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Recent Articles in BMC Neuroscience

Zadicario P, Ronen S, Eilam D
Modulation of quinpirole-induced compulsive-like behavior in rats by environmental changes: implications for OCD rituals and for exploration and navigation.
BMC Neurosci. 2007;823.
BACKGROUND: Rats treated chronically with the D2-3 dopamine agonist quinpirole were previously proposed as an animal model of obsessive-compulsive disorder (OCD) since their behavior is based on repeated, compulsive-like persistent traveling between a few places in the open field. The aim of the present study was to determine properties of the physical environment that shape such behavior. For this, quinpirole-treated rats were first exposed to an arena with an array of objects (landmarks) and after the development of compulsive-like behavior, the arena was manipulated by multiplying the number of objects, changing their spacing, relocating object array, or removing the objects. RESULTS: When the number of objects was retained but they were spaced further apart, rat routes converged at 1-2 of the objects and at the corner at which the rats had been introduced into the arena (start corner). When object spacing was retained but their number was increased, the rats traveled between the objects with the routes converging only at the start corner. Finally, when object array was relocated to different places within the arena, the rats extended their routes from the start corner to the object array, regardless of array location. CONCLUSION: Quinpirole-treated rats organized and updated their progression primarily according to the proximal layout of landmarks, but did so with excessive repetitions compared with saline-treated rats. The behavior of quinpirole-treated rats paralleled human OCD rituals that are linked to the immediate physical environment, featuring an excessive rate of performance. Finally, when only a few objects were present, they were perceived by the rats as positional cues (beacons) that routes converged at them. In contrast, in the presence of many objects, the routes passed between the objects as if using them as directional cues. [Abstract/Link to Full Text]

Li Q, Gordon M, Cao C, Ugen KE, Morgan D
Improvement of a low pH antigen-antibody dissociation procedure for ELISA measurement of circulating anti-Abeta antibodies.
BMC Neurosci. 2007;822.
BACKGROUND: Prior work from our group found that acid dissociation (pH 2.5 incubation) of serum from APP transgenic mice vaccinated against Abeta increased the apparent anti-Abeta titers, suggesting antibody masking by antigen in the ELISA assay. Subsequently, we found that pH 2.5 incubation of serum from unvaccinated non-transgenic mice showed antibody binding to Abeta1-42, but no increase when other proteins, including shorter Abeta peptides, coated the ELISA plate. To investigate further the effects of low pH incubation on apparent anti-Abeta1-42 signals, we examined normal sera from nonTg unvaccinated mice, nonTg mice vaccinated with Abeta peptide (to produce authentic anti-Abeta antibodies) or a monoclonal antibody against Abeta (6E10) using competitive-inhibition ELISA and Abeta epitope mapping assays. In addition, we examined use of a less stringent low pH procedure at pH 3.5, to ascertain if it had the same effects as the pH 2.5 procedure. RESULTS: We believe there are three distinct effects of pH 2.5 incubation.; A) an artifactual increase in binding to full length Abeta by mouse immunoglobulin which has low affinity for Abeta, B) an inactivation of anti-Abeta antibodies that is time dependent and C) unmasking of high affinity anti-Abeta antibodies when high levels of circulating Abeta is present in APP transgenic mice. All three reactions can interact to produce the final ELISA signal. Incubation of sera from unvaccinated nonTg mice at pH 2.5 enhanced ELISA signals by process A. Conversely, pH 2.5 incubation of sera from vaccinated nonTg mice with caused a time dependent reduction of antibody signal by process B (overcoming the increase caused by A). The artifactual anti-Abeta ELISA signal enhanced by pH 2.5 incubation of normal mouse sera could not be effectively competed by low to moderate concentrations of Abeta, nor bind to shorter Abeta peptides in a manner similar to authentic anti-Abeta antibodies. Incubation of mouse sera at pH 3.5 caused neither an apparent increase in anti-Abeta ELISA signal, nor an inactivation of the ELISA signals resulting from either vaccination or monoclonal antibodies. However, incubation at pH 3.5 was able to completely reverse the reduction in ELISA signal caused by Abeta complexing with antibodies in sera from vaccinated mice or monoclonal anti-Abeta antibodies. CONCLUSION: Incubation at pH 3.5 is sufficient to dissociate Abeta bound to anti-Abeta antibodies without producing artifactual increases in the signal, or inactivating authentic antibody binding. Thus, use of pH 3.5 is a considerable improvement over pH 2.5 incubation for unmasking anti-Abeta antibodies in ELISA assays to measure antibodies in APP transgenic mouse sera. [Abstract/Link to Full Text]

Zhu Z, Disbrow EA, Zumer JM, McGonigle DJ, Nagarajan SS
Spatiotemporal integration of tactile information in human somatosensory cortex.
BMC Neurosci. 2007;821.
BACKGROUND: Our goal was to examine the spatiotemporal integration of tactile information in the hand representation of human primary somatosensory cortex (anterior parietal somatosensory areas 3b and 1), secondary somatosensory cortex (S2), and the parietal ventral area (PV), using high-resolution whole-head magnetoencephalography (MEG). To examine representational overlap and adaptation in bilateral somatosensory cortices, we used an oddball paradigm to characterize the representation of the index finger (D2; deviant stimulus) as a function of the location of the standard stimulus in both right- and left-handed subjects. RESULTS: We found that responses to deviant stimuli presented in the context of standard stimuli with an interstimulus interval (ISI) of 0.33 s were significantly and bilaterally attenuated compared to deviant stimulation alone in S2/PV, but not in anterior parietal cortex. This attenuation was dependent upon the distance between the deviant and standard stimuli: greater attenuation was found when the standard was immediately adjacent to the deviant (D3 and D2 respectively), with attenuation decreasing for non-adjacent fingers (D4 and opposite D2). We also found that cutaneous mechanical stimulation consistently elicited not only a strong early contralateral cortical response but also a weak ipsilateral response in anterior parietal cortex. This ipsilateral response appeared an average of 10.7 +/- 6.1 ms later than the early contralateral response. In addition, no hemispheric differences either in response amplitude, response latencies or oddball responses were found, independent of handedness. CONCLUSION: Our findings are consistent with the large receptive fields and long neuronal recovery cycles that have been described in S2/PV, and suggest that this expression of spatiotemporal integration underlies the complex functions associated with this region. The early ipsilateral response suggests that anterior parietal fields also receive tactile input from the ipsilateral hand. The lack of a hemispheric difference in responses to digit stimulation supports a lack of any functional asymmetry in human somatosensory cortex. [Abstract/Link to Full Text]

Pfenning AR, Schwartz R, Barth AL
A comparative genomics approach to identifying the plasticity transcriptome.
BMC Neurosci. 2007;820.
BACKGROUND: Neuronal activity regulates gene expression to control learning and memory, homeostasis of neuronal function, and pathological disease states such as epilepsy. A great deal of experimental evidence supports the involvement of two particular transcription factors in shaping the genomic response to neuronal activity and mediating plasticity: CREB and zif268 (egr-1, krox24, NGFI-A). The gene targets of these two transcription factors are of considerable interest, since they may help develop hypotheses about how neural activity is coupled to changes in neural function. RESULTS: We have developed a computational approach for identifying binding sites for these transcription factors within the promoter regions of annotated genes in the mouse, rat, and human genomes. By combining a robust search algorithm to identify discrete binding sites, a comparison of targets across species, and an analysis of binding site locations within promoter regions, we have defined a group of candidate genes that are strong CREB- or zif268 targets and are thus regulated by neural activity. Our analysis revealed that CREB and zif268 share a disproportionate number of targets in common and that these common targets are dominated by transcription factors. CONCLUSION: These observations may enable a more detailed understanding of the regulatory networks that are induced by neural activity and contribute to the plasticity transcriptome. The target genes identified in this study will be a valuable resource for investigators who hope to define the functions of specific genes that underlie activity-dependent changes in neuronal properties. [Abstract/Link to Full Text]

Li Y, Semaan SJ, Schlamp CL, Nickells RW
Dominant inheritance of retinal ganglion cell resistance to optic nerve crush in mice.
BMC Neurosci. 2007;819.
BACKGROUND: Several neurodegenerative diseases are influenced by complex genetics that affect an individual's susceptibility, disease severity, and rate of progression. One such disease is glaucoma, a chronic neurodegenerative condition of the eye that targets and stimulates apoptosis of CNS neurons called retinal ganglion cells. Since ganglion cell death is intrinsic, it is reasonable that the genes that control this process may contribute to the complex genetics that affect ganglion cell susceptibility to disease. To determine if genetic background influences susceptibility to optic nerve damage, leading to ganglion cell death, we performed optic nerve crush on 15 different inbred lines of mice and measured ganglion cell loss. Resistant and susceptible strains were used in a reciprocal breeding strategy to examine the inheritance pattern of the resistance phenotype. Because earlier studies had implicated Bax as a susceptibility allele for ganglion cell death in the chronic neurodegenerative disease glaucoma, we conducted allelic segregation analysis and mRNA quantification to assess this gene as a candidate for the cell death phenotype. RESULTS: Inbred lines showed varying levels of susceptibility to optic nerve crush. DBA/2J mice were most resistant and BALB/cByJ mice were most susceptible. F1 mice from these lines inherited the DBA/2J phenotype, while N2 backcross mice exhibited the BALB/cByJ phenotype. F2 mice exhibited an intermediate phenotype. A Wright Formula calculation suggested as few as 2 dominant loci were linked to the resistance phenotype, which was corroborated by a Punnett Square analysis of the distribution of the mean phenotype in each cross. The levels of latent Bax mRNA were the same in both lines, and Bax alleles did not segregate with phenotype in N2 and F2 mice. CONCLUSION: Inbred mice show different levels of resistance to optic nerve crush. The resistance phenotype is heritable in a dominant fashion involving relatively few loci. Bax was excluded as a candidate gene for this phenotype. [Abstract/Link to Full Text]

Mueller JL, Hirotani M, Friederici AD
ERP evidence for different strategies in the processing of case markers in native speakers and non-native learners.
BMC Neurosci. 2007;818.
BACKGROUND: The present experiments were designed to test how the linguistic feature of case is processed in Japanese by native and non-native listeners. We used a miniature version of Japanese as a model to compare sentence comprehension mechanisms in native speakers and non-native learners who had received training until they had mastered the system. In the first experiment we auditorily presented native Japanese speakers with sentences containing incorrect double nominatives and incorrect double accusatives, and with correct sentences. In the second experiment we tested trained non-natives with the same material. Based on previous research in German we expected an N400-P600 biphasic ERP response with specific modulations depending on the violated case and whether the listeners were native or non-native. RESULTS: For native Japanese participants the general ERP response to the case violations was an N400-P600 pattern. Double accusatives led to an additional enhancement of the P600 amplitude. For the learners a native-like P600 was present for double accusatives and for double nominatives. The additional negativity, however, was present in learners only for double nominative violations, and it was characterized by a different topographical distribution. CONCLUSION: The results indicate that native listeners use case markers for thematic as well as syntactic structure building during incremental sentence interpretation. The modulation of the P600 component for double accusatives possibly reflects case specific syntactic restrictions in Japanese. For adult language learners later processes, as reflected in the P600, seem to be more native-like compared to earlier processes. The anterior distribution of the negativity and its selective emergence for canonical sentences were taken to suggest that the non-native learners resorted to a rather formal processing strategy whereby they relied to a large degree on the phonologically salient nominative case marker. [Abstract/Link to Full Text]

Gammie SC, Bethea ED, Stevenson SA
Altered maternal profiles in corticotropin-releasing factor receptor 1 deficient mice.
BMC Neurosci. 2007;817.
BACKGROUND: During lactation, the CNS is less responsive to the anxiogenic neuropeptide, corticotropin-releasing factor (CRF). Further, central injections of CRF inhibit maternal aggression and some maternal behaviors, suggesting decreased CRF neurotransmission during lactation supports maternal behaviors. In this study, we examined the maternal profile of mice missing the CRF receptor 1 (CRFR1). Offspring of knockout (CRFR1-/-) mice were heterozygote to offset possible deleterious effects of low maternal glucocorticoids on pup survival and all mice contained a mixed 50:50 inbred/outbred background to improve overall maternal profiles and fecundity. RESULTS: Relative to littermate wild-type (WT) controls, CRFR1-/- mice exhibited significant deficits in total time nursing, including high arched-back, on each test day. Consistent with decreased nursing, pups of CRFR1-deficient dams weighed significantly less than WT offspring. Licking and grooming of pups was significantly higher in WT mice on postpartum Day 2 and when both test days were averaged, but not on Day 3. Time off nest was higher for CRFR1-/- mice on Day 2, but not on Day 3 or when test days were averaged. Licking and grooming of pups did not differ on Day 2 when this measure was examined as a proportion of time on nest. CRFR1-/- mice showed significantly higher nest building on Day 3 and when tests were averaged. Mean pup number was almost identical between groups and no pup mortality occurred. Maternal aggression was consistently lower in CRFR1-/- mice and in some measures these differences approached, but did not reach significance. Because of high variance, general aggression results are viewed as preliminary. In terms of sites of attacks on intruders, CRFR1-/- mice exhibited significantly fewer attacks to the belly of the intruder on Day 5 and when tests were averaged. Performance on the elevated plus maze was similar between genotypes. Egr-1 expression differences in medial preoptic nucleus and c-Fos expression differences in bed nucleus of stria terminalis between genotype suggest possible sites where loss of gene alters behavioral output. CONCLUSION: Taken together, the results suggest that the presence of an intact CRFR1 receptor supports some aspects of nurturing behavior. [Abstract/Link to Full Text]

Schupp HT, Stockburger J, Bublatzky F, Junghöfer M, Weike AI, Hamm AO
Explicit attention interferes with selective emotion processing in human extrastriate cortex.
BMC Neurosci. 2007;816.
BACKGROUND: Brain imaging and event-related potential studies provide strong evidence that emotional stimuli guide selective attention in visual processing. A reflection of the emotional attention capture is the increased Early Posterior Negativity (EPN) for pleasant and unpleasant compared to neutral images (approximately 150-300 ms poststimulus). The present study explored whether this early emotion discrimination reflects an automatic phenomenon or is subject to interference by competing processing demands. Thus, emotional processing was assessed while participants performed a concurrent feature-based attention task varying in processing demands. RESULTS: Participants successfully performed the primary visual attention task as revealed by behavioral performance and selected event-related potential components (Selection Negativity and P3b). Replicating previous results, emotional modulation of the EPN was observed in a task condition with low processing demands. In contrast, pleasant and unpleasant pictures failed to elicit increased EPN amplitudes compared to neutral images in more difficult explicit attention task conditions. Further analyses determined that even the processing of pleasant and unpleasant pictures high in emotional arousal is subject to interference in experimental conditions with high task demand. Taken together, performing demanding feature-based counting tasks interfered with differential emotion processing indexed by the EPN. CONCLUSION: The present findings demonstrate that taxing processing resources by a competing primary visual attention task markedly attenuated the early discrimination of emotional from neutral picture contents. Thus, these results provide further empirical support for an interference account of the emotion-attention interaction under conditions of competition. Previous studies revealed the interference of selective emotion processing when attentional resources were directed to locations of explicitly task-relevant stimuli. The present data suggest that interference of emotion processing by competing task demands is a more general phenomenon extending to the domain of feature-based attention. Furthermore, the results are inconsistent with the notion of effortlessness, i.e., early emotion discrimination despite concurrent task demands. These findings implicate to assess the presumed automatic nature of emotion processing at the level of specific aspects rather than considering automaticity as an all-or-none phenomenon. [Abstract/Link to Full Text]

Modirrousta M, Mainville L, Jones BE
Dynamic changes in GABAA receptors on basal forebrain cholinergic neurons following sleep deprivation and recovery.
BMC Neurosci. 2007;815.
BACKGROUND: The basal forebrain (BF) cholinergic neurons play an important role in cortical activation and arousal and are active in association with cortical activation of waking and inactive in association with cortical slow wave activity of sleep. In view of findings that GABAA receptors (Rs) and inhibitory transmission undergo dynamic changes as a function of prior activity, we investigated whether the GABAARs on cholinergic cells might undergo such changes as a function of their prior activity during waking vs. sleep. RESULTS: In the brains of rats under sleep control (SC), sleep deprivation (SD) or sleep recovery (SR) conditions in the 3 hours prior to sacrifice, we examined immunofluorescent staining for beta2-3 subunit GABAARs on choline acetyltransferase (ChAT) immunopositive (+) cells in the magnocellular BF. In sections also stained for c-Fos, beta2-3 GABAARs were present on ChAT+ neurons which expressed c-Fos in the SD group alone and were variable or undetectable on other ChAT+ cells across groups. In dual-immunostained sections, the luminance of beta2-3 GABAARs over the membrane of ChAT+ cells was found to vary significantly across conditions and to be significantly higher in SD than SC or SR groups. CONCLUSION: We conclude that membrane GABAARs increase on cholinergic cells as a result of activity during sustained waking and reciprocally decrease as a result of inactivity during sleep. These changes in membrane GABAARs would be associated with increased GABA-mediated inhibition of cholinergic cells following prolonged waking and diminished inhibition following sleep and could thus reflect a homeostatic process regulating cholinergic cell activity and thereby indirectly cortical activity across the sleep-waking cycle. [Abstract/Link to Full Text]

Meyer M, Baumann S, Marchina S, Jancke L
Hemodynamic responses in human multisensory and auditory association cortex to purely visual stimulation.
BMC Neurosci. 2007;814.
BACKGROUND: Recent findings of a tight coupling between visual and auditory association cortices during multisensory perception in monkeys and humans raise the question whether consistent paired presentation of simple visual and auditory stimuli prompts conditioned responses in unimodal auditory regions or multimodal association cortex once visual stimuli are presented in isolation in a post-conditioning run. To address this issue fifteen healthy participants partook in a "silent" sparse temporal event-related fMRI study. In the first (visual control) habituation phase they were presented with briefly red flashing visual stimuli. In the second (auditory control) habituation phase they heard brief telephone ringing. In the third (conditioning) phase we coincidently presented the visual stimulus (CS) paired with the auditory stimulus (UCS). In the fourth phase participants either viewed flashes paired with the auditory stimulus (maintenance, CS-) or viewed the visual stimulus in isolation (extinction, CS+) according to a 5:10 partial reinforcement schedule. The participants had no other task than attending to the stimuli and indicating the end of each trial by pressing a button. RESULTS: During unpaired visual presentations (preceding and following the paired presentation) we observed significant brain responses beyond primary visual cortex in the bilateral posterior auditory association cortex (planum temporale, planum parietale) and in the right superior temporal sulcus whereas the primary auditory regions were not involved. By contrast, the activity in auditory core regions was markedly larger when participants were presented with auditory stimuli. CONCLUSION: These results demonstrate involvement of multisensory and auditory association areas in perception of unimodal visual stimulation which may reflect the instantaneous forming of multisensory associations and cannot be attributed to sensation of an auditory event. More importantly, we are able to show that brain responses in multisensory cortices do not necessarily emerge from associative learning but even occur spontaneously to simple visual stimulation. [Abstract/Link to Full Text]

Bu L, Lephart ED
AVPV neurons containing estrogen receptor-beta in adult male rats are influenced by soy isoflavones.
BMC Neurosci. 2007;813.
BACKGROUND: Isoflavones, the most abundant phytoestrogens in soy foods, are structurally similar to 17beta-estradiol. It is known that 17beta-estradiol induces apoptosis in anteroventral periventricular nucleus (AVPV) in rat brain. Also, there is evidence that consumption of soy isoflavones reduces the volume of AVPV in male rats. Therefore, in this study, we examined the influence of dietary soy isoflavones on apoptosis in AVPV of 150 day-old male rats fed either a soy isoflavone-free diet (Phyto-free) or a soy isoflavone-rich diet (Phyto-600). RESULTS: The occurrence of apoptosis in AVPV was examined by TUNEL staining. The incidence of apoptosis was about 10 times higher in the Phyto-600 group (33.1 +/- 1.7%) than in the Phyto-free group (3.6 +/- 1.0%). Furthermore, these apoptotic cells were identified as neurons by dual immunofluorescent staining of GFAP and NeuN as markers of astrocytes and neurons, respectively. Then the dopaminergic neurons in AVPV were detected by immunohistochemistry staining of tyrosine hydroxylase (TH). No significant difference in the number of TH neurons was observed between the diet treatment groups. When estrogen receptor (ER) alpha and beta were examined by immunohistochemistry, we observed a 22% reduction of ERbeta-positive cell numbers in AVPV with consumption of soy isoflavones, whereas no significant change in ERalpha-positive cell numbers was detected. Furthermore, almost all the apoptotic cells were ERbeta-immunoreactive (ir), but not ERalpha-ir. Last, subcutaneous injections of equol (a major isoflavone metabolite) that accounts for approximately 70-90% of the total circulating plasma isoflavone levels did not alter the volume of AVPV in adult male rats. CONCLUSION: In summary, these findings provide direct evidence that consumption of soy isoflavones, but not the exposure to equol, influences the loss of ERbeta-containing neurons in male AVPV. [Abstract/Link to Full Text]

Hemelt ME, Keller A
Superior sensation: superior colliculus participation in rat vibrissa system.
BMC Neurosci. 2007;812.
BACKGROUND: The superior colliculus, usually considered a visuomotor structure, is anatomically positioned to perform sensorimotor transformations in other modalities. While there is evidence for its potential participation in sensorimotor loops of the rodent vibrissa system, little is known about its functional role in vibrissa sensation or movement. In anesthetized rats, we characterized extracellularly recorded responses of collicular neurons to different types of vibrissa stimuli. RESULTS: Collicular neurons had large receptive fields (median = 14.5 vibrissae). Single units displayed responses with short latencies (5.6 +/- 0.2 msec, median = 5.5) and relatively large magnitudes (1.2 +/- 0.1 spikes/stimulus, median = 1.2). Individual neurons could entrain to repetitive vibrissa stimuli delivered at < or = 20 Hz, with little reduction in phase locking, even when response magnitude was decreased. Neurons responded preferentially to vibrissa deflections at particular angles, with 43% of the cells having high (> or = 5) angular selectivity indices. CONCLUSION: Results are consistent with a proposed role of the colliculus in somatosensory-mediated orienting. These properties, together with the connections of the superior colliculus in sensorimotor loops, are consistent with its involvement in orienting, alerting and attentive functions related to the vibrissa system. [Abstract/Link to Full Text]

