Neural Markers of Auditory Response and Habituation in Phelan-McDermid Syndrome.

Phelan-McDermid Syndrome (PMS) is a rare genetic disorder caused by deletion or sequence variation in the SHANK3 gene at terminal chromosome 22 that confers high likelihood of comorbid autism spectrum disorder (ASD). Whereas individuals with idiopathic ASD (iASD) can demonstrate diverse patterns of sensory differences, PMS is mainly characterized by sensory hyporesponsiveness. This study used electrophysiology and a passive auditory habituation paradigm to test for neural markers of hyporesponsiveness. EEG was recorded from 15 individuals with PMS, 15 with iASD, and 16 with neurotypical development (NT) while a series of four consecutive 1,000 Hz tones was repeatedly presented. We found intact N1, P2, and N2 event-related potentials (ERPs) and habituation to simple auditory stimuli, both in individuals with iASD and in those with PMS. Both iASD and PMS groups showed robust responses to the initial tone and decaying responses to each subsequent tone, at levels comparable to the NT control group. However, in PMS greater initial N1 amplitude and habituation were associated with auditory hypersensitivity, and P2 habituation correlated with ASD symptomatology. Additionally, further classification of the PMS cohort into genetic groupings revealed dissociation of initial P2 amplitude and habituation of N1 based on whether the deletions included additional genes beyond solely SHANK3 and those not thought to contribute to phenotype. These results provide preliminary insight into early auditory processing in PMS and suggest that while neural response and habituation is generally preserved in PMS, genotypic and phenotypic characteristics may drive some variability. These initial findings provide early evidence that the robust pattern of behavioral hyporesponsiveness in PMS may be due, at least in audition, to higher order factors.

Visual Evoked Potential Abnormalities in Phelan-McDermid Syndrome.

OBJECTIVE: The current study used visual evoked potentials (VEPs) to examine excitatory and inhibitory postsynaptic activity in children with Phelan-McDermid syndrome (PMS) and the association with genetic factors. PMS is caused by haploinsufficiency of SHANK3 on chromosome 22 and represents a common single-gene cause of autism spectrum disorder (ASD) and intellectual disability. METHOD: Transient VEPs were obtained from 175 children, including 31 with PMS, 79 with idiopathic ASD, 45 typically developing controls, and 20 unaffected siblings of children with PMS. Stimuli included standard and short-duration contrast-reversing checkerboard conditions, and the reliability between these 2 conditions was assessed. Test-retest reliability and correlations with deletion size were explored in the group with PMS. RESULTS: Children with PMS and, to a lesser extent, those with idiopathic ASD displayed significantly smaller amplitudes and decreased beta and gamma band activity relative to TD controls and PMS siblings. Across groups, high intraclass correlation coefficients were obtained between standard and short-duration conditions. In children with PMS, test-retest reliability was strong. Deletion size was significantly correlated with P60-N75 amplitude for both conditions. CONCLUSION: Children with PMS displayed distinct transient VEP waveform abnormalities in both time and frequency domains that might reflect underlying glutamatergic deficits that were associated with deletion size. A similar response pattern was observed in a subset of children with idiopathic ASD. VEPs offer a noninvasive measure of excitatory and inhibitory neurotransmission that holds promise for stratification and surrogate endpoints in ongoing clinical trials in PMS and ASD.

Investigating Motor Preparation in Autism Spectrum Disorder With and Without Attention Deficit/Hyperactivity Disorder.

This study investigated motor preparation and action-consequence prediction using the lateralized readiness potential (LRP). Motor impairments are common in autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), which commonly co-occur. Alterations in predictive processes may impact motor planning. Whether motor planning deficits are characteristic of ASD broadly or magnified in the context of co-morbid ADHD is unclear. ASD children with (ASD + ADHD; n = 12) and without (ASD - ADHD; n = 9) comorbid ADHD and typical controls (n = 29) performed voluntary motor actions that either did or did not result in auditory consequences. ASD - ADHD children demonstrated LRP enhancement when their action produced an effect while ASD + ADHD children had attenuated responses regardless of action-effect pairings. Findings suggest influence of ADHD comorbidity on motor preparation and prediction in ASD.

Social visual attentional engagement and memory in Phelan-McDermid syndrome and autism spectrum disorder: a pilot eye tracking study.

