active caspase 3) of apoptosis. After 24 hours of treatment with QUIN 500 nM and 1200 nM respectively 10 and 14% of astrocytes were undergoing apoptosis. This would be expected to lead to a relative lack of trophic support factors with consequent neuronal dysfunction and possibly death. Astroglial apoptosis induced by QUIN provides another potential mechanism for the neurotoxicity of QUIN during ADC. [Abstract/Link to Full Text]

Craft JM, Watterson DM, Hirsch E, Van Eldik LJ
Interleukin 1 receptor antagonist knockout mice show enhanced microglial activation and neuronal damage induced by intracerebroventricular infusion of human beta-amyloid.
J Neuroinflammation. 2005 Jun 20;215.
BACKGROUND: Interleukin 1 (IL-1) is a key mediator of immune responses in health and disease. Although classically the function of IL-1 has been studied in the systemic immune system, research in the past decade has revealed analogous roles in the CNS where the cytokine can contribute to the neuroinflammation and neuropathology seen in a number of neurodegenerative diseases. In Alzheimer's disease (AD), for example, pre-clinical and clinical studies have implicated IL-1 in the progression of a pathologic, glia-mediated pro-inflammatory state in the CNS. The glia-driven neuroinflammation can lead to neuronal damage, which, in turn, stimulates further glia activation, potentially propagating a detrimental cycle that contributes to progression of pathology. A prediction of this neuroinflammation hypothesis is that increased IL-1 signaling in vivo would correlate with increased severity of AD-relevant neuroinflammation and neuronal damage. METHODS: To test the hypothesis that increased IL-1 signaling predisposes animals to beta-amyloid (Abeta)-induced damage, we used IL-1 receptor antagonist Knock-Out (IL1raKO) and wild-type (WT) littermate mice in a model that involves intracerebroventricular infusion of human oligomeric Abeta1-42. This model mimics many features of AD, including robust neuroinflammation, Abeta plaques, synaptic damage and neuronal loss in the hippocampus. IL1raKO and WT mice were infused with Abeta for 28 days, sacrificed at 42 days, and hippocampal endpoints analyzed. RESULTS: IL1raKO mice showed increased vulnerability to Abeta-induced neuropathology relative to their WT counterparts. Specifically, IL1raKO mice exhibited increased mortality, enhanced microglial activation and neuroinflammation, and more pronounced loss of synaptic markers. Interestingly, Abeta-induced astrocyte responses were not significantly different between WT and IL1raKO mice, suggesting that enhanced IL-1 signaling predominately affects microglia. CONCLUSION: Our data are consistent with the neuroinflammation hypothesis whereby increased IL-1 signaling in AD enhances glia activation and leads to an augmented neuroinflammatory process that increases the severity of neuropathologic sequelae. [Abstract/Link to Full Text]

Croisier E, Moran LB, Dexter DT, Pearce RK, Graeber MB
Microglial inflammation in the parkinsonian substantia nigra: relationship to alpha-synuclein deposition.
J Neuroinflammation. 2005 Jun 3;214.
BACKGROUND: The role of both microglial activation and alpha-synuclein deposition in Parkinson's disease remain unclear. We have tested the hypothesis that if microglia play a primary role in Parkinson's disease pathogenesis, the microglial "activated" phenotype should be associated with histopathological and/or clinical features of the disease. METHODS: We have examined microglial MHC class II expression, a widely used marker of microglial activation, the occurrence of CD68-positive phagocytes and alpha-synuclein immunoreactivity in post-mortem human substantia nigra affected by idiopathic Parkinson's disease (PD). Using semi-quantitative severity ratings, we have examined the relationship between microglial activation, alpha-synuclein deposition, classical neuropathological criteria for PD, subtype of the disease and clinical course. RESULTS: While we did not observe an association between microglial MHC class II expression and clinical parameters, we did find a correlation between disease duration and the macrophage marker CD68 which is expressed by phagocytic microglia. In addition, we observed a significant correlation between the degree of MHC class II expression and alpha-synuclein deposition in the substantia nigra in PD. CONCLUSION: While microglia appeared to respond to alpha-synuclein deposition, MHC class II antigen expression by microglia in the substantia nigra cannot be used as an indicator of clinical PD severity or disease progression. In addition, a contributory or even causative role for microglia in the neuronal loss associated with PD as suggested by some authors seems unlikely. Our data further suggest that an assessment of microglial activation in the aged brain on the basis of immunohistochemistry for MHC class II antigens alone should be done with caution. [Abstract/Link to Full Text]

Adamashvili I, Minagar A, Gonzalez-Toledo E, Featherston L, Kelley RE
Soluble HLA measurement in saliva and cerebrospinal fluid in Caucasian patients with multiple sclerosis: a preliminary study.
J Neuroinflammation. 2005 Jun 2;213.
BACKGROUND: Measurement of soluble HLA in body fluids has a potential role in assessing disease activity in autoimmune disorders. METHODS: We applied a solid phase, enzyme-linked immunoassay to measure soluble HLA class I (sHLA-I) and class II (sHLA-II) molecules in the saliva and cerebrospinal fluid (CSF) in 13 untreated patients with relapsing-remitting form of multiple sclerosis (MS). For comparison purposes, we also studied saliva from 53 healthy subjects. RESULTS: Saliva from normal controls had detectable sHLA-I levels in 41 of 53 individuals studied, with values ranging from 9-100 ng/ml (mean = 41 +/- 2.8 ng/ml). sHLA-I was undetectable in the saliva in 11 of 13 MS patients, and in none of the CSF specimens. In contrast, mean sHLA-II concentration in the saliva of MS patients was significantly increased compared to controls (386 +/- 52 unit/ml vs. 222 +/- 18.4 unit/ml, t = 8.68, P < 0.005). The mean CSF sHLA-II level (369 +/- 16 unit/ml) was equivalent to the mean sHLA-II concentration measured in saliva (mean = 386 +/- 52 unit/ml) (P = 0.7). In patients with brain magnetic resonance imaging (MRI) enhancing lesions (n = 5), reflective of more active disease, CSF sHLA-II averaged 356 +/- 26 unit/ml compared to 380 +/- 51 in saliva. Similarly, in patients with non-enhancing lesions (n = 8), CSF sHLA-II averaged 377 +/- 18 unit/ml compared to 390 +/- 77 unit/ml in saliva. Thus, the mean sHLA-II concentration in saliva and CSF was essentially equivalent for MS patients with or without enhancing plaques. CONCLUSION: Our data suggest that the measurement of soluble HLA in saliva, specifically sHLA-II, correlates with the level found in the CSF. Therefore, if sHLA correlates with disease activity in MS, as has been proposed, saliva measurements provide a noninvasive correlate of CSF measurement. [Abstract/Link to Full Text]

Peluffo H, Acarin L, Faiz M, Castellano B, Gonzalez B
Cu/Zn superoxide dismutase expression in the postnatal rat brain following an excitotoxic injury.
J Neuroinflammation. 2005 Jun 1;2(1):12.
BACKGROUND: In the nervous system, as in other organs, Cu/Zn superoxide dismutase (Cu/Zn SOD) is a key antioxidant enzyme involved in superoxide detoxification in normal cellular metabolism and after cell injury. Although it has been suggested that immature brain has a different susceptibility to oxidative damage than adult brain, the distribution and cell-specific expression of this enzyme in immature brain and after postnatal brain damage has not been documented. METHODS: In this study, we used immunohistochemistry and western blot to analyze the expression of Cu/Zn SOD in intact immature rat brain and in immature rat brain after an NMDA-induced excitotoxic cortical injury performed at postnatal day 9. Double immunofluorescence labelling was used to identify Cu/Zn SOD-expressing cell populations. RESULTS: In intact immature brain, Cu/Zn SOD enzyme was widely expressed at high levels in neurons mainly located in cortical layers II, III and V, in the sub-plate, in the pyriform cortex, in the hippocampus, and in the hypothalamus. Glial fibrillary acidic protein-positive cells only showed Cu/Zn SOD expression in the glia limitans and in scattered cells of the ventricle walls. No expression was detected in interfascicular oligodendroglia, microglia or endothelial cells. Following excitotoxic damage, neuronal Cu/Zn SOD was rapidly downregulated (over 2-4 hours) at the injection site before neurodegeneration signals and TUNEL staining were observed. Later, from 1 day post-lesion onward, an upregulation of Cu/Zn SOD was found due to increased expression in astroglia. A further increase was observed at 3, 5 and 7 days that corresponded to extensive induction of Cu/Zn SOD in highly reactive astrocytes and in the astroglial scar. CONCLUSION: We show here that, in the intact immature brain, the expression of Cu/Zn SOD was mainly found in neurons. When damage occurs, a strong and very rapid downregulation of this enzyme precedes neuronal degeneration, and is followed by an upregulation of Cu/Zn SOD in astroglial cells. [Abstract/Link to Full Text]