Pang IH, Zeng H, Fleenor DL, Clark AF
Pigment epithelium-derived factor protects retinal ganglion cells.
BMC Neurosci. 2007;811.
BACKGROUND: Retinal ganglion cells (RGCs) are responsible for the transmission of visual signals to the brain. Progressive death of RGCs occurs in glaucoma and several other retinal diseases, which can lead to visual impairment and blindness. Pigment epithelium-derived factor (PEDF) is a potent antiangiogenic, neurotrophic and neuroprotective protein that can protect neurons from a variety of pathologic insults. We tested the effects of PEDF on the survival of cultured adult rat RGCs in the presence of glaucoma-like insults, including cytotoxicity induced by glutamate or withdrawal of trophic factors. RESULTS: Cultured adult rat RGCs exposed to glutamate for 3 days showed signs of cytotoxicity and death. The toxic effect of glutamate was concentration-dependent (EC50 = 31 microM). In the presence of 100 microM glutamate, RGC number decreased to 55 +/- 4% of control (mean +/- SEM, n = 76; P < 0.001). The glutamate effect was completely eliminated by MK801, an NMDA receptor antagonist. Trophic factor withdrawal also caused a similar loss of RGCs (54 +/- 4%, n = 60, P < 0.001). PEDF protected against both insults with EC50 values of 13.6 ng/mL (glutamate) and 3.4 ng/mL (trophic factor withdrawal), respectively. At 100 ng/mL, PEDF completely protected the cells from both insults. Inhibitors of the nuclear factor kappaB (NFkappaB) and extracellular signal-regulated kinases 1/2 (ERK1/2) significantly reduced the protective effects of PEDF. CONCLUSION: We demonstrated that PEDF potently and efficaciously protected adult rat RGCs from glutamate- and trophic factor withdrawal-mediated cytotoxicity, via the activation of the NFkappaB and ERK1/2 pathways. The neuroprotective effect of PEDF represents a novel approach for potential treatment of retinopathies, such as glaucoma. [Abstract/Link to Full Text]

Persson AS, Westman E, Wang FH, Khan FH, Spenger C, Lavebratt C
Kv1.1 null mice have enlarged hippocampus and ventral cortex.
BMC Neurosci. 2007;810.
BACKGROUND: Mutations in the Shaker-like voltage-gated potassium channel Kv1.1 are known to cause episodic ataxia type 1 and temporal lobe epilepsy. Mice that express a malfunctional, truncated Kv1.1 (BALB/cByJ-Kv1.1mceph/mceph) show a markedly enlarged hippocampus and ventral cortex in adulthood. RESULTS: To determine if mice lacking Kv1.1 also develop a brain enlargement similar to mceph/mceph, we transferred Kv1.1 null alleles to the BALB/cByJ background. Hippocampus and ventral cortex was then studied using in vivo 3D-magnetic resonance imaging and volume segmentation in adult Kv1.1 null mice, BALB/cByJ-Kv1.1mceph/mceph, BALB/cByJ-Kv1.1mceph/+, BALB.C3HeB -Kv1.1-/+ and wild type littermates. The Kv1.1 null brains had dramatically enlarged hippocampus and ventral cortex. Mice heterozygous for either the null allele or the mceph allele had normal-sized hippocampus and ventral cortex. CONCLUSION: Total absence of Kv1.1 can induce excessive overgrowth of hippocampus and ventral cortex in mice with a BALB/cByJ background, while mice with one wild type Kv1.1 allele develop normal-sized brains. [Abstract/Link to Full Text]

Nie CL, Wang XS, Liu Y, Perrett S, He RQ
Amyloid-like aggregates of neuronal tau induced by formaldehyde promote apoptosis of neuronal cells.
BMC Neurosci. 2007;89.
BACKGROUND: The microtubule associated protein tau is the principle component of neurofibrillar tangles, which are a characteristic marker in the pathology of Alzheimer's disease; similar lesions are also observed after chronic alcohol abuse. Formaldehyde is a common environmental contaminant and also a metabolite of methanol. Although many studies have been done on methanol and formaldehyde intoxication, none of these address the contribution of protein misfolding to the pathological mechanism, in particular the effect of formaldehyde on protein conformation and polymerization. RESULTS: We found that unlike the typical globular protein BSA, the natively-unfolded structure of human neuronal tau was induced to misfold and aggregate in the presence of ~0.01% formaldehyde, leading to formation of amyloid-like deposits that appeared as densely staining granules by electron microscopy and atomic force microscopy, and bound the amyloid-specific dyes thioflavin T and Congo Red. The amyloid-like aggregates of tau were found to induce apoptosis in the neurotypic cell line SH-SY5Y and in rat hippocampal cells, as observed by Hoechst 33258 staining, assay of caspase-3 activity, and flow cytometry using Annexin V and Propidium Iodide staining. Further experiments showed that Congo Red specifically attenuated the caspase-3 activity induced by amyloid-like deposits of tau. CONCLUSION: The results suggest that low concentrations of formaldehyde can induce human tau protein to form neurotoxic aggregates, which could play a role in the induction of tauopathies. [Abstract/Link to Full Text]

Mizuno T, Schmauss C, Rayport S
Distinct roles of presynaptic dopamine receptors in the differential modulation of the intrinsic synapses of medium-spiny neurons in the nucleus accumbens.
BMC Neurosci. 2007;88.
BACKGROUND: In both schizophrenia and addiction, pathological changes in dopamine release appear to induce alterations in the circuitry of the nucleus accumbens that affect coordinated thought and motivation. Dopamine acts principally on medium-spiny GABA neurons, which comprise 95% of accumbens neurons and give rise to the majority of inhibitory synapses in the nucleus. To examine dopamine action at single medium-spiny neuron synapses, we imaged Ca2+ levels in their presynaptic varicosities in the acute brain slice using two-photon microscopy. RESULTS: Presynaptic Ca2+ rises were differentially modulated by dopamine. The D1/D5 selective agonist SKF81297 was exclusively facilitatory. The D2/D3 selective agonist quinpirole was predominantly inhibitory, but in some instances it was facilitatory. Studies using D2 and D3 receptor knockout mice revealed that quinpirole inhibition was either D2 or D3 receptor-mediated, while facilitation was mainly D3 receptor-mediated. Subsets of varicosities responded to both D1 and D2 agonists, showing that there was significant co-expression of these receptor families in single medium-spiny neurons. Neighboring presynaptic varicosities showed strikingly heterogeneous responses to DA agonists, suggesting that DA receptors may be differentially trafficked to individual varicosities on the same medium-spiny neuron axon. CONCLUSION: Dopamine receptors are present on the presynaptic varicosities of medium-spiny neurons, where they potently control GABAergic synaptic transmission. While there is significant coexpression of D1 and D2 family dopamine receptors in individual neurons, at the subcellular level, these receptors appear to be heterogeneously distributed, potentially explaining the considerable controversy regarding dopamine action in the striatum, and in particular the degree of dopamine receptor segregation on these neurons. Assuming that post-receptor signaling is restricted to the microdomains of medium-spiny neuron varicosities, the heterogeneous distribution of dopamine receptors on individual varicosities is likely to encode patterns in striatal information processing. [Abstract/Link to Full Text]

Henriksson M, Stenman E, Vikman P, Edvinsson L
Protein kinase C inhibition attenuates vascular ETB receptor upregulation and decreases brain damage after cerebral ischemia in rat.
BMC Neurosci. 2007;87.
BACKGROUND: Protein kinase C (PKC) is known to be involved in the pathophysiology of experimental cerebral ischemia. We have previously shown that after transient middle cerebral artery occlusion, there is an upregulation of endothelin receptors in the ipsilateral middle cerebral artery. The present study aimed to examine the effect of the PKC inhibitor Ro-32-0432 on endothelin receptor upregulation, infarct volume and neurology outcome after middle cerebral artery occlusion in rat. RESULTS: At 24 hours after transient middle cerebral artery occlusion (MCAO), the contractile endothelin B receptor mediated response and the endothelin B receptor protein expression were upregulated in the ipsilateral but not the contralateral middle cerebral artery. In Ro-32-0432 treated rats, the upregulated endothelin receptor response was attenuated. Furthermore, Ro-32-0432 treatment decreased the ischemic brain damage significantly and improved neurological scores. Immunohistochemistry showed fainter staining of endothelin B receptor protein in the smooth muscle cells of the ipsilateral middle cerebral artery of Ro-32-0432 treated rats compared to control. CONCLUSION: The results suggest that treatment with Ro-32-0432 in ischemic stroke decreases the ischemic infarction area, neurological symptoms and associated endothelin B receptor upregulation. This provides a new perspective on possible mechanisms of actions of PKC inhibition in cerebral ischemia. [Abstract/Link to Full Text]

Tremblay L, Elliott D
Sex differences in judging self-orientation: the morphological horizon and body pitch.
BMC Neurosci. 2007;86.
BACKGROUND: Sex differences exist for many spatial tasks. This is true for circular vection, field dependence, and perception of veridical vertical with body tilt. However, explanations for these sex differences is lacking in the literature. In this study, we investigated the nature of individual differences in the perception of self-orientation in humans. Male and female participants were asked to identify their Morphological Horizon (i.e., line perpendicular to saggital plane at eye-level) in different body orientations relative to gravity (i.e., 45 deg and 135 deg body pitch) with and without prior whole body rotation. RESULTS: Sex explained the observed differences in the perception of self-orientation only when blood distribution was least altered (i.e., 45 deg body pitch) and without prior whole body rotation. Specifically, females presented a more footward bias than males in these conditions. CONCLUSION: These results add to the literature on sex differences for spatial orientation tasks. As the differences were only observed with static conditions and when blood distribution was least affected, we concluded that sex differences in the perception of self-orientation are associated with gravireceptors (e.g., otoliths). [Abstract/Link to Full Text]

Ma H, Yang R, Thomas SM, Kinnamon JC
Qualitative and quantitative differences between taste buds of the rat and mouse.
BMC Neurosci. 2007;85.
BACKGROUND: Numerous electrophysiological, ultrastructural, and immunocytochemical studies on rodent taste buds have been carried out on rat taste buds. In recent years, however, the mouse has become the species of choice for molecular and other studies on sensory transduction in taste buds. Do rat and mouse taste buds have the same cell types, sensory transduction markers and synaptic proteins? In the present study we have used antisera directed against PLCbeta2, alpha-gustducin, serotonin (5-HT), PGP 9.5 and synaptobrevin-2 to determine the percentages of taste cells expressing these markers in taste buds in both rodent species. We also determined the numbers of taste cells in the taste buds as well as taste bud volume. RESULTS: There are significant differences (p < 0.05) between mouse and rat taste buds in the percentages of taste cells displaying immunoreactivity for all five markers. Rat taste buds display significantly more immunoreactivity than mice for PLCbeta2 (31.8% vs 19.6%), alpha-gustducin (18% vs 14.6%), and synaptobrevin-2 (31.2% vs 26.3%). Mice, however, have more cells that display immunoreactivity to 5-HT (15.9% vs 13.7%) and PGP 9.5 (14.3% vs 9.4%). Mouse taste buds contain an average of 85.8 taste cells vs 68.4 taste cells in rat taste buds. The average volume of a mouse taste bud (42,000 microm3) is smaller than a rat taste bud (64,200 microm3). The numerical density of taste cells in mouse circumvallate taste buds (2.1 cells/1000 microm3) is significantly higher than that in the rat (1.2 cells/1000 microm3). CONCLUSION: These results suggest that rats and mice differ significantly in the percentages of taste cells expressing signaling molecules. We speculate that these observed dissimilarities may reflect differences in their gustatory processing. [Abstract/Link to Full Text]

Lemberger T, Parlato R, Dassesse D, Westphal M, Casanova E, Turiault M, Tronche F, Schiffmann SN, Schütz G
Expression of Cre recombinase in dopaminoceptive neurons.
BMC Neurosci. 2007;84.
BACKGROUND: Dopamine-activated signaling regulates locomotor and emotional responses and alterations in dopamine-signaling are responsible of several psychomotor disorders. In order to identify specific functions of these pathways, the Cre/loxP system has been used. Here, we describe the generation and the characterization of a transgenic mouse line expressing the Cre recombinase in dopaminoceptive neurons. To this purpose, we used as expression vector a 140 kb yeast artificial chromosome (YAC) containing the dopamine D1 receptor gene (Drd1a). RESULTS: In the chosen line, D1Cre, the spatio-temporal pattern of Cre expression closely recapitulated that of the endogenous Drd1a gene, as assessed by immunohistological approaches in embryonic and adult stages. Efficiency of recombination was confirmed by crossing D1Cre with three different loxP lines (Creb1loxP, CaMKIVloxP and GRloxP) and with the R26R reporter. In the three loxP lines studied, recombination was restricted to the area of Cre expression. CONCLUSION: In view of the patterns of recombination restricted to the major dopaminoceptive regions as seen in the context of the CREB, CaMKIV and GR mutations, the D1Cre line will be a useful tool to dissect the contributions of specific genes to biological processes involving dopamine signaling. [Abstract/Link to Full Text]

Milner R
A novel three-dimensional system to study interactions between endothelial cells and neural cells of the developing central nervous system.
BMC Neurosci. 2007;83.
BACKGROUND: During angiogenesis in the developing central nervous system (CNS), endothelial cells (EC) detach from blood vessels growing on the brain surface, and migrate into the expanding brain parenchyma. Brain angiogenesis is regulated by growth factors and extracellular matrix (ECM) proteins secreted by cells of the developing CNS. In addition, recent evidence suggests that EC play an important role in establishing the neural stem cell (NSC) niche. Therefore, two-way communication between EC and neural cells is of fundamental importance in the developing CNS. To study the interactions between brain EC and neural cells of the developing CNS, a novel three-dimensional (3-D) murine co-culture system was developed. Fluorescent-labelled brain EC were seeded onto neurospheres; floating cellular aggregates that contain NSC/neural precursor cells (NPC) and smaller numbers of differentiated cells. Using this system, brain EC attachment, survival and migration into neurospheres was evaluated and the role of integrins in mediating the early adhesive events addressed. RESULTS: Brain EC attached, survived and migrated deep into neurospheres over a 5-day period. Neurospheres express the ECM proteins fibronectin and laminin, and brain EC adhesion to neurospheres was inhibited by RGD peptides and antibodies specific for the beta1, but not the alpha6 integrin subunit. CONCLUSION: A novel 3-D co-culture system for analysing the interactions between EC and neural cells of the developing CNS is presented. This system could be used to investigate the reciprocal influence of EC and NSC/NPC; to examine how NSC/NPC influence cerebral angiogenesis, and conversely, to examine how EC regulate the maintenance and differentiation of NSC/NPC. Using this system it is demonstrated that EC attachment to neurospheres is mediated by the fibronectin receptor, alpha5beta1 integrin. [Abstract/Link to Full Text]

Steiner J, Bernstein HG, Bielau H, Berndt A, Brisch R, Mawrin C, Keilhoff G, Bogerts B
Evidence for a wide extra-astrocytic distribution of S100B in human brain.
BMC Neurosci. 2007;82.
BACKGROUND: S100B is considered an astrocytic in-situ marker and protein levels in cerebrospinal fluid (CSF) or serum are often used as biomarker for astrocytic damage or dysfunction. However, studies on S100B in the human brain are rare. Thus, the distribution of S100B was studied by immunohistochemistry in adult human brains to evaluate its cell-type specificity. RESULTS: Contrary to glial fibrillary acidic protein (GFAP), which selectively labels astrocytes and shows only faint ependymal immunopositivity, a less uniform staining pattern was seen in the case of S100B. Cells with astrocytic morphology were primarily stained by S100B in the human cortex, while only 20% (14-30%) or 14% (7-35%) of all immunopositive cells showed oligodendrocytic morphology in the dorsolateral prefrontal and temporal cortices, respectively. In the white matter, however, most immunostained cells resembled oligodendrocytes [frontal: 75% (57-85%); temporal: 73% (59-87%); parietal: 79% (62-89%); corpus callosum: 93% (86-97%)]. S100B was also found in ependymal cells, the choroid plexus epithelium, vascular endothelial cells, lymphocytes, and several neurones. Anti-myelin basic protein (MBP) immunolabelling showed an association of S100B with myelinated fibres, whereas GFAP double staining revealed a distinct subpopulation of cells with astrocytic morphology, which solely expressed S100B but not GFAP. Some of these cells showed co-localization of S100B and A2B5 and may be characterized as O2A glial progenitor cells. However, S100B was not detected in microglial cells, as revealed by double-immunolabelling with HLA-DR. CONCLUSION: S100B is localized in many neural cell-types and is less astrocyte-specific than GFAP. These are important results in order to avoid misinterpretation in the identification of normal and pathological cell types in situ and in clinical studies since S100B is continuously used as an astrocytic marker in animal models and various human diseases. [Abstract/Link to Full Text]

Fünfschilling U, Saher G, Xiao L, Möbius W, Nave KA
Survival of adult neurons lacking cholesterol synthesis in vivo.
BMC Neurosci. 2007;81.
BACKGROUND: Cholesterol, an essential component of all mammalian plasma membranes, is highly enriched in the brain. Both during development and in the adult, brain cholesterol is derived from local cholesterol synthesis and not taken up from the circulation. However, the contribution of neurons and glial cells to total brain cholesterol metabolism is unknown. RESULTS: Using conditional gene inactivation in the mouse, we disrupted the squalene synthase gene (fdft1), which is critical for cholesterol synthesis, in cerebellar granule cells and some precerebellar nuclei. Mutant mice showed no histological signs of neuronal degeneration, displayed ultrastructurally normal synapses, and exhibited normal motor coordination. This revealed that these adult neurons do not require cell-autonomous cholesterol synthesis for survival or function. CONCLUSION: We conclude that at least some adult neurons no longer require endogenous cholesterol synthesis and can fully meet their cholesterol needs by uptake from their surrounding. Glia are a likely source of cholesterol in the central nervous system. [Abstract/Link to Full Text]

Keith TA, Radhakrishnan V, Moredock S, García DM
Uptake of 3H-cAMP by retinal pigment epithelium isolated from bluegill sunfish (Lepomis macrochirus).
BMC Neurosci. 2006;782.
BACKGROUND: In bluegill sunfish, the melanin-containing pigment granules of the retinal pigment epithelium undergo cyclic movements in response both to ambient lighting and circadian cues. Pigment granules aggregate into the cell body at night (in the dark), and disperse into apical processes during the day (in the light). Regulation of pigment granule aggregation in a number of fishes depends on modulating the intracellular levels of cyclic adenosine monophosphate. RESULTS: Here we show isolated RPE takes up cyclic adenosine monophosphate (cAMP) in a saturable manner, exogenously applied cAMP induces pigment granule aggregation in retinal pigment epithelium isolated from bluegill, and aggregation induced in this manner is inhibited by treatment with probenecid, an organic anion transport inhibitor. CONCLUSION: Our results raise the possibility that cAMP functions as a messenger secreted from the neural retina to signal darkness to the RPE, which takes it up. It further suggests that organic anion transport systems are the route by which cAMP crosses RPE cell membranes since probenecid inhibits extracellular cAMP from causing pigment granule aggregation. [Abstract/Link to Full Text]

Colas D, Gharib A, Bezin L, Morales A, Guidon G, Cespuglio R, Sarda N
Regional age-related changes in neuronal nitric oxide synthase (nNOS), messenger RNA levels and activity in SAMP8 brain.
BMC Neurosci. 2006;781.
BACKGROUND: Nitric oxide (NO) is a multifunctional molecule synthesized by three isozymes of the NO synthase (NOSs) acting as a messenger/modulator and/or a potential neurotoxin. In rodents, the role of NOSs in sleep processes and throughout aging is now well established. For example, sleep parameters are highly deteriorated in senescence accelerated-prone 8 (SAMP8) mice, a useful animal model to study aging or age-associated disorders, while the inducible form of NOS (iNOS) is down-regulated within the cortex and the sleep-structures of the brainstem. Evidence is now increasing for a role of iNOS and resulting oxidative stress but not for the constitutive expressed isozyme (nNOS). To better understand the role of nNOS in the behavioural impairments observed in SAMP8 versus SAMR1 (control) animals, we evaluated age-related variations occurring in the nNOS expression and activity and nitrites/nitrates (NOx-) levels, in three brain areas (n = 7 animals in each group). Calibrated reverse transcriptase (RT) and real-time polymerase chain reaction (PCR) and biochemical procedures were used. RESULTS: We found that the levels of nNOS mRNA decreased in the cortex and the hippocampus of 8- vs 2-month-old animals followed by an increase in 12-vs 8-month-old animals in both strains. In the brainstem, levels of nNOS mRNA decreased in an age-dependent manner in SAMP8, but not in SAMR1. Regional age-related changes were also observed in nNOS activity. Moreover, nNOS activity in hippocampus was found lower in 8-month-old SAMP8 than in SAMR1, while in the cortex and the brainstem, nNOS activities increased at 8 months and afterward decreased with age in SAMP8 and SAMR1. NOx- levels showed profiles similar to nNOS activities in the cortex and the brainstem but were undetectable in the hippocampus of SAMP8 and SAMR1. Finally, NOx- levels were higher in the cortex of 8 month-old SAMP8 than in age-matched SAMR1. CONCLUSION: Concomitant variations occurring in NO levels derived from nNOS and iNOS at an early age constitute a major factor of risk for sleep and/or memory impairments in SAMP8. [Abstract/Link to Full Text]

