Genetic variation in the vaspin gene affects circulating serum vaspin concentrations.

OBJECTIVE: Visceral adipose tissue-derived serine protease inhibitor (vaspin) is an adipokine potentially linking obesity, insulin resistance and type 2 diabetes. Here, we searched for genetic determinants that could explain the variability in serum vaspin concentrations. RESEARCH DESIGN AND METHODS: First, we conducted a genome-wide association study (GWAS) for serum vaspin in the Sorbs cohort (N=826). Subsequently, 26 single-nucleotide polymorphisms (SNPs) covering genetic variation in the vaspin locus were genotyped in the Sorbs. In addition, we measured serum vaspin concentrations in 1806 samples from Augsburg/the Cooperative Health Research in the Region of Augsburg (KORA) for replication of the association signals. Finally, we conducted association analyses of vaspin SNPs with metabolic traits in the Sorbs (N=1013), KORA (N=1813) and a further cohort from Germany (Leipzig: N=1857). RESULTS: Six SNPs mapping between serpinA1 and serpinA4, including the vaspin locus, on chromosome 14 reached P-values < or = 10(-8) in the GWAS in the Sorbs. The fine mapping of variants within the vaspin locus in the Sorbs and subsequent replication in the KORA sample revealed several SNPs significantly associated with serum vaspin concentrations reaching P-values of up to 10(-35). However, no significant association with type 2 diabetes or related traits was found in either cohort after the Bonferroni correction for multiple comparisons. CONCLUSION: Our data show that the variability in serum vaspin concentrations might be explained by its genetic variants.

Attentional orienting induced by arrows and eye-gaze compared with an endogenous cue.

Exogenous orienting has been widely studied by using peripheral cues whereas endogenous orienting has been studied with directional central cues. However, recent evidence has shown that centrally presented eye-gaze and arrows may produce an automatic rather than voluntary orienting of attention. Therefore, the aim of the present study was to investigate the behavioural and electrophysiological (event-related potentials-ERP) correlates of the attentional shift induced by arrows and eye-gaze. In order to have a control condition, we compared arrows and eye-gaze with a purely endogenous cue, i.e., a texture arbitrarily coding one direction. We analyzed the ERP components (P1, N1, P2a, P2p, P3) elicited by the cue stimuli and the early lateralised attentional effect (early directing attention negativity-EDAN). In addition, in order to investigate the topography of the neural mechanisms underlying the cortical activity in each cueing condition, we applied a temporal segmentation procedure. The results showed that the three cueing conditions induced a different strength of activation within the same cortical network. Occipito-parietal regions were involved in the early processing of visual information, followed by an involvement of frontal areas, likely implicated in learning associations. These data confirm the assumption that, in contrast to purely endogenous cues, arrows and eye-gaze induce a very fast attentional shift. However, the similarity of the ERP components and of the topographical cortical maps among conditions suggest that this early orienting of attention is more likely related to an overlearned association mechanism rather than to a real exogenous attentional process.

Blindsight following visual cortex deafferentation disappears with purple and red stimuli: a case study.

We employed a redundant signal effect (RSE) paradigm to ascertain the role of the superior colliculus (SC) in blindsight. The RSE consists of the speeding of reaction time (RT) to double versus single stimuli. One patient with a unilateral lesion of the optic radiation and consequent hemianopia showed a RSE with pairs of visual stimuli presented across the vertical meridian despite seeing only stimuli in the intact hemifield. However, when, instead of achromatic stimuli we used short or long wavelength stimuli the implicit RSE disappeared. This result raises the possibility that implicit chromatic processing in the affected hemifield might have a different neural substrate following deafferentation with respect to lesion of the primary visual cortex.

Interhemispheric transfer and integration of imagined visual stimuli.

