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.

Orienting of attention with eye and arrow cues and the effect of overtraining.

In contrast to the classical distinction between a controlled orienting of attention induced by central cues and an automatic capture induced by peripheral cues, recent studies suggest that central cues, such as eyes and arrows, may trigger a reflexive-like attentional shift. Yet, it is not clear if the attention shifts induced by these two cues are similar or if they differ in some important aspect. To answer this question, in Experiment 1 we directly compared eye and arrow cues in a counter-predictive paradigm while in Experiment 2 we compared the above cues with a different symbolic cue. Finally, in Experiment 3 we tested the role of over-learned associations in cueing effects. The results provide evidence that eyes and arrows induce identical behavioural effects. Moreover, they show that over-learned associations between spatially neutral symbols and the cued location play an important role in yielding early attentional effects.

Right temporal-parietal junction engagement during spatial reorienting does not depend on strategic attention control.

Targets presented outside the focus of attention trigger stimulus-driven spatial reorienting and activation of the right temporal-parietal junction (rTPJ). However, event-related functional resonance imaging (fMRI) studies that used task-irrelevant non-predictive cues systematically failed to activate rTPJ, suggesting that this region controls reorienting only when attention is shifted between two task-relevant locations. Here we challenge this view showing that non-predictive peripheral cues can affect activity in rTPJ, but only when they share a feature with the target: i.e. when they are set-relevant. Trials including a set-relevant cue plus a target on the uncued/unattended side produced the slowest reaction times and selective activation of the rTPJ. These findings demonstrate that rTPJ is not involved only in reorienting between two task-relevant locations, but engages also when non-predictive cues are set-relevant, thereby, irrespective of voluntary attention and breaches of task-related expectations.

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.

Evidence of midline retinal nasotemporal overlap in healthy humans: a model for foveal sparing in hemianopia?

The existence of midline retinal nasotemporal overlap in humans is controversial. Here we used the Poffenberger paradigm and monocular vision to assess the existence of a midline retinal area projecting to both hemispheres and of a possible differential contribution of the two hemiretinae. When brief visual stimuli were presented at 1 degrees eccentricity they were responded to equally quickly with either hand while at 6 degrees the hand on the same side as the stimulated hemifield was consistently faster than the contralateral hand. This pattern of results is consistent with a nasotemporal overlap at 1 degrees and a complete lateralization at 6 degrees . Both hemiretinae contribute to the overlap area which can be considered as responsible for foveal sparing in hemianopic patients.

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.

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.

Variants of the transcription factor 7-like 2 gene (TCF7L2) are strongly associated with type 2 diabetes but not with the metabolic syndrome in the MONICA/KORA surveys.

Recently, significant associations between common variants of the transcription factor 7-like 2 gene ( TCF7L2) and type 2 diabetes have been reported. This study was designed to replicate the reported associations of the two highly correlated (r (2)=0.86) TCF7L2 single nucleotide polymorphisms rs12255372 and rs7903146 with type 2 diabetes in a case-control study of 2369 MONICA/KORA participants (678 cases/1691 controls from Augsburg, Germany). To further investigate the pathogenic mechanism underlying these associations, we extended our analyses to the metabolic syndrome (IDF, NCEP definitions) and its components in a population-based study comprising 1404 male and female KORA participants aged 55-74 years. Results of our analyses strongly confirmed the minor T alleles as risk variants for type 2 diabetes (rs7903146: OR (TvsC) [95% CI]=1.36 [1.18;1.58], p=0.00003, and rs12255372: OR (TvsG) [95% CI]=1.31 [1.13;1.51], p=0.0003). Moreover, the T allele at rs7903146 was inversely associated with log-transformed, HOMA-%B (beta=-0.07, p=0.005) as a measure of basal insulin secretion, and log-transformed fasting insulin (beta=-0.06, p=0.02). No association was found with insulin resistance (HOMA-IR) and the metabolic syndrome. These findings support replication evidence that TCF7L2 variants increase type 2 diabetes risk. TCF7L2 may primarily affect pancreatic beta cell function.

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.

ERP and fMRI correlates of endogenous and exogenous focusing of visual-spatial attention.

The aim of this study was to investigate the neural correlates of the functional distinction underlying attentional mechanisms of endogenous-sustained and exogenous-transient spatial selection. We recorded event related potentials (ERPs) and used functional magnetic resonance imaging (fMRI) in separate experiments while subjects performed a simple reaction time (RT) to the same visual stimulus displayed to one of several field locations. Endogenous-sustained or exogenous-transient focusing of attention onto target location were obtained by presenting the stimulus in blocks of same-point vs. randomised-point trials, respectively. Same-point stimuli yielded overall faster RT than randomised stimuli, indicating a facilitating effect of endogenous-sustained spatial attention on the perceptual processing of the impending stimulus. Moreover, same-point vs. randomised presentations revealed significant increases in the fMRI signal in the bilateral lingual and fusiform gyri as well as in the right calcarine sulcus, in conjunction with a larger amplitude of the posterior P1 component of ERPs, but no modulation of the amplitude of the N1 component. Rather, a larger amplitude of N1 was found in the reverse contrast, randomised minus same-point trials, which revealed increases in the fMRI signal along the posterior left superior frontal sulcus and bilaterally in the superior precuneus. These findings indicate that N1 indexes exogenous orienting of attention and is likely to represent the activity of frontal and parietal components of the attention network involved in eliciting attention changes. In contrast, the effects of those changes, resulting in a modulation of activation in visual occipital areas, are indexed by P1.