Van Raamsdonk JM, Pearson J, Murphy Z, Hayden MR, Leavitt BR
Wild-type huntingtin ameliorates striatal neuronal atrophy but does not prevent other abnormalities in the YAC128 mouse model of Huntington disease.
BMC Neurosci. 2006;780.
BACKGROUND: Huntington disease (HD) is an adult onset neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin (htt) protein. Htt function is essential for embryonic survival as well as normal function during the postnatal period. In addition to having roles in transcription and transport, recent evidence demonstrates that wild-type htt is neuroprotective in vivo. To determine whether treatment with wild-type htt would be beneficial in HD, we crossed the YAC128 mouse model of HD with mice that over-express wild-type htt (YAC18 mice) to generate YAC128 mice that over-express wild-type htt (YAC18/128 mice). RESULTS: YAC18/128 mice were found to express mutant htt at the same level as YAC128 mice and wild-type htt at the same level as YAC18 mice. YAC18/128 mice show no significant behavioural improvement compared to YAC128 mice in the rotarod test of motor coordination or in an automated open field test. In the brain, YAC18/128 mice show no significant improvement in striatal volume, striatal neuronal numbers or striatal DARPP-32 expression compared to YAC128 mice. In contrast, striatal neuronal cross-sectional area showed significant improvement in YAC18/128 mice compared to YAC128 mice. CONCLUSION: While the over-expression of wild-type htt results in a mild improvement in striatal neuropathology in YAC128 mice, our findings suggest that treatment with wild-type htt may not be sufficient to ameliorate the symptoms of HD in this model. [Abstract/Link to Full Text]

Saito DN, Okada T, Honda M, Yonekura Y, Sadato N
Practice makes perfect: the neural substrates of tactile discrimination by Mah-Jong experts include the primary visual cortex.
BMC Neurosci. 2006;779.
BACKGROUND: It has yet to be determined whether visual-tactile cross-modal plasticity due to visual deprivation, particularly in the primary visual cortex (V1), is solely due to visual deprivation or if it is a result of long-term tactile training. Here we conducted an fMRI study with normally-sighted participants who had undergone long-term training on the tactile shape discrimination of the two dimensional (2D) shapes on Mah-Jong tiles (Mah-Jong experts). Eight Mah-Jong experts and twelve healthy volunteers who were naïve to Mah-Jong performed a tactile shape matching task using Mah-Jong tiles with no visual input. Furthermore, seven out of eight experts performed a tactile shape matching task with unfamiliar 2D Braille characters. RESULTS: When participants performed tactile discrimination of Mah-Jong tiles, the left lateral occipital cortex (LO) and V1 were activated in the well-trained subjects. In the naïve subjects, the LO was activated but V1 was not activated. Both the LO and V1 of the well-trained subjects were activated during Braille tactile discrimination tasks. CONCLUSION: The activation of V1 in subjects trained in tactile discrimination may represent altered cross-modal responses as a result of long-term training. [Abstract/Link to Full Text]

Zhu F, Qian C
Berberine chloride can ameliorate the spatial memory impairment and increase the expression of interleukin-1beta and inducible nitric oxide synthase in the rat model of Alzheimer's disease.
BMC Neurosci. 2006;778.
BACKGROUND: Berberine is the major alkaloidal component of Rhizoma coptidis, and has multiple pharmacological effects including inhibiting acetylcholinesterase, reducing cholesterol and glucose, lowering mortality in patients with chronic congestive heart failure and anti-inflammation etc. Thus berberine is a promising drug for diabetes, hyperlipemia, coronary artery disease and ischemic stroke etc. The present study was carried out to investigate the effect of berberine chloride on the spatial memory, inflammation factors interleukin-1 beta (IL-1beta) and inducible nitric oxide synthase (iNOS) expression in the rat model of Alzheimer's disease (AD) which was established by injecting Abeta (1-40) (5 microgram) into the rats hippocampuses bilaterally. RESULTS: The rats were given berberine chloride (50 mg/kg) by intragastric administration once daily for 14 days. The spatial memory was assayed by Morris water maze test, IL-1beta and iNOS in the hippocampus were assayed by immunohistochemistry and real time polymerase chain reaction (PCR). Intragastric administration of berberine significantly ameliorated the spatial memory impairment and increased the expression of IL-1beta, iNOS in the rat model of AD. CONCLUSION: Berberine might be beneficial to AD by intragastric administration though it might exaggerate the inflammation reaction. [Abstract/Link to Full Text]

Graham BP, van Ooyen A
Mathematical modelling and numerical simulation of the morphological development of neurons.
BMC Neurosci. 2006 Oct 30;7 Suppl 1S9.
ABSTRACT : BACKGROUND : The morphological development of neurons is a very complex process involving both genetic and environmental components. Mathematical modelling and numerical simulation are valuable tools in helping us unravel particular aspects of how individual neurons grow their characteristic morphologies and eventually form appropriate networks with each other. METHODS : A variety of mathematical models that consider (1) neurite initiation (2) neurite elongation (3) axon pathfinding, and (4) neurite branching and dendritic shape formation are reviewed. The different mathematical techniques employed are also described. RESULTS : Some comparison of modelling results with experimental data is made. A critique of different modelling techniques is given, leading to a proposal for a unified modelling environment for models of neuronal development. CONCLUSION : A unified mathematical and numerical simulation framework should lead to an expansion of work on models of neuronal development, as has occurred with compartmental models of neuronal electrical activity. [Abstract/Link to Full Text]

Ambesi-Impiombato A, Bansal M, Liò P, di Bernardo D
Computational framework for the prediction of transcription factor binding sites by multiple data integration.
BMC Neurosci. 2006 Oct 30;7 Suppl 1S8.
ABSTRACT : Control of gene expression is essential to the establishment and maintenance of all cell types, and its dysregulation is involved in pathogenesis of several diseases. Accurate computational predictions of transcription factor regulation may thus help in understanding complex diseases, including mental disorders in which dysregulation of neural gene expression is thought to play a key role. However, biological mechanisms underlying the regulation of gene expression are not completely understood, and predictions via bioinformatics tools are typically poorly specific.We developed a bioinformatics workflow for the prediction of transcription factor binding sites from several independent datasets. We show the advantages of integrating information based on evolutionary conservation and gene expression, when tackling the problem of binding site prediction. Consistent results were obtained on a large simulated dataset consisting of 13050 in silico promoter sequences, on a set of 161 human gene promoters for which binding sites are known, and on a smaller set of promoters of Myc target genes.Our computational framework for binding site prediction can integrate multiple sources of data, and its performance was tested on different datasets. Our results show that integrating information from multiple data sources, such as genomic sequence of genes' promoters, conservation over multiple species, and gene expression data, indeed improves the accuracy of computational predictions. [Abstract/Link to Full Text]

Recent Articles in BMC Neurology

Baraniuk JN, Casado B, Maibach H, Clauw DJ, Pannell LK, Hess S S
A Chronic Fatigue Syndrome - related proteome in human cerebrospinal fluid.
BMC Neurol. 2005;522.
BACKGROUND: Chronic Fatigue Syndrome (CFS), Persian Gulf War Illness (PGI), and fibromyalgia are overlapping symptom complexes without objective markers or known pathophysiology. Neurological dysfunction is common. We assessed cerebrospinal fluid to find proteins that were differentially expressed in this CFS-spectrum of illnesses compared to control subjects. METHODS: Cerebrospinal fluid specimens from 10 CFS, 10 PGI, and 10 control subjects (50 mul/subject) were pooled into one sample per group (cohort 1). Cohort 2 of 12 control and 9 CFS subjects had their fluids (200 mul/subject) assessed individually. After trypsin digestion, peptides were analyzed by capillary chromatography, quadrupole-time-of-flight mass spectrometry, peptide sequencing, bioinformatic protein identification, and statistical analysis. RESULTS: Pooled CFS and PGI samples shared 20 proteins that were not detectable in the pooled control sample (cohort 1 CFS-related proteome). Multilogistic regression analysis (GLM) of cohort 2 detected 10 proteins that were shared by CFS individuals and the cohort 1 CFS-related proteome, but were not detected in control samples. Detection of >or=1 of a select set of 5 CFS-related proteins predicted CFS status with 80% concordance (logistic model). The proteins were alpha-1-macroglobulin, amyloid precursor-like protein 1, keratin 16, orosomucoid 2 and pigment epithelium-derived factor. Overall, 62 of 115 proteins were newly described. CONCLUSION: This pilot study detected an identical set of central nervous system, innate immune and amyloidogenic proteins in cerebrospinal fluids from two independent cohorts of subjects with overlapping CFS, PGI and fibromyalgia. Although syndrome names and definitions were different, the proteome and presumed pathological mechanism(s) may be shared. [Abstract/Link to Full Text]

Nguyen-Huynh MN, Johnston SC
Regional variation in hospitalization for stroke among Asians/Pacific Islanders in the United States: a nationwide retrospective cohort study.
BMC Neurol. 2005;521.
BACKGROUND: In Asia, stroke incidence varies dramatically from country to country. Little is known about stroke incidence in Asians/Pacific Islanders in the US, where regional heterogeneity in Asian/Pacific Islander sub-populations is great. We sought to characterize both the national and regional incidences of first and recurrent hospitalized acute ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage in Asians/Pacific Islanders compared to non-Hispanic whites. METHODS: We used the National Inpatient Sample of the 1997 Healthcare Cost and Utilization Project. It is a 20% stratified sample of hospitalizations to nonfederal hospitals in the US. National and regional projections were made using sampling weights specific for patients and hospitals. We identified stroke subtypes using previously validated ICD-9 codes. Age-adjusted incidence rates were calculated using the direct method with the US population in 2000 as the standard. RESULTS: There were 169,386 stroke hospitalizations in the database. Nationally, compared to whites, Asians/Pacific Islanders were more likely to have subarachnoid hemorrhage (incidence rate ratio {RR} female: 1.53, 95% CI 1.41-1.65; male RR: 1.13, 95% CI 1.00-1.27) and intracerebral hemorrhage (female RR 1.29, 95% CI 1.22-1.36; male RR: 1.58, 95% CI 1.50-1.67). However, when examined by geographic regions, Asians/Pacific Islanders had higher incidence rates of subarachnoid hemorrhage and intracerebral hemorrhage predominantly in the West, and lower rates of stroke elsewhere. CONCLUSION: Stroke incidence varies 3-fold among Asians/Pacific Islanders residing in different US regions. Geographic variation is less dramatic in whites. Whether genetic or cultural differences are responsible for dramatic heterogeneity among Asian/Pacific Islander populations is unclear and deserves further study. [Abstract/Link to Full Text]

Lisabeth LD, Smith MA, Brown DL, Uchino K, Morgenstern LB
Family history and stroke outcome in a bi-ethnic, population-based stroke surveillance study.
BMC Neurol. 2005;520.
BACKGROUND: The genetic epidemiology of ischemic stroke remains relatively unstudied, and information about the genetic epidemiology of ischemic stroke in populations with significant minority representation is currently unavailable. METHODS: The Brain Attack Surveillance in Corpus Christi project (BASIC) is a population-based stroke surveillance study conducted in the bi-ethnic community of Nueces County, Texas, USA. Completed ischemic strokes were identified among patients 45 years or older seen at hospitals in the county between January 1, 2000-December 31, 2002. A random sample of ischemic stroke patients underwent an in-person interview and detailed medical record abstraction (n = 400). Outcomes, including initial stroke severity (NIH stroke scale), age at stroke onset, 90-day mortality and functional outcome (modified Rankin scale > or = 2), were studied for their association with family history of stroke among a first degree relative using multivariable logistic and linear regression. A chi-square test was used to test the association between family history of stroke and ischemic stroke subtype. RESULTS: The study population was 53.0% Mexican American and 58.4% female. Median age was 73.2 years. Forty percent reported a family history of stroke among a first degree relative. Family history of stroke was borderline significantly associated with stroke subtype (p = 0.0563). Family history was associated with poor functional outcome in the multivariable model (OR = 1.87; 95% CI: 1.14-3.09). Family history was not significantly related to initial stroke severity, age at stroke onset, or 90-day mortality. CONCLUSION: Family history of stroke was related to ischemic stroke subtype and to functional status at discharge. More research is needed to understand whether stroke subtype would be a useful selection criterion for genetic association studies and to hypothesize about a possible genetic link to recovery following ischemic stroke. [Abstract/Link to Full Text]

Martínez A, Mas A, de las Heras V, Arroyo R, Fernández-Arquero M, de la Concha EG, Urcelay E
Early B-cell Factor gene association with multiple sclerosis in the Spanish population.
BMC Neurol. 2005;519.
BACKGROUND: The etiology of multiple sclerosis (MS) is at present not fully elucidated, although it is considered to result from the interaction of environmental and genetic susceptibility factors. In this work we aimed at testing the Early B-cell Factor (EBF1) gene as a functional and positional candidate risk factor for this neurological disease. Axonal damage is a hallmark for multiple sclerosis clinical disability and EBF plays an evolutionarily conserved role in the expression of proteins essential for axonal pathfinding. Failure of B-cell differentiation was found in EBF-deficient mice and involvement of B-lymphocytes in MS has been suggested from their presence in cerebrospinal fluid and lesions of patients. METHODS: The role of the EBF1 gene in multiple sclerosis susceptibility was analyzed by performing a case-control study with 356 multiple sclerosis patients and 540 ethnically matched controls comparing the EBF1 polymorphism rs1368297 and the microsatellite D5S2038. RESULTS: Significant association of an EBF1-intronic polymorphism (rs1368297, A vs. T: p = 0.02; OR = 1.26 and AA vs. [TA+TT]: p = 0.02; OR = 1.39) was discovered. This association was even stronger after stratification for the well-established risk factor of multiple sclerosis in the Major Histocompatibility Complex, DRB1*1501 (AA vs. [TA+TT]: p = 0.005; OR = 1.78). A trend for association in the case-control study of another EBF1 marker, the allele 5 of the very informative microsatellite D5S2038, was corroborated by Transmission Disequilibrium Test of 53 trios (p = 0.03). CONCLUSION: Our data support EBF1 gene association with MS pathogenesis in the Spanish white population. Two genetic markers within the EBF1 gene have been found associated with this neurological disease, indicative either of their causative role or that of some other polymorphism in linkage disequilibrium with them. [Abstract/Link to Full Text]

Tsushima Y, Taketomi-Takahashi A, Endo K
Prevalence of abnormal findings on brain magnetic resonance (MR) examinations in adult participants of brain docking.
BMC Neurol. 2005;518.
BACKGROUND: To determine the prevalence of abnormal findings on brain magnetic resonance (MR) examinations in adult participants of brain docking in order to assess its usefulness. METHODS: We analyzed screening brain MR examinations for 1113 adults (age, 52.6+/-8.5 years; range, 22-84; 761 male and 352 female) performed during 6-year period from April 1998 to March 2004. All participants voluntarily sought a brain MR examination at their own expense. All subjects were studied using the same 1.0-T MR scanner, on axial T1-weighted spin echo (SE) images, proton-density-weighted and T2-weighted fast SE images, and intracranial MR angiography (MRA). All abnormal findings were classified into three basic categories: (1) findings with no referral necessary; (2) findings not requiring further evaluation, but which needed to be reported to the referring physician; (3) findings requiring further evaluation. RESULTS: Participants with abnormal MR findings requiring further evaluation accounted for 1.3 %, but five of seven suspected intracranial aneurysms were not confirmed by other imaging modalities (false positive). No malignant tumors or other life-threatening pathology was detected, and only three participants (0.27 %) with abnormalities underwent surgical treatment. No participant groups were identified from our data as being high risk for MR abnormal findings requiring further evaluation. CONCLUSION: Brain-docking participants had a variety of abnormalities on brain MR examinations, but only a small percentage of these findings required further evaluation. The usefulness of the brain docking with MRI and MRA has yet to be proven, and at this time we cannot approve this screening procedure. [Abstract/Link to Full Text]

Seghier ML, Lazeyras F, Zimine S, Saudan-Frei S, Safran AB, Huppi PS
Visual recovery after perinatal stroke evidenced by functional and diffusion MRI: case report.
BMC Neurol. 2005;517.
BACKGROUND: After perinatal brain injury, clinico-anatomic correlations of functional deficits and brain plasticity remain difficult to evaluate clinically in the young infant. Thus, new non-invasive methods capable of early functional diagnosis are needed in young infants. CASE PRESENTATION: The visual system recovery in an infant with perinatal stroke is assessed by combining diffusion tensor imaging (DTI) and event-related functional MRI (ER-fMRI). All experiments were done at 1.5T. A first DTI experiment was performed at 12 months of age. At 20 months of age, a second DTI experiment was performed and combined with an ER-fMRI experiment with visual stimuli (2 Hz visual flash). At 20 months of age, ER-fMRI showed significant negative activation in the visual cortex of the injured left hemisphere that was not previously observed in the same infant. DTI maps suggest recovery of the optic radiation in the vicinity of the lesion. Optic radiations in the injured hemisphere are more prominent in DTI at 20 months of age than in DTI at 12 months of age. CONCLUSION: Our data indicate that functional cortical recovery is supported by structural modifications that concern major pathways of the visual system. These neuroimaging findings might contribute to elaborate a pertinent strategy in terms of diagnosis and rehabilitation. [Abstract/Link to Full Text]

Lukas C, Keyvani K, Börnke C
Primary angiitis of the central nervous system presenting with subacute and fatal course of disease: a case report.
BMC Neurol. 2005;516.
BACKGROUND: Primary angiitis of the central nervous system is an idiopathic disorder characterized by vasculitis within the dural confines. The clinical presentation shows a wide variation and the course and the duration of disease are heterogeneous. This rare but treatable disease provides a diagnostic challenge owing to the lack of pathognomonic tests and the necessity of a histological confirmation. CASE PRESENTATION: A 28-year-old patient presenting with headache and fluctuating signs of encephalopathy was treated on the assumption of viral meningoencephalitis. The course of the disease led to his death 10 days after hospital admission. Postmortem examination revealed primary angiitis of the central nervous system. CONCLUSION: Primary angiitis of the central nervous system should always be taken into consideration when suspected infectious inflammation of the central nervous system does not respond to treatment adequately. In order to confirm the diagnosis with the consequence of a modified therapy angiography and combined leptomeningeal and brain biopsy should be considered immediately. [Abstract/Link to Full Text]

Ishihara LS, Khaw KT, Luben R, Bingham S, Welch A, Day N, Brayne C
Self-reported parkinsonian symptoms in the EPIC-Norfolk cohort.
BMC Neurol. 2005;515.
BACKGROUND: Parkinsonian symptoms have been associated with increased morbidity and mortality. Several studies have reported on the prevalence of signs and symptoms. Symptoms questionnaires can identify potential PD cases for further neurological examination to save resources. They can also provide information about how much of the population reports specific signs and symptoms. The objective of the study was to determine the self-reported prevalence of parkinsonian symptoms from a questionnaire, and to examine their association with age and self-reported Parkinson's disease in a large cohort. METHODS: A cross-sectional study was conducted within a sub-cohort of the EPIC-Norfolk (European Prospective Investigation of Cancer) cohort study. RESULTS: The prevalence of six self-reported parkinsonian symptoms are reported for 11,539 individuals who answered all symptoms questions (62% of sub-cohort): rest tremor (4%), difficulty starting to walk (4%), difficulty getting out of a chair (6%), slower walking (34%), smaller handwriting (micrographia- 9%), and less acute sense of smell (olfactory dysfunction- 9%). The presence of individual symptoms increased with age except for difficulty getting out of a chair. CONCLUSION: The results support previous findings that the presence of self-reported parkinsonian symptoms is strongly associated with age and self-reported PD diagnosis. The data also provide information regarding the prevalence of symptoms in a large, younger population of adults than previously reported in the literature. [Abstract/Link to Full Text]

Thömke F, Marx JJ, Sauer O, Hundsberger T, Hägele S, Wiechelt J, Weilemann SL
Observations on comatose survivors of cardiopulmonary resuscitation with generalized myoclonus.
BMC Neurol. 2005;514.
BACKGROUND: There is only limited data on improvements of critical medical care is resulting in a better outcome of comatose survivors of cardiopulmonary resuscitation (CPR) with generalized myoclonus. There is also a paucity of data on the temporal dynamics of electroenephalographic (EEG) abnormalities in these patients. METHODS: Serial EEG examinations were done in 50 comatose survivors of CPR with generalized myoclonus seen over an 8 years period. RESULTS: Generalized myoclonus occurred within 24 hours after CPR. It was associated with burst-suppression EEG (n = 42), continuous generalized epileptiform discharges (n = 5), alpha-coma-EEG (n = 52), and low amplitude (10 microV <) recording (n = 1). Except in 3 patients, these EEG-patterns were followed by another of these always nonreactive patterns within one day, mainly alpha-coma-EEG (n = 10) and continuous generalized epileptiform discharges (n = 9). Serial recordings disclosed a variety of EEG-sequences composed of these EEG-patterns, finally leading to isoelectric or flat recordings. Forty-five patients died within 2 weeks, 5 patients survived and remained in a permanent vegetative state. CONCLUSION: Generalized myoclonus in comatose survivors of CPR still implies a poor outcome despite advances in critical care medicine. Anticonvulsive drugs are usually ineffective. All postanoxic EEG-patterns are transient and followed by a variety of EEG sequences composed of different EEG patterns, each of which is recognized as an unfavourable sign. Different EEG-patterns in anoxic encephalopathy may reflect different forms of neocortical dysfunction, which occur at different stages of a dynamic process finally leading to severe neuronal loss. [Abstract/Link to Full Text]

