Pupillary response in reward processing in adults with major depressive disorder in remission.

OBJECTIVE: Major depressive disorder (MDD) is associated with impaired reward processing and reward learning. The literature is inconclusive regarding whether these impairments persist after remission. The current study examined reward processing during a probabilistic learning task in individuals in remission from MDD (n = 19) and never depressed healthy controls (n = 31) matched for age and sex. The outcome measures were pupil dilation (an indirect index of noradrenergic activity and arousal) and computational modeling parameters. METHOD: Participants completed two versions (facial/nonfacial feedback) of probabilistic reward learning task with changing contingencies. Pupil dilation was measured with a corneal reflection eye tracker. The hypotheses and analysis plan were preregistered. RESULT: Healthy controls had larger pupil dilation following losses than gains (p <.001), whereas no significant difference between outcomes was found in individuals with a history of MDD, resulting in an interaction between group and outcome (ß = 0.81, SE = 0.34, t = 2.37, p = .018). The rMDD group also achieved lower mean score at the last trial (t[46.77] = 2.12, p = .040) as well as a smaller proportion of correct choices (t[46.70] = 2.09, p = .041) compared with healthy controls. CONCLUSION: Impaired reward processing may persist after remission from MDD and could constitute a latent risk factor for relapse. Measuring pupil dilation in a reward learning task is a promising method for identifying reward processing abnormalities linked to MDD. The task is simple and noninvasive, which makes it feasible for clinical research.

Cognitive profile in adult women with turner syndrome: IQ split and associations with ADHD and ASD.

INTRODUCTION: The behavioural phenotype in Turner syndrome (TS) is associated with an uneven cognitive profile and social and executive difficulties. Still, studies in adult populations of TS are scarce, and the interactions between different behavioural domains are unclear. The aim of this study was to examine the cognitive profile in relation to measures of ADHD and ASD in a Swedish sample of 30 adult women with TS. METHODS: Standardized psychological tests and questionnaires were used for behavioural assessments in a sample of adult women with a diagnosis of TS (n = 30). Both frequentist and Bayesian statistics were applied. RESULTS: The cognitive profile was characterized by a verbal > non-verbal intelligence quotient (IQ) split, and 77% of the sample displayed a split exceeding cut-off for clinical significance. Symptoms on screening measures reaching thresholds for ADHD were reported in two of the 30 participants (7%) and thresholds for autism spectrum disorders (ASD) in one participant (3%). Bayesian statistics gave substantial evidence for no association between the IQ split and symptoms of ADHD/ASD. CONCLUSIONS: These results show that the TS phenotype in adulthood is associated with a clinically significant uneven cognitive profile, and particular impairments in integrative executive functions.

Disrupted Attention to Other's Eyes is Linked to Symptoms of ADHD in Childhood.

Attention-deficit/hyperactivity disorder (ADHD) is associated with impaired social interaction. Other's eyes are important for understanding the social world. Here, we examined concurrent and longitudinal links between attention to other's eyes and symptoms of ADHD and comorbid externalizing and internalizing symptoms. Eighty-two 8 to 13-year-old children (40% with ADHD) participated. The latency to a first gaze shift to and away from the eye region of human faces, when primed to look at either the eyes or the mouth, was recorded with eye tracking. Parents rated ADHD, externalizing and internalizing symptoms at the time of testing and at 2-year follow-up. The results show that longer looking at the eyes before reorienting was specifically associated with concurrent and future symptoms of inattention, even when accounting for comorbid symptoms. We conclude that the temporal microstructure of attention to other's eyes is altered in children with symptoms of ADHD, which may contribute to social impairments.

Increased pupil dilation to happy faces in children with hyperactive/impulsive symptoms of ADHD.

Attention-deficit/hyperactivity disorder (ADHD) is associated with disrupted emotional processes including impaired regulation of approach behavior and positive affect, irritability, and anger. Enhanced reactivity to emotional cues may be an underlying process. Pupil dilation is an indirect index of arousal, modulated by the autonomic nervous system and activity in the locus coeruleus-noradrenergic system. In the current study, pupil dilation was recorded while 8- to 12- year old children (n = 71, 26 with a diagnosis of ADHD and 45 typically developing), viewed images of emotional faces. Parent-rated hyperactive/impulsive symptoms were uniquely linked to higher pupil dilation to happy, but not fearful, angry, or neutral faces. This was not explained by comorbid externalizing symptoms. Together, these results suggest that hyperactive/impulsive symptoms are associated with hyperresponsiveness to approach-related emotional cues across a wide range of symptom severity.