Sattayaprasert P, Choi HB, Chongthammakun S, McLarnon JG
Platelet-activating factor enhancement of calcium influx and interleukin-6 expression, but not production, in human microglia.
J Neuroinflammation. 2005 Apr 15;2(1):11.
Calcium-sensitive fluorescence microscopy and molecular biology analysis have been used to study the effects of platelet-activating factor (PAF) on intracellular calcium [Ca2+]i and IL-6 expression in human microglia. PAF (applied acutely at 100 nM) elicited a biphasic response in [Ca2+]i consisting of an initial rapid increase of [Ca2+]i due to release from internal stores, followed by a sustained influx. The latter phase of the [Ca2+]i increase was blocked by SKF96365, a non-selective store-operated channel (SOC) inhibitor. RT-PCR analysis showed PAF treatment of microglia induced expression of the pro-inflammatory cytokine IL-6 in a time-dependent manner which was blocked in the presence of SKF96365. However, ELISA assay showed no production of IL-6 was elicited at any time point (1-24 h) for microglial exposures to PAF. These findings suggest that PAF stimulation of human microglia induces expression, but not production, of IL-6 and that SOC-mediated [Ca2+]i influx contributes to the enhanced expression of the cytokine. [Abstract/Link to Full Text]

Kagitani-Shimono K, Mohri I, Fujitani Y, Suzuki K, Ozono K, Urade Y, Taniike M
Anti-inflammatory therapy by ibudilast, a phosphodiesterase inhibitor, in demyelination of twitcher, a genetic demyelination model.
J Neuroinflammation. 2005 Apr 6;2(1):10.
BACKGROUND: Twitcher mouse (twi/twi) is an authentic murine model of Krabbe's disease. Accumulation of psychosine, resulting in apoptosis of oligodendrocytes and subsequent demyelination, is a cardinal event to the pathogenesis of this disease. Moreover, recruitment of inflammatory cells plays a significant role in the pathological process in the twi/twi central and peripheral nervous systems. In this study, we investigated the 1) the relationship between tumor necrosis factor-alpha (TNFalpha), pro-inflammatory cytokine, and the progression of this disease and 2) effect of the anti-inflammatory therapy by ibudilast, a phosphodiesterase inhibitor. METHODS: We quantified the expression level of TNFalpha and TNF-receptor mRNA in twi/twi using semi-quantitative RT-PCR. The relationship between TNFalpha expression, apoptosis of oligodendrocytes and demyelination was studied with immunohistochemistry and TUNEL method. We then treated twi/twi with a daily intraperitoneal injection of ibudilast (10 mg/kg), which suppress TNFalpha production in the brain. RESULTS: We found that TNFalpha-immunoreactive microglia/macrophages appeared in the twi/twi brain and that the mRNA levels of TNFalpha and TNF-receptor 1 was increased with the progression of demyelination. The distribution profile of TNFalpha-immunoreactive microglia/macrophages overlapped that of TUNEL-positive oligodendrocytes in the twi/twi brain. When twi/twi was treated with ibudilast from PND30, the number of oligodendrocytes undergoing apoptosis was markedly reduced and demyelination was milder. Obvious improvement of clinical symptom was noted in two of five. The failure of constant clinical improvement by ibudilast may result from hepatotoxicity and/or the inhibition of proliferation of NG2-positive oligodendrocyte precursors. CONCLUSION: We conclude that anti-inflammatory therapy by a phosphodiesterase inhibitor can be considered as a novel alternative therapy for Krabbe's disease. [Abstract/Link to Full Text]

Patel NS, Paris D, Mathura V, Quadros AN, Crawford FC, Mullan MJ
Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer's disease.
J Neuroinflammation. 2005 Mar 11;2(1):9.
BACKGROUND: Inflammation is believed to play an important role in the pathology of Alzheimer's disease (AD) and cytokine production is a key pathologic event in the progression of inflammatory cascades. The current study characterizes the cytokine expression profile in the brain of two transgenic mouse models of AD (TgAPPsw and PS1/APPsw) and explores the correlations between cytokine production and the level of soluble and insoluble forms of Abeta. METHODS: Organotypic brain slice cultures from 15-month-old mice (TgAPPsw, PS1/APPsw and control littermates) were established and multiple cytokine levels were analyzed using the Bio-plex multiple cytokine assay system. Soluble and insoluble forms of Abeta were quantified and Abeta-cytokine relationships were analyzed. RESULTS: Compared to control littermates, transgenic mice showed a significant increase in the following pro-inflammatory cytokines: TNF-alpha, IL-6, IL-12p40, IL-1beta, IL-1alpha and GM-CSF. TNF-alpha, IL-6, IL-1alpha and GM-CSF showed a sequential increase from control to TgAPPsw to PS1/APPsw suggesting that the amplitude of this cytokine response is dependent on brain Abeta levels, since PS1/APPsw mouse brains accumulate more Abeta than TgAPPsw mouse brains. Quantification of Abeta levels in the same slices showed a wide range of Abeta soluble:insoluble ratio values across TgAPPsw and PS1/APPsw brain slices. Abeta-cytokine correlations revealed significant relationships between Abeta1-40, 1-42 (both soluble and insoluble) and all the above cytokines that changed in the brain slices. CONCLUSION: Our data confirm that the brains of transgenic APPsw and PS1/APPsw mice are under an active inflammatory stress, and that the levels of particular cytokines may be directly related to the amount of soluble and insoluble Abeta present in the brain suggesting that pathological accumulation of Abeta is a key driver of the neuroinflammatory response. [Abstract/Link to Full Text]

Tomita M, Holman BJ, Santoro CP, Santoro TJ
Astrocyte production of the chemokine macrophage inflammatory protein-2 is inhibited by the spice principle curcumin at the level of gene transcription.
J Neuroinflammation. 2005 Feb 25;2(1):8.
BACKGROUND: In neuropathological processes associated with neutrophilic infiltrates, such as experimental allergic encephalitis and traumatic injury of the brain, the CXC chemokine, macrophage inflammatory protein-2 (MIP-2) is thought to play a pivotal role in the induction and perpetuation of inflammation in the central nervous system (CNS). The origin of MIP-2 in inflammatory disorders of the brain has not been fully defined but astrocytes appear to be a dominant source of this chemokine.Curcumin is a spice principle in, and constitutes approximately 4 percent of, turmeric. Curcumin's immunomodulating and antioxidant activities suggest that it might be a useful adjunct in the treatment of neurodegenerative illnesses characterized by inflammation. Relatively unexplored, but relevant to its potential therapeutic efficacy in neuroinflammatory syndromes is the effect of curcumin on chemokine production. To examine the possibility that curcumin may influence CNS inflammation by mechanisms distinct from its known anti-oxidant activities, we studied the effect of this spice principle on the synthesis of MIP-2 by astrocytes. METHODS: Primary astrocytes were prepared from neonatal brains of CBA/CaJ mice. The cells were stimulated with lipopolysaccharide in the presence or absence of various amount of curcumin or epigallocatechin gallate. MIP-2 mRNA was analyzed using semi-quantitative PCR and MIP-2 protein production in the culture supernatants was quantified by ELISA. Astrocytes were transfected with a MIP-2 promoter construct, pGL3-MIP-2, and stimulated with lipopolysaccharide in the presence or absence of curcumin. RESULTS: The induction of MIP-2 gene expression and the production of MIP-2 protein were inhibited by curcumin. Curcumin also inhibited lipopolysaccharide-induced transcription of the MIP-2 promoter reporter gene construct in primary astrocytes. However MIP-2 gene induction by lipopolysaccharide was not inhibited by another anti-oxidant, epigallocatechin gallate. CONCLUSION: Our results indicate that curcumin potently inhibits MIP-2 production at the level of gene transcription and offer further support for its potential use in the treatment of inflammatory conditions of the CNS. [Abstract/Link to Full Text]