Ghavanini MA, Ashraf A, Sadeghi S, Emad M
A new approach to estimation of the number of central synapse(s) included in the H-reflex.
BMC Neurol. 2005;5(1):13.
BACKGROUND: Among the main clinical applications of the H-reflex are the evaluation of the S1 nerve root conductivity such as radiculopathy and measurement of the excitability of the spinal motoneurons in neurological conditions. An attempt has been made to reduce the pathway over which H-reflex can be obtained in a hope to localize a lesion to the S1 nerve root, so the S1 central loop has been suggested. The main goal of this study is the estimation of the H-reflex number of synapse(s) for better understanding of the physiology of this practical reflex. METHODS: Forty healthy adult volunteers (22 males, 18 females) with the mean age of (37.7 +/- 10.2) years participated in this study. They were positioned comfortably in the prone position, with their feet off the edge of the plinth. Recording electrodes were positioned at the mid point of a line connecting the mid popliteal crease to the proximal flare of the medial malleolus. Stimulation was applied at the tibial nerve in the popliteal fossa and H, F and M waves were recorded. Without any change in the location of the recording electrodes, a monopolar needle was inserted as cathode at a point 1 cm medial to the posterior superior iliac spine, perpendicular to the frontal plane. The anode electrode was placed over the anterior superior iliac spine, and then M and H waves of the central loop were recorded. After processing the data, sacral cord conduction delay was determined by this formula: sacral cord conduction delay = central loop of H-reflex - (delays of the proximal motor and sensory fibers in the central loop). RESULTS: The central loop of H-reflex was (6.77 +/- 0.28) msec and the sacral cord conduction delay was (1.09 +/- 0.06) msec. CONCLUSION: The sacral cord conduction time was estimated to be about 1.09 msec in this study and because at least 1 msec is required to transmit the signal across the synapse between the sensory ending and the motor cell, so this estimated time was sufficient for only one central synapse in this reflex. [Abstract/Link to Full Text]

Oedit R, van Kooten F, Bakker SL, Dippel DW
Efficacy of the epidural blood patch for the treatment of post lumbar puncture headache BLOPP: a randomised, observer-blind, controlled clinical trial [ISRCTN 71598245].
BMC Neurol. 2005;5(1):12.
BACKGROUND: Post dural punction headache (PDPH) occurs in 10% to 40% of the patients who had a lumbar puncture. Its symptoms can be severe and incapacitating. The epidural blood patch is widely accepted as the treatment of choice for postdural puncture headache. Uncontrolled studies report rapid recovery after patching in 90% to 100% of treated patients. However, sufficient evidence from randomised, controlled clinical trials is lacking. METHODS: BLOPP (blood patch for post dural puncture headache) is a randomised, single centre, observer-blind clinical trial. Patients with PDPH for at least 24 hours and at most 7 days after lumbar puncture will be randomised to treatment with an epidural blood patch (EDBP) or to conventional treatment, i.e. 24 hours bed rest and ample fluid intake. PDPH 24 hours after treatment, classified on a 4-point scale (no, mild, moderate, severe) is the primary outcome. The secondary outcome is the presence of PDPH 7 days after treatment. We estimated that a sample size of 2 x 20 patients would provide us with a power of 80% to detect a relative reduction in number of patients with persisting PDPH after 24 hours of 50% at the usual significance level alpha = 5%, taking into account that in approximately 10% of the patients the PDPH will have resolved spontaneously after one day. DISCUSSION: The EDBP is accepted as the treatment of choice for PDPH although randomised, controlled data is scarce. Our randomised, observer-blind clinical trial enables us to compare the efficacy of two clinically practiced methods of PDPH treatment; EDBP versus conventional treatment, as they are applied in clinical practise. [Abstract/Link to Full Text]

Clarimon J, Xiromerisiou G, Eerola J, Gourbali V, Hellström O, Dardiotis E, Peuralinna T, Papadimitriou A, Hadjigeorgiou GM, Tienari PJ, Singleton AB
Lack of evidence for a genetic association between FGF20 and Parkinson's disease in Finnish and Greek patients.
BMC Neurol. 2005;511.
BACKGROUND: Fibroblast growth factor 20 (FGF20) is a neurotrophic factor preferentially expressed in the substantia nigra of rat brain and could be involved in dopaminergic neurons survival. Recently, a strong genetic association has been found between FGF20 gene and the risk of suffering from Parkinson's disease (PD). Our aim was to replicate this association in two independent populations. METHODS: Allelic, genotypic, and haplotype frequencies of four biallelic polymorphisms were assessed in 151 sporadic PD cases and 186 controls from Greece, and 144 sporadic PD patients and 135 controls from Finland. RESULTS: No association was found in any of the populations studied. CONCLUSION: Taken together, these findings suggest that common genetic variants in FGF20 are not a risk factor for PD in, at least, some European populations. [Abstract/Link to Full Text]

Selim M, Savitz S, Linfante I, Caplan L, Schlaug G
Effect of pre-stroke use of ACE inhibitors on ischemic stroke severity.
BMC Neurol. 2005;5(1):10.
BACKGROUND: Recent trials suggest that angiotensin-converting enzyme inhibitors (ACEI) are effective in prevention of ischemic stroke, as measured by reduced stroke incidence. We aimed to compare stroke severity between stroke patients who were taking ACEI before their stroke onset and those who were not, to examine the effects of pretreatment with ACEI on ischemic stroke severity. METHODS: We retrospectively studied 126 consecutive patients presenting within 24 hours of ischemic stroke onset, as confirmed by diffusion-weighted magnetic resonance imaging (DWI). We calculated the NIHSS score at presentation, as the primary measure of clinical stroke severity, and categorized stroke severity as mild (NIHSS [less than or equal to] 7), moderate (NIHSS 8-13) or severe (NIHSS [greater than or equal to] 14). We analyzed demographic data, risk-factor profile, blood pressure (BP) and medications on admissions, and determined stroke mechanism according to TOAST criteria. We also measured the volumes of admission diffusion- and perfusion-weighted (DWI /PWI) magnetic resonance imaging lesions, as a secondary measure of ischemic tissue volume. We compared these variables among patients on ACEI and those who were not. RESULTS: Thirty- three patients (26%) were on ACE-inhibitors. The overall median baseline NIHSS score was 5.5 (range 2-21) among ACEI-treated patients vs. 9 (range 1-36) in non-ACEI patients (p = 0.036). Patients on ACEI prior to their stroke had more mild and less severe strokes, and smaller DWI and PWI lesion volumes compared to non-ACEI treated patients. However, none of these differences were significant. Predictably, a higher percentage of patients on ACEI had a history of heart failure (p = 0.03). Age, time-to-imaging or neurological evaluation, risk-factor profile, concomitant therapy with lipid lowering, other antihypertensives or antithrombotic agents, or admission BP were comparable between the two groups. CONCLUSION: Our results suggest that ACE-inhibitors may reduce the clinical severity of stroke, as measured by NIHSS score. Further, larger-scale, prospective studies are needed to validate our findings, and to elucidate the mechanism(s) of ACEImediated benefits in patients with ischemic stroke. [Abstract/Link to Full Text]

Arboix A, Rivas A, García-Eroles L, de Marcos L, Massons J, Oliveres M
Cerebral infarction in diabetes: clinical pattern, stroke subtypes, and predictors of in-hospital mortality.
BMC Neurol. 2005;5(1):9.
BACKGROUND: To compare the characteristics and prognostic features of ischemic stroke in patients with diabetes and without diabetes, and to determine the independent predictors of in-hospital mortality in people with diabetes and ischemic stroke. METHODS: Diabetes was diagnosed in 393 (21.3%) of 1,840 consecutive patients with cerebral infarction included in a prospective stroke registry over a 12-year period. Demographic characteristics, cardiovascular risk factors, clinical events, stroke subtypes, neuroimaging data, and outcome in ischemic stroke patients with and without diabetes were compared. Predictors of in-hospital mortality in diabetic patients with ischemic stroke were assessed by multivariate analysis. RESULTS: People with diabetes compared to people without diabetes presented more frequently atherothrombotic stroke (41.2% vs 27%) and lacunar infarction (35.1% vs 23.9%) (P < 0.01). The in-hospital mortality in ischemic stroke patients with diabetes was 12.5% and 14.6% in those without (P = NS). Ischemic heart disease, hyperlipidemia, subacute onset, 85 years old or more, atherothrombotic and lacunar infarcts, and thalamic topography were independently associated with ischemic stroke in patients with diabetes, whereas predictors of in-hospital mortality included the patient's age, decreased consciousness, chronic nephropathy, congestive heart failure and atrial fibrillation CONCLUSION: Ischemic stroke in people with diabetes showed a different clinical pattern from those without diabetes, with atherothrombotic stroke and lacunar infarcts being more frequent. Clinical factors indicative of the severity of ischemic stroke available at onset have a predominant influence upon in-hospital mortality and may help clinicians to assess prognosis more accurately. [Abstract/Link to Full Text]

Crooks VC, Clark L, Petitti DB, Chui H, Chiu V
Validation of multi-stage telephone-based identification of cognitive impairment and dementia.
BMC Neurol. 2005;5(1):8.
BACKGROUND: Many types of research on dementia and cognitive impairment require large sample sizes. Detailed in-person assessment using batteries of neuropyschologic testing is expensive. This study evaluates whether a brief telephone cognitive assessment strategy can reliably classify cognitive status when compared to an in-person "gold-standard" clinical assessment. METHODS: The gold standard assessment of cognitive status was conducted at the University of Southern California Alzheimer Disease Research Center (USC ADRC). It involved an examination of patients with a memory complaint by a neurologist or psychiatrist specializing in cognitive disorders and administration of a battery of neuropsychologic tests. The method being evaluated was a multi-staged assessment using the Telephone Interview of Cognitive Status-modified (TICSm) with patients and the Telephone Dementia Questionnaire (TDQ) with a proxy. Elderly male and female patients who had received the gold standard in-person assessment were asked to also undergo the telephone assessment. The unweighted kappa statistic was calculated to compare the gold standard and the multistage telephone assessment methods. Sensitivity for classification with dementia and specificity for classification as normal were also calculated. RESULTS: Of 50 patients who underwent the gold standard assessment and were referred for telephone assessment, 38 (76%) completed the TICS. The mean age was 78.1 years and 26 (68%) were female. When comparing the gold standard assessment and the telephone method for classifying subjects as having dementia or no dementia, the sensitivity of the telephone method was 0.83 (95% confidence interval 0.36, 1.00), the specificity was 1.00 (95% confidence interval 0.89,1.00). Kappa was 0.89 (95% confidence interval 0.69, 1.000). Considering a gold-standard assessment of age-associated memory impairment as cognitive impairment, the sensitivity of the telephone approach is 0.38 (95% confidence interval 0.09, 0.76) specificity 0.96 (CI 0.45, 0.89) and kappa 0.61 (CI 0.37, 0.85). CONCLUSION: Use of a telephone interview to identify people with dementia or cognitive impairment is a promising and relatively inexpensive strategy for identifying potential participants in intervention and clinical research studies and for classifying subjects in epidemiologic studies. [Abstract/Link to Full Text]

Girgenrath M, Kostek CA, Miller JB
Diseased muscles that lack dystrophin or laminin-alpha2 have altered compositions and proliferation of mononuclear cell populations.
BMC Neurol. 2005;5(1):7.
BACKGROUND: Multiple types of mononucleate cells reside among the multinucleate myofibers in skeletal muscles and these mononucleate cells function in muscle maintenance and repair. How neuromuscular disease might affect different types of muscle mononucleate cells had not been determined. In this study, therefore, we examined how two neuromuscular diseases, dystrophin-deficiency and laminin-alpha2-deficiency, altered the proliferation and composition of different subsets of muscle-derived mononucleate cells. METHODS: We used fluorescence-activated cell sorting combined with bromodeoxyuridine labeling to examine proliferation rates and compositions of mononuclear cells in diseased and healthy mouse skeletal muscle. We prepared mononucleate cells from muscles of mdx (dystrophin-deficient) or Lama2-/- (laminin-alpha2-deficient) mice and compared them to cells from healthy control muscles. We enumerated subsets of resident muscle cells based on Sca-1 and CD45 expression patterns and determined the proliferation of each cell subset in vivo by BrdU incorporation. RESULTS: We found that the proliferation and composition of the mononucleate cells in dystrophin-deficient and laminin-alpha2-deficient diseased muscles are different than in healthy muscle. The mdx and Lama2-/- muscles showed similar significant increases in CD45+ cells compared to healthy muscle. Changes in proliferation, however, differed between the two diseases with proliferation increased in mdx and decreased in Lama2-/- muscles compared to healthy muscles. In particular, the most abundant Sca-1-/CD45- subset, which contains muscle precursor cells, had increased proliferation in mdx muscle but decreased proliferation in Lama2-/- muscles. CONCLUSION: The similar increases in CD45+ cells, but opposite changes in proliferation of muscle precursor cells, may underlie aspects of the distinct pathologies in the two diseases. [Abstract/Link to Full Text]

Sörös P, Vo O, Gerding H, Husstedt IW, Evers S
Enucleation and development of cluster headache: a retrospective study.
BMC Neurol. 2005 Mar 22;5(1):6.
BACKGROUND: Cluster headache (CH) is a neurovascular, primary headache disorder. There are, however, several case reports about patients whose CH started shortly after a structural brain disease or trauma. Motivated by a patient who developed CH 3 weeks after the removal of an eye and by similar case reports, we tested the hypothesis that the removal of an eye is a risk factor for CH. METHODS: A detailed headache questionnaire was filled out by 112 patients on average 8 years after enucleation or evisceration of an eye. RESULTS: While 21 % of these patients experienced previously unknown headaches after the removal of an eye, no patient fulfilled the diagnostic criteria for CH. CONCLUSION: Our data does not suggest that the removal of an eye is a major risk factor for the development of CH. [Abstract/Link to Full Text]

Janno S, Holi MM, Tuisku K, Wahlbeck K
Validity of Simpson-Angus Scale (SAS) in a naturalistic schizophrenia population.
BMC Neurol. 2005 Mar 17;5(1):5.
BACKGROUND: Simpson-Angus Scale (SAS) is an established instrument for neuroleptic-induced parkinsonism (NIP), but its statistical properties have been studied insufficiently. Some shortcomings concerning its content have been suggested as well. According to a recent report, the widely used SAS mean score cut-off value 0.3 of for NIP detection may be too low. Our aim was to evaluate SAS against DSM-IV diagnostic criteria for NIP and objective motor assessment (actometry). METHODS: Ninety-nine chronic institutionalised schizophrenia patients were evaluated during the same interview by standardised actometric recording and SAS. The diagnosis of NIP was based on DSM-IV criteria. Internal consistency measured by Cronbach's alpha, convergence to actometry and the capacity for NIP case detection were assessed. RESULTS: Cronbach's alpha for the scale was 0.79. SAS discriminated between DSM-IV NIP and non-NIP patients. The actometric findings did not correlate with SAS. ROC-analysis yielded a good case detection power for SAS mean score. The optimal threshold value of SAS mean score was between 0.65 and 0.95, i.e. clearly higher than previously suggested threshold value. CONCLUSION: We conclude that SAS seems a reliable and valid instrument. The previously commonly used cut-off mean score of 0.3 has been too low resulting in low specificity, and we suggest a new cut-off value of 0.65, whereby specificity could be doubled without loosing sensitivity. [Abstract/Link to Full Text]

Poorkaj P, Moses L, Montimurro JS, Nutt JG, Schellenberg GD, Payami H
Parkin mutation dosage and the phenomenon of anticipation: a molecular genetic study of familial parkinsonism.
BMC Neurol. 2005 Feb 22;5(1):4.
BACKGROUND: parkin mutations are a common cause of parkinsonism. Possessing two parkin mutations leads to early-onset parkinsonism, while having one mutation may predispose to late-onset disease. This dosage pattern suggests that some parkin families should exhibit intergenerational variation in age at onset resembling anticipation. A subset of familial PD exhibits anticipation, the cause of which is unknown. The aim of this study was to determine if anticipation was due to parkin mutation dosage. METHODS: We studied 19 kindreds that had early-onset parkinsonism in the offspring generation, late-onset parkinsonism in the parent generation, and > or = 20 years of anticipation. We also studied 28 early-onset parkinsonism cases without anticipation. Patients were diagnosed by neurologists at a movement disorder clinic. parkin analysis included sequencing and dosage analysis of all 12 exons. RESULTS: Only one of 19 cases had compound parkin mutations, but contrary to our postulate, the affected relative with late-onset parkinsonism did not have a parkin mutation. In effect, none of the anticipation cases could be attributed to parkin. In contrast, 21% of early-onset parkinsonism patients without anticipation had parkin mutations. CONCLUSION: Anticipation is not linked to parkin, and may signify a distinct disease entity. [Abstract/Link to Full Text]

McGibbon CA, Krebs DE, Parker SW, Scarborough DM, Wayne PM, Wolf SL
Tai Chi and vestibular rehabilitation improve vestibulopathic gait via different neuromuscular mechanisms: preliminary report.
BMC Neurol. 2005 Feb 18;5(1):3.
BACKGROUND: Vestibular rehabilitation (VR) is a well-accepted exercise program intended to remedy balance impairment caused by damage to the peripheral vestibular system. Alternative therapies, such as Tai Chi (TC), have recently gained popularity as a treatment for balance impairment. Although VR and TC can benefit people with vestibulopathy, the degree to which gait improvements may be related to neuromuscular adaptations of the lower extremities for the two different therapies are unknown. METHODS: We examined the relationship between lower extremity neuromuscular function and trunk control in 36 older adults with vestibulopathy, randomized to 10 weeks of either VR or TC exercise. Time-distance measures (gait speed, step length, stance duration and step width), lower extremity sagittal plane mechanical energy expenditures (MEE), and trunk sagittal and frontal plane kinematics (peak and range of linear and angular velocity), were measured. RESULTS: Although gait time-distance measures were improved in both groups following treatment, no significant between-groups differences were observed for the MEE and trunk kinematic measures. Significant within groups changes, however, were observed. The TC group significantly increased ankle MEE contribution and decreased hip MEE contribution to total leg MEE, while no significant changes were found within the VR group. The TC group exhibited a positive relationship between change in leg MEE and change in trunk velocity peak and range, while the VR group exhibited a negative relationship. CONCLUSION: Gait function improved in both groups consistent with expectations of the interventions. Differences in each group's response to therapy appear to suggest that improved gait function may be due to different neuromuscular adaptations resulting from the different interventions. The TC group's improvements were associated with reorganized lower extremity neuromuscular patterns, which appear to promote a faster gait and reduced excessive hip compensation. The VR group's improvements, however, were not the result of lower extremity neuromuscular pattern changes. Lower-extremity MEE increases corresponded to attenuated forward trunk linear and angular movement in the VR group, suggesting better control of upper body motion to minimize loss of balance. These data support a growing body of evidence that Tai Chi may be a valuable complementary treatment for vestibular disorders. [Abstract/Link to Full Text]

Wasay M, Khealani BA, Talati N, Shamsi R, Syed NA, Salahuddin N
Autonomic nervous system dysfunction predicts poor prognosis in patients with mild to moderate tetanus.
BMC Neurol. 2005 Jan 31;5(1):2.
BACKGROUND: Autonomic nervous system (ANS) dysfunction is present in up to one third of patients with tetanus. The prognostic value of ANS dysfunction is known in severe tetanus but its value is not well established in mild to moderate tetanus. METHODS: Medical records of all patients admitted with tetanus at two academic tertiary care centers in Karachi, Pakistan were reviewed. The demographic, clinical and laboratory data was recorded and analyzed. ANS dysfunction was defined as presence of labile or persistent hypertension or hypotension and sinus tachycardia, tachyarrythmia or bradycardia on EKG. Patients were divided into two groups based on presence of ANS dysfunction (ANS group and non ANS group). Tetanus severity was classified on the basis of Ablett criteria. RESULTS: Ninety six (64 males; 32 females) patients were admitted with the diagnosis over a period of 10 years. ANS group had 31 (32%) patients while non ANS group comprised of 65 (68%) patients. Both groups matched for age, gender, symptom severity, use of tetanus immunoglobulin and antibiotics. Twelve patients in ANS group had mild to moderate tetanus (Ablett I and II) and 19 patients had severe/very severe tetanus (Ablett III and IV). Fifteen (50%) patients in ANS group required ventilation as compared to 28 (45%) in non-ANS group (p = 0.09). Fourteen (47%) patients died in ANS group as compared to 10 (15%) in non ANS group (p= 0.002). Out of those 14 patients died in ANS group, six patients had mild to moderate tetanus and eight patients had severe/very severe tetanus. Major cause of death was cardiac arrhythmias (13/14; 93%) in ANS group and respiratory arrest (7/10; 70%) in non ANS group. Ten (33%) patients had complete recovery in ANS group while in non ANS group 35(48%) patients had complete recovery (p= 0.05). CONCLUSIONS: ANS dysfunction was present in one third of our tetanus population. 40% patients with ANS dysfunction had only mild to moderate tetanus. ANS dysfunction, irrespective of the need of mechanical ventilation or severity of tetanus, predicted poor outcome. [Abstract/Link to Full Text]