We employed two reaction time paradigms to find out whether imagined visual stimuli can be integrated between the two cerebral hemispheres. In a first experiment we found that interhemispheric transfer time, as assessed with the Poffenberger paradigm, was much longer for imagined than visible stimuli and this suggests that the callosal site of transfer is different in the two conditions. In a second experiment we found that interhemispheric summation, as assessed with the redundant signal effect paradigm, was present for both visible and imagined stimuli and could be accounted for by a neural coactivation mechanism rather than by a probabilistic explanation. Taken together, these results support the view that that there is an equivalence between perceptual and imagery processes that goes beyond early processing stages and includes the interhemispheric exchange of information.

Abnormally speeded saccades to ipsilesional targets in patients with spatial neglect.

We mapped the distribution of saccadic reaction times (SRTs) in the visual field of patients with spatial neglect in order to characterise the topography of the bias in spatial orientation peculiar to this disorder. LED-generated stimuli were lit randomly in one of four positions (+/-5 degrees , +/-10 degrees , +/-20 degrees , +/-30 degrees ) along the horizontal meridian in blocks of either ipsilesional or contralesional presentations. Patients were asked to move the gaze as quickly as possible from central fixation to target upon its appearance. Unlike control subjects, patients with neglect showed an asymmetric distribution of visuo-motor performance in the two hemifields with an increasing impairment in target detection and saccadic reaction at increasing eccentricities in the contralesional field. In contrast, in the ipsilesional field they showed abnormally speeded SRTs at 5 degrees and 10 degrees , outperforming even healthy subjects. Latency of saccades increased again at more peripheral ipsilesional locations (20 degrees and 30 degrees ) where there was also a tendency for a higher omission rate as compared to control groups. These results indicate that in neglect patients the spatial orientation bias, as witnessed by saccadic performance, specifically affects an off-centred sector of the ipsilesional space, and this is in keeping with evidence from a previous study using a manual RT paradigm. The generality of this phenomenon across different types of motor response suggests that it depends upon abnormal mechanisms of spatial coding interfering with perceptual processing and orienting behaviour.

Retinal eccentricity effects on reaction time to imagined stimuli.

To cast light on the possible neural substrate of visual imagery we tested normal participants and one hemianopic patient on simple reaction time (RT) to real and imagined visual stimuli. In one experiment participants were to detect as quickly as possible a luminous square presented at one out of two different retinal eccentricities. A well known effect with visual stimuli is that RT is slower for peripheral versus central stimuli. We found that imagined stimuli showed an eccentricity effect similar to that obtained with real stimuli. However, this was not the case in a patient with a hemianopic visual field loss (quadrantanopia) as a result of damage to the optic radiation. Even though the patient showed no difficulty in imaging stimuli in the affected hemifield she did not show an eccentricity effect as was the case in her intact side. In a second experiment, normal participants showed faster RT to stimuli of larger size with either real or imagined stimuli. Overall, these results show that visual perception and imagination share a similar visuotopic organisation that is disrupted following deafferentation of the visual cortex.

Modulation of brain activity by selective task sets observed using event-related potentials.

We investigated the ability of subjects to shift dynamically between selective task sets, using informative trial-by-trial cues. Two tasks were used which involved non-overlapping neural systems and different hemispheric specialization. In a verbal task, subjects decided whether a letter string was a real word or a non-word. In a spatial task, subjects decided whether an angle was acute or obtuse. A behavioural experiment showed that performance improved when cues predicted the upcoming task (80% validity), compared to when neutral cues did not afford selective task sets. Event-related potentials (ERPs) revealed brain activity related to forming selective task expectations, to switching tasks, and to the modulation of target processing as a function of such expectations and switches. Activity predicting the probable task started over parietal electrodes 160 ms after cue presentation, while activity related to task switching started at frontal electrodes around 280 ms. Both types of activities developed before target onset. Target processing was significantly influenced by the validity of the cue prediction, including strong modulation of language-related potentials. These results show that it is possible to switch dynamically between task sets involving distinct neural systems, even before the appearance of an imperative target stimulus, and that the nature of the task sets can influence neural activity related to task-set reconfiguration. Selective task sets can in turn modulate the processing of target stimuli. The effects also apply to the case of foveally presented words, whose processing has often been hypothesized to be automatic and outside the influence of selective attention.