Banisor I, Leist TP, Kalman B
Involvement of beta-chemokines in the development of inflammatory demyelination.
J Neuroinflammation. 2005 Feb 24;2(1):7.
The importance of beta-chemokines (or CC chemokine ligands - CCL) in the development of inflammatory lesions in the central nervous system of patients with multiple sclerosis and rodents with experimental allergic encephalomyelitis is strongly supported by descriptive studies and experimental models. Our recent genetic scans in families identified haplotypes in the genes of CCL2, CCL3 and CCL11-CCL8-CCL13 which showed association with multiple sclerosis. Complementing the genetic associations, we also detected a distinct regional expression regulation for CCL2, CCL7 and CCL8 in correlation with chronic inflammation in multiple sclerosis brains. These observations are in consensus with previous studies, and add new data to support the involvement of CCL2, CCL7, CCL8 and CCL3 in the development of inflammatory demyelination. Along with our own data, here we review the literature implicating CCLs and their receptors (CCRs) in multiple sclerosis and experimental allergic encephalomyelitis. The survey reflects that the field is in a rapid expansion, and highlights some of the pathways which might be suitable to pharmaceutical interventions. [Abstract/Link to Full Text]

Harding DR, Dhamrait S, Devadason D, Humphries SE, Whitelaw A, Marlow N, Montgomery HE
Does angiotensin-1 converting enzyme genotype influence motor or cognitive development after pre-term birth?
J Neuroinflammation. 2005 Feb 22;2(1):6.
ABSTRACT : BACKGROUND : Raised activity of the renin-angiotensin system (RAS) may both amplify inflammatory and free radical responses and decrease tissue metabolic efficiency and thus enhance cerebral injury in the preterm infant. The angiotensin-converting enzyme (ACE) DD genotype is associated with raised ACE and RAS activity as well as potentially adverse stimuli such as inflammation. The DD genotype has been associated with neurological impairments in the elderly, and thus may be also associated with poorer motor or cognitive development amongst children born preterm prematurely. METHODS : The association of DD genotype with developmental progress amongst 176 Caucasian children born at less than 33 weeks gestation (median birthweight 1475 g, range 645-2480 g; gestation 30 weeks, range 22-32; 108 male) was examined at 2 and 5 1/2 years of age. Measured neuro-cognitive outcomes were cranial ultrasound abnormalities, cerebral palsy, disability, Griffiths Developmental Quotient [DQ] at 2 yrs, and General Cognitive Ability [British Ability Scales-11] and motor performance [ABC Movement], both performed at 5 1/2 yrs. All outcomes were correlated with ACE genotype. RESULTS : The DD genotype was not associated with lower developmental quotients even after accounting for important social variables. CONCLUSION : These data do not support either a role for ACE in the development of cognitive or motor function in surviving infants born preterm or inhibition of ACE as a neuroprotective therapy. [Abstract/Link to Full Text]

Carbonell WS, Murase SI, Horwitz AF, Mandell JW
Infiltrative microgliosis: activation and long-distance migration of subependymal microglia following periventricular insults.
J Neuroinflammation. 2005 Jan 28;2(1):5.
BACKGROUND: Subventricular microglia (SVMs) are positioned at the interface of the cerebrospinal fluid and brain parenchyma and may play a role in periventricular inflammatory reactions. However, SVMs have not been previously investigated in detail due to the lack of a specific methodology for their study exclusive of deeper parenchymal microglia. METHODS: We have developed and characterized a novel model for the investigation of subventricular microglial reactions in mice using intracerebroventricular (ICV) injection of high-dose rhodamine dyes. Dynamic studies using timelapse confocal microscopy in situ complemented the histopathological analysis. RESULTS: We demonstrate that high-dose ICV rhodamine dye injection resulted in selective uptake by the ependyma and ependymal death within hours. Phagocytosis of ependymal debris by activated SVMs was evident by 1d as demonstrated by the appearance of rhodamine-positive SVMs. In the absence of further manipulation, labelled SVMs remained in the subventricular space. However, these cells exhibited the ability to migrate several hundred microns into the parenchyma towards a deafferentation injury of the hippocampus. This "infiltrative microgliosis" was verified in situ using timelapse confocal microscopy. Finally, supporting the disease relevance of this event, the triad of ependymal cell death, SVM activation, and infiltrative microgliosis was recapitulated by a single ICV injection of HIV-1 tat protein. CONCLUSIONS: Subependymal microglia exhibit robust activation and migration in periventricular inflammatory responses. Further study of this population of microglia may provide insight into neurological diseases with tendencies to involve the ventricular system and periventricular tissues. [Abstract/Link to Full Text]

De Simone R, Ajmone-Cat MA, Carnevale D, Minghetti L
Activation of alpha7 nicotinic acetylcholine receptor by nicotine selectively up-regulates cyclooxygenase-2 and prostaglandin E2 in rat microglial cultures.
J Neuroinflammation. 2005 Jan 25;2(1):4.
BACKGROUND: Nicotinic acetylcholine (Ach) receptors are ligand-gated pentameric ion channels whose main function is to transmit signals for the neurotransmitter Ach in peripheral and central nervous system. However, the alpha7 nicotinic receptor has been recently found in several non-neuronal cells and described as an important regulator of cellular function. Nicotine and ACh have been recently reported to inhibit tumor necrosis factor-alpha (TNF-alpha) production in human macrophages as well as in mouse microglial cultures. In the present study, we investigated whether the stimulation of alpha7 nicotinic receptor by the specific agonist nicotine could affect the functional state of activated microglia by promoting and/or inhibiting the release of other important pro-inflammatory and lipid mediator such as prostaglandin E2. METHODS: Expression of alpha7 nicotinic receptor in rat microglial cell was examined by RT-PCR, immunofluorescence staining and Western blot. The functional effects of alpha7 receptor activation were analyzed in resting or lipopolysaccharide (LPS) stimulated microglial cells pre-treated with nicotine. Culture media were assayed for the levels of tumor necrosis factor, interleukin-1beta, nitric oxide, interleukin-10 and prostaglandin E2. Total RNA was assayed by RT-PCR for the expression of COX-2 mRNA. RESULTS: Rat microglial cells express alpha7 nicotinic receptor, and its activation by nicotine dose-dependently reduces the LPS-induced release of TNF-alpha, but has little or no effect on nitric oxide, interleukin-10 and interleukin-1beta. By contrast, nicotine enhances the expression of cyclooxygenase-2 and the synthesis of one of its major products, prostaglandin E2. CONCLUSIONS: Since prostaglandin E2 modulates several macrophage and lymphocyte functions, which are instrumental for inflammatory resolution, our study further supports the existence of a brain cholinergic anti-inflammatory pathway mediated by alpha7 nicotinic receptor that could be potentially exploited for novel treatments of several neuropathologies in which local inflammation, sustained by activated microglia, plays a crucial role. [Abstract/Link to Full Text]