BACKGROUND: The current study used eye tracking to investigate attention and recognition memory in Phelan-McDermid syndrome (PMS), a rare genetic disorder characterized by intellectual disability, motor delays, and a high likelihood of comorbid autism spectrum disorder (ASD). Social deficits represent a core feature of ASD, including decreased propensity to orient to or show preference for social stimuli. METHODS: We used a visual paired-comparison task with both social and non-social images, assessing looking behavior to a novel image versus a previously viewed familiar image to characterize social attention and recognition memory in PMS (n = 22), idiopathic ASD (iASD, n = 38), and typically developing (TD) controls (n = 26). The idiopathic ASD cohort was divided into subgroups with intellectual disabilities (ID; developmental quotient < 70) and without (developmental quotient > 70) and the PMS group into those with and without a co-morbid ASD diagnosis. RESULTS: On measures of attention, the PMS group with a comorbid ASD diagnosis spent less time viewing the social images compared to non-social images; the rate of looking back and forth between images was lowest in the iASD with ID group. Furthermore, while all groups demonstrated intact recognition memory when novel non-social stimuli were initially presented (pre-switch), participants with PMS showed no preference during the post-switch memory presentation. In iASD, the group without ID, but not the group with ID, showed a novelty preference for social stimuli. Across indices, individuals with PMS and ASD performed more similarly to PMS without ASD and less similarly to the iASD group. CONCLUSION: These findings demonstrate further evidence of differences in attention and memory for social stimuli in ASD and provide contrasts between iASD and PMS.

Oculomotor corollary discharge signaling is related to repetitive behavior in children with autism spectrum disorder.

Corollary discharge (CD) signals are "copies" of motor signals sent to sensory regions that allow animals to adjust sensory consequences of self-generated actions. Autism spectrum disorder (ASD) is characterized by sensory and motor deficits, which may be underpinned by altered CD signaling. We evaluated oculomotor CD using the blanking task, which measures the influence of saccades on visual perception, in 30 children with ASD and 35 typically developing (TD) children. Participants were instructed to make a saccade to a visual target. Upon saccade initiation, the presaccadic target disappeared and reappeared to the left or right of the original position. Participants indicated the direction of the jump. With intact CD, participants can make accurate perceptual judgements. Otherwise, participants may use saccade landing site as a proxy of the presaccadic target and use it to inform perception. We used multilevel modeling to examine the influence of saccade landing site on trans-saccadic perceptual judgements. We found that, compared with TD participants, children with ASD were more sensitive to target displacement and less reliant on saccade landing site when spatial uncertainty of the post-saccadic target was high. This pattern was driven by ASD participants with less severe restricted and repetitive behaviors. These results suggest a relationship between altered CD signaling and core ASD symptoms.

Reduced engagement of visual attention in children with autism spectrum disorder.

LAY ABSTRACT: Limited eye contact and difficulty tracking where others are looking are common in people with autism spectrum disorder. It is unclear, however, whether these are specifically social differences; it is possible that they are a result of broader alterations in engaging and disengaging visual attention. We used eye-tracking technology with children with autism spectrum disorder (n = 35) and typical development (n = 32), showing them both social and nonsocial imaging to test their visual attention. Children with autism spectrum disorder had a significant difference in how long it took them to look from an image in the middle to one on the side, depending on whether the middle image stayed on the screen or flashed off before the one on the side appeared. This difference was present for both social and nonsocial images, and was related to cognitive ability for only the children with autism spectrum disorder. Our findings suggest that children with autism spectrum disorder have differences in general processes of engaging visual attention that are not specifically social in nature, and that these processes may relate to cognitive ability in autism spectrum disorder. Affected processes of visual engagement in autism spectrum disorder may contribute to symptoms like reduced eye contact, but social-specific symptoms of autism spectrum disorder likely do not stem from reduced visual engagement alone.

Prospective and detailed behavioral phenotyping in DDX3X syndrome.