What kind of visual spatial attention is impaired in neglect?

The distribution of spatial attention across the horizontal meridian of the visual field, as assessed by a simple reaction time (RT) paradigm, is dramatically abnormal in neglect patients. In the contralesional hemifield, RT increases sharply from centre to periphery, while in the ipsilesional hemifield, it decreases paradoxically from centre to mid-periphery. In the present study, we firstly asked whether this abnormal distribution of spatial attention is still present when patients know in advance the location of the impending stimulus, and second whether and to which extent it may be influenced by the concomitant presence of hemianopia. In Experiment 1, the stimuli were presented either predictably (blocks of same-point presentations) or unpredictably (blocks of randomised presentations) to one of several contralesional and ipsilesional field locations. As was the case for control subjects, neglect patients showed an overall RT decrease with same-point presentations. However, their abnormal contralesional RT lengthening and ipsilesional speeding were still present. In Experiment 2, the trials were blocked to same-hemifield presentations. In the ipsilesional field condition, neglect patients with and without hemianopia showed the same distorted distribution of attention favouring mid-periphery over central field locations. Two conclusions can be drawn from these experiments: first, the bulk of the abnormal deployment of spatial attention in neglect patients is related to an impairment of exogenous attention which cannot be compensated for by a spared endogenous control. Second, hemianopia does not affect the paradoxical speeding up of RT typically found in the mid-periphery of the ipsilesional field of neglect patients.

Binocular Interactions in the Lateral Suprasylvian Visual Area of Strabismic Cats Following Section of the Corpus Callosum.

Visually responsive neurons have been recorded in the lateral suprasylvian area (LSA) of cats raised with either a convergent or a divergent strabismus. In contrast to areas 17 and 18, where many studies have documented a profound loss of binocularly activated neurons following early strabismus, in the LSA the majority of cells could still be binocularly driven. Acute or chronic section of the splenium of the corpus callosum reduced but did not abolish binocularity in the LSA. We propose that the widespread callosal connections, the large size of the receptive fields and the peculiar internal circuitry of the LSA all concur in permitting the maintenance of binocular coding in spite of early misalignment of the eyes.

Behavioral and electrophysiological effects of unilateral optic tract section in ordinary and Siamese cats.

In ordinary cats, section of one optic tract produced a complete contralateral hemianopsia in both eyes. Single-unit recordings showed a normal representation of the contralateral nasal retina and ipsilateral temporal retina in the SC on the side of the intact optic tract. In addition, in the rostral portion of this SC there was a representation of a small portion of the contralateral temporal retina. This portion was apposed to the vertical meridian and its width was at most 6 degrees. In the anterior half of the SC on the side of the optic tract section, despite the interruption of any direct optic input, there was an extensive representation of the ipsilateral nasal retina and the contralateral temporal retina. This indirect visual input to the SC ipsilateral to the optic tract section was absent in a cat with a section of the forebrain commissures. In Boston Siamese cats, section of one optic tract led to a virtually complete blindness in the eye contralateral to the section, whereas the other eye retained a full visual field, although the responsiveness of the temporal retina beyond 20 degrees from the vertical meridian was reduced. Similarly, the nasal hemiretina and most of the temporal hemiretina on the side of the section were represented in the opposite SC, whereas stimulation of the eye contralateral to the section could not drive SC units. There was some evidence that the visual field of the eye on the side of the section could at least in part be represented in the SC on the same side. The findings indicate that the crossed projections from temporal hemiretina in the ordinary cat, and the uncrossed projections from temporal hemiretina in the Siamese cat are insufficient by themselves to sustain visual orientation and to drive SC neurons. Each half of the visual field in the ordinary cat, and the field of each eye in the Siamese cat, can be represented in the ipsilateral SC via across-the-midline, indirect connections.

Differences in binocular interactions between cortical areas 17 and 18 and superior colliculus of Siamese cats.