Candelario-Jalil E, Mhadu NH, Gonz�lez-Falc�n A, Garc�a-Cabrera M, Mu�oz E, Le�n OS, Fiebich BL
Effects of the cyclooxygenase-2 inhibitor nimesulide on cerebral infarction and neurological deficits induced by permanent middle cerebral artery occlusion in the rat.
J Neuroinflammation. 2005 Jan 18;2(1):3.
BACKGROUND: Previous studies suggest that the cyclooxygenase-2 (COX-2) inhibitor nimesulide has a remarkable protective effect against different types of brain injury including ischemia. Since there are no reports on the effects of nimesulide on permanent ischemic stroke and because most cases of human stroke are caused by permanent occlusion of cerebral arteries, the present study was conducted to assess the neuroprotective efficacy of nimesulide on the cerebral infarction and neurological deficits induced by permanent middle cerebral artery occlusion (pMCAO) in the rat. METHODS: Ischemia was induced by permanent occlusion of the middle cerebral artery in rats, via surgical insertion of a nylon filament into the internal carotid artery. Infarct volumes (cortical, subcortical and total) and functional recovery, assessed by neurological score evaluation and rotarod performance test, were performed 24 h after pMCAO. In initial experiments, different doses of nimesulide (3, 6 and 12 mg/kg; i.p) or vehicle were administered 30 min before pMCAO and again at 6, 12 and 18 h after stroke. In later experiments we investigated the therapeutic time window of protection of nimesulide by delaying its first administration 0.5-4 h after the ischemic insult. RESULTS: Repeated treatments with nimesulide dose-dependently reduced cortical, subcortical and total infarct volumes as well as the neurological deficits and motor impairment resulting from permanent ischemic stroke, but only the administration of the highest dose (12 mg/kg) was able to significantly (P < 0.01) diminish infarct volume. The lower doses failed to significantly reduce infarction but showed a beneficial effect on neurological function. Nimesulide (12 mg/kg) not only reduced infarct volume but also enhanced functional recovery when the first treatment was given up to 2 h after stroke. CONCLUSIONS: These data show that nimesulide protects against permanent focal cerebral ischemia, even with a 2 h post-treatment delay. These findings have important implications for the therapeutic potential of using COX-2 inhibitors in the treatment of stroke. [Abstract/Link to Full Text]

Barger SW
Vascular consequences of passive Abeta immunization for Alzheimer's disease. Is avoidance of "malactivation" of microglia enough?
J Neuroinflammation. 2005 Jan 11;2(1):2.
The role of inflammation in Alzheimer's disease (AD) has been controversial since its first consideration. As with most instances of neuroinflammation, the possibility must be considered that activation of glia and cytokine networks in AD arises merely as a reaction to neurodegeneration. Active, healthy neurons produce signals that suppress inflammatory events, and dying neurons activate phagocytic responses in microglia at the very least. But simultaneous with the arrival of a more complex view of microglia, evidence that inflammation plays a causal or exacerbating role in AD etiology has been boosted by genetic, physiological, and epidemiological studies. In the end, it may be that the semantics of "inflammation" and glial "activation" must be regarded as too simplistic for the advancement of our understanding in this regard. It is clear that elaboration of the entire repertoire of activated microglia - a phenomenon that may be termed "malactivation" - must be prevented for healthy brain structure and function. Nevertheless, recent studies have suggested that phagocytosis of Abeta by microglia plays an important role in clearance of amyloid plaques, a process boosted by immunization paradigms. To the extent that this clearance might produce clinical improvements (still an open question), this relationship thus obligates a more nuanced consideration of the factors that indicate and control the various activities of microglia and other components of neuroinflammation. [Abstract/Link to Full Text]

Recent Articles in Journal of Vision

Wolfson SS, Graham N
An unusual kind of contrast adaptation: shifting a contrast comparison level.
J Vis. 2007;7(8):12.
We have found an unusual kind of contrast adaptation in human pattern vision that seems fundamentally different from previously reported effects. As the observer adapts to different levels of contrast, the visibility of some contrast-defined (second-order) patterns dramatically increases and that of others dramatically decreases. Oddly, visibility is poor for patterns containing contrasts both above and below the recent average contrast. To explain these effects, we hypothesize a new kind of process acting in concert with a known contrast-gain control of the normalization type. The new process compares current contrast to an adaptable comparison level; this level reflects the recent average contrast. Such a process existing at an early stage of visual processing is likely to have widespread effects at higher stages. [Abstract/Link to Full Text]

Nagai M, Bennett PJ, Sekuler AB
Spatiotemporal templates for detecting orientation-defined targets.
J Vis. 2007;7(8):11.
Using the classification image technique, the present experiments revealed several characteristics of human observers' spatiotemporal templates for the detection of orientation-defined targets. The stimulus consisted of a spatial 5 x 5 array of elements displayed in 5 (Experiments 1 and 2) or 15 (Experiment 3) temporal frames. A target was defined by the first- or the second-order characteristics of the textures. In Experiment 1, a target signal was presented across all five frames, and observers typically relied on the most reasonable cues in all five frames for detecting targets. In other words, they used the first-order cue for detecting the first-order target and used the second-order cue for detecting the second-order target. Moreover, the spatial profile for detecting the first-order sustained target was localized at the border of the target area, but that for the second-order sustained target showed broader spatial tuning. Presenting the target in just the third temporal frame, as was done in Experiment 2, changed the temporal profile of the observers' templates in the expected manner: Observers used the first-order cue for the first-order target detection and the second-order cue for the second-order target detection only in the third frame. However, changing the temporal characteristics also affected the kinds of spatial cues that were used to detect a target. For example, the classification images revealed that observers used second-order cues (as well as first-order cues) to detect a first-order target, and there was a trend toward increasing the extent of spatial information used when the temporal information was restricted. In Experiment 3, we found similar results for detecting the first-order flashed target with finer, 15-temporal-frame presentation. Lastly, we showed that the classification image is a useful way to reveal individual differences that are not shown with traditional psychophysical techniques. [Abstract/Link to Full Text]

Noest AJ, van Ee R, Nijs MM, van Wezel RJ
Percept-choice sequences driven by interrupted ambiguous stimuli: a low-level neural model.
J Vis. 2007;7(8):10.
Existing neural explanations of spontaneous percept switching under steady viewing of an ambiguous stimulus do not fit the fact that stimulus interruptions cause the same percept to reappear across many ON/OFF cycles. We present a simple neural model that explains the observed behavior and predicts several more complicated percept sequences, without invoking any "high-level" decision making or memory. Percept choice at stimulus onset, which differs fundamentally from standard percept switching, depends crucially on a hitherto neglected interaction between local "shunting" adaptation and a near-threshold neural baseline. Stimulus ON/OFF timing then controls the generation of repeating, alternating, or more complex choice sequences. Our model also explains "priming" versus "habituation" effects on percept choice, reinterprets recent neurophysiological data, and predicts the emergence of hysteresis at the level of percept sequences, with occasional noise-induced sequence "hopping." [Abstract/Link to Full Text]

Gepshtein S, Kubovy M
The lawful perception of apparent motion.
J Vis. 2007;7(8):9.
Visual apparent motion is the experience of motion from the successive stimulation of separate spatial locations. How spatial and temporal distances interact to determine the strength of apparent motion has been controversial. Some studies report space-time coupling: If we increase spatial or temporal distance between successive stimuli, we must also increase the other distance between them to maintain a constant strength of apparent motion (Korte's third law of motion). Other studies report space-time tradeoff: If we increase one of these distances, we must decrease the other to maintain a constant strength of apparent motion. In this article, we resolve the controversy. Starting from a normative theory of motion measurement and data on human spatiotemporal sensitivity, we conjecture that both coupling and tradeoff should occur, but at different speeds. We confirm the prediction in two experiments, using suprathreshold multistable apparent-motion displays called motion lattices. Our results show a smooth transition between the tradeoff and coupling as a function of speed: Tradeoff occurs at low speeds and coupling occurs at high speeds. From our data, we reconstruct the suprathreshold equivalence contours that are analogous to isosensitivity contours obtained at the threshold of visibility. [Abstract/Link to Full Text]

Gepshtein S, Tyukin I, Kubovy M
The economics of motion perception and invariants of visual sensitivity.
J Vis. 2007;7(8):8.
Neural systems face the challenge of optimizing their performance with limited resources, just as economic systems do. Here, we use tools of neoclassical economic theory to explore how a frugal visual system should use a limited number of neurons to optimize perception of motion. The theory prescribes that vision should allocate its resources to different conditions of stimulation according to the degree of balance between measurement uncertainties and stimulus uncertainties. We find that human vision approximately follows the optimal prescription. The equilibrium theory explains why human visual sensitivity is distributed the way it is and why qualitatively different regimes of apparent motion are observed at different speeds. The theory offers a new normative framework for understanding the mechanisms of visual sensitivity at the threshold of visibility and above the threshold and predicts large-scale changes in visual sensitivity in response to changes in the statistics of stimulation and system goals. [Abstract/Link to Full Text]