Reduced left visual field bias for faces in adolescents with social anxiety disorder.

Introduction: Individuals tend to explore the left side of a face first and for a longer time in comparison to the right side. This left visual field (LVF) bias is suggested to reflect right hemispheric dominance for face processing. Social anxiety disorder (SAD) is associated with maladaptive interpretations of facial expressions, but it is not known whether this is linked to an atypical LVF bias. Previous studies have reported a reduced LVF bias in autism, a condition overlapping with SAD. This pre-registered study examined the LVF bias in adolescents with SAD. Methods: Eye-tracking was used to investigate the ratio of first fixations to the left on upright and inverted face stimuli in 26 adolescents (13-17 years) with SAD and 23 healthy controls primed to look either between the eyes or at the mouth. Results: The SAD group showed a smaller LVF bias and an atypical face inversion effect when primed to look at the eyes. Autistic traits predicted a smaller LVF bias, independently of social anxiety level. Conclusions: Results suggest that SAD is associated with impaired processing of faces at an early stage of visual scanning. The findings contribute to a better understanding of SAD and its overlap with autism.

Can auditory warning signals normalize eye movements in children with ADHD?

Attenuated baseline arousal has been hypothesized to underlie symptoms of attention deficit/hyperactivity disorder (ADHD). A behavioral signature of reduced baseline arousal is an increased beneficiary effect of warning signals in reaction tasks. This paradoxical effect is believed to be caused by a temporary increase in arousal induced by warning signals. In a preregistered study, we tested the hypothesis that children with high levels of ADHD symptoms would be hyperresponsive to warning signals in a well-established visual attention task (the gap/overlap paradigm). Previous studies using this task have found slower and more variable saccadic reaction times in children with ADHD compared to typically developing children, suggesting that these eye movement metrics are candidate biomarkers. We examined 71 children, of which 1/3 had a diagnosis of ADHD, using both dimensional analyses and group comparisons. Previously reported findings of reduced saccadic latency and increased latency variability were replicated. Importantly, saccadic latency was normalized by auditory warning signals. Analyses of pupil dilation, a physiological index of arousal and locus coeruleus-noradrenergic activity, confirmed that warning signals led to enhanced arousal. Our findings are novel and contribute to our understanding of arousal and attention in ADHD and have implications for treatment and interventions.

How Infants' Arousal Influences Their Visual Search.

The influence of arousal on visual attention was examined in 6.5-month-old infants (N = 42) in the context of a visual search task. Phasic increases in arousal were induced with brief sounds and measured with pupil dilation. Evidence was found for an inverted U-shaped relation between pupil dilation amplitude and visual orienting, with highest likelihood of a target fixation at intermediate levels of arousal. Effects were similar for facial stimuli and simple objects. Together, these results contribute to our understanding of the relation between arousal and attention in infancy. The study also demonstrates that infants have a bias to orient to human eyes, even when presented in isolation.

Resting state arousal and functional connectivity in autism spectrum disorder.

A recent study (Eilam-Stock T, Xu P, Cao M, Gu X, Van Dam NT, Anagnostou E, Kolevzon A, Soorya L, Park Y, Siller M, He Y, Hof PR, Fan J. Brain 137: 153-171, 2014) demonstrated that resting state electrodermal activity is correlated with different patterns of brain activity in subjects with autism spectrum disorder (ASD) than in typical controls. These results are considered in light of theories of atypical arousal in ASD.

Symptoms of autism in Williams syndrome: a transdiagnostic approach.

Williams syndrome (WS) is associated with atypical social communication and cognition reminiscent of the behaviours observed in autism. Nonetheless, WS also differs significantly from autism, such as regarding social motivation, which is typically enhanced in WS and reduced in autism. This study sought to examine the conditions' transdiagnostic similarities and differences for autistic symptoms and social functioning, and their developmental trajectories, by comparing individuals with WS (n = 24) and those diagnosed with idiopathic autism (n = 24) and attention deficit hyperactivity disorder (ADHD; n = 24), aged 9 to 53 years, on measures of autism, social functioning, IQ and cooccurring psychiatric conditions. Although only 12.5% in the WS group met the criteria for an autism diagnosis, a majority exhibited distinct difficulties within social communication, social cognition, repetitive behaviours, and atypical sensory reactivity resembling autism. Conversely, elevated social motivation and a high number of social initiatives accompany these characteristics. No group differences in the developmental trajectories of autism symptoms were found. Our results demonstrate that autistic behaviours are more frequent in individuals with WS, than in individuals with idiopathic ADHD, and emphasize the need for clinical management of these behaviours.