In Siamese cats most retinal projections are crossed and almost all neurons in cortical areas 17 and 18 respond exclusively to the contralateral eye. However, neurons in visual areas in the suprasylvian sulci (LSA) can be activated from both eyes, since the input from the ipsilateral eye is relayed to them by the corpus callosum (Marzi et al., '80). This study shows that the superior colliculus (SC) is also the site of binocular interactions in Siamese cats with a predominantly monocular organization of areas 17 and 18. In 8 unanesthetized, brainstem-sectioned Siamese cats, identified as "Boston" on the basis of the pattern of visual field representation in areas 17 and 18 (Hubel and Wiesel, '71; Shatz, '77a), only 25 out of 140 neurons in these areas could be driven from both eyes, whereas as many as 124 out of 143 SC neurons showed a clear binocular input. The input from each eye to the ipsilateral SC and the resulting binocular interactions in our Siamese cats might have depended on corticotectal projections from LSA. If so, since a posterior callosal section abolishes the input from each eye to ipsilateral LSA, the SC should similarly be affected by callosotomy. The posterior half of the corpus callosum was sectioned acutely in three Siamese cats after recording from SC; the input from the ipsilateral eye to SC was suppressed by this operation in one cat (which, however, also had an unintended interruption of the posterior, habenular, and anterior intertectal commissures), and drastically reduced in the other two. In a fourth cat, in which callosotomy was performed three weeks before recording from SC, the number of SC neurons responsive to the ipsilateral eye was significantly inferior to that of Siamese cats with an intact corpus callosum. These findings indicate the importance of the corpus callosum for ipsilateral eye-SC relations, as well as for SC binocularity, in Siamese cats. At the same time they imply that noncallosal routes can also transmit information from each eye to the ipsilateral SC in callosotomized Siamese cats.

Position of axons in the cat's optic tract in relation to their retinal origin and chiasmatic pathway.

The positions of the crossed and uncrossed optic axons of distinct diameter classes has been examined in the optic tract of the adult cat. In addition, the retinal origin of axons occupying different positions within the tract has been studied. Since the position of a fibre within the optic tract reflects its time of arrival during development, we have used axonal position as an indicator of age and have related this to the chiasmatic pathway choice of the axons. Cats were either monocularly enucleated, to reveal the position and diameter of surviving crossed and uncrossed optic axons in semithin and thin sections, or implants of horseradish peroxidase (HRP) were placed so as to retrogradely label the ganglion cells giving rise to axons within the deep (early arriving), or superficial (later arriving) parts of the tract selectively. This was accomplished by either 1) surgically implanting HRP into the superficial portion of the optic tract, via a transbuccal approach, or 2) making such a transbuccal transection of the superficial fibres, followed by intracerebral injections of HRP to retrogradely label the surviving, deeper, optic axons from their target nuclei. The deep parts of the optic tract contain fine and medium, crossed and uncrossed axons arising from mainly medium sized cells in the contralateral nasal and the ipsilateral temporal retina; there is a clear line of decussation. In contrast, the superficial parts of the tract contain mainly fine diameter axons arising from small cells in the whole contralateral retina, and a small proportion of large diameter axons arising from large, alpha cells in the whole contralateral retina and in the ipsilateral temporal retina. The likelihood that axons from the temporal retina will project contralaterally therefore increases as development proceeds, since these axons are found in the superficial parts of the tract only. This suggests that a time-dependent signal that weakens with age is responsible for directing early arriving optic axons from the temporal retina to take an exclusively uncrossed course.

Is interhemispheric transfer of visuomotor information asymmetric? Evidence from a meta-analysis.

Using a meta-analytic procedure we have analysed 16 studies employing a simple unimanual reaction time (RT) paradigm and lateralized visual stimuli to provide an estimate of interhemispheric transfer time in normal right-handed subjects. We found a significant overall RT advantage of the left visual field over the right and of the right hand over the left. These asymmetries can be explained by a superiority of the right hemisphere for the detection of simple visual stimuli and by a corresponding superiority of the left hemisphere for the execution of the manual response, respectively. Alternatively, they may be interpreted as related to an asymmetry of interhemispheric transmission of visuomotor information, with transfer from the right hemisphere (side of stimulus entry) to the left (side of response generation) faster than in the reverse direction. Although a direct test of these hypotheses is still lacking, we think that the evidence available is more in keeping with the latter possibility.