Hayashi R, Nishida S, Tolias A, Logothetis NK
A method for generating a "purely first-order" dichoptic motion stimulus.
J Vis. 2007;7(8):7.
In the present technical article, we describe a method for generating a new dichoptic motion stimulus, the monocular components of which are dynamic random noise without constant figural cues for feature-tracking-based motion. Our dichoptic motion stimulus adds a new line of evidence, which supports the original conclusion of M. Shadlen and T. Carney (1986) that motion detection can be solely derived from early binocular motion processing. Further, we describe novel motion displays in which monocular motion and binocular motion are in opposite directions with variable intensity ratios. Our dichoptic stimuli will serve as a useful tool to investigate the interaction between low-level binocular motion detectors and monocular motion detectors without requiring feature extraction before motion detection. [Abstract/Link to Full Text]

Wachtler T, Doi E, Lee T, Sejnowski TJ
Cone selectivity derived from the responses of the retinal cone mosaic to natural scenes.
J Vis. 2007;7(8):6.
To achieve color vision, the brain has to process signals of the cones in the retinal photoreceptor mosaic in a cone-type-specific way. We investigated the possibility that cone-type-specific wiring is an adaptation to the statistics of the cone signals. We analyzed estimates of cone responses to natural scenes and found that there is sufficient information in the higher order statistics of L- and M-cone responses to distinguish between cones of different types, enabling unsupervised learning of cone-type specificity. This was not the case for a fourth cone type with spectral sensitivity between L and M cones, suggesting an explanation for the lack of strong tetrachromacy in heterozygous carriers of color deficiencies. [Abstract/Link to Full Text]

Radhakrishnan H, Charman WN
Refractive changes associated with oblique viewing and reading in myopes and emmetropes.
J Vis. 2007;7(8):5.
The effect of brief periods of monocular oblique viewing on axial refractive error in myopes and emmetropes was studied in 20 normal subjects. Refractive error and higher order aberrations were measured either with the subject's head positioned such that the subject looked straight into an aberrometer with the right eye or the subject's head rotated to the right or left by approximately 30 degrees so that the subject had to make an eye rotation of the same angle to see the aberrometer's fixation target. In the first experiment, 10 measurements of wavefront aberration were taken over a period of 3 min at each head position. The refractive changes with oblique viewing showed high levels of intersubject variability. Some subjects showed evidence of systematic change in refraction with oblique viewing. All subjects showed pupil constriction. In the second experiment, after the initial measurement of central and oblique refraction, subjects were made to binocularly read a text placed at 25 cm for 20 min, and the refraction measurements were repeated. No systematic changes in refraction were noted during oblique viewing after 20 min of reading. The data from Experiment 1 give some support for the view that short-term pressures from structures external to the eye may affect its axial refraction. However, the results from Experiment 2 suggest that any such pressures during short-term reading tasks have no significant impact on the axial refraction. [Abstract/Link to Full Text]

Stockman A, Sharpe LT, Tufail A, Kell PD, Ripamonti C, Jeffery G
The effect of sildenafil citrate (Viagra) on visual sensitivity.
J Vis. 2007;7(8):4.
The erectile dysfunction medicine sildenafil citrate (Viagra) inhibits phosphodiesterase type 6 (PDE6), an essential enzyme involved in the activation and modulation of the phototransduction cascade. Although Viagra might thus be expected to impair visual performance, reports of deficits following its ingestion have so far been largely inconclusive or anecdotal. Here, we adopt tests sensitive to the slowing of the visual response likely to result from the inhibition of PDE6. We measured temporal acuity (critical fusion frequency) and modulation sensitivity in four subjects before and after the ingestion of a 100-mg dose of Viagra under conditions chosen to isolate the responses of either their short-wavelength-sensitive (S-) cone photoreceptors or their long- and middle-wavelength-sensitive (L- and M-) cones. When vision was mediated by S-cones, all subjects exhibited some statistically significant losses in sensitivity, which varied from mild to moderate. The two individuals who showed the largest S-cone sensitivity losses also showed comparable losses when their vision was mediated by the L- and M-cones. Some of the losses appear to increase with frequency, which is broadly consistent with Viagra interfering with the ability of PDE6 to shorten the time over which the visual system integrates signals as the light level increases. However, others appear to represent a roughly frequency-independent attenuation of the visual signal, which might also be consistent with Viagra lengthening the integration time (because it has the effect of increasing the effectiveness of steady background lights), but such changes are also open to other interpretations. Even for the more affected observers, however, Viagra is unlikely to impair common visual tasks, except under conditions of reduced visibility when objects are already near visual threshold. [Abstract/Link to Full Text]

Jacques C, d'Arripe O, Rossion B
The time course of the inversion effect during individual face discrimination.
J Vis. 2007;7(8):3.
Human faces look more similar to each other when they are presented upside down, leading to an increase in error rate and response time during individual face discrimination tasks. This face inversion effect (FIE) is one of the most robust findings in the face processing literature. Recent neuroimaging studies using adaptation to face identity have shown that the "fusiform face area" was the primary neural source of the behavioral FIE. However, the time course of the FIE, that is, when inversion affects the coding of facial identity in the human brain, remains unclear. Here, we addressed this question by recording event-related potentials (ERPs) on the scalp during an adaptation paradigm with upright and inverted faces. Subjects were presented first with an adapting face stimulus for 3,000 ms, followed by a second face of either the same identity or a different identity. Starting at about 160 ms after stimulus onset, the ERP response to the second face stimulus was markedly reduced over occipitotemporal electrode sites when it was identical to the adapting face, during the N170 time window. When the exact same stimuli were presented upside down, the reduction of signal was smaller and took place about 30 ms later, in line with the behavioral effect of inversion. This result shows that face inversion affects the early encoding of face identity in the occipitotemporal cortex at about 160 ms. Because inversion is known to disrupt massively the integration of facial features, these observations provide indirect evidence that individual faces are processed holistically as early as 160 ms after stimulus onset. [Abstract/Link to Full Text]

Fowlkes CC, Martin DR, Malik J
Local figure-ground cues are valid for natural images.
J Vis. 2007;7(8):2.
Figure-ground organization refers to the visual perception that a contour separating two regions belongs to one of the regions. Recent studies have found neural correlates of figure-ground assignment in V2 as early as 10-25 ms after response onset, providing strong support for the role of local bottom-up processing. How much information about figure-ground assignment is available from locally computed cues? Using a large collection of natural images, in which neighboring regions were assigned a figure-ground relation by human observers, we quantified the extent to which figural regions locally tend to be smaller, more convex, and lie below ground regions. Our results suggest that these Gestalt cues are ecologically valid, and we quantify their relative power. We have also developed a simple bottom-up computational model of figure-ground assignment that takes image contours as input. Using parameters fit to natural image statistics, the model is capable of matching human-level performance when scene context limited. [Abstract/Link to Full Text]

Schofield AJ, Ledgeway T, Hutchinson CV
Asymmetric transfer of the dynamic motion aftereffect between first- and second-order cues and among different second-order cues.
J Vis. 2007;7(8):1.
Recent work on motion processing has suggested a distinction between first-order cues (such as luminance modulation [LM]) and second-order cues (such as local contrast modulation [CM]). We studied interactions between moving LM, CM, and orientation modulation (OM) first comparing their spatial- and temporal-frequency sensitivity. We then tested for the transfer of the dynamic motion aftereffect (dMAE) between the three cues, matched for visibility. Observers adapted to moving, 0.5-c/deg horizontal modulations for 2 min (with 10 s top-ups). Relatively strong dMAEs were found when the adaptation and test patterns were defined by the same cue (i.e., both LM, both CM, or both OM); these effects were tuned for spatial frequency in the case of LM and CM. There was a partial transfer of the dMAE from LM to CM and OM; this transferred effect seemed to lose its tuning. The aftereffect transferred well from CM to OM and retained its tuning. There was little or no transfer from CM to LM or from OM to CM or LM. This asymmetric transfer of the dMAE between first- and second-order cues and between the second-order cues suggests some degree of separation between the mechanisms that process them. [Abstract/Link to Full Text]