Eye-movement indices of arousal predict ADHD and comorbid externalizing symptoms over a 2-year period.

Attention-deficit/hyperactivity disorder (ADHD) follows a variable course across childhood. Disrupted arousal has been hypothesized to underlie core symptoms as well as comorbid internalizing and externalizing conditions. The current study examined eye-movement and pupil-dilation metrics indexing arousal as longitudinal predictors of ADHD, externalizing, and internalizing symptoms over a 2-year period. Participants aged 8-13 years (N = 54, 30% with a diagnosis of ADHD) completed a modified version of the gap-overlap task including arousal-inducing auditory warning signals. Parents rated symptoms at the time of testing and at 2 years follow-up. Phasic alerting (reaction-time reduction after alerting cues) is an index of arousal. Here, larger phasic alerting effects predicted higher ADHD-symptom levels 2 years later. Blunted pupil-dilation responses predicted externalizing symptoms at T2, controlling for ADHD and externalizing at T1. Our results support the theory that ADHD is associated with altered arousal. Blunted arousal reactivity may be a longitudinal risk factor for externalizing problems in children with ADHD symptoms.

Social Attention: Developmental Foundations and Relevance for Autism Spectrum Disorder.

The use of the term "social attention" (SA) in the cognitive neuroscience and developmental psychopathology literature has increased exponentially in recent years, in part motivated by the aim to understand the early development of autism spectrum disorder (ASD). Unfortunately, theoretical discussions around the term have lagged behind its various uses. Here, we evaluate SA through a review of key candidate SA phenotypes emerging early in life, from newborn gaze cueing and preference for face-like configurations to later emerging skills such as joint attention. We argue that most of the considered SA phenotypes are unlikely to represent unique socioattentional processes and instead have to be understood in the broader context of bottom-up and emerging top-down (domain-general) attention. Some types of SA behaviors (e.g., initiation of joint attention) are linked to the early development of ASD, but this may reflect differences in social motivation rather than attention per se. Several SA candidates are not linked to ASD early in life, including the ones that may represent uniquely socioattentional processes (e.g., orienting to faces, predicting others' manual action goals). Although SA may be a useful superordinate category under which one can organize certain research questions, the widespread use of the term without proper definition is problematic. Characterizing gaze patterns and visual attention in social contexts in infants at elevated likelihood of ASD may facilitate early detection, but conceptual clarity regarding the underlying processes at play is needed to sharpen research questions and identify potential targets for early intervention.

Autistic Children Quickly Orient Away from Both Eyes and Mouths During Face Observation.

Studies have supported two different hypotheses of reduced eye gaze in people with ASD; gaze avoidance and gaze indifference, while less is known about the role of anxiety. We tested these hypotheses using an eye-tracking paradigm that cued the eyes or mouth of emotional faces. Autistic children (n = 12, mean age 7 years) looked faster away from both eyes and mouths than controls (n = 22). This effect was not explained by anxiety symptoms. No difference was found in latency towards either area. These results indicate that attentional avoidance of autistic children is not specific to eyes, and that they do not show attentional indifference to eyes compared to controls. Atypicalities in visual scanning in ASD are possibly unrelated to specific facial areas.

Neurocognition and mean radiotherapy dose to vulnerable brain structures: new organs at risk?