Corpus callosum and simple visuomotor integration.

Malcolm Jeeves was the first to demonstrate lengthened interhemispheric transmission times in subjects with agenesis of the corpus callosum by using a simple reaction time paradigm with lateralized unstructured light stimuli and crossed and uncrossed hand responses. Uncrossed responses can be integrated within one hemisphere, whereas crossed responses require a communication between the two hemispheres. In the normal brain this communication is effected rapidly by the corpus callosum, whereas in the acallosal brain it must occur much more slowly by way of less efficient alternative interhemispheric pathways. Using a similar experimental paradigm we have studied normal subjects, subjects with a complete callosal agenesis and epileptic patients with surgical callosal sections, either complete or partial. All subjects with complete callosal defects showed much lengthened interhemispheric times compared to normal controls. Virtually normal interhemispheric transmission times were found in subjects with partial callosal defects, whether anterior or posterior, suggesting a possible equipotentiality of different portions of the corpus callosum in the mediation of crossed manual responses. In both normals and acallosals there were no crossed-uncrossed differences in reaction time when responses were made unilaterally with lower limb effectors or para-axial upper limb effectors, as well as bilaterally with upper-limb proximal and para-axial effectors. Since these effectors can be controlled directly from either side of the brain via bilaterally distributed motor pathways, crossed responses using them, unlike crossed manual responses, do not require an interhemispheric integration.

Distribution in the visual field of the costs of voluntarily allocated attention and of the inhibitory after-effects of covert orienting.

By using a simple reaction time (RT) paradigm we have investigated the spatial distribution of the benefits and costs of voluntarily directed attention and of the inhibitory after-effects of covert orienting. In the first experiment subjects deliberately allocated attention to each one of five stimulus positions disposed along the horizontal meridian, while at the same time fixing their eyes on the central position. The separation in visual angle between the central position and the two nearest positions, one on the left and the other on the right, was 10 degrees; that between the central position and the two most eccentric positions was 30 degrees. By comparing RT to brief flashes of light presented at each position during directed attention with RT to identical flashes at the same position during diffuse attention (i.e. in a condition in which subjects paid equal attention to all five positions), it was possible to determine that benefits, that is RT decreases relative to the diffuse-attention condition, were strictly limited to the attended position. Costs, i.e. RT increases relative to the diffuse-attention condition, showed a more diffuse and complex spatial pattern. When attention was directed to one of the noncentral positions, costs were apparent at the two contralateral positions and at the central position, but not at the ipsilateral position. When attention was directed to the central position, costs occurred at all other positions. This suggests a special role for the vertical meridian in delimiting the area of costs when one covertly orients towards the opposite right or left visual half field. Work of others and our preliminary evidence indicate that the area of costs is similarly limited by the horizontal meridian when one orients toward the opposite upper or lower visual field. In the second experiment we studied the inhibitory after-effect of covert orienting. Orienting to a light stimulus without moving the eyes to it may induce a short-lived facilitation of the speed of response to a second stimulus presented at the same position, but this facilitation is followed by a profound and prolonged RT retardation. By using a two-flashes paradigm we observed this RT retardation not only when the two stimuli appeared at the same position, but also when they occurred at different locations in the same altitudinal or lateral visual hemifield. There were no inhibitory after-effects when the two stimuli appeared on opposite sides of the vertical or horizontal meridian.(ABSTRACT TRUNCATED AT 400 WORDS)

Spatial summation across the vertical meridian in hemianopics: a test of blindsight.