Radhakrishnan H, Charman WN
Age-related changes in ocular aberrations with accommodation.
J Vis. 2007;7(7):11.1-21.
This study investigates the changes in aberrations with monocular accommodation as a function of age. Second-order and higher order wavefront aberrations and pupil size were measured as a function of accommodation demand over the range of 0-4 D in the right eyes of 47 normal subjects with ages between 17 and 56 years. Higher order ocular Zernike aberrations were analyzed for the natural pupil size in terms of their equivalent defocus and were also determined for fixed pupil diameters of 4.5 mm in the unaccommodated eyes and 2.5 mm in the accommodating eyes. With relaxed accommodation (0 D accommodation stimulus), the major change with age was in the value of C4(0), which increased in positive value over the age range studied, although the total higher order RMS wavefront aberration did not increase. When the data were analyzed for natural pupils, spherical aberration was again found to change systematically in the positive direction with age. The equivalent defocus of total higher order RMS error for natural pupils showed no significant correlation with age (p > .05). With active accommodation, spherical aberration was found to decrease and become negative as the accommodative response increased in the younger subjects (<40 years). Near-zero spherical aberration was found at accommodation levels of about 0.50 D in the youngest subjects (<20 years) and at around 2-3 D in subjects between 20 and 39 years. In the older subjects (>40 years), the spherical aberration showed only small changes, some of which were positive, within the limited amplitude of accommodation available. Other higher order aberrations and the RMS of higher order aberrations did not appear to change systematically with accommodation, except in the oldest subjects. The change with age in the relationship between aberration and accommodation is interpreted in terms of the changing gradients of refractive index and surface curvatures of the crystalline lens. [Abstract/Link to Full Text]

Dubbelman M, Sicam VA, van der Heijde RG
The contribution of the posterior surface to the coma aberration of the human cornea.
J Vis. 2007;7(7):10.1-8.
Scheimpflug imaging was used to measure in six meridians the shape of the anterior and posterior cornea of the right eye of 114 subjects, ranging in age from 18 to 65 years. Subsequently, a three-dimensional model of the shape of the whole cornea was reconstructed, from which the coma aberration of the anterior and whole cornea could be calculated. This made it possible to investigate the compensatory role of the posterior surface to the coma aberration of the anterior corneal surface with age. Results show that, on average, the posterior surface compensates approximately 3.5% of the coma of the anterior surface. The compensation tends to be larger for young subjects (6%) than for older subjects (0%). This small effect of the posterior cornea on the coma aberration makes it clear that for the coma aberration of the whole eye, only the anterior corneal surface and the crystalline lens play a role. Consequently, for the design of an intraocular lens that is able to correct for coma aberration, it would be sufficient to only take the anterior corneal surface into account. [Abstract/Link to Full Text]

Pestilli F, Viera G, Carrasco M
How do attention and adaptation affect contrast sensitivity?
J Vis. 2007;7(7):9.1-12.
Attention and adaptation are both mechanisms that optimize visual performance. Attention optimizes performance by increasing contrast sensitivity for and neural response to attended stimuli while decreasing them for unattended stimuli; adaptation optimizes performance by increasing contrast sensitivity for and neural response to changing stimuli while decreasing them for unchanging stimuli. We investigated whether and how the adaptation state and the attentional effect on contrast sensitivity interact. We measured contrast sensitivity with an orientation-discrimination task, in two adaptation conditions--adapt to 0% or 100% contrast--in focused, distributed, and withdrawn attentional conditions. We used threshold and asymptotic performance to index the magnitude of the attentional effect--enhancement or impairment in contrast sensitivity--before and after adapting to high-contrast stimuli. The results show that attention and adaptation affect the contrast psychometric function in a similar but opposite way: Attention increases stimulus salience, whereas adaptation reduces stimulus salience. An interesting finding is that the adaptation state does not modulate the magnitude of the attentional effect. This suggests that attention affects the normalized signal once the effect of contrast adaptation has taken place and that these two mechanisms act separately to change contrast sensitivity. Attention can overcome adaptation to restore contrast sensitivity. [Abstract/Link to Full Text]

van Mierlo CM, Brenner E, Smeets JB
Temporal aspects of cue combination.
J Vis. 2007;7(7):8.1-11.
The human brain processes different kinds of information (or cues) independently with different neural latencies. How does the brain deal with these differences in neural latency when it combines cues into one estimate? To find out, we introduced artificial asynchronies between the moments that monocular and binocular cues indicated that the slant of a surface had suddenly changed. Subjects had to detect changes in slant or to indicate their direction. We found that the cues were combined to improve performance even when the artificial asynchrony between them was about 100 ms. We conclude that neural latency differences of tens of milliseconds between cues are irrelevant because of the low temporal resolution of neural processing. [Abstract/Link to Full Text]

Arnold DH, Grove PM, Wallis TS
Staying focused: a functional account of perceptual suppression during binocular rivalry.
J Vis. 2007;7(7):7.1-8.
Presenting different images to either eye can induce perceptual switching, with alternating disappearances of each image--a phenomenon called binocular rivalry. We believe that disappearances during binocular rivalry can be driven by a process that facilitates visibility near the point of fixation. As the point of fixation is tied neither to a particular stimulus nor to a specific eye, indifference to both would be an essential characteristic for the process we envisage. Many factors that influence disappearances during binocular rivalry scale with distance in depth from fixation. Of these, here we use blur. We break the links between this cue and both eye of origin and stimulus type. We find that perceptual dominance can track a better focused image as it is swapped between the eyes and that perceptual switches can be driven by alternating the focus of images fixed in each eye. This implies that, as a determinant of suppression selectivity, blur is functionally independent from both eye of origin and stimulus type. Our data and theoretical account suggest that binocular rivalry is not an irrelevant laboratory curiosity but, rather, that it is a product of a functional adaptation that promotes visibility in cluttered environments. [Abstract/Link to Full Text]

Koene AR, Zhaoping L
Feature-specific interactions in salience from combined feature contrasts: evidence for a bottom-up saliency map in V1.
J Vis. 2007;7(7):6.1-14.
Items that stand out from their surroundings, that is, those that attract attention, are considered to be salient. Salience is generated by input features in many stimulus dimensions, like motion (M), color (C), orientation (O), and others. We focus on bottom-up salience generated by contrast between the feature properties of an item and its surroundings. We compare the singleton search reaction times (RTs) of items that differ from their surroundings in more than one feature (e.g., C + O, denoted as CO) against the RTs of items that differ from their surroundings in only a single feature (e.g., O or C). The measured RTs for the double-feature singletons are compared against "race model" predictions to evaluate whether salience in the double-feature conditions is greater than the salience of either of its feature components. Affirmative answers were found in MO and CO but not in CM. These results are consistent with some V1 neurons being conjunctively selective to MO, others to CO, but almost none to CM. They provide support for the V1 hypothesis of bottom-up salience (Z. Li, 2002) but are contrary to expectation from the "feature summation" hypothesis, in which different stimulus features are initially analyzed independently and subsequently summed to form a single salience map (L. Itti & C. Koch, 2001; C. Koch & S. Ullman, 1985; J. M. Wolfe, K. R. Cave, & S. L. Franzel, 1989). [Abstract/Link to Full Text]