Hashimoto T, Matsumoto MM, Li JF, Lawton MT, Young WL
Suppression of MMP-9 by doxycycline in brain arteriovenous malformations.
BMC Neurol. 2005 Jan 24;5(1):1.
BACKGROUND: The primary aim of this study is to demonstrate the feasibility of utilizing doxycycline to suppress matrix metalloproteinase-9 (MMP-9) in brain arteriovenous malformations (AVMs). METHODS: Ex-vivo treatment of AVM tissues: Intact AVM tissues were treated with doxycycline for 48 hours. Active and total MMP-9 in the medium were measured. Pilot trial: AVM patients received either doxycycline (100 mg) or placebo twice a day for one week prior to AVM resection. Active and total MMP-9 in BVM tissues were measured. RESULTS: Ex-vivo treatment of AVM tissues: Doxycycline at 10 and 100 microg/ml significantly decreased MMP-9 levels in AVM tissues ex-vivo (total: control vs 10 vs 100 microg/ml = 100 +/- 6 vs 60 +/- 16 vs 61 +/- 9%; active: 100 +/- 8 vs 48 +/- 16 vs 59 +/- 10%). Pilot trial: 10 patients received doxycycline, and 4 patients received placebo. There was a trend for both MMP-9 levels to be lower in the doxycycline group than in the placebo group (total: 2.18 +/- 1.94 vs 3.26 +/- 3.58, P = .50; active: 0.48 +/- 0.48 vs 0.95 +/- 1.01 ng/100 microg protein, P = .25). CONCLUSIONS: A clinically relevant concentration of doxycycline decreased MMP-9 in ex-vivo AVM tissues. Furthermore, there was a trend that oral doxycycline for as short as one week resulted in a decrease in MMP-9 in AVM tissues. Further studies are warranted to justify a clinical trial to test effects of doxycycline on MMP-9 expression in AVM tissues. [Abstract/Link to Full Text]

Jönsson H, Johnsson P, Bäckström M, Alling C, Dautovic-Bergh C, Blomquist S
Controversial significance of early S100B levels after cardiac surgery.
BMC Neurol. 2004 Dec 16;4(1):24.
BACKGROUND: The brain-derived protein S100B has been shown to be a useful marker of brain injury of different etiologies. Cognitive dysfunction after cardiac surgery using cardiopulmonary bypass has been reported to occur in up to 70% of patients. In this study we tried to evaluate S100B as a marker for cognitive dysfunction after coronary bypass surgery with cardiopulmonary bypass in a model where the inflow of S100B from shed mediastinal blood was corrected for. METHODS: 56 patients scheduled for coronary artery bypass grafting underwent prospective neuropsychological testing. The test scores were standardized and an impairment index was constructed. S100B was sampled at the end of surgery, hourly for the first 6 hours, and then 8, 10, 15, 24 and 48 hours after surgery. None of the patients received autotransfusion. RESULTS: In simple linear analysis, no significant relation was found between S100B levels and neuropsychological outcome. In a backwards stepwise regression analysis the three variables, S100B levels at the end of cardiopulmonary bypass, S100B levels 1 hour later and the age of the patients were found to explain part of the neuropsychological deterioration (r = 0.49, p < 0.005). CONCLUSIONS: In this study we found that S100B levels 1 hour after surgery seem to be the most informative. Our attempt to control the increased levels of S100B caused by contamination from the surgical field did not yield different results. We conclude that the clinical value of S100B as a predictive measurement of postoperative cognitive dysfunction after cardiac surgery is limited. [Abstract/Link to Full Text]

Jäncke L, Hänggi J, Steinmetz H
Morphological brain differences between adult stutterers and non-stutterers.
BMC Neurol. 2004 Dec 10;4(1):23.
BACKGROUND: The neurophysiological and neuroanatomical foundations of persistent developmental stuttering (PDS) are still a matter of dispute. A main argument is that stutterers show atypical anatomical asymmetries of speech-relevant brain areas, which possibly affect speech fluency. The major aim of this study was to determine whether adults with PDS have anomalous anatomy in cortical speech-language areas. METHODS: Adults with PDS (n = 10) and controls (n = 10) matched for age, sex, hand preference, and education were studied using high-resolution MRI scans. Using a new variant of the voxel-based morphometry technique (augmented VBM) the brains of stutterers and non-stutterers were compared with respect to white matter (WM) and grey matter (GM) differences. RESULTS: We found increased WM volumes in a right-hemispheric network comprising the superior temporal gyrus (including the planum temporale), the inferior frontal gyrus (including the pars triangularis), the precentral gyrus in the vicinity of the face and mouth representation, and the anterior middle frontal gyrus. In addition, we detected a leftward WM asymmetry in the auditory cortex in non-stutterers, while stutterers showed symmetric WM volumes. CONCLUSIONS: These results provide strong evidence that adults with PDS have anomalous anatomy not only in perisylvian speech and language areas but also in prefrontal and sensorimotor areas. Whether this atypical asymmetry of WM is the cause or the consequence of stuttering is still an unanswered question. [Abstract/Link to Full Text]

Sahraian MA, Mottamedi M, Azimi AR, Moghimi B
Androgen-induced cerebral venous sinus thrombosis in a young body builder: case report.
BMC Neurol. 2004 Dec 3;4(1):22.
BACKGROUND: Cerebral venous sinus thrombosis is an infrequent disease with a variety of causes. Pregnancy, puerperium, contraceptive pills and intracranial infections are the most common causes. The patient may present with headache, focal neurological deficits and seizures.The clinical outcome is highly variable and treatment with heparin is advised. CASE PRESENTATION: The patient is a 22 year old male who presented with headache, repeated vomiting and papilledema.He was a bodybuilder doing exercise since 5 years ago, who had used nandrolone decaonoate 25 milligrams intramuscularly during the previous 5 months. Brain MRI and MRV showed superior sagital and transverse sinus thrombosis and extensive investigations did not reveal any known cause. CONCLUSIONS: We suggested that androgen was the predisposing factor in our patient. Androgens may increase coagulation factors or platelet activity and cause arterial or venous thrombosis.As athletes may hide using androgens it should be considered as a predisposing factor for thrombotic events in such patients. [Abstract/Link to Full Text]

Cole JW, Roberts SC, Gallagher M, Giles WH, Mitchell BD, Steinberg KK, Wozniak MA, Macko RF, Reinhart LJ, Kittner SJ
Thrombomodulin Ala455Val Polymorphism and the risk of cerebral infarction in a biracial population: the Stroke Prevention in Young Women Study.
BMC Neurol. 2004 Dec 1;4(1):21.
BACKGROUND: The genes encoding proteins in the thrombomodulin-protein C pathway are promising candidate genes for stroke susceptibility because of their importance in thrombosis regulation and inflammatory response. Several published studies have shown that the Ala455Val thrombomodulin polymorphism is associated with ischemic heart disease, but none has examined the association with stroke. Using data from the Stroke Prevention in Young Women Study, we sought to determine the association between the Ala455Val thrombomodulin polymorphism and the occurrence of ischemic stroke in young women. METHODS: All 59 hospitals in the greater Baltimore-Washington area participated in a population-based case-control study of stroke in young women. We compared 141 cases of first ischemic stroke (44% black) among women 15 to 44 years of age with 210 control subjects (35% black) who were identified by random digit dialing and frequency matched to the cases by age and geographical region of residence. Data on historical risk factors were collected by standardized interview. Genotyping of the thrombomodulin Ala455Val polymorphism was performed by pyrosequencing. RESULTS: The A allele (frequency = 0.85) was associated with stroke under the recessive model. After adjustment for age, race, cigarette smoking, hypertension, and diabetes, the AA genotype, compared with the AV and VV genotypes combined, was significantly associated with stroke (odds ratio 1.9, 95% CI 1.1-3.3). The AA genotype was more common among black than white control subjects (81% versus 68%) but there was no significant interaction between the risk genotype and race (adjusted odds ratio 2.7 for blacks and 1.6 for whites). A secondary analysis removing all probable (n = 16) and possible (n = 15) cardioembolic strokes demonstrated an increased association (odds ratio 2.2, 95% CI 1.2-4.2). CONCLUSIONS: Among women aged 15 to 44 years, the AA genotype is more prevalent among blacks than whites and is associated with increased risk of early onset ischemic stroke. Removing strokes potentially related to cardioembolic phenomena increased this association. Further studies are needed to determine whether this polymorphism is functionally related to thrombomodulin expression or whether the association is due to population stratification or linkage to a nearby functional polymorphism. [Abstract/Link to Full Text]

Lynex CN, Carr IM, Leek JP, Achuthan R, Mitchell S, Maher ER, Woods CG, Bonthon DT, Markham AF
Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders.
BMC Neurol. 2004 Nov 30;4(1):20.
BACKGROUND: Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families. METHODS: Here we present data that refine this locus to a 0.5 cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene GAD1, which encodes a glutamate decarboxylase isoform (GAD67), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). RESULTS: A novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals. CONCLUSIONS: This result is interesting because auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. Further investigation seems merited of the possibility that variation in the GAD1 sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts. [Abstract/Link to Full Text]

Saft C, Andrich JE, Neuen-Jacob E, Schmid G, Schols L, Amoiridis G
Supracubital perineurioma misdiagnosed as carpal tunnel syndrome: case report.
BMC Neurol. 2004 Nov 21;4(1):19.
BACKGROUND: Perineuriomas have been defined as tumorous lesions of the peripheral nerves which derive from perineurial cell proliferation and may be associated with abnormalities on chromosome 22. CASE PRESENTATION: Three years after a painful cubital vein procaine injection, a 33 year-old man developed a median nerve lesion, initially diagnosed as carpal tunnel syndrome. Symptoms progressed despite appropriate surgery. Clinical and electrophysiological re-evaluation revealed a fusiform mass at the distal upper arm, confirmed by MRI. Immunohistochemical studies classified the tumor as a mixed perineurioma and neuroma. CONCLUSIONS: Perineurioma mixed with neuroma may potentially caused by the previous trauma or cytotoxic effects of procaine. [Abstract/Link to Full Text]

Hellwig K, Stein FJ, Przuntek H, Müller T
Efficacy of repeated intrathecal triamcinolone acetonide application in progressive multiple sclerosis patients with spinal symptoms.
BMC Neurol. 2004 Nov 7;4(1):18.
BACKGROUND: There are controversial results on the efficacy of the abandoned, intrathecal predominant methylprednisolone application in multiple sclerosis (MS) in contrast to the proven effectiveness in intractable postherpetic neuralgia. METHODS: We performed an analysis of the efficacy of the application of 40 mg of the sustained release steroid triamcinolone acetonide (TCA). We intrathecally injected in sterile saline dissolved TCA six times within three weeks on a regular basis every third day in 161 hospitalized primary and predominant secondary progressive MS patients with spinal symptoms. The MS patients did not experience an acute onset of exacerbation or recent distinct increased progression of symptoms. We simultaneously scored the MS patients with the EDSS and the Barthel index, estimated the walking distance and measured somatosensory evoked potentials. Additionally the MS patients received a standardized rehabilitation treatment. RESULTS: EDSS score and Barthel index improved, walking distance increased, latencies of somatosensory evoked potentials of the median and tibial nerves shortened in all MS patients with serial evaluation (p < 0.0001 for all variables). Side effects were rare, five patients stopped TCA application due to onset of a post lumbar puncture syndrome. CONCLUSIONS: Repeated intrathecal TCA application improves spinal symptoms, walking distance and SSEP latencies in progressive MS patients in this uncontrolled study. Future trials should evaluate the long-term benefit of this invasive treatment. [Abstract/Link to Full Text]

Haas DC
Traumatic-event headaches.
BMC Neurol. 2004 Oct 29;4(1):17.
BACKGROUND: Chronic headaches from head trauma and whiplash injury are well-known and common, but chronic headaches from other sorts of physical traumas are not recognized. METHODS: Specific information was obtained from the medical records of 15 consecutive patients with chronic headaches related to physically injurious traumatic events that did not include either head trauma or whiplash injury. The events and the physical injuries produced by them were noted. The headaches' development, characteristics, duration, frequency, and accompaniments were recorded, as were the patients' use of pain-alleviative drugs. From this latter information, the headaches were classified by the diagnostic criteria of the International Headache Society as though they were naturally-occurring headaches. The presence of other post-traumatic symptoms and litigation were also recorded. RESULTS: The intervals between the events and the onset of the headaches resembled those between head traumas or whiplash injuries and their subsequent headaches. The headaches themselves were, as a group, similar to those after head trauma and whiplash injury. Thirteen of the patients had chronic tension-type headache, two had migraine. The sustained bodily injuries were trivial or unidentifiable in nine patients. Fabrication of symptoms for financial remuneration was not evident in these patients of whom seven were not even seeking payments of any kind. CONCLUSIONS: This study suggests that these hitherto unrecognized post-traumatic headaches constitute a class of headaches characterized by a relation to traumatic events affecting the body but not including head or whiplash traumas. The bodily injuries per se can be discounted as the cause of the headaches. So can fabrication of symptoms for financial remuneration. Altered mental states, not systematically evaluated here, were a possible cause of the headaches. The overall resemblance of these headaches to the headaches after head or whiplash traumas implies that these latter two headache types may likewise not be products of structural injuries. [Abstract/Link to Full Text]

Recent Articles in Journal of Neuroinflammation

Fan R, Tenner AJ
Differential regulation of Abeta42-induced neuronal C1q synthesis and microglial activation.
J Neuroinflammation. 2005 Jan 10;2(1):1.
Expression of C1q, an early component of the classical complement pathway, has been shown to be induced in neurons in hippocampal slices, following accumulation of exogenous Abeta42. Microglial activation was also detected by surface marker expression and cytokine production. To determine whether C1q induction was correlated with intraneuronal Abeta and/or microglial activation, D-(-)-2-amino-5-phosphonovaleric acid (APV, an NMDA receptor antagonist) and glycine-arginine-glycine-aspartic acid-serine-proline peptide (RGD, an integrin receptor antagonist), which blocks and enhances Abeta42 uptake, respectively, were assessed for their effect on neuronal C1q synthesis and microglial activation. APV inhibited, and RGD enhanced, microglial activation and neuronal C1q expression. However, addition of Abeta10-20 to slice cultures significantly reduced Abeta42 uptake and microglial activation, but did not alter the Abeta42-induced neuronal C1q expression. Furthermore, Abeta10-20 alone triggered C1q production in neurons, demonstrating that neither neuronal Abeta42 accumulation, nor microglial activation is required for neuronal C1q upregulation. These data are compatible with the hypothesis that multiple receptors are involved in Abeta injury and signaling in neurons. Some lead to neuronal C1q induction, whereas other(s) lead to intraneuronal accumulation of Abeta and/or stimulation of microglia. [Abstract/Link to Full Text]

Wilcock DM, Rojiani A, Rosenthal A, Subbarao S, Freeman MJ, Gordon MN, Morgan D
Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage.
J Neuroinflammation. 2004 Dec 8;1(1):24.
BACKGROUND: Anti-Abeta immunotherapy in transgenic mice reduces both diffuse and compact amyloid deposits, improves memory function and clears early-stage phospho-tau aggregates. As most Alzheimer disease cases occur well past midlife, the current study examined adoptive transfer of anti-Abeta antibodies to 19- and 23-month old APP-transgenic mice. METHODS: We investigated the effects of weekly anti-Abeta antibody treatment on radial-arm water-maze performance, parenchymal and vascular amyloid loads, and the presence of microhemorrhage in the brain. 19-month-old mice were treated for 1, 2 or 3 months while 23-month-old mice were treated for 5 months. Only the 23-month-old mice were subject to radial-arm water-maze testing. RESULTS: After 3 months of weekly injections, this passive immunization protocol completely reversed learning and memory deficits in these mice, a benefit that was undiminished after 5 months of treatment. Dramatic reductions of diffuse Abeta immunostaining and parenchymal Congophilic amyloid deposits were observed after five months, indicating that even well-established amyloid deposits are susceptible to immunotherapy. However, cerebral amyloid angiopathy increased substantially with immunotherapy, and some deposits were associated with microhemorrhage. Reanalysis of results collected from an earlier time-course study demonstrated that these increases in vascular deposits were dependent on the duration of immunotherapy. CONCLUSIONS: The cognitive benefits of passive immunotherapy persist in spite of the presence of vascular amyloid and small hemorrhages. These data suggest that clinical trials evaluating such treatments will require precautions to minimize potential adverse events associated with microhemorrhage. [Abstract/Link to Full Text]

Kunjathoor VV, Tseng AA, Medeiros LA, Khan T, Moore KJ
beta-Amyloid promotes accumulation of lipid peroxides by inhibiting CD36-mediated clearance of oxidized lipoproteins.
J Neuroinflammation. 2004 Nov 16;1(1):23.
BACKGROUND: Recent studies suggest that hypercholesterolemia, an established risk factor for atherosclerosis, is also a risk factor for Alzheimer's disease. The myeloid scavenger receptor CD36 binds oxidized lipoproteins that accumulate with hypercholesterolemia and mediates their clearance from the circulation and peripheral tissues. Recently, we demonstrated that CD36 also binds fibrillar beta-amyloid and initiates a signaling cascade that regulates microglial recruitment and activation. As increased lipoprotein oxidation and accumulation of lipid peroxidation products have been reported in Alzheimer's disease, we investigated whether beta-amyloid altered oxidized lipoprotein clearance via CD36. METHODS: The availability of mice genetically deficient in class A (SRAI & II) and class B (CD36) scavenger receptors has facilitated studies to discriminate their individual actions. Using primary microglia and macrophages, we assessed the impact of Abeta on: (a) cholesterol ester accumulation by GC-MS and neutral lipid staining, (b) binding, uptake and degradation of 125I-labeled oxidized lipoproteins via CD36, SR-A and CD36/SR-A-independent pathways, (c) expression of SR-A and CD36. In addition, using mice with targeted deletions in essential kinases in the CD36-signaling cascade, we investigated whether Abeta-CD36 signaling altered metabolism of oxidized lipoproteins. RESULTS: In primary microglia and macrophages, Abeta inhibited binding, uptake and degradation of oxidized low density lipoprotein (oxLDL) in a dose-dependent manner. While untreated cells accumulated abundant cholesterol ester in the presence of oxLDL, cells treated with Abeta were devoid of cholesterol ester. Pretreatment of cells with Abeta did not affect subsequent degradation of oxidized lipoproteins, indicating that lysosomal accumulation of Abeta did not disrupt this degradation pathway. Using mice with targeted deletions of the scavenger receptors, we demonstrated that Abeta inhibited oxidized lipoprotein binding and its subsequent degradation via CD36, but not SRA, and this was independent of Abeta-CD36-signaling. Furthermore, Abeta treatment decreased CD36, but not SRA, mRNA and protein, thereby reducing cell surface expression of this oxLDL receptor. CONCLUSIONS: Together, these data demonstrate that in the presence of beta-amyloid, CD36-mediated clearance of oxidized lipoproteins is abrogated, which would promote the extracellular accumulation of these pro-inflammatory lipids and perpetuate lipid peroxidation. [Abstract/Link to Full Text]

Rönnbäck L, Hansson E
On the potential role of glutamate transport in mental fatigue.
J Neuroinflammation. 2004 11 4;1(1):22.
Mental fatigue, with decreased concentration capacity, is common in neuroinflammatory and neurodegenerative diseases, often appearing prior to other major mental or physical neurological symptoms. Mental fatigue also makes rehabilitation more difficult after a stroke, brain trauma, meningitis or encephalitis. As increased levels of proinflammatory cytokines are reported in these disorders, we wanted to explore whether or not proinflammatory cytokines could induce mental fatigue, and if so, by what mechanisms.It is well known that proinflammatory cytokines are increased in major depression, "sickness behavior" and sleep deprivation, which are all disorders associated with mental fatigue. Furthermore, an influence by specific proinflammatory cytokines, such as interleukin (IL)-1, on learning and memory capacities has been observed in several experimental systems. As glutamate signaling is crucial for information intake and processing within the brain, and due to the pivotal role for glutamate in brain metabolism, dynamic alterations in glutamate transmission could be of pathophysiological importance in mental fatigue. Based on this literature and observations from our own laboratory and others on the role of astroglial cells in the fine-tuning of glutamate neurotransmission we present the hypothesis that the proinflammatory cytokines tumor necrosis factor-alpha, IL-1beta and IL-6 could be involved in the pathophysiology of mental fatigue through their ability to attenuate the astroglial clearance of extracellular glutamate, their disintegration of the blood brain barrier, and effects on astroglial metabolism and metabolic supply for the neurons, thereby attenuating glutamate transmission. To test whether our hypothesis is valid or not, brain imaging techniques should be applied with the ability to register, over time and with increasing cognitive loading, the extracellular concentrations of glutamate and potassium (K+) in humans suffering from mental fatigue. At present, this is not possible for technical reasons. Therefore, more knowledge of neuronal-glial signaling in in vitro systems and animal experiments is important.In summary, we provide a hypothetic explanation for a general neurobiological mechanism, at the cellular level, behind one of our most common symptoms during neuroinflammation and other long-term disorders of brain function. Understanding pathophysiological mechanisms of mental fatigue could result in better treatment. [Abstract/Link to Full Text]

Yao Y, Chinnici C, Tang H, Trojanowski JQ, Lee VM, Praticò D
Brain inflammation and oxidative stress in a transgenic mouse model of Alzheimer-like brain amyloidosis.
J Neuroinflammation. 2004 10 22;1(1):21.
BACKGROUND: An increasing body of evidence implicates both brain inflammation and oxidative stress in the pathogenesis of Alzheimer's disease (AD). The relevance of their interaction in vivo, however, is unknown. Previously, we have shown that separate pharmacological targeting of these two components results in amelioration of the amyloidogenic phenotype of a transgenic mouse model of AD-like brain amyloidosis (Tg2576). METHODS: In the present study, we investigated the therapeutic effects of a combination of an anti-inflammatory agent, indomethacin, and a natural anti-oxidant, vitamin E, in the Tg2576 mice. For this reason, animals were treated continuously from 8 (prior to Abeta deposition) through 15 (when Abeta deposits are abundant) months of age. RESULTS: At the end of the study, these therapeutic interventions suppressed brain inflammatory and oxidative stress responses in the mice. This effect was accompanied by significant reductions of soluble and insoluble Abeta1-40 and Abeta1-42 in neocortex and hippocampus, wherein the burden of Abeta deposits also was significantly decreased. CONCLUSIONS: The results of the present study support the concept that brain oxidative stress and inflammation coexist in this animal model of AD-like brain amyloidosis, but they represent two distinct therapeutic targets in the disease pathogenesis. We propose that a combination of anti-inflammatory and anti-oxidant drugs may be a useful strategy for treating AD. [Abstract/Link to Full Text]