BACKGROUND: Children with brain tumors are at high risk of neurocognitive decline after radiotherapy (RT). However, there is a lack of studies on how RT doses to organs at risk (OARs) impacts neurocognition. The aim of this study was to examine dose-risk relationships for mean RT dose to different brain structures important for neurocognitive networks. We explored previously established OARs and potentially new OARs. METHODS: A sample of 44 pediatric brain tumor survivors who had received proton and/or photon RT were included. Correlations between mean RT doses to OARs and IQ were analyzed. Previously established OARs were cochleae, optic chiasm, optic nerve, pituitary gland, hypothalamus, hippocampus and pons. Potential new OARs for RT-induced neurocognitive decline were cerebellum, vermis and thalamus. RESULTS: Mean RT dose to different OARs correlated with several IQ subtests. Higher mean RT dose to cochleae, optic nerve, cerebellum, vermis and pons was correlated with lower performance on particularly full-scale IQ (FIQ), Perceptual Reasoning (PRI), Working Memory (WMI) and Processing Speed Index (PSI). Higher mean RT dose to hippocampus correlated with lower performance on processing speed and working memory. For those receiving whole brain RT (WBRT), higher mean RT dose to the pituitary gland correlated with lower performance on working memory. CONCLUSION: A high dose-risk correlation was found between IQ subtests and mean RT dose in established and potential new OARs. Thus, in the lack of validated dose constraints for vulnerable brain structures, a parsimonious approach in RT planning should be considered to preserve neurocognitive networks.

Manipulation of phasic arousal by auditory cues is associated with subsequent changes in visual orienting to faces in infancy.

This eye-tracking study investigated the effect of sound-induced arousal on social orienting under different auditory cue conditions in 5-month-old (n = 25; n = 13 males) and 10-month-old infants (n = 21; n = 14 males) participating in a spontaneous visual search task. Results showed: (1) larger pupil dilation discriminating between high and low volume (b = 0.02, p = 0.007), but not between social and non-social sounds (b = 0.004, p = 0.64); (2) faster visual orienting (b = - 0.09, p < 0.001) and better social orienting at older age (b = 0.94, p < 0.001); (3) a fast habituation effect on social orienting after high-volume sounds (χ2(2) = 7.39, p = 0.025); (4) a quadratic association between baseline pupil size and target selection (b = - 1.0, SE = 0.5, χ2(1) = 4.04, p = 0.045); (5) a positive linear association between pupil dilation and social orienting (b = 0.09, p = 0.039). Findings support adaptive gain theories of arousal, extending the link between phasic pupil dilation and task performance to spontaneous social orienting in infancy.

Reduced effects of social feedback on learning in Turner syndrome.

Turner syndrome is a genetic condition caused by a complete or partial loss of one of the X chromosomes. Previous studies indicate that Turner syndrome is associated with challenges in social skills, but the underlying mechanisms remain largely unexplored. A possible mechanism is a reduced social influence on learning. The current study examined the impact of social and non-social feedback on learning in women with Turner syndrome (n = 35) and a sex- and age-matched control group (n = 37). Participants were instructed to earn points by repeatedly choosing between two stimuli with unequal probabilities of resulting in a reward. Mastering the task therefore required participants to learn through feedback which of the two stimuli was more likely to be rewarded. Data were analyzed using computational modeling and analyses of choice behavior. Social feedback led to a more explorative choice behavior in the control group, resulting in reduced learning compared to non-social feedback. No effects of social feedback on learning were found in Turner syndrome. The current study thus indicates that women with Turner syndrome may be less sensitive to social influences on reinforcement learning, than the general population.

Social feedback enhances learning in Williams syndrome.

Williams syndrome (WS) is a rare genetic condition characterized by high social interest and approach motivation as well as intellectual disability and anxiety. Despite the fact that social stimuli are believed to have an increased intrinsic reward value in WS, it is not known whether this translates to learning and decision making. Genes homozygously deleted in WS are linked to sociability in the general population, making it a potential model condition for understanding the social brain. Probabilistic reinforcement learning was studied with either social or non-social rewards for correct choices. Social feedback improved learning in individuals with Williams syndrome but not in typically developing controls or individuals with other intellectual disabilities. Computational modeling indicated that these effects on social feedback were mediated by a shift towards higher weight given to rewards relative to punishments and increased choice consistency. We conclude that reward learning in WS is characterized by high volatility and a tendency to learn how to avoid punishment rather than how to gain rewards. Social feedback can partly normalize this pattern and promote adaptive reward learning.

No transfer of arousal from other's eyes in Williams syndrome.