Knill DC
Robust cue integration: a Bayesian model and evidence from cue-conflict studies with stereoscopic and figure cues to slant.
J Vis. 2007;7(7):5.1-24.
Most research on depth cue integration has focused on stimulus regimes in which stimuli contain the small cue conflicts that one might expect to normally arise from sensory noise. In these regimes, linear models for cue integration provide a good approximation to system performance. This article focuses on situations in which large cue conflicts can naturally occur in stimuli. We describe a Bayesian model for nonlinear cue integration that makes rational inferences about scenes across the entire range of possible cue conflicts. The model derives from the simple intuition that multiple properties of scenes or causal factors give rise to the image information associated with most cues. To make perceptual inferences about one property of a scene, an ideal observer must necessarily take into account the possible contribution of these other factors to the information provided by a cue. In the context of classical depth cues, large cue conflicts most commonly arise when one or another cue is generated by an object or scene that violates the strongest form of constraint that makes the cue informative. For example, when binocularly viewing a slanted trapezoid, the slant interpretation of the figure derived by assuming that the figure is rectangular may conflict greatly with the slant suggested by stereoscopic disparities. An optimal Bayesian estimator incorporates the possibility that different constraints might apply to objects in the world and robustly integrates cues with large conflicts by effectively switching between different internal models of the prior constraints underlying one or both cues. We performed two experiments to test the predictions of the model when applied to estimating surface slant from binocular disparities and the compression cue (the aspect ratio of figures in an image). The apparent weight that subjects gave to the compression cue decreased smoothly as a function of the conflict between the cues but did not shrink to zero; that is, subjects did not fully veto the compression cue at large cue conflicts. A Bayesian model that assumes a mixed prior distribution of figure shapes in the world, with a large proportion being very regular and a smaller proportion having random shapes, provides a good quantitative fit for subjects' performance. The best fitting model parameters are consistent with the sensory noise to be expected in measurements of figure shape, further supporting the Bayesian model as an account of robust cue integration. [Abstract/Link to Full Text]

Caetta F, Gorea A, Bonneh Y
Sensory and decisional factors in motion-induced blindness.
J Vis. 2007;7(7):4.1-12.
The processes underlying motion-induced blindness (MIB) are widely debated. Ultimately, however, they must reduce to a sensitivity drop and/or to an upward shift of the decision criterion. The first possibility was tested by assessing the detection threshold for a contrast (or luminance) increment applied to the MIB target under its visible and suppressed phases. This was performed over a whole range of reference target contrasts (yielding the standard Threshold vs. Contrast [TvC] function) with a 2AFC staircase procedure. The second possibility was tested with a Yes/No procedure, allowing the assessment of both the sensitivities (d') and decision criteria (c) yielded by four contrast increments applied to a fixed reference target contrast (the psychometric function). The 2AFC procedure yielded a global upward shift of the TvC function of about 5.3 dB (a factor of 1.84) under the suppressed phase. The Yes/No procedure yielded a commensurate d' drop (of about 0.8 sigma) under the suppressed phase with no change in the slope of the psychometric function and an upward shift of c of about 0.7 sigma. The presently observed vertical shift (in log-log coordinates) of the TvC function in the suppressed phase is indicative of a divisive inhibition occurring after the transducing stage. The invariance of the psychometric function slope under the visible and suppressed MIB phases supports this conclusion. The present experiments cannot settle the issue of whether the upward shift of the decision criteria is yet another cause of the MIB or a consequence of its underlying inhibitory process. Instead, they make clear that MIB (and perhaps other unstable perceptual phenomena) is associated with both sensory and decisional processes. [Abstract/Link to Full Text]

Fernandez JM, Farell B
Shape constancy and depth-order violations in structure from motion: a look at non-frontoparallel axes of rotation.
J Vis. 2007;7(7):3.1-18.
Humans can recover the structure of a 3D object from motion cues alone. Recovery of structure from motion (SFM) from the projected 2D motion field of a rotating object has been studied almost exclusively in one particular condition, that in which the axis of rotation lies in the frontoparallel plane. Here, we assess the ability of humans to recover SFM in the general case, where the axis of rotation may be slanted out of the frontoparallel plane. Using elliptical cylinders whose cross section was constant along the axis of rotation, we find that, across a range of parameters, subjects accurately matched the simulated shape of the cylinder regardless of how much the axis of rotation is inclined away from the frontoparallel plane. Yet, we also find that subjects do not perceive the inclination of the axis of rotation veridically. This combination of results violates a relationship between perceived angle of inclination and perceived shape that must hold if SFM is to be recovered from the instantaneous velocity field. The contradiction can be resolved if the angular speed of rotation is not consistently estimated from the instantaneous velocity field. This, in turn, predicts that variation in object size along the axis of rotation can cause depth-order violations along the line of sight. This prediction was verified using rotating circular cones as stimuli. Thus, as the axis of rotation changes its inclination, shape constancy is maintained through a trade-off. Humans perceive the structure of the object relative to a changing axis of rotation as unchanging by introducing an inconsistency between the perceived speed of rotation and the first-order optic flow. The observed depth-order violations are the cost of the trade-off. [Abstract/Link to Full Text]

Pearson J, Tadin D, Blake R
The effects of transcranial magnetic stimulation on visual rivalry.
J Vis. 2007;7(7):2.1-11.
One extensively investigated form of perceptual bistability is binocular rivalry--When dissimilar patterns are presented one to each eye, these patterns compete for perceptual dominance. Here, we report that transcranial magnetic stimulation (TMS) over early visual areas induces alternations during binocular rivalry. The effect of TMS on binocular rivalry was retinotopic, suggesting that rivalry mechanisms are localized in the cortical representation of visual space. The timing of perturbations was highly dependent on individual differences in rivalry alternation frequencies, with more delayed effects found in slower alternators. This finding suggests that both binocular rivalry and TMS dynamics might be contingent on individual differences among observers. We performed an analogous set of experiments by replacing TMS with transient visual stimulation. The results, however, qualitatively and quantitatively differed from those reported with TMS. Finally, we found that TMS over early visual areas does not produce any time-locked effects on another dynamical process--eye-swapping stimulus rivalry. These findings constitute the first causative evidence that binocular rivalry is contingent on neural activity in early visual areas and suggest that binocular rivalry and stimulus rivalry have different neural correlates, supporting multilevel theories of visual rivalry. [Abstract/Link to Full Text]

Linares D, L�pez-Moliner J, Johnston A
Motion signal and the perceived positions of moving objects.
J Vis. 2007;7(7):1.1-7.
When a flash is presented in spatial alignment with a moving stimulus, the flash appears to lag behind (the flash-lag effect). The motion of the object can influence the position of the flash, but there may also be a reciprocal effect of the flash on the moving object. Here, we demonstrate that this is the case. We show that when a flash is presented near the moving object, the flash-lag effect does not depend greatly on the duration of the preflash trajectory. However, when the flash is presented sufficiently far from the moving object, the flash-lag effect increases with the duration of the preflash trajectory, until it reaches an asymptotic level. We also show that the interaction of the near flash can occur when it is task irrelevant. Finally, using the motion aftereffect, we demonstrate that motion signals are involved in the time evolution of the flash-lag effect. [Abstract/Link to Full Text]

Peirce JW
The potential importance of saturating and supersaturating contrast response functions in visual cortex.
J Vis. 2007;7(6):13.
Most cortical visual neurons do not respond linearly with contrast. Generally, they show saturated responses to stimuli of high contrast, a feature often characterized by a divisive normalization function. This nonlinearity is generally thought to be useful in focusing the dynamic response range of the neuron on a particular region of contrast space, optimizing contrast gain. Some neurons not only saturate but also supersaturate; at high contrast, the response of the neuron decreases rather than plateaus. Under the contrast gain control theory, these cells would seem to reflect a nonoptimal normalization pool that provides excessive inhibition to the neurons. Since very few data on supersaturation are available, this article examines the frequency with which such neurons occur in macaque visual cortex by considering an extension of the Naka-Rushton equation with the capacity to represent nonmonotonic functions. The prevalence of gain-control theories for saturation has occluded an additional computational function for saturation, namely, in detecting the conjunction of certain features. A saturating nonlinearity is a critical part of the selective detection of compound stimuli over their components. In this role, the existence of saturating contrast response functions might be considered necessary rather than simply optimal. [Abstract/Link to Full Text]