Milatovic D, Zaja-Milatovic S, Montine KS, Shie FS, Montine TJ
Neuronal oxidative damage and dendritic degeneration following activation of CD14-dependent innate immune response in vivo.
J Neuroinflammation. 2004 10 21;1(1):20.
The cause-and-effect relationship between innate immune activation and neurodegeneration has been difficult to prove in complex animal models and patients. Here we review findings from a model of direct innate immune activation via CD14 stimulation using intracerebroventricular injection of lipopolysaccharide. These data show that CD14-dependent innate immune activation in cerebrum leads to the closely linked outcomes of neuronal membrane oxidative damage and dendritic degeneration. Both forms of neuronal damage could be blocked by ibuprofen and alpha-tocopherol, but not naproxen or gamma-tocopherol, at pharmacologically relevant concentrations. This model provides a convenient method to determine effective agents and their appropriate dose ranges for protecting neurons from CD14-activated innate immunity-mediated damage, and can guide drug development for diseases, such as Alzheimer disease, that are thought to derive in part from CD14-activated innate immune response. [Abstract/Link to Full Text]

Mrak RE, Griffin WS
Funding free and universal access to Journal of Neuroinflammation.
J Neuroinflammation. 2004 10 14;1(1):19.
Journal of Neuroinflammation is an Open Access, online journal published by BioMed Central. Open Access publishing provides instant and universal availability of published work to any potential reader, worldwide, completely free of subscriptions, passwords, and charges. Further, authors retain copyright for their work, facilitating its dissemination. Open Access publishing is made possible by article-processing charges assessed "on the front end" to authors, their institutions, or their funding agencies. Beginning November 1, 2004, the Journal of Neuroinflammation will introduce article-processing charges of around US$525 for accepted articles. This charge will be waived for authors from institutions that are BioMed Central members, and in additional cases for reasons of genuine financial hardship. These article-processing charges pay for an electronic submission process that facilitates efficient and thorough peer review, for publication costs involved in providing the article freely and universally accessible in various formats online, and for the processes required for the article's inclusion in PubMed and its archiving in PubMed Central, e-Depot, Potsdam and INIST. There is no remuneration of any kind provided to the Editors-in-Chief, to any members of the Editorial Board, or to peer reviewers; all of whose work is entirely voluntary. Our article-processing charge is less than charges frequently levied by traditional journals: the Journal of Neuroinflammation does not levy any additional page or color charges on top of this fee, and there are no reprint costs as publication-quality pdf files are provided, free, for distribution in lieu of reprints. Our article-processing charge will enable full, immediate, and continued Open Access for all work published in Journal of Neuroinflammation. The benefits from such Open Access will accrue to readers, through unrestricted access; to authors, through the widest possible dissemination of their work; and to science and society in general, through facilitation of information availability and scientific advancement. [Abstract/Link to Full Text]

Loeffler DA
Using animal models to determine the significance of complement activation in Alzheimer's disease.
J Neuroinflammation. 2004 10 12;1(1):18.
Complement inflammation is a major inflammatory mechanism whose function is to promote the removal of microorganisms and the processing of immune complexes. Numerous studies have provided evidence for an increase in this process in areas of pathology in the Alzheimer's disease (AD) brain. Because complement activation proteins have been demonstrated in vitro to exert both neuroprotective and neurotoxic effects, the significance of this process in the development and progression of AD is unclear. Studies in animal models of AD, in which brain complement activation can be experimentally altered, should be of value for clarifying this issue. However, surprisingly little is known about complement activation in the transgenic animal models that are popular for studying this disorder. An optimal animal model for studying the significance of complement activation on Alzheimer's - related neuropathology should have complete complement activation associated with senile plaques, neurofibrillary tangles (if present), and dystrophic neurites. Other desirable features include both classical and alternative pathway activation, increased neuronal synthesis of native complement proteins, and evidence for an increase in complement activation prior to the development of extensive pathology. In order to determine the suitability of different animal models for studying the role of complement activation in AD, the extent of complement activation and its association with neuropathology in these models must be understood. [Abstract/Link to Full Text]

Hosokawa M, Klegeris A, McGeer PL
Human oligodendroglial cells express low levels of C1 inhibitor and membrane cofactor protein mRNAs.
J Neuroinflammation. 2004 Aug 24;1(1):17.
BACKGROUND: Oligodendrocytes, neurons, astrocytes, microglia, and endothelial cells are capable of synthesizing complement inhibitor proteins. Oligodendrocytes are vulnerable to complement attack, which is particularly observed in multiple sclerosis. This vulnerability may be related to a deficiency in their ability to express complement regulatory proteins. METHODS: This study compared the expression level of complement inhibitor mRNAs by human oligodendrocytes, astrocytes and microglia using semi-quantitative RT-PCR. RESULTS: Semi-quantitative RT-PCR analysis showed that C1 inhibitor (C1-inh) mRNA expression was dramatically lower in oligodendroglial cells compared with astrocytes and microglia. The mRNA expression level of membrane cofactor protein (MCP) by oligodendrocytes was also significantly lower than for other cell types. CONCLUSION: The lower mRNA expression of C1-inh and MCP by oligodendrocytes could contribute to their vulnerability in several neurodegenerative and inflammatory diseases of the central nervous system. [Abstract/Link to Full Text]

Kielian T
Immunopathogenesis of brain abscess.
J Neuroinflammation. 2004 Aug 17;1(1):16.
Brain abscess represents a significant medical problem despite recent advances made in detection and therapy. Due to the emergence of multi-drug resistant strains and the ubiquitous nature of bacteria, the occurrence of brain abscess is likely to persist. Our laboratory has developed a mouse experimental brain abscess model allowing for the identification of key mediators in the CNS anti-bacterial immune response through the use of cytokine and chemokine knockout mice. Studies of primary microglia and astrocytes from neonatal mice have revealed that S. aureus, one of the main etiologic agents of brain abscess in humans, is a potent stimulus for proinflammatory mediator production. Recent evidence from our laboratory indicates that Toll-like receptor 2 plays a pivotal role in the recognition of S. aureus and its cell wall product peptidoglycan by glia, although other receptors also participate in the recognition event. This review will summarize the consequences of S. aureus on CNS glial activation and the resultant neuroinflammatory response in the experimental brain abscess model. [Abstract/Link to Full Text]

Sweeney D, Martins R, LeVine H, Smith JD, Gandy S
Similar promotion of Abeta1-42 fibrillogenesis by native apolipoprotein E epsilon3 and epsilon4 isoforms.
J Neuroinflammation. 2004 Aug 16;1(1):15.
The apolipoprotein E epsilon4 allele contributes to the genetic susceptibility underlying a large proportion (~40-60%) of typical, sporadic Alzheimer disease. Apolipoprotein E deficient mice made transgenic for human apolipoprotein E epsilon4 accumulate excess cerebral amyloid when compared to similarly prepared mice expressing human apolipoprotein E epsilon3. Therefore, it is important to search for relevant interactions(s) between apolipoprotein E epsilon4 and Abeta in order to clarify the biological role for apolipoprotein E epsilon4 in Alzheimer disease. Using a thioflavine T (ThT)-based assay, we have investigated the effects of native human apolipoprotein E isoforms on the kinetics of Abeta fibrillogenesis. No obvious profibrillogenic activity was detected in Abeta1-40-based assays of any native apolipoprotein E isoform. However, when ThT assays were repeated using Abeta1-42, modest, but statistically significant, profibrillogenic activity was detected in both apolipoprotein E epsilon3- and apolipoprotein E epsilon4-containing media and was similar in magnitude for the two isoforms. These data demonstrate that native apolipoprotein E possesses "pathological chaperone"-type activity for Abeta: in other words, the data indicate that a chaperone-like misfolding reaction can occur between native apolipoprotein E and Abeta. However, the equipotent activities of the apolipoprotein E epsilon3 and epsilon4 isoforms suggests the possibility that either extended co-incubation of apolipoprotein E and Abeta, or, perhaps, the inclusion in the reaction of other fibrillogenesis-modulation co-factors (such as metal ions, or inflammatory mediators such as reactive oxygen species, alpha2-macroglobulin, apolipoprotein J, etc.) may be required for modeling in vitro the apolipoprotein E-isoform-specific-regulation of extracellular Abeta accumulation that occurs in vivo. Alternatively, other events, such as differential apolipoprotein E-isoform-mediated clearance of Abeta or of apolipoprotein E/Abeta complexes may underlie apolipoprotein E-isoform-dependent Abeta accumulation. [Abstract/Link to Full Text]

Mrak RE, Griffin WS
Welcome to the Journal of Neuroinflammation!
J Neuroinflammation. 2004 Apr 20;1(1):1.
Welcome to the Journal of Neuroinflammation, an open-access, peer-reviewed, online journal that focuses on innate immunological responses of the central nervous system, involving microglia, astrocytes, cytokines, chemokines, and related molecular processes. 'Neuroinflammation' is an encapsulization of the idea that microglial and astrocytic responses and actions in the central nervous system have a fundamentally inflammation-like character, and that these responses are central to the pathogenesis and progression of a wide variety of neurological disorders. This concept has its roots in the discoveries of inflammatory cytokines and proteins in the plaques of Alzheimer disease, and these ideas have been extended to other neurodegenerative diseases, to ischemic/toxic diseases, to tumor biology and even to normal brain development. The Journal of Neuroinflammation, published by BioMed Central, will bring together work focusing on microglia, astrocytes, cytokines, chemokines, and related molecular processes in the central nervous system. All articles published in the Journal of Neuroinflammation will be immediately listed in PubMed, and access to published articles will be universal and free through the internet. [Abstract/Link to Full Text]

Buckwalter MS, Wyss-Coray T
Modelling neuroinflammatory phenotypes in vivo.
J Neuroinflammation. 2004 Jul 1;1(1):10.
Inflammation of the central nervous system is an important but poorly understood part of neurological disease. After acute brain injury or infection there is a complex inflammatory response that involves activation of microglia and astrocytes and increased production of cytokines, chemokines, acute phase proteins, and complement factors. Antibodies and T lymphocytes may be involved in the response as well. In neurodegenerative disease, where injury is more subtle but consistent, the inflammatory response is continuous. The purpose of this prolonged response is unclear, but it is likely that some of its components are beneficial and others are harmful. Animal models of neurological disease can be used to dissect the specific role of individual mediators of the inflammatory response and assess their potential benefit. To illustrate this approach, we discuss how mutant mice expressing different levels of the cytokine transforming growth factor beta-1 (TGF-beta1), a major modulator of inflammation, produce important neuroinflammatory phenotypes. We then demonstrate how crosses of TGF-beta1 mutant mice with mouse models of Alzheimer's disease (AD) produced important new information on the role of inflammation in AD and on the expression of different neuropathological phenotypes that characterize this disease. [Abstract/Link to Full Text]

Lacombe P, Mathews PM, Schmidt SD, Breidert T, Heneka MT, Landreth GE, Feinstein DL, Galea E
Effect of anti-inflammatory agents on transforming growth factor beta over-expressing mouse brains: a model revised.
J Neuroinflammation. 2004 Jul 2;1(1):11.
BACKGROUND: The over-expression of transforming growth factor beta-1(TGF-beta1) has been reported to cause hydrocephalus, glia activation, and vascular amyloidbeta (Abeta) deposition in mouse brains. Since these phenomena partially mimic the cerebral amyloid angiopathy (CAA) concomitant to Alzheimer's disease, the findings in TGF-beta1 over-expressing mice prompted the hypothesis that CAA could be caused or enhanced by the abnormal production of TGF-beta1. This idea was in accordance with the view that chronic inflammation contributes to Alzheimer's disease, and drew attention to the therapeutic potential of anti-inflammatory drugs for the treatment of Abeta-elicited CAA. We thus studied the effect of anti-inflammatory drug administration in TGF-beta1-induced pathology. METHODS: Two-month-old TGF-beta1 mice and littermate controls were orally administered pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, or ibuprofen, a non steroidal anti-inflammatory agent, for two months. Glia activation was assessed by immunohistochemistry and western blot analysis; Abeta precursor protein (APP) by western blot analysis; Abeta deposition by immunohistochemistry, thioflavin-S staining and ELISA; and hydrocephalus by measurements of ventricle size on autoradiographies of brain sections. Results are expressed as means +/- SD. Data comparisons were carried with the Student's T test when two groups were compared, or ANOVA analysis when more than three groups were analyzed. RESULTS: Animals displayed glia activation, hydrocephalus and a robust thioflavin-S-positive vascular deposition. Unexpectedly, these deposits contained no Abeta or serum amyloid P component, a common constituent of amyloid deposits. The thioflavin-S-positive material thus remains to be identified. Pioglitazone decreased glia activation and basal levels of Abeta42- with no change in APP contents - while it increased hydrocephalus, and had no effect on the thioflavin-S deposits. Ibuprofen mimicked the reduction of glia activation caused by pioglitazone and the lack of effect on the thioflavin-S-labeled deposits. CONCLUSIONS: i) TGF-beta1 over-expressing mice may not be an appropriate model of Abeta-elicited CAA; and ii) pioglitazone has paradoxical effects on TGF-beta1-induced pathology suggesting that anti-inflammatory therapy may reduce the damage resulting from active glia, but not from vascular alterations or hydrocephalus. Identification of the thioflavin-S-positive material will facilitate the full appraisal of the clinical implication of the effects of anti-inflammatory drugs, and provide a more thorough understanding of TGF-beta1 actions in brain. [Abstract/Link to Full Text]

Rosi S, Ramirez-Amaya V, Hauss-Wegrzyniak B, Wenk GL
Chronic brain inflammation leads to a decline in hippocampal NMDA-R1 receptors.
J Neuroinflammation. 2004 Jul 7;1(1):12.
BACKGROUND: Neuroinflammation plays a prominent role in the progression of Alzheimer's disease and may be responsible for degeneration in vulnerable regions such as the hippocampus. Neuroinflammation is associated with elevated levels of extracellular glutamate and potentially an enhanced stimulation of glutamate N-methyl-D-aspartate receptors. This suggests that neurons that express these glutamate receptors might be at increased risk of degeneration in the presence of chronic neuroinflammation. METHODS: We have characterized a novel model of chronic brain inflammation using a slow infusion of lipopolysaccharide into the 4th ventricle of rats. This model reproduces many of the behavioral, electrophysiological, neurochemical and neuropathological changes associated with Alzheimer's disease. RESULTS: The current study demonstrated that chronic neuroinflammation is associated with the loss of N-methyl-D-aspartate receptors, as determined both qualitatively by immunohistochemistry and quantitatively by in vitro binding studies using [3H]MK-801, within the hippocampus and entorhinal cortex. CONCLUSION: The gradual loss of function of this critical receptor within the temporal lobe region may contribute to some of the cognitive deficits observed in patients with Alzheimer's disease. [Abstract/Link to Full Text]

Schmidt OI, Morganti-Kossmann MC, Heyde CE, Perez D, Yatsiv I, Shohami E, Ertel W, Stahel PF
Tumor necrosis factor-mediated inhibition of interleukin-18 in the brain: a clinical and experimental study in head-injured patients and in a murine model of closed head injury.
J Neuroinflammation. 2004 Jul 28;1(1):13.
Tumor necrosis factor (TNF) and interleukin-(IL)-18 are important mediators of neuroinflammation after closed head injury (CHI). Both mediators have been previously found to be significantly elevated in the intracranial compartment after brain injury, both in patients as well as in experimental model systems. However, the interrelation and regulation of these crucial cytokines within the injured brain has not yet been investigated. The present study was designed to assess a potential regulation of intracranial IL-18 levels by TNF based on a clinical study in head-injured patients and an experimental model in mice. In the first part, we investigated the interrelationship between the daily TNF and IL-18 cerebrospinal fluid levels in 10 patients with severe CHI for up to 14 days after trauma. In the second part of the study, the potential TNF-dependent regulation of intracerebral IL-18 levels was further characterized in an experimental set-up in mice: (1) in a standardized model of CHI in TNF/lymphotoxin-alpha gene-deficient mice and wild-type (WT) littermates, and (2) by intracerebro-ventricular injection of mouse recombinant TNF in WT C57BL/6 mice. The results demonstrate an inverse correlation of intrathecal TNF and IL-18 levels in head-injured patients and a TNF-dependent inhibition of IL-18 after intracerebral injection in mice. These findings imply a potential new anti-inflammatory mechanism of TNF by attenuation of IL-18, thus confirming the proposed "dual" function of this cytokine in the pathophysiology of traumatic brain injury. [Abstract/Link to Full Text]

Streit WJ, Mrak RE, Griffin WS
Microglia and neuroinflammation: a pathological perspective.
J Neuroinflammation. 2004 Jul 30;1(1):14.
Microglia make up the innate immune system of the central nervous system and are key cellular mediators of neuroinflammatory processes. Their role in central nervous system diseases, including infections, is discussed in terms of a participation in both acute and chronic neuroinflammatory responses. Specific reference is made also to their involvement in Alzheimer's disease where microglial cell activation is thought to be critically important in the neurodegenerative process. [Abstract/Link to Full Text]

Wu SZ, Bodles AM, Porter MM, Griffin WS, Basile AS, Barger SW
Induction of serine racemase expression and D-serine release from microglia by amyloid beta-peptide.
J Neuroinflammation. 2004 Apr 20;1(1):2.
BACKGROUND: Roles for excitotoxicity and inflammation in Alzheimer's disease have been hypothesized. Proinflammatory stimuli, including amyloid beta-peptide (Abeta), elicit a release of glutamate from microglia. We tested the possibility that a coagonist at the NMDA class of glutamate receptors, D-serine, could respond similarly. METHODS: Cultured microglial cells were exposed to Abeta. The culture medium was assayed for levels of D-serine by HPLC and for effects on calcium and survival on primary cultures of rat hippocampal neurons. Microglial cell lysates were examined for the levels of mRNA and protein for serine racemase, the enzyme that forms D-serine from L-serine. The racemase mRNA was also assayed in Alzheimer hippocampus and age-matched controls. A microglial cell line was transfected with a luciferase reporter construct driven by the putative regulatory region of human serine racemase. RESULTS: Conditioned medium from Abeta-treated microglia contained elevated levels of D-serine. Bioassays of hippocampal neurons with the microglia-conditioned medium indicated that Abeta elevated a NMDA receptor agonist that was sensitive to an antagonist of the D-serine/glycine site (5,7-dicholorokynurenic acid; DCKA) and to enzymatic degradation of D-amino acids by D-amino acid oxidase (DAAOx). In the microglia, Abeta elevated steady-state levels of dimeric serine racemase, the apparent active form of the enzyme. Promoter-reporter and mRNA analyses suggest that serine racemase is transcriptionally induced by Abeta. Finally, the levels of serine racemase mRNA were elevated in Alzheimer's disease hippocampus, relative to age-matched controls. CONCLUSIONS: These data suggest that Abeta could contribute to neurodegeneration through stimulating microglia to release cooperative excitatory amino acids, including D-serine. [Abstract/Link to Full Text]

Pershadsingh HA, Heneka MT, Saini R, Amin NM, Broeske DJ, Feinstein DL
Effect of pioglitazone treatment in a patient with secondary multiple sclerosis.
J Neuroinflammation. 2004 Apr 20;1(1):3.
BACKGROUND: Ligands of the peroxisome proliferator-activated receptor-gamma (PPARgamma) induce apoptosis in activated T-lymphocytes and exert anti-inflammatory effects in glial cells. Preclinical studies have shown that the thiazolidinedione pioglitazone, an FDA-approved PPARgamma agonist used to treat type 2 diabetes, delays the onset and reduces the severity of clinical symptoms in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS). We therefore tested the safety and therapeutic potential of oral pioglitazone in a patient with secondary MS. CASE PRESENTATION: The rationale and risks of taking pioglitazone were carefully explained to the patient, consent was obtained, and treatment was initiated at 15 mg per day p.o. and then increased by 15 mg biweekly to 45 mg per day p.o. for the duration of the treatment. Safety was assessed by measurements of metabolic profiles, blood pressure, and edema; effects on clinical symptoms were assessed by measurement of cognition, motor function and strength, and MRI. Within 4 weeks the patient exhibited increased appetite, cognition and attention span. After 12 months treatment, body weight increased from 27.3 to 35.9 kg (32%) and maintained throughout the duration of the study. Upper extremity strength and coordination improved, and increased fine coordination was noted unilaterally after 8 months and bilaterally after 15 months. After 8 months therapy, the patient demonstrated improvement in orientation, short-term memory, and attention span. MRIs carried out after 10 and 18 months of treatment showed no perceptible change in overall brain atrophy, extent of demyelination, or in Gd-enhancement. After 3.0 years on pioglitazone, the patient continues to be clinically stable, with no adverse events. CONCLUSIONS: In a patient with secondary progressive MS, daily treatment with 45 mg p.o. pioglitazone for 3 years induced apparent clinical improvement without adverse events. Pioglitazone should therefore be considered for further testing of therapeutic potential in MS patients. [Abstract/Link to Full Text]

