Psychophysiological perspectives on autism

Autism is a severe developmental neuropsychiatric disorder, with an onset in the first three years of life. It essentially affects aspects of behaviour which are generally regarded as 'human'. Core characteristics of autism are abnormalities in language, communication and soical interaction, narrowed interests and stereotyped behaviour. Although theories of different nature exists on what the underlying deficit for these abnormalities might be, a common aspect of all theories may be a defect in attention. Event-related potentials (ERPs) are, due to their very high temporal resolution, very well suited for the study of attentional processing in the brain. ERP studies of the P3, a large positivity occurring around 300 milliseconds after a stimulus is presented, have pointed out that this component is much smaller in autistic individuals than in controls, especially over posterior parts of the brain. However, none of these studies have made a detailed study of attentional processing before 300 milliseconds. In this thesis, visual and auditory selective attention tasks are described in groups of high functioning autistic children and adolescents. It was found that autistic children show profoundly smaller P3 amplitudes than controls, but that these abnormalities were not preceded by abnormalities in selective attention. However, autistic children already showed abnormalities in visual processing around 100 milliseconds after stimulus presentation, as seen in much smaller P1 amplitudes. In autistic adolescents such amplitude reductions were not observed, but this group did show abnormal selective attention. These abnormalities in selective attention were interpreted as compensatory mechanisms, normalizing P3. Whether abnormal P3 was a reflection of deficiencies in attentional capacity was studied with a probe task. In this task, autistic individuals did not show the same trade-off between task- and probe-stimuli as was seen in controls. When probe stimuli became increasingly irrelevant, controls invested less capacity in processing these stimuli as evident in smaller P3 amplitudes to those stimuli. Autistic patients did not show such a decrease in P3 amplitude. Therefore, autistic patients seem to have a deficiency in the allocation of processing capacity. In order to gain more insight in the underlying neural sources of the scalp recorded ERPs, the data from the visual selective attention task were subjected to high-resolution source localization techniques based on individual head models derived from Magnetic Resonance Images (MRI). It was found that autistic children showed a more superior location of the sources for P1, which is discussed in light of functional and structural MRI findings in autism. The use of the technique described in this thesis is new in the field of autism and provides valuable new insights in the disorde

Good Vibrations: Global Processing Can Increase the Pleasantness of Touch.

Visual-tactile carry-over effects of global/local processing (attention to the whole, versus the details) have been reported under active touch conditions. We investigated whether carry-over effects of global/local processing also occur for passive touch and whether global/local processing has differential effects on affective and discriminative aspects of touch. Participants completed two tactile tasks involving pleasantness rating and discrimination of a set of tactile vibrations before and after completing a version of the Navon task that encouraged a focus on the global (n = 30), local (n = 30), or both (n = 30) features of a series of visual stimuli. In line with previous research suggesting a link between global processing and positive emotion, global processing increased pleasantness ratings of high (but not low) frequency tactile vibrations. Local processing did not improve the ability to discriminate between vibrations of different frequencies, however. There was some evidence of a tactile-visual carry-over effect; prior local processing of tactile vibrations reduced global precedence during the Navon task in the control group. We have shown carry-over effects of global versus local processing on passive touch perception. These findings provide further evidence suggesting that a common perceptual mechanism determines processing level across modalities and show for the first time that prior global processing affects the pleasantness of touch

Feeling Bad and Looking Worse: Negative Affect Is Associated with Reduced Perceptions of Face-Healthiness

Some people perceive themselves to look more, or less attractive than they are in reality. We investigated the role of emotions in enhancement and derogation effects; specifically, whether the propensity to experience positive and negative emotions affects how healthy we perceive our own face to look and how we judge ourselves against others. A psychophysical method was used to measure healthiness of self-image and social comparisons of healthiness. Participants who self-reported high positive (N = 20) or negative affectivity (N = 20) judged themselves against healthy (red-tinged) and unhealthy looking (green-tinged) versions of their own and stranger’s faces. An adaptive staircase procedure was used to measure perceptual thresholds. Participants high in positive affectivity were un-biased in their face health judgement. Participants high in negative affectivity on the other hand, judged themselves as equivalent to less healthy looking versions of their own face and a stranger’s face. Affective traits modulated self-image and social comparisons of healthiness. Face health judgement was also related to physical symptom perception and self-esteem; high physical symptom reports were associated a less healthy self-image and high self-reported (but not implicit) self-esteem was associated with more favourable social comparisons of healthiness. Subject to further validation, our novel face health judgement task could have utility as a perceptual measure of well-being. We are currently investigating whether face health judgement is sensitive to laboratory manipulations of mood