Edelman JA, Kristj�nsson A, Nakayama K
The influence of object-relative visuomotor set on express saccades.
J Vis. 2007;7(6):12.
Express saccades are considered to have the shortest latency (70-110 ms) of all saccadic eye movements. The influence of visuomotor set, preparatory processes that spatially affect a sensorimotor response, on express saccades was examined by instructing human subjects to make a saccade to one of two simultaneously appearing spots defined by its position relative to the other. A temporal gap between fixation point disappearance and target appearance was used to facilitate the production of express saccades. For all subjects, the instruction influenced the vector of express saccades without increasing saccade latency. The effect on express saccades was only slightly weaker than that for longer latency saccades. Saccade curvature was minimal and did not depend strongly on task. Further experiments demonstrated that the effect of instruction on express saccade vector was much weaker when saccades were instructed to be made to one side of a single small spot, that the effect of instruction was equally strong when directing saccades to the less salient of two stimuli, and that an instruction could not only determine the direction of the effect but also modulate the effect's magnitude. The effect of instruction on saccade vector was no higher when blocked than when varied across trials. These results suggest that express saccades are influenced by object-relative spatial preparatory processes without increasing their reaction time and, thus, that high-level cognitive processes can influence the most reflexive of saccadic eye movements. [Abstract/Link to Full Text]

Cardoso-Leite P, Gorea A, Mamassian P
Temporal order judgment and simple reaction times: evidence for a common processing system.
J Vis. 2007;7(6):11.
We present a simple reaction time (RT) versus temporal order judgment (TOJ) experiment as a test of the perception-action relationship. The experiment improves on previous ones in that it assesses for the first time RT and TOJ on a trial-by-trial basis, hence allowing the study of the two behaviors within the same task context and, most importantly, the association of RT to "correct" and "incorrect" TOJs. RTs to pairs of stimuli are significantly different depending on the associated TOJs, an indication that perceptual and motor decisions are based on the same internal response. Simulations with the simplest one-system model (J. Gibbon & R. Rutschmann, 1969) using the means and standard deviations of the RT to stimuli presented in isolation yield excellent fits of the mean RT to these increments when presented in sequence and moderately good fits of the RT when classified according to the TOJ categories. The present observation that the point of subjective simultaneity for stimulus pairs is systematically smaller than the difference in RT to each of the two increments in the same pairs pleads, however, in favor of distinct decision criteria for perception and action with the former below the latter. For such a case, standard one-system race models require that the internal noise associated with the TOJ be less than the one associated with the RT to the same stimulus pair. The present data show the reverse state of affairs. In short, data and simulations comply with "one-system-two-decision" models of perceptual and motor behaviors, while prompting further testing and modeling to account for the apparent discrepancy between the ordering of the two decisions. [Abstract/Link to Full Text]

Rieger JW, Gr�schow M, Heinze HJ, Fendrich R
The appearance of figures seen through a narrow aperture under free viewing conditions: effects of spontaneous eye motions.
J Vis. 2007;7(6):10.
When moving figures are occluded and revealed piecemeal as they move across a narrow slit, observers may perceive them as integrated but distorted. They may also perceive much more of the figure as simultaneously visible than is actually presented at any moment. We obtained quantitative measures of both the perceived distortion and perceived simultaneity under free viewing conditions and related these phenomena to spontaneous pursuit eye movements, the retinal painting produced by this pursuit, and the occurrence of saccades. We found both shape compressions and expansions, depending on figure velocity. We also obtained quantitative evidence that observers perceived slices of the moving figures far wider than the slit through which they were presented. Eye-motion records and retinal stabilization revealed that spontaneous pursuit and the spatially extended images that could have been painted out by this pursuit played no role in the perceived global shape distortions and made only a small contribution to the perceived simultaneity. Therefore, under free viewing conditions, both the distortions and simultaneity of these "anorthoscopic" figure percepts must be the consequence of a postretinal process that integrates the figures over space and time independent of eye motions. [Abstract/Link to Full Text]

Thaler L, Todd JT, Spering M, Gegenfurtner KR
Illusory bending of a rigidly moving line segment: effects of image motion and smooth pursuit eye movements.
J Vis. 2007;7(6):9.
Four experiments in which observers judged the apparent "rubberiness" of a line segment undergoing different types of rigid motion are reported. The results reveal that observers perceive illusory bending when the motion involves certain combinations of translational and rotational components and that the illusion is maximized when these components are presented at a frequency of approximately 3 Hz with a relative phase angle of approximately 120 degrees . Smooth pursuit eye movements can amplify or attenuate the illusion, which is consistent with other results reported in the literature that show effects of eye movements on perceived image motion. The illusion is unaffected by background motion that is in counterphase with the motion of the line segment but is significantly attenuated by background motion that is in-phase. This is consistent with the idea that human observers integrate motion signals within a local frame of reference, and it provides strong evidence that visual persistency cannot be the sole cause of the illusion as was suggested by J. R. Pomerantz (1983). An analysis of the motion patterns suggests that the illusory bending motion may be due to an inability of observers to accurately track the motions of features whose image displacements undergo rapid simultaneous changes in both space and time. A measure of these changes is presented, which is highly correlated with observers' numerical ratings of rubberiness. [Abstract/Link to Full Text]

Elliott SL, Hardy JL, Webster MA, Werner JS
Aging and blur adaptation.
J Vis. 2007;7(6):8.
Color appearance remains remarkably stable in the aging visual system despite large changes in the spectral distribution of the retinal stimulus and losses in chromatic sensitivity (P. B. Delahunt, J. L. Hardy, K. Okajima, & J. S. Werner, 2005; J. S. Werner, 1996). This stability could reflect adaptive adjustments in peripheral or central chromatic mechanisms that compensate for sensitivity losses in senescence. We asked whether similar compensatory adjustments play a role in maintaining spatial vision--and whether the adaptation itself shows changes with aging-by examining the effects of adaptation on judgments of image focus. Perceptual aftereffects following adaptation to a uniform field and blurred or sharpened images were compared between younger adults and older observers. Subjects adapted to a sequence of blurred or sharpened images for 120 s, and a two-alternative forced-choice staircase task was used to vary the filter exponent of the test to define the subjective point of best focus. There was a small but significant difference between younger and older observers in the level perceived as best focused in all three adaptation conditions, possibly reflecting differences in the ambient blur level the groups are routinely exposed to. However, the magnitude of the blur aftereffect did not differ between the two age groups. These results suggest that although there may be small differences in the long-term adaptation to blur, younger and older observers do not differ in the strength of adaptation to transient changes in blur. The neural processes mediating adaptation to blur thus appear to remain largely intact with aging. [Abstract/Link to Full Text]

Saunders JA, Backus BT
Both parallelism and orthogonality are used to perceive 3D slant of rectangles from 2D images.
J Vis. 2007;7(6):7.
A 2D perspective image of a slanted rectangular object is sufficient for a strong 3D percept. Two computational assumptions that could be used to interpret 3D from images of rectangles are as follows: (1) converging lines in an image are parallel in the world, and (2) skewed angles in an image are orthogonal in the world. For an accurate perspective image of a slanted rectangle, either constraint implies the same 3D interpretation. However, if an image is rescaled, the 3D interpretations based on parallelism and orthogonality generally conflict. We tested the roles of parallelism and orthogonality by measuring perceived depth within scaled perspective images. Stimuli were monocular images of squares, slanted about a horizontal axis, with an elliptical hole. Subjects judged the length-to-width ratio of the holes, which provided a measure of perceived depth along the object. The rotational alignment of squares within their surface plane was varied from 0 degrees (trapezoidal projected contours) to 20 degrees (skewed projected contours). In consistent-cue conditions, images were accurate projections of either a 10 degree- or 20 degree-wide square, with slants of 75 degrees and 62 degrees, respectively. In cue-conflict conditions, images were generated either by magnifying a 10 degrees image to have a projected size of 20 degrees or by minifying a 20 degree image to have a projected size of 10 degrees. For the aligned squares, which do not produce a conflicting skew cue, we found that subjects' judgments depended primarily on projected size and not on the size used to generate the prescaled images. This is consistent with reliance on the convergence cue, corresponding to a parallelism assumption. As squares were rotated away from alignment, producing skewed projected contours, judgments were increasingly determined by the original image size. This is consistent with use of the skew cue, corresponding to an orthogonality assumption. Our results demonstrate that both parallelism and orthogonality constraints are used to perceive depth from linear perspective. [Abstract/Link to Full Text]