Bate C, Salmona M, Williams A
Ginkgolide B inhibits the neurotoxicity of prions or amyloid-beta1-42.
J Neuroinflammation. 2004 May 11;1(1):4.
BACKGROUND: Neuronal loss in Alzheimer's or prion diseases is preceded by the accumulation of fibrillar aggregates of toxic proteins (amyloid-beta1-42 or the prion protein). Since some epidemiological studies have demonstrated that the EGb 761 extract, from the leaves of the Ginkgo biloba tree, has a beneficial effect on Alzheimer's disease, the effect of some of the major components of the EGb 761 extract on neuronal responses to amyloid-beta1-42, or to a synthetic miniprion (sPrP106), were investigated. METHODS: Components of the EGb 761 extract were tested in 2 models of neurodegeneration. SH-SY5Y neuroblastoma cells were pre-treated with ginkgolides A or B, quercetin or myricetin, and incubated with amyloid-beta1-42, sPrP106, or other neurotoxins. After 24 hours neuronal survival and the production of prostaglandin E2 that is closely associated with neuronal death was measured. In primary cortical neurons apoptosis (caspase-3) in response to amyloid-beta1-42 or sPrP106 was measured, and in co-cultures the effects of the ginkgolides on the killing of amyloid-beta1-42 or sPrP106 damaged neurons by microglia was tested. RESULTS: Neurons treated with ginkgolides A or B were resistant to amyloid-beta1-42 or sPrP106. Ginkgolide-treated cells were also resistant to platelet activating factor or arachidonic acid, but remained susceptible to hydrogen peroxide or staurosporine. The ginkgolides reduced the production of prostaglandin E2 in response to amyloid-beta1-42 or sPrP106. In primary cortical neurons, the ginkgolides reduced caspase-3 responses to amyloid-beta1-42 or sPrP106, and in co-culture studies the ginkgolides reduced the killing of amyloid-beta1-42 or sPrP106 damaged neurons by microglia. CONCLUSION: Nanomolar concentrations of the ginkgolides protect neurons against the otherwise toxic effects of amyloid-beta1-42 or sPrP106. The ginkgolides also prevented the neurotoxicity of platelet activating factor and reduced the production of prostaglandin E2 in response to platelet activating factor, amyloid-beta1-42 or sPrP106. These results are compatible with prior reports that ginkgolides inhibit platelet-activating factor, and that platelet-activating factor antagonists block the toxicity of amyloid-beta1-42 or sPrP106. The results presented here suggest that platelet-activating factor antagonists such as the ginkgolides may be relevant treatments for prion or Alzheimer's diseases. [Abstract/Link to Full Text]

Mrak RE, Landreth GE
PPARgamma, neuroinflammation, and disease.
J Neuroinflammation. 2004 May 14;1(1):5.
BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) are a class of nuclear transcription factors that are activated by fatty acids and their derivatives. One of these, PPARgamma, regulates responsiveness to insulin in adipose cells, and PPARgamma-activating drugs such as pioglitazone are used in the treatment of type 2 diabetes. PPARgamma acts in myeloid-lineage cells, including T-cells and macrophages, to suppress their activation and their elaboration of inflammatory molecules. PPARgamma activation also suppresses the activated phenotype in microglia, suggesting that PPARgamma-activating drugs may be of benefit in chronic neuroinflammatory diseases. Some, but not all, nonsteroidal anti-inflammatory agents (indomethacin and ibuprofen in particular) also have activating effects on PPARgamma. DISCUSSION AND CONCLUSIONS: These observations suggest on the one hand a role for PPARgamma-activating drugs in the treatment of chronic neuroinflammatory diseases-as shown for a patient with secondary progressive multiple sclerosis by Pershadsingh et al. in this issue of the Journal of Neuroinflammation-and suggest on the other hand a possible explanation for confusing and contradictory results in trials of nonsteroidal anti-inflammatory agents in Alzheimer's disease. [Abstract/Link to Full Text]

Sánchez-Pernaute R, Ferree A, Cooper O, Yu M, Brownell AL, Isacson O
Selective COX-2 inhibition prevents progressive dopamine neuron degeneration in a rat model of Parkinson's disease.
J Neuroinflammation. 2004 May 17;1(1):6.
Several lines of evidence point to a significant role of neuroinflammation in Parkinson's disease (PD) and other neurodegenerative disorders. In the present study we examined the protective effect of celecoxib, a selective inhibitor of the inducible form of cyclooxygenase (COX-2), on dopamine (DA) cell loss in a rat model of PD. We used the intrastriatal administration of 6-hydroxydopamine (6-OHDA) that induces a retrograde neuronal damage and death, which progresses over weeks. Animals were randomized to receive celecoxib (20 mg/kg/day) or vehicle starting 1 hour before the intrastriatal administration of 6-OHDA. Evaluation was performed in vivo using micro PET and selective radiotracers for DA terminals and microglia. Post mortem analysis included stereological quantification of tyrosine hydroxylase, astrocytes and microglia. 12 days after the 6-OHDA lesion there were no differences in DA cell or fiber loss between groups, although the microglial cell density and activation was markedly reduced in animals receiving celecoxib (p < 0.01). COX-2 inhibition did not reduce the typical astroglial response in the striatum at any stage. Between 12 and 21 days, there was a significant progression of DA cell loss in the vehicle group (from 40 to 65%) that was prevented by celecoxib. Therefore, inhibition of COX-2 by celecoxib appears to be able, either directly or through inhibition of microglia activation to prevent or slow down DA cell degeneration. [Abstract/Link to Full Text]

Iskander S, Walsh KA, Hammond RR
Human CNS cultures exposed to HIV-1 gp120 reproduce dendritic injuries of HIV-1-associated dementia.
J Neuroinflammation. 2004 May 27;1(1):7.
HIV-1-associated dementia remains a common subacute to chronic central nervous system degeneration in adult and pediatric HIV-1 infected populations. A number of viral and host factors have been implicated including the HIV-1 120 kDa envelope glycoprotein (gp120). In human post-mortem studies using confocal scanning laser microscopy for microtubule-associated protein 2 and synaptophysin, neuronal dendritic pathology correlated with dementia. In the present study, primary human CNS cultures exposed to HIV-1 gp120 at 4 weeks in vitro suffered gliosis and dendritic damage analogous to that described in association with HIV-1-associated dementia. [Abstract/Link to Full Text]

Walsh KA, Megyesi JF, Wilson JX, Crukley J, Laubach VE, Hammond RR
Antioxidant protection from HIV-1 gp120-induced neuroglial toxicity.
J Neuroinflammation. 2004 May 27;1(1):8.
BACKGROUND: The pathogenesis of HIV-1 glycoprotein 120 (gp120) associated neuroglial toxicity remains unresolved, but oxidative injury has been widely implicated as a contributing factor. In previous studies, exposure of primary human central nervous system tissue cultures to gp120 led to a simplification of neuronal dendritic elements as well as astrocytic hypertrophy and hyperplasia; neuropathological features of HIV-1-associated dementia. Gp120 and proinflammatory cytokines upregulate inducible nitric oxide synthase (iNOS), an important source of nitric oxide (NO) and nitrosative stress. Because ascorbate scavenges reactive nitrogen and oxygen species, we studied the effect of ascorbate supplementation on iNOS expression as well as the neuronal and glial structural changes associated with gp120 exposure. METHODS: Human CNS cultures were derived from 16-18 week gestation post-mortem fetal brain. Cultures were incubated with 400 microM ascorbate-2-O-phosphate (Asc-p) or vehicle for 18 hours then exposed to 1 nM gp120 for 24 hours. The expression of iNOS and neuronal (MAP2) and astrocytic (GFAP) structural proteins was examined by immunohistochemistry and immunofluorescence using confocal scanning laser microscopy (CSLM). RESULTS: Following gp120 exposure iNOS was markedly upregulated from undetectable levels at baseline. Double label CSLM studies revealed astrocytes to be the prime source of iNOS with rare neurons expressing iNOS. This upregulation was attenuated by the preincubation with Asc-p, which raised the intracellular concentration of ascorbate. Astrocytic hypertrophy and neuronal injury caused by gp120 were also prevented by preincubation with ascorbate. CONCLUSIONS: Ascorbate supplementation prevents the deleterious upregulation of iNOS and associated neuronal and astrocytic protein expression and structural changes caused by gp120 in human brain cell cultures. [Abstract/Link to Full Text]

Dello Russo C, Boullerne AI, Gavrilyuk V, Feinstein DL
Inhibition of microglial inflammatory responses by norepinephrine: effects on nitric oxide and interleukin-1beta production.
J Neuroinflammation. 2004 Jun 30;1(1):9.
BACKGROUND: Under pathological conditions, microglia produce proinflammatory mediators which contribute to neurologic damage, and whose levels can be modulated by endogenous factors including neurotransmitters such as norepinephrine (NE). We investigated the ability of NE to suppress microglial activation, in particular its effects on induction and activity of the inducible form of nitric oxide synthase (NOS2) and the possible role that IL-1beta plays in that response. METHODS: Rat cortical microglia were stimulated with bacterial lipopolysaccharide (LPS) to induce NOS2 expression (assessed by nitrite and nitrate accumulation, NO production, and NOS2 mRNA levels) and IL-1beta release (assessed by ELISA). Effects of NE were examined by co-incubating cells with different concentrations of NE, adrenergic receptor agonists and antagonists, cAMP analogs, and protein kinase (PK) A and adenylate cyclase (AC) inhibitors. Effects on the NFkappaB:IkappaB pathway were examined by using selective a NFkappaB inhibitor and measuring IkappaBalpha protein levels by western blots. A role for IL-1beta in NOS2 induction was tested by examining effects of caspase-1 inhibitors and using caspase-1 deficient cells. RESULTS: LPS caused a time-dependent increase in NOS2 mRNA levels and NO production; which was blocked by a selective NFkappaB inhibitor. NE dose-dependently reduced NOS2 expression and NO generation, via activation of beta2-adrenergic receptors (beta2-ARs), and reduced loss of inhibitory IkBalpha protein. NE effects were replicated by dibutyryl-cyclic AMP. However, co-incubation with either PKA or AC inhibitors did not reverse suppressive effects of NE, but instead reduced nitrite production. A role for IL-1beta was suggested since NE potently blocked microglial IL-1beta production. However, incubation with a caspase-1 inhibitor, which reduced IL-1beta levels, had no effect on NO production; incubation with IL-receptor antagonist had biphasic effects on nitrite production; and NE inhibited nitrite production in caspase-1 deficient microglia. CONCLUSIONS: NE reduces microglial NOS2 expression and IL-1beta production, however IL-1beta does not play a critical role in NOS2 induction nor in mediating NE suppressive effects. Changes in magnitude or kinetics of cAMP may modulate NOS2 induction as well as suppression by NE. These results suggest that dysregulation of the central cathecolaminergic system may contribute to detrimental inflammatory responses and brain damage in neurological disease or trauma. [Abstract/Link to Full Text]

Recent Articles in Journal of Vision

Heinrich SP, Andrés M, Bach M
Attention and visual texture segregation.
J Vis. 2007;7(6):6.
Visual texture segregation is believed to be performed preattentively. Recent evidence, however, suggests that attention does play an important role. Using visual evoked potentials (VEPs), we investigated the effect of different tasks on texture segregation. Stimuli consisted of Gabor-filtered binary noise patterns. In segregated stimuli, local texture orientation contrasts defined global checkerboard patterns. VEP responses specific to texture segregation were obtained by computing the difference between VEPs to homogeneous and segregated stimuli. Four conditions were examined that required attending either the global pattern, the local structure, random numbers displayed on the screen, or a series of tones. Responses specific to texture segregation were dominated by two occipital negativities peaking around 110 and 230 ms. The earlier one was not affected by the task, whereas the later one was completely abolished when the subjects attended to either numbers or tones (p = .0005 and p = .006, respectively). The results suggest that early stages of texture segregation are not affected by attention, whereas task relevance is crucial for later processes. The timing is compatible with a recurrent processing pattern with initial bottom-up processing of basic stimulus characteristics and a subsequent top-down flow of higher level modulatory information. As attention effects occur across modalities, they cannot be simply explained by competition within the visual cortex. [Abstract/Link to Full Text]

Rutishauser U, Koch C
Probabilistic modeling of eye movement data during conjunction search via feature-based attention.
J Vis. 2007;7(6):5.
Where the eyes fixate during search is not random; rather, gaze reflects the combination of information about the target and the visual input. It is not clear, however, what information about a target is used to bias the underlying neuronal responses. We here engage subjects in a variety of simple conjunction search tasks while tracking their eye movements. We derive a generative model that reproduces these eye movements and calculate the conditional probabilities that observers fixate, given the target, on or near an item in the display sharing a specific feature with the target. We use these probabilities to infer which features were biased by top-down attention: Color seems to be the dominant stimulus dimension for guiding search, followed by object size, and lastly orientation. We use the number of fixations it took to find the target as a measure of task difficulty. We find that only a model that biases multiple feature dimensions in a hierarchical manner can account for the data. Contrary to common assumptions, memory plays almost no role in search performance. Our model can be fit to average data of multiple subjects or to individual subjects. Small variations of a few key parameters account well for the intersubject differences. The model is compatible with neurophysiological findings of V4 and frontal eye fields (FEF) neurons and predicts the gain modulation of these cells. [Abstract/Link to Full Text]

Landy MS, Goutcher R, Trommershäuser J, Mamassian P
Visual estimation under risk.
J Vis. 2007;7(6):4.
We investigate whether observers take into account their visual uncertainty in an optimal manner in a perceptual estimation task with explicit rewards and penalties for performance. Observers judged the mean orientation of a briefly presented texture consisting of a collection of line segments. The mean and, in some experiments, the variance of the distribution of line orientations changed from trial to trial. Subjects tried to maximize the number of points won in a "bet" on the mean texture orientation. They placed their bet by rotating a visual display that indicated two ranges of orientations: a reward region and a neighboring penalty region. Subjects won 100 points if the mean texture orientation fell within the reward region, and subjects lost points (0, 100, or 500, in separate blocks) if the mean orientation fell in the penalty region. We compared each subject's performance to a decision strategy that maximizes expected gain (MEG). For the nonzero-penalty conditions, this ideal strategy predicts subjects will adjust the payoff display to shift the center of the reward region away from the perceived mean texture orientation, putting the perceived mean orientation on the opposite side of the reward region from the penalty region. This shift is predicted to be larger for (1) larger penalties, (2) penalty regions located closer to the payoff region, and (3) larger stimulus variability. While some subjects' performance was nearly optimal, other subjects displayed a variety of suboptimal strategies when stimulus variability was high and changed unpredictably from trial to trial. [Abstract/Link to Full Text]

Rosas P, Wichmann FA, Wagemans J
Texture and object motion in slant discrimination: failure of reliability-based weighting of cues may be evidence for strong fusion.
J Vis. 2007;7(6):3.
Different types of texture produce differences in slant-discrimination performance (P. Rosas, F. A. Wichmann, & J. Wagemans, 2004). Under the assumption that the visual system is sensitive to the reliability of different depth cues (M. O. Ernst & M. S. Banks, 2002; L. T. Maloney & M. S. Landy, 1989), it follows that the texture type should affect the influence of the texture cue in depth-cue combination. We tested this prediction by combining different texture types with object motion in a slant-discrimination task in two experiments. First, we used consistent cues to observe whether our subjects behaved as linearly combining independent estimates from texture and motion in a statistical optimal fashion (M. O. Ernst & M. S. Banks, 2002). Only 4% of our results were consistent with such an optimal combination of uncorrelated estimates, whereas about 46% of the data were consistent with an optimal combination of correlated estimates from cues. Second, we measured the weights for the texture and motion cues using perturbation analysis. The results showed a large influence of the motion cue and an increasing weight for the texture cue for larger slants. However, in general, the texture weights did not follow the reliability of the textures. Finally, we fitted the correlation coefficients of estimates individually for each texture, motion condition, and observer. This allows us to fit our data from both experiments to an optimal cue combination model with correlated estimates, but inspection of the fitted parameters shows no clear, psychophysically interpretable pattern. Furthermore, the fitted motion thresholds as a function of texture type are correlated with the slant thresholds as a function of texture type. One interpretation of such a finding is a strong coupling of cues. [Abstract/Link to Full Text]

Tripathy SP, Narasimhan S, Barrett BT
On the effective number of tracked trajectories in normal human vision.
J Vis. 2007;7(6):2.
Z. W. Pylyshyn and R. W. Storm (1988) have shown that human observers can accurately track four to five items at a time. However, when a threshold paradigm is used, observers are unable to track more than a single trajectory accurately (S. P. Tripathy & B. T. Barrett, 2004). This difference between the two studies is examined systematically using substantially suprathreshold stimuli. The stimuli consisted of one (Experiment 1) or more (Experiments 2 and 3) bilinear target trajectories embedded among several linear distractor trajectories. The target trajectories deviated clockwise (CW) or counterclockwise (CCW) (by 19 degrees, 38 degrees, or 76 degrees in Experiments 1 and 2 and by 19 degrees, 38 degrees, or 57 degrees in Experiment 3), and observers reported the direction of deviation. From the percentage of correct responses, the "effective" number of tracked trajectories was estimated for each experimental condition. The total number of trajectories in the stimulus and the number of deviating trajectories had only a small effect on the effective number of tracked trajectories; the effective number tracked was primarily influenced by the angle of deviation of the targets and ranged from four to five trajectories for a +/-76 degrees deviation to only one to two trajectories for a +/-19 degrees deviation, regardless of whether the different magnitudes of deviation were blocked (Experiment 2) or interleaved (Experiment 3). Simple hypotheses based on "averaging of orientations," "preallocation of resources," or pop-out, crowding, or masking of the target trajectories are unlikely to explain the relationship between the effective number tracked and the angle of deviation of the target trajectories. This study reconciles the difference between the studies cited above in terms of the number of trajectories that can be tracked at a time. [Abstract/Link to Full Text]

Fecteau JH
Priming of pop-out depends upon the current goals of observers.
J Vis. 2007;7(6):1.
What you have seen before helps you see it again. This effect has been shown in visual search studies looking at the consequence of the previous trial: Reaction times are shorter when the features defining a target and distractors are repeated. Here, I explore whether this bias in attentional selection occurs automatically or whether it depends upon the current goals of observers. Participants performed a visual search task, in which both a color singleton and a shape singleton appeared in the search array. The observers were instructed at the beginning of every trial as to which singleton was relevant. The data show that repeating the color or shape from the previous trial benefits performance only when this information is relevant to the observers' current goals. [Abstract/Link to Full Text]

Szczepanowski R, Pessoa L
Fear perception: can objective and subjective awareness measures be dissociated?
J Vis. 2007;7(4):10.
Whereas previous studies of fearful-face perception have probed visual awareness according to either objective or subjective criteria, in the present study, we probed the perception of briefly presented and masked fearful faces by assessing both types of perception within the same task. Both objective and subjective sensitivity measures were assessed within a common signal detection theory framework. To evaluate single-participant awareness, we employed a nonparametric receiver operating characteristic (ROC) analysis of the behavioral data, which involved collecting a large number of trials over multiple sessions. Our findings revealed that nearly all subjects could reliably detect 17-ms fearful-face targets, thus exhibiting above-chance objective perception at this target duration. Reliable subjective sensitivity was also observed for 33-ms fearful-face targets and, for some subjects, even for 17-ms targets. The analysis of single-session data suggests that previous experiments may have lacked sufficient statistical power to establish above-chance performance. Taken together, our findings are consistent with a dissociation of fear perception according to objective and subjective criteria, which could be assessed for each individual participant. The determination of such a dissociation zone may help in understanding the conditions linked to aware and unaware fear perception. [Abstract/Link to Full Text]

Lewis TL, Kingdon A, Ellemberg D, Maurer D
Orientation discrimination in 5-year-olds and adults tested with luminance-modulated and contrast-modulated gratings.
J Vis. 2007;7(4):9.
We compared thresholds for discriminating orientation by 5-year-olds and adults for first-order (luminance-modulated) and second-order (contrast-modulated) gratings. To achieve equal visibility, we set the contrast for each age and condition at a fixed multiple of the contrast threshold for discriminating horizontal from vertical gratings. The minimum tilt that could be discriminated from vertical was four to five times larger in 5-year-olds than in adults, even when the noise was removed from the first-order stimuli and amplitude modulation increased to 0.90. Thresholds at both ages were significantly worse (1.2-1.5 times worse) for second-order modulation than for equally visible first-order modulation, and 5-year-olds were equally immature for both types of pattern. Together, the findings suggest that orientation discrimination is slow to develop and worse for second-order than first-order patterns in both children and adults. [Abstract/Link to Full Text]

Stockman A, Smithson HE, Michaelides M, Moore AT, Webster AR, Sharpe LT
Residual cone vision without alpha-transducin.
J Vis. 2007;7(4):8.
Behavioral experiments in humans with a rare genetic mutation that compromises the function of alpha-transducin (Galpha the alpha-subunit of the G-protein in the primary cone phototransduction cascade) reveal a residual cone response only viable at high light levels and at low temporal frequencies. It has three characteristic properties. First, it limits temporal frequency sensitivity to the equivalent of a simple first order reaction with a time constant of approximately 140 ms. Second, it delays the visual response by an amount that is also consistent with such a reaction. Third, it causes temporal acuity to be linearly related to the logarithm of the amount of bleached pigment. We suggest that these properties are consistent with the residual function depending on a sluggishly generated cone photobleaching product, which we tentatively identify as a cone metarhodopsin. By activating the transduction cascade, this bleaching product mimics the effects of real light and is therefore one of the molecular origins of "background equivalence," the long-established observation that the aftereffects of photopigment bleaches and the effects of real background lights are equivalent. Alternative explanations for the residual cone response include the possibilities that there is a secondary phototransduction mechanism that bypasses alpha-transduction, or that the truncated alpha-transduction that results from the mutation retains some minimal functionality. [Abstract/Link to Full Text]

Meese TS, Summers RJ, Holmes DJ, Wallis SA
Contextual modulation involves suppression and facilitation from the center and the surround.
J Vis. 2007;7(4):7.
In psychophysics, cross-orientation suppression (XOS) and cross-orientation facilitation (XOF) have been measured by investigating mask configuration on the detection threshold of a centrally placed patch of sine-wave grating. Much of the evidence for XOS and XOF comes from studies using low and high spatial frequencies, respectively, where the interactions are thought to arise from within (XOS) and outside (XOF) the footprint of the classical receptive field. We address the relation between these processes here by measuring the effects of various sizes of superimposed and annular cross-oriented masks on detection thresholds at two spatial scales (1 and 7 c/deg) and on contrast increment thresholds at 7 c/deg. A functional model of our results indicates the following (1) XOS and XOF both occur for superimposed and annular masks. (2) XOS declines with spatial frequency but XOF does not. (3) The spatial extent of the interactions does not scale with spatial frequency, meaning that surround-effects are seen primarily at high spatial frequencies. (4) There are two distinct processes involved in XOS: direct divisive suppression and modulation of self-suppression. (5) Whether XOS or XOF wins out depends upon their relative weights and mask contrast. These results prompt enquiry into the effect of spatial frequency at the single-cell level and place new constraints on image-processing models of early visual processing. [Abstract/Link to Full Text]