BACKGROUND: DDX3X syndrome is a recently identified genetic disorder that accounts for 1-3% of cases of unexplained developmental delay and/or intellectual disability (ID) in females, and is associated with motor and language delays, and autism spectrum disorder (ASD). To date, the published phenotypic characterization of this syndrome has primarily relied on medical record review; in addition, the behavioral dimensions of the syndrome have not been fully explored. METHODS: We carried out multi-day, prospective, detailed phenotyping of DDX3X syndrome in 14 females and 1 male, focusing on behavioral, psychological, and neurological measures. Three participants in this cohort were previously reported with limited phenotype information and were re-evaluated for this study. We compared results against population norms and contrasted phenotypes between individuals harboring either (1) protein-truncating variants or (2) missense variants or in-frame deletions. RESULTS: Eighty percent (80%) of individuals met criteria for ID, 60% for ASD and 53% for attention-deficit/hyperactivity disorder (ADHD). Motor and language delays were common as were sensory processing abnormalities. The cohort included 5 missense, 3 intronic/splice-site, 2 nonsense, 2 frameshift, 2 in-frame deletions, and one initiation codon variant. Genotype-phenotype correlations indicated that, on average, missense variants/in-frame deletions were associated with more severe language, motor, and adaptive deficits in comparison to protein-truncating variants. LIMITATIONS: Sample size is modest, however, DDX3X syndrome is a rare and underdiagnosed disorder. CONCLUSION: This study, representing a first, prospective, detailed characterization of DDX3X syndrome, extends our understanding of the neurobehavioral phenotype. Gold-standard diagnostic approaches demonstrated high rates of ID, ASD, and ADHD. In addition, sensory deficits were observed to be a key part of the syndrome. Even with a modest sample, we observe evidence for genotype-phenotype correlations with missense variants/in-frame deletions generally associated with more severe phenotypes.

Sensory Reactivity Symptoms Are a Core Feature of ADNP Syndrome Irrespective of Autism Diagnosis.

Background: Activity dependent neuroprotective protein (ADNP) syndrome is one of the most common single-gene causes of autism spectrum disorder (ASD) and intellectual disability, however, the phenotypes remain poorly described. Here we examine the sensory reactivity phenotype in children and adolescents with ADNP syndrome. Methods: Twenty-two individuals with ADNP syndrome received comprehensive clinical evaluations including standardized observations, caregiver interviews, and questionnaires to assess sensory reactivity symptoms. Relationships between sensory symptoms and age, sex, ASD, IQ, and adaptive behavior were examined. Genotype-phenotype correlations with the recurrent p.Tyr719* variant were also explored. Results: Sensory reactivity symptoms were observed and reported in all participants. A syndrome-specific phenotype was identified, characterized by high levels of sensory seeking across tactile, auditory, and visual domains. Tactile hyporeactivity, characterized by pain insensitivity, was reported in the majority of participants. Sensory symptoms were identified across individuals regardless of age, sex, IQ, adaptive ability, genetic variant, and most importantly, ASD status. No significant differences were identified between participants with and without the recurrent p.Tyr719* variant on any sensory measure. Conclusions: Sensory reactivity symptoms are a common clinical feature of ADNP syndrome. Quantifying sensory reactivity using existing standardized measures will enhance understanding of sensory reactivity in individuals with ADNP syndrome and will aid in clinical care. The sensory domain may also represent a promising target for treatment in clinical trials.

Abnormally Large Baseline P300 Amplitude Is Associated With Conversion to Psychosis in Clinical High Risk Individuals With a History of Autism: A Pilot Study.

Psychosis rates in autism spectrum disorder (ASD) are 5-35% higher than in the general population. The overlap in sensory and attentional processing abnormalities highlights the possibility of related neurobiological substrates. Previous research has shown that several electroencephalography (EEG)-derived event-related potential (ERP) components that are abnormal in schizophrenia, including P300, are also abnormal in individuals at Clinical High Risk (CHR) for psychosis and predict conversion to psychosis. Yet, it is unclear whether P300 is similarly sensitive to psychosis risk in help-seeking CHR individuals with ASD history. In this exploratory study, we leveraged data from the North American Prodrome Longitudinal Study (NAPLS2) to probe for the first time EEG markers of longitudinal psychosis profiles in ASD. Specifically, we investigated the P300 ERP component and its sensitivity to psychosis conversion across CHR groups with (ASD+) and without (ASD-) comorbid ASD. Baseline EEG data were analyzed from 304 CHR patients (14 ASD+; 290 ASD-) from the NAPLS2 cohort who were followed longitudinally over two years. We examined P300 amplitude to infrequent Target (10%; P3b) and Novel distractor (10%; P3a) stimuli from visual and auditory oddball tasks. Whereas P300 amplitude attenuation is typically characteristic of CHR and predictive of conversion to psychosis in non-ASD sample, in our sample, history of ASD moderated this relationship such that, in CHR/ASD+ individuals, enhanced - rather than attenuated - visual P300 (regardless of stimulus type) was associated with psychosis conversion. This pattern was also seen for auditory P3b amplitude to Target stimuli. Though drawn from a small sample of CHR individuals with ASD, these preliminary results point to a paradoxical effect, wherein those with both CHR and ASD history who go on to develop psychosis have a unique pattern of enhanced neural response during attention orienting to both visual and target stimuli. Such a pattern stands out from the usual finding of P300 amplitude reductions predicting psychosis in non-ASD CHR populations and warrants follow up in larger scale, targeted, longitudinal studies of those with ASD at clinical high risk for psychosis.