Twenty hemianopic patients with retrochiasmatic lesions have been tested for spatial summation of pairs of flashes simultaneously presented either to the same hemifield or to opposite hemifields across the vertical meridian. In such a task normal subjects show summation, i.e. a faster reaction time in response to a pair of stimuli than in response to a single stimulus. Such an effect is present both for pairs of stimuli presented within the same hemifield and for pairs of stimuli in which the two flashes are presented one in the right and the other in the left hemifield. In contrast to normals, hemianopics as a group did not show interfield summation although, like normals, showed summation within one hemifield. A single-case analysis, however, revealed that in one patient there was a reliable overall interfield summation and that in three others there was evidence of summation in at least one testing session. The presence of interfield spatial summation between the normal and the affected hemifield of hemianopics thus provides further evidence of blindsight in a task paradigm in which guessing strategies and stimulus artefacts can be eliminated. The very small proportion of patients showing blindsight can be in part related to the relatively low stimulus intensity and the very brief stimulus exposure duration used.

What exactly is extinguished in unilateral visual extinction? Neurophysiological evidence.

We propose a model of unilateral visual extinction following right hemisphere lesions based on competition between contralesional and ipsilesional input to access a decision centre located in the left hemisphere. During bilateral presentations, the contralesional signal is on average less likely to activate the decision centre than the ipsilesional signal. This is because an intra-hemispheric lack of top-down attentional influences and an inter-hemispheric impairment of callosal transmission delay and/or weaken the contralesional input. Here we provide behavioural as well as event-related potential evidence for both these impairments. Finally, we argue that an essential prerequisite for contralesional extinction is the presence of a restricted general attentional capacity which often follows large right hemisphere damage.

Spatial distribution of the inhibitory effect of peripheral non-informative cues on simple reaction time to non-fixated visual targets.

It is known that reaction time (RT) for the detection of a light target at extrafoveal locations is lengthened by a previous non-informative light cue at the same location. We describe an additional inhibitory effect from cues remote from the target but occurring within the same lateral or altitudinal visual hemifield. Subjects made a speeded key-press response to the second of two successive light flashes in a pair while maintaining fixation. Each of the two flashes could appear at random in one of four positions, two in the right and two in the left visual fields, or two in the upper and two in the lower visual fields. We found an RT prolongation not only for cued over uncued positions, but also for within-field non-coincident cue-target pairs over between-fields cue-target pairs. The within-field inhibitory effect, though smaller than the same-location effect, was fully apparent even when the target occurred at 1 degree of visual angle from the midline and at 29 degrees from the cue. Both effects were seen with cue-target asynchronies ranging from 0.2 to 1.5 sec. The results are relevant to the understanding of the neural mechanisms for covert shifts of attention across the main meridians of the visual field.

Can expectancy influence hemispheric asymmetries?

We carried out three experiments with the aim of verifying a critical assumption of Kinsbourne's (Acta Psychol., 33 (1970), 193-201; Attention and Performance V, London: Academic press, (1975), pp. 81-96) 'dynamic' attentional hypothesis of hemispheric asymmetries, namely, that asymmetries arise only when subjects know in advance what type of stimulus and/or cognitive mode they are about to be engaged with. We used a paradigm modified from Posner (J. Exp. Psychol., 109 (1980), 160-174) to study the effects of non-spatial 'cognitive' cueing on hemispheric asymmetries using a lexical decision and a visuo-spatial discrimination task (acute vs. obtuse angles). While we did not find significant overall hemispheric asymmetries with the spatial material, we found a consistent advantage of the left hemisphere in the lexical decision task. In Experiment 2 where the cue was presented in central vision and only the stimuli were lateralised and in Experiment 3 where both cue and stimuli were lateralised to the same hemisphere, the left hemisphere advantage did not interact with the effect of cueing. In contrast, in Experiment 4, where only the cue was lateralised and the stimuli were centrally presented, the left hemisphere advantage in the lexical decision task emerged only following invalid cueing. While the results of Experiments 2 and 3 are not in keeping with Kinsbourne's hypothesis, the result of Experiment 4 shows that some pre-exposural mechanisms may indeed affect the emergence of hemispheric asymmetries. A differential susceptibility in 'disengaging' from the processing mode induced by an invalid cue might represent another interesting example of hemispheric difference.