Davidenko N
Silhouetted face profiles: a new methodology for face perception research.
J Vis. 2007;7(4):6.
We present a new methodology for constructing face stimuli for psychological experiments based on silhouetted face profiles. Face silhouettes carry a number of theoretical and methodological advantages compared to more complex face stimuli and lend themselves to a simple yet powerful parameterization. In five behavioral studies, we show that face silhouettes are processed like regular face stimuli: They provide enough information for accurate gender judgments (Study 1), age estimations (Study 2), and reliable and cross-valid attractiveness ratings (Study 3). Furthermore, face silhouettes elicit an inversion effect (Study 4) and allow for remarkably accurate cross-identification with front-view photographs (Study 5). We then describe a shape-based parameterization that relies on a small set of landmark points and show that face silhouettes can be effectively represented in a 20-dimensional "silhouette face space" (Study 6). We show that in this physical space, distance from the center of the space corresponds to perceived distinctiveness (Study 7), confirming a key axiom in the formulation of the face space model. Finally, we discuss straightforward applications of the face silhouette methodology and address some limitations. [Abstract/Link to Full Text]

Erkelens CJ, van Ee R
Monocular symmetry in binocular vision.
J Vis. 2007;7(4):5.
Human vision is highly sensitive to bilateral symmetry in 2-D images. It is, however, not clear yet whether this visual sensitivity relates to symmetry of 3-D objects or whether it relates to symmetry of the 2-D image itself. We used a stereoscopically presented stimulus and a 3-D bisection task that enable us to dissociate object symmetry from image symmetry. The bisection stimulus consisted of three parallel lines, of which two lines were located in one depth plane and the third line in another. Bisection judgments were different for horizontal and vertical lines, which can be explained by taking into account the distinct viewpoints of the left and right eyes for either of the visible sides of the 3-D object. Image symmetry from a monocular vantage point predicts 3-D bisection better than object symmetry. We conclude that observers use either of the two monocular 2-D images separately but not a single cyclopean view-nicely dovetailing with what they do when they assess both 3-D visual direction and 3-D shape-to assess 3-D symmetry. [Abstract/Link to Full Text]

Schneider BL, DeLong JE, Busey TA
Added noise affects the neural correlates of upright and inverted faces differently.
J Vis. 2007;7(4):4.
In five experiments, we examine the neural correlates of the interaction between upright faces, inverted faces, and visual noise. In Experiment 1, we examine a component termed the N170 for upright and inverted faces presented with and without noise. Results show a smaller amplitude for inverted faces than upright faces when presented in noise, whereas the reverse is true without noise. In Experiment 2, we show that the amplitude reversal is robust for full faces but not eyes alone across all noise levels. In Experiment 3, we vary contrast to see if this reversal is a result of degrading a face. We observe no reversal effects. Thus, across conditions, adding noise to full faces is a sufficient condition for the N170 reversal. In Experiment 4, we delay the onsets of the faces presented in noise. We replicate the smaller N170 for inverted faces at no delay but observe partial recovery of the N170 for inverted faces at longer delays in static noise. Experiment 5 demonstrates the interaction in low contrast at a behavioral level. We propose a model in which noise interacts with the processing properties of inverted faces more so than upright faces. [Abstract/Link to Full Text]

Eagleman DM, Sejnowski TJ
Motion signals bias localization judgments: a unified explanation for the flash-lag, flash-drag, flash-jump, and Frohlich illusions.
J Vis. 2007;7(4):3.
In the flash-lag illusion, a moving object aligned with a flash is perceived to be offset in the direction of motion following the flash. In the "flash-drag" illusion, a flash is mislocalized in the direction of nearby motion. In the "flash-jump" illusion, a transient change in the appearance of a moving object (e.g., color) is mislocalized in the direction of subsequent motion. Finally, in the Frohlich illusion, the starting position of a suddenly appearing moving object is mislocalized in the direction of the subsequent motion. We demonstrate, in a series of experiments, a unified explanation for all these illusions: Perceptual localization is influenced by motion signals collected over approximately 80 ms after a query is triggered. These demonstrations rule out "latency difference" and asynchronous feature binding models, in which objects appear in their real positions but misaligned in time. Instead, the illusions explored here are best understood as biases in localization caused by motion signals. We suggest that motion biasing exists because it allows the visual system to account for neural processing delays by retrospectively "pushing" an object closer to its true physical location, and we propose directions for exploring the neural mechanisms underlying the dynamic updating of location by the activity of motion-sensitive neurons. [Abstract/Link to Full Text]

Hansen T, Walter S, Gegenfurtner KR
Effects of spatial and temporal context on color categories and color constancy.
J Vis. 2007;7(4):2.
Color constancy is the ability to assign a constant color to an object independent of changes in illumination. Color constancy is achieved by taking context information into account. Previous approaches that have used matching paradigms to quantify color constancy found degrees of constancy between 20% and 80%. Here, we studied color constancy in a color-naming task under different conditions of surround illumination and patch size. Observers categorized more than 400 patches for each illumination condition. This allows one to overcome inherent limitations in color naming and to study the changes in color categories under illumination changes. When small central test patches with a full context illumination were categorized, observers followed the illumination shift almost completely, showing a high degree of constancy (99%). Reducing the available context information or increasing the patch size decreased the degree of constancy to about 50%. Moderate degrees of constancy (66%) occurred even when the test patches were never viewed simultaneously but only in temporal alternation with the illumination. Boundaries between color categories were largely stable within and across observers under neutral illumination. Under changing illumination, there were small but systematic variations in the color category boundaries. Color category boundaries tended to rotate away from the illumination color. This variation was largest under full context conditions where highest degrees of color constancy were obtained. [Abstract/Link to Full Text]

van Hateren JH, Snippe HP
Simulating human cones from mid-mesopic up to high-photopic luminances.
J Vis. 2007;7(4):1.
A computational model of human cones for intensities ranging from 1 td up to full bleaching levels is presented. The model conforms well with measurements made in primate horizontal cells, follows Weber's law at high intensities, and performs range compression consistent with what is known of cones in other vertebrates. The model consists entirely of processes with a clear physiological interpretation: pigment bleaching, saturation of cGMP hydrolysis, calcium feedback on cGMP synthesis, and a nonlinear membrane. The model is implemented according to a very fast computational scheme useful for simulations, and sample programs in Matlab and Fortran are provided as supplementary material. [Abstract/Link to Full Text]

Renninger LW, Verghese P, Coughlan J
Where to look next? Eye movements reduce local uncertainty.
J Vis. 2007;7(3):6.
How do we decide where to look next? During natural, active vision, we move our eyes to gather task-relevant information from the visual scene. Information theory provides an elegant framework for investigating how visual stimulus information combines with prior knowledge and task goals to plan an eye movement. We measured eye movements as observers performed a shape-learning and -matching task, for which the task-relevant information was tightly controlled. Using computational models, we probe the underlying strategies used by observers when planning their next eye movement. One strategy is to move the eyes to locations that maximize the total information gained about the shape, which is equivalent to reducing global uncertainty. Observers' behavior may appear highly similar to this strategy, but a rigorous analysis of sequential fixation placement reveals that observers may instead be using a local rule: fixate only the most informative locations, that is, reduce local uncertainty. [Abstract/Link to Full Text]

Smith MA, Kohn A, Movshon JA
Glass pattern responses in macaque V2 neurons.
J Vis. 2007;7(3):5.
Area V2 of macaque visual cortex is known to respond well to conventional oriented bar and grating stimuli, but some recent physiological data have shown that it may play an important role in coding more complicated patterns. Most of these data come from testing done with stimuli presented within the classical receptive field (CRF), whereas relatively little attention has been paid to the role played by the extra-classical surround. We have previously shown that neurons in primary visual cortex (V1) respond to translational Glass patterns in a manner that is predictable from their responses to grating stimuli. In this article, we first extend our experiments and modeling of Glass pattern responses in V1 to include V2. We explored the sensitivity of V2 cells to global form cues in Glass patterns confined to the CRF. Our results indicate that V2 neurons respond to the local signals in Glass patterns in a manner similar to V1 and that those responses are not influenced by global form present in the surround. It appears that the coding of the more complicated global structure in Glass patterns takes place further downstream in the visual system. [Abstract/Link to Full Text]

Stockman A, Langendörfer M, Sharpe LT
Human short-wavelength-sensitive cone light adaptation.
J Vis. 2007;7(3):4.
The cone-driven visual system is able to regulate its sensitivity effectively from twilight to bright sunlight. On the basis of a novel combination of short-wavelength-sensitive (S-) cone measurements of temporal sensitivity and temporal delay, we show that S-cone light adaptation is achieved not only by trading unwanted sensitivity for speed but also by an additional process that counterintuitively increases the overall sensitivity as the light level rises. Our results are consistent with comparable middle-wavelength-sensitive (M-) cone measurements made in protanopic observers and can be accounted for by the same two-parameter model developed to account for the M-cone data (A. Stockman, M. Langendörfer, H. E. Smithson, & L. T. Sharpe, 2006). Each stage of the model can be linked to molecular mechanisms occurring within the photoreceptor: the speeding up to increases in the rates of decay of active and messenger molecules, the unexpected sensitivity increases to increased rates of molecular resynthesis and changes in channel sensitivity, and the sensitivity decreases to bleaching. Together, these mechanisms act to maintain vision in an optimal operating range and to protect it from overload. [Abstract/Link to Full Text]

van Hateren JH
A model of spatiotemporal signal processing by primate cones and horizontal cells.
J Vis. 2007;7(3):3.
A model of spatiotemporal signal processing by the cone-horizontal cell circuit in the primate outer retina is developed and validated using measurements on the H1 horizontal cell from the literature. The model extends an earlier temporal model that mainly addressed the regulation of sensitivity by the cones. Three elements are added to the earlier model to describe the full spatiotemporal processing by horizontal cells. First, the feedback gain from horizontal cells to cones is made adaptive, depending on field size. Second, the spatial filtering by the horizontal dendritic tree is modeled as a two-component spatial filter. Third, an adaptive temporal low-pass filter is added, also depending on field size. The resulting model adequately describes all available measurements on spatiotemporal processing in macaque H1 cells. The adaptive feedback gain is argued to contribute to negative afterimages and chromatic adaptation in human vision. [Abstract/Link to Full Text]

Muller CM, Brenner E, Smeets JB
Living up to optimal expectations.
J Vis. 2007;7(3):2.
Natural visual scenes contain several independent sources of information (cues) about a single property such as slant. It is widely assumed that the visual system processes such cues separately and then combines them with an averaging operation that takes the reliabilities of the individual cues into account. Does that mean that people lose access to information about inconsistencies between the cues, or are all inconsistencies revealed in a distorted surface appearance? To find out, we let observers match the slant and appearance of a simulated test surface to those of an identical, simultaneously visible, simulated reference surface and analyzed the variability in the settings. We also let observers match surfaces under conditions that were manipulated in ways that were expected to favor certain cues (monocular or binocular) or to selectively disrupt certain comparisons between the surfaces (slant or structure). The patterns in the variability between the settings were consistent with predictions based on the use of all available information. We argue that information about discrepancies is only "lost" during cue combination if there is no benefit in retaining the information. [Abstract/Link to Full Text]

Tsuchiya N, Braun J
Contrast thresholds for component motion with full and poor attention.
J Vis. 2007;7(3):1.
We compare luminance-contrast-masking thresholds for fully and poorly attended stimuli, controlling attention with a demanding concurrent task. We use dynamic displays composed of discrete spatiotemporal wavelets, comparing three conditions ("single," "parallel," and "random"). In contrast to static displays, we do not find that attention modulates the "dipper" regime for masks of low luminance contrast. Nor does attention alter direction-selective masking by multiple wavelets moving in random directions, a condition designed to isolate effects on component motion. However, direction-selective masking by multiple wavelets moving in parallel is significantly reduced by attention. As the latter condition is expected to excite both component and pattern motion mechanisms, this implies that attention may alter the visual representation of pattern motion. In addition, attention exhibits its well-known effect of reducing lateral masking between nearby spatiotemporal wavelets. [Abstract/Link to Full Text]

Fei-Fei L, Iyer A, Koch C, Perona P
What do we perceive in a glance of a real-world scene?
J Vis. 2007;7(1):10.
What do we see when we glance at a natural scene and how does it change as the glance becomes longer? We asked naive subjects to report in a free-form format what they saw when looking at briefly presented real-life photographs. Our subjects received no specific information as to the content of each stimulus. Thus, our paradigm differs from previous studies where subjects were cued before a picture was presented and/or were probed with multiple-choice questions. In the first stage, 90 novel grayscale photographs were foveally shown to a group of 22 native-English-speaking subjects. The presentation time was chosen at random from a set of seven possible times (from 27 to 500 ms). A perceptual mask followed each photograph immediately. After each presentation, subjects reported what they had just seen as completely and truthfully as possible. In the second stage, another group of naive individuals was instructed to score each of the descriptions produced by the subjects in the first stage. Individual scores were assigned to more than a hundred different attributes. We show that within a single glance, much object- and scene-level information is perceived by human subjects. The richness of our perception, though, seems asymmetrical. Subjects tend to have a propensity toward perceiving natural scenes as being outdoor rather than indoor. The reporting of sensory- or feature-level information of a scene (such as shading and shape) consistently precedes the reporting of the semantic-level information. But once subjects recognize more semantic-level components of a scene, there is little evidence suggesting any bias toward either scene-level or object-level recognition. [Abstract/Link to Full Text]

Anderson ND, Murphy KM, Jones DG
Temporal aspects of orientation pooling using visual noise stimuli.
J Vis. 2007;7(1):9.
Previous psychophysical studies have shown that oriented signals are pooled over space to support better perceptual performance. We have investigated whether oriented signals may also be pooled over time. Using an orientation-in-noise paradigm, the threshold to discriminate large orientation differences was measured as the minimum amount of signal required to discriminate an oriented stimulus from unoriented noise. Discrimination thresholds were better with dynamic stimuli, containing multiple independent samples over time, than with static stimuli presented for an equal duration. Thresholds for dynamic stimuli showed gradual improvement from very brief (12 ms) to remarkably long presentation times (>4 s). Spatial integration of orientation signals is very efficient and can be understood in terms of a model based on signal detection theory, with performance limited by early and late stages of intrinsic noise. The nature of temporal integration is different, however, and is more consistent with probability summation of the outputs from low-level orientation detectors operating at a very brief timescale but whose outputs can be combined over a very long duration to yield better perceptual performance. [Abstract/Link to Full Text]

Franssen L, Coppens JE, van den Berg TJ
Modulation depth threshold in the Compensation Comparison approach.
J Vis. 2007;7(1):8.
Recently, the "Compensation Comparison" method was introduced for measuring retinal straylight. In this article, basic aspects are described, in particular a generalization of the approach using the concept of "precompensation," and including flicker threshold as parameter in the psychophysical model. The model was experimentally verified in lab measurements with and without artificially increased straylight and was tested on the data from the multi-center GLARE study. The resulting flicker threshold estimates were analyzed to better understand their origin. An effect of flicker adaptation over distance was found. The new approach proved suitable to describe Compensation Comparison measurements including precompensation, and also for subjects with poor psychometric behavior. [Abstract/Link to Full Text]

Duangudom V, Francis G, Herzog MH
What is the strength of a mask in visual metacontrast masking?
J Vis. 2007;7(1):7.
After more than a century of research, the mechanisms underlying visual masking are still hotly debated. One key characteristic of masking is that variations in the stimulus onset asynchrony (SOA) between the target and the mask can lead to either monotonic reductions in the effect of the mask on the target (A-type masking) or an increase in masking for intermediate SOAs and then a decrease in masking for longer SOAs (B-type masking). Past experimental and theoretical work suggested that the type of the masking function depends on the strength of the mask relative to the target. Usually, mask strength is related to energy (stimulus intensity x duration). Here, we show that the overall spatial layout of the mask is a much stronger factor than classical energy to explain the type of masking function. [Abstract/Link to Full Text]

Pitts MA, Nerger JL, Davis TJ
Electrophysiological correlates of perceptual reversals for three different types of multistable images.
J Vis. 2007;7(1):6.
Electrophysiological recordings were made in 21 observers to investigate whether differences in signature components (P1, N1, selection negativity [SN]) would be revealed during perceptual reversals of three different multistable figures. Using a lattice of Necker cubes as a stimulus, J. Kornmeier and M. Bach (2004, 2005) reported differences in P1 amplitudes as well a broad reversal-related negativity occurring 200-400 ms poststimulus. The current study investigated whether these event-related potentials of Necker cube reversals represent general "perceptual switching" mechanisms and would, therefore, be common to other types of multistable figures. Three different types of multistable stimuli were utilized: a modified Rubin's face/vase, a modified Schröder's staircase, and a novel natural stimulus, Lemmo's cheetahs. Results revealed the broad reversal-related negativity for the face/vase and the reversible staircase but not for the cheetahs. This component is comparable to the SN in polarity, latency, and scalp topography. An effect of early visual spatial attention on figure reversals was suggested by an analysis of the occipital P1 and N1 components. The P1, N1, or both were enhanced for trials in which the observer reported perceptual reversals compared with trials in which no reversals were reported for the face/vase and reversible staircase stimuli. These results support a model of multistable perception in which changes in early spatial attention (indicated by P1 and N1 enhancement) modulate perceptual reversals (indicated by the reversal negativity or SN). [Abstract/Link to Full Text]

Burke MR, Barnes GR
Sequence learning in two-dimensional smooth pursuit eye movements in humans.
J Vis. 2007;7(1):5.
Sequence learning is common to all motor systems and is an essential aspect of human behavior necessary for the acquisition of motor skill. Many previous studies have demonstrated the ability to observe, store, and repeat sequences in a variety of modalities resulting in reduced reaction time. Recently, it has been found that subjects can make predictive smooth eye movements to a sequence of discrete horizontal target motions (C. J. Collins & Barnes, 2005). The present study extends that paradigm into two dimensions of motion in order to investigate qualitative and quantitative differences in sequences of vertical (V) and horizontal (H) eye movements. The subjects performed sequences of four discrete velocity ramps repeated either four or eight times in succession. Baseline measurements were obtained to discrete individual smooth pursuit velocity ramps to H and V predictable (PRD) and randomized (RND) targets. We found that subjects could rapidly learn and anticipate individual components of a four-ramp sequence in two dimensions. The results showed clear asymmetries in the eye movements made to horizontal and vertical targets. We found that the latencies to H targets were shorter than latencies to V targets in both the PRD and RND conditions. We also found higher initial eye velocity (50 ms after target onset) to H targets than vertical targets during the PRD condition. Because these differences in H and V eye movements are present in both RND and PRD trials, this suggests that the observed differences are not due to retention of information but are inherent asymmetries within the system. [Abstract/Link to Full Text]

Michel MM, Jacobs RA
Parameter learning but not structure learning: a Bayesian network model of constraints on early perceptual learning.
J Vis. 2007;7(1):4.
Visual scientists have shown that people are capable of perceptual learning in a large variety of circumstances. Are there constraints on such learning? We propose a new constraint on early perceptual learning, namely, that people are capable of parameter learning-they can modify their knowledge of the prior probabilities of scene variables or of the statistical relationships among scene and perceptual variables that are already considered to be potentially dependent-but they are not capable of structure learning-they cannot learn new relationships among variables that are not considered to be potentially dependent, even when placed in novel environments in which these variables are strongly related. These ideas are formalized using the notation of Bayesian networks. We report the results of five experiments that evaluate whether subjects can demonstrate cue acquisition, which means that they can learn that a sensory signal is a cue to a perceptual judgment. In Experiment 1, subjects were placed in a novel environment that resembled natural environments in the sense that it contained systematic relationships among scene and perceptual variables that which are normally dependent. In this case, cue acquisition requires parameter learning and, as predicted, subjects succeeded in learning a new cue. In Experiments 2-5, subjects were placed in novel environments that did not resemble natural environments-they contained systematic relationships among scene and perceptual variables that are not normally dependent. Cue acquisition requires structure learning in these cases. Consistent with our hypothesis, subjects failed to learn new cues in Experiments 2-5. Overall, the results suggest that the mechanisms of early perceptual learning are biased such that people can only learn new contingencies between scene and sensory variables that are considered to be potentially dependent. [Abstract/Link to Full Text]

Henning GB, Wichmann FA
Some observations on the pedestal effect.
J Vis. 2007;7(1):3.
The pedestal or dipper effect is the large improvement in the detectability of a sinusoidal grating observed when it is added to a masking or pedestal grating of the same spatial frequency, orientation, and phase. We measured the pedestal effect in both broadband and notched noise-noise from which a 1.5-octave band centered on the signal frequency had been removed. Although the pedestal effect persists in broadband noise, it almost disappears in the notched noise. Furthermore, the pedestal effect is substantial when either high- or low-pass masking noise is used. We conclude that the pedestal effect in the absence of notched noise results principally from the use of information derived from channels with peak sensitivities at spatial frequencies different from that of the signal and the pedestal. We speculate that the spatial-frequency components of the notched noise above and below the spatial frequency of the signal and the pedestal prevent "off-frequency looking," that is, prevent the use of information about changes in contrast carried in channels tuned to spatial frequencies that are very much different from that of the signal and the pedestal. Thus, the pedestal or dipper effect measured without notched noise appears not to be a characteristic of individual spatial-frequency-tuned channels. [Abstract/Link to Full Text]