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.

Attention and interhemispheric transfer: a behavioral and fMRI study.

When both detections and responses to visual stimuli are performed within one and the same hemisphere, manual reaction times (RTs) are faster than when the two operations are carried out in different hemispheres. A widely accepted explanation for this difference is that it reflects the time lost in callosal transmission. Interhemispheric transfer time can be estimated by subtracting RTs for uncrossed from RTs for crossed responses (crossed-uncrossed difference, or CUD). In the present study, we wanted to ascertain the role of spatial attention in affecting the CUD and to chart the brain areas whose activity is related to these attentional effects on interhemispheric transfer. To accomplish this, we varied the proportion of crossed and uncrossed trials in different blocks. With this paradigm subjects are likely to focus attention either on the hemifield contralateral to the responding hand (blocks with 80% crossed trials) or on the ipsilateral hemifield (blocks with 80% uncrossed trials). We found an inverse correlation between the proportion of crossed trials in a block and the CUD and this effect can be attributed to spatial attention. As to the imaging results, we found that in the crossed minus uncrossed subtraction, an operation that highlights the neural processes underlying interhemispheric transfer, there was an activation of the genu of the corpus callosum as well as of a series of cortical areas. In a further commonality analysis, we assessed those areas which were activated specifically during focusing of attention onto one hemifield either contra- or ipsilateral to the responding hand. We found an activation of a number of cortical and subcortical areas, notably, parietal area BA 7 and the superior colliculi. We believe that the main thrust of the present study is to have teased apart areas important in interhemispheric transmission from those involved in spatial attention.

At what stage of manual visual reaction time does interhemispheric transmission occur: controlled or ballistic?

Interhemispheric transfer (IT) time through the corpus callosum can be measured with a manual reaction time (RT) to lateralized visual stimuli (the so-called Poffenberger paradigm) by subtracting mean RT of faster uncrossed hemifield-hand combinations (not requiring an IT) from slower crossed combinations (requiring an IT). That the corpus callosum is involved in IT has been demonstrated by its dramatic lengthening in patients with a section of the corpus callosum. However, it is still unclear whether the signal transmitted by the corpus callosum concerns perceptual or motor stages of RT. To try and cast light on this question, in a first experiment we tested normal subjects on a partially modified Poffenberger paradigm with stop trials intermingled with go trials. In the former, subjects are supposed to refrain from responding following a stop signal (stop-signal paradigm). This paradigm can tease apart the contribution of the controlled and ballistic stages to overall RT and, used together with the Poffenberger task, enables one to assess the stage at which IT occurs. The controlled stage lies before the point of no return, i.e. the point beyond which the response cannot be inhibited, and concerns perceptual and pre-motor processes, while the ballistic stage occurs after the point of no return and concerns the motoric aspect of the response. We found that the slower responses typically obtained in the crossed conditions were more likely to be inhibited than the faster uncrossed responses and this suggests that IT occurs prior to the point of no return. Since the precise locus of the point of no return is uncertain, in a second experiment we used response force as a dependent variable reflecting the activation of the motor cortex. We found that none of the force parameters studied differed between crossed and uncrossed conditions while the temporal parameters confirmed the presence of an advantage of the uncrossed combinations. Altogether these results suggest that callosal IT of visuomotor information occurs at the stage of controlled (perceptual and pre-motor) processes and rule out the possibility of an IT at the motoric stage.

Is blindsight in normals akin to blindsight following brain damage?

The aim of this chapter is to discuss evidence bearing on two related issues, namely, first, whether the neural pathways of subliminal perception are the same as those subserving suprathreshold perception. Second, whether the pathways for subliminal perception in normals are similar to those subserving blindsight in brain-damaged patients. As to the former question, the overall balance is in favor of the different-pathway hypothesis while a tentative answer to the second question might be that blindsight is basically similar to subliminal perception in normals. The differences undoubtedly existing between the two conditions depend mainly on the differences in the stimuli used to reveal them.

Interhemispheric transmission of visuomotor information in humans: fMRI evidence.

Normal human subjects underwent functional magnetic resonance imaging (fMRI) while performing a simple visual manual reaction-time (RT) task with lateralized brief stimuli, the so-called Poffenberger's paradigm. This paradigm was employed to measure interhemispheric transmission (IT) time by subtracting mean RT for the uncrossed hemifield-hand conditions, that is, those conditions not requiring an IT, from the crossed hemifield-hand conditions, that is, those conditions requiring an IT to relay visual information from the hemisphere of entry to the hemisphere subserving the response. The obtained difference is widely believed to reflect callosal conduction time, but so far there is no direct physiological evidence in humans. The aim of our experiment was twofold: first, to test the hypothesis that IT of visuomotor information requires the corpus callosum and to identify the cortical areas specifically activated during IT. Second, we sought to discover whether IT occurs mainly at premotor or perceptual stages of information processing. We found significant activations in a number of frontal, parietal, and temporal cortical areas and in the genu of the corpus callosum. These activations were present only in the crossed conditions and therefore were specifically related to IT. No selective activation was present in the uncrossed conditions. The location of the activated callosal and cortical areas suggests that IT occurs mainly, but not exclusively, at premotor level. These results provide clear cut evidence in favor of the hypothesis that the crossed-uncrossed difference in the Poffenberger paradigm depends on IT rather than on a differential hemispheric activation.