Typically developing humans automatically synchronize their arousal levels, resulting in pupillary contagion, or spontaneous adaptation of pupil size to that of others. This phenomenon emerges in infancy and is believed to facilitate social interaction. Williams syndrome (WS) is a genetic condition characterized by a hyper-social personality and social interaction challenges. Pupillary contagion was examined in individuals with WS (n = 44), age-parallel-matched typically developing children and adults (n = 65), and infants (n = 79). Bayesian statistics were used. As a group, people with WS did not show pupillary contagion (Bayes factors supporting the null: 25-50) whereas control groups did. This suggests a very early emerging atypical developmental trajectory. In WS, higher pupillary contagion was associated with lower autistic symptoms of social communication. Diminished synchronization of arousal may explain why individuals with WS have social challenges, whereas synchronization of arousal is not a necessary correlate of high social motivation.

Williams syndrome: reduced orienting to other's eyes in a hypersocial phenotype.

Williams syndrome (WS) is a rare genetic condition associated with high sociability, intellectual disability, and social cognitive challenges. Attention to others' eyes is crucial for social understanding. Orienting to, and from other's eyes was studied in WS (n = 37, mean age = 23, age range 9-53). The WS group was compared to a typically developing comparison participants (n = 167) in stratified age groups from infancy to adulthood. Typically developing children and adults were quicker and more likely to orient to eyes than the mouth. This bias was absent in WS. The WS group had reduced peak saccadic velocities, indicating hypo-arousal. The current study indicates reduced orienting to others' eyes in WS, which may affect social interaction skills.

Pupil dilation during negative prediction errors is related to brain choline concentration and depressive symptoms in adolescents.

Depressive symptoms are associated with altered pupillary responses during learning and reward prediction as well as with changes in neurometabolite levels, including brain concentrations of choline, glutamate and gamma-aminobutyric acid (GABA). However, the full link between depressive symptoms, reward-learning-related pupillary responses and neurometabolites is yet to be established as these constructs have not been assessed in the same individuals. The present pilot study, investigated these relations in a sample of 24 adolescents aged 13 years. Participants completed the Revised Child Anxiety and Depression Scale (RCADS) and underwent a reward learning task while measuring pupil dilation and a single voxel dorsal anterior cingulate cortex (dACC) MEGA-PRESS magnetic resonance spectroscopy scan assessing choline, glutamate and GABA concentrations. Pupil dilation was related to prediction errors (PE) during learning, which was captured by a prediction error-weighted pupil dilation response index (PE-PDR) for each individual. Higher PE-PDR scores, indicating larger pupil dilations to negative prediction errors, were related to lower depressive symptoms and lower dACC choline concentrations. Dorsal ACC choline was positively associated with depressive symptoms, whereas glutamate and GABA were not related to PE-PDR or depressive symptoms. The findings support notions of cholinergic involvement in depressive symptoms and cholinergic influence on reward-related pupillary response, suggesting that pupillary responses to negative prediction errors may hold promise as a biomarker of depressive states.

Neurocognitive Functions Before and After Radiotherapy in Pediatric Brain Tumor Survivors.

BACKGROUND: The numbers of pediatric brain tumor survivors are increasing due to improved treatment protocols and multimodal treatments. Many survivors have neurocognitive sequelae, especially after radiotherapy. Neuropsychologic assessment is therefore essential to interpret clinical outcome, evaluate treatments protocol, and implement rehabilitation interventions. The overall aim of this study was to describe neurocognitive functions before and after radiotherapy. We also aimed to explore potential confounding risk factors that could affect the interpretation of radiotherapy-induced neurocognitive decline. METHODS: Fifty pediatric brain tumor survivors who had received radiotherapy (five years or more ago) were included. Clinical characteristics, potential confounding risk factors, radiotherapy plans, and neurocognitive functions on intelligence quotient (IQ) and neuropsychologic measurements were analyzed before and after radiotherapy. RESULTS: Neurocognitive functions were affected before radiotherapy and were progressively aggravated thereafter. The last neuropsychologic assessment after radiotherapy varied between two and 139 months. Nineteen patients were tested five years after radiotherapy, and 90% of them performed ≥1 S.D. below the normative mean on IQ measurements. Several potential confounding risk factors including those induced by radiotherapy were associated with lower performance on perceptual function, working memory, and processing speed. Longer time after radiotherapy was particularly associated with lower performance on working memory and processing speed. Importantly, the neuropsychologic assessments revealed more comprehensive problems than could be inferred from IQ measurements alone. CONCLUSIONS: Our study underpins the importance of systematic and structured neuropsychologic assessment before and after radiotherapy. The timing of the assessment is important, and potential confounding risk factors need to be identified to better evaluate radiotherapy-induced neurocognitive decline.