The effects of odor and body posture on perceived duration

This study reports an examination of the internal clock model, according to which subjective time duration is influenced by attention and arousal state. In a time production task, we examine the hypothesis that an arousing odor and an upright body posture affect perceived duration. The experimental task was performed while participants were exposed to an odor and either sitting upright (arousing condition) or lying down in a relaxing chair (relaxing condition). They were allocated to one of three experimental odor conditions: rosemary (arousing condition), peppermint (relaxing condition), and no odor (control condition). The predicted effects of the odors were not borne out by the results. Self-reported arousal (SRA) and pleasure (PL) states were measured before, during (after each body posture condition) and postexperimentally. Heart rate (HR) and skin conductance were measured before and during the experiment. As expected, odor had an effect on perceived duration. When participants were exposed to rosemary odor, they produced significantly shorter time intervals than in the no odor condition. This effect, however, could not be explained by increased arousal. There was no effect of body posture on perceived duration, even though body posture did induce arousal. The results do not support the proposed arousal mechanism of the internal clock model

Reduced error monitoring in children with autism spectrum disorder:an ERP study

This study investigated self-monitoring in children with autism spectrum disorder (ASD) with event-related potentials looking at both the error-related negativity (ERN) and error-related positivity (Pe). The ERN is related to early error/conflict detection, and the Pe has been associated with conscious error evaluation or attention allocation. In addition, post-error slowing in reaction times (RTs) was measured. Children with ASD and age- and IQ- matched controls were administered an easy and a hard version of an auditory decision task. Results showed that the ERN was smaller in children with ASD but localized in the anterior cingulate cortex (ACC) in both groups. In addition we found a negativity on correct trials (CRN) that did not differ between the groups. Furthermore, a reduced Pe and a lack of post-error slowing in RTs were found in children with ASD. The reduced ERN in children with ASD, in the presence of an intact CRN, might suggest a specific insensitivity to detect situations in which the chance of making errors is enhanced. This might in turn lead to reduced error awareness/attention allocation to the erroneous event (reduced Pe) and eventually in a failure in change of strategy to deal with a situation, as becomes evident from the lack of post-error slowing in the ASD group. This relates well to the perseverative behaviour that is seen in children with ASD. We discuss these results in terms of a general deficit in self-monitoring, underlying social disturbance in ASD and the involvement of the ACC

Average 50% thresholds on the self and stranger face health judgement task.

<p>The x-axis shows 50% thresholds ranging from −12 (very green) to 12 (very red). In both versions of the task, participants indicated how they judged themselves in comparison either to different versions of their own face or to different versions of a stranger’s face. Self 50% thresholds indicate how participants perceived themselves. Stranger 50% thresholds indicate how participants judged themselves in comparison to the stranger. The negative affect group (unhappy participants, left hand side) had significantly lower 50% thresholds on both versions of the face health judgement task compared to the positive affect group (happy participants, right hand side). That is, the negative affect group judged themselves as equivalent to greener, less healthy looking versions of their own and a stranger’s face. Error bars reflect ±1 standard error of the mean.</p

The five block IAT procedure¹.

1<p>Critical blocks are shown in italics. The IAT effect is computed as the difference in mean response latency between Blocks three and five. Including forty practice trials in Block four is recommended to compensate for the extraneous influence of the order of the combined blocks <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0107912#pone.0107912-Nosek1" target="_blank">[48]</a>.</p><p>The five block IAT procedure^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0107912#nt101" target="_blank">1</a>}.</p

Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting its Protein-Protein Interactions

We developed a new class of inhibitors of protein-protein interactions of the SHP2 phosphatase, which is pivotal in multiple signaling pathways and a central target in the therapy of cancer and rare diseases. Currently available SHP2 inhibitors target the catalytic site or an allosteric pocket but lack specificity or are ineffective on disease-associated SHP2 mutants. Based on the consideration that pathogenic lesions cause signaling hyperactivation due to increased SHP2 association with cognate proteins, we developed peptide-based molecules with low nM affinity for the N-terminal Src homology domain of SHP2, good selectivity, stability to degradation and an affinity for pathogenic variants of SHP2 up to 20 times higher than for the wild-type protein. The best peptide reverted the effects of a pathogenic variant (D61G) in zebrafish embryos. Our results provide a novel route for SHP2-targeted therapies and a tool to investigate the role of protein-protein interactions in the function of SHP2.Competing Interest StatementAuthors L. Stella, B. Biondi, G. Bocchinfuso, S. Martinelli and M. Tartaglia are the inventors of a patent application, covering the peptides described in the manuscript. The patent application (A 142707) has been filed in Italy by the University of Rome Tor Vergata and by the Ospedale Pediatrico Bambino Gesu.ALLacute lymphoblastic leukemiaAmoLacute monocytic leukemiaCagAcytotoxicity-associated immunodominant antigenJMMLjuvenile myelomonocytic leukemiaNSNoonan syndromeNSMLNoonan syndrome with multiple lentiginesPTKprotein-tyrosine kinasePTPprotein tyrosine phosphatasepYphosphotyrosineRTKreceptor tyrosine kinaseSH2Src homology 2SHP2SH2 domain-containing phosphatase 2shRNAshort hairpin ribonucleic acidWTwild typ