Persistence and Accumulation of Visual Memories for Objects in Scenes in 12-Month-Old Infants.

Visual memory for objects has been studied extensively in infants over the past 20 years, however, little is known about how they are formed when objects are embedded in naturalistic scenes. In adults, memory for objects in a scene show information accumulation over time as well as persistence despite interruptions (Melcher, 2001, 2006). In the present study, eye-tracking was used to investigate these two processes in 12-month-old infants (N = 19) measuring: (1) whether longer encoding time can improve memory performance (accumulation), and (2) whether multiple shorter exposures to a scene are equivalent to a single exposure of the same total duration (persistence). A control group of adults was also tested in a closely matched paradigm (N = 23). We found that increasing exposure time led to gains in memory performance in both groups. Infants were found to be successful in remembering objects with continuous exposures to a scene, but unlike adults, were not able to perform better than chance when interrupted. However, infants' scan patterns showed evidence of memory as they continued the exploration of the scene in a strategic way following the interruption. Our findings provide insight into how infants are able to build representations of their visual environment by accumulating information about objects embedded in scenes.

Quantifying attentional effects on the fidelity and biases of visual working memory in young children.

Attentional control enables us to direct our limited resources to accomplish goals. The ability to flexibly allocate resources helps to prioritize information and inhibit irrelevant/distracting information. We examined developmental changes in visual working memory (VWM) fidelity in 4- to 7-year-old children and the effects that a distracting non-target object can exert in biasing their memory representations. First, we showed that VWM fidelity improves from early childhood to adulthood. Second, we found evidence of working memory load on recall variability in children and adults. Next, using cues to manipulate attention, we found that older children are able to construct a more durable memory representation for an object presented following a non-target using a pre-cue (that biases encoding before presentation) compared with a retro-cue (that signals which item to recall after presentation). In addition, younger children had greater difficulties maintaining an item in memory when an intervening item was presented. Lastly, we found that memory representations are biased toward a non-target when it is presented following the target and away from a non-target when it precedes the target. These bias effects were more pronounced in children compared with adults. Together, these results demonstrate changes in attention over development that influence VWM memory fidelity.

Off to a Good Start: The Early Development of the Neural Substrates Underlying Visual Working Memory.

Current neuroscientific models describe the functional neural architecture of visual working memory (VWM) as an interaction of the frontal-parietal control network and more posterior areas in the ventral visual stream (Jonides et al., 2008; D'Esposito and Postle, 2015; Eriksson et al., 2015). These models are primarily based on adult neuroimaging studies. However, VWM undergoes significant development in infancy and early childhood, and the goal of this mini-review is to examine how recent findings from neuroscientific studies of early VWM development can be reconciled with this model. We surveyed 29 recent empirical reports that present neuroimaging findings in infants, toddlers, and preschoolers (using EEG, fNIRS, rs-fMRI) and neonatal lesion studies in non-human primates. We conclude that (1) both the frontal-parietal control network and the posterior cortical storage areas are active from early infancy; (2) this system undergoes focalization and some reorganization during early development; (3) and the MTL plays a significant role in this process as well. Motivated by both theoretical and methodological considerations, we offer some recommendations for future directions for the field.

Comparison of brain activation patterns during executive function tasks in hoarding disorder and non-hoarding OCD.

We examined differences in regional brain activation during tests of executive function in individuals with Hoarding Disorder (HD), Obsessive Compulsive Disorder (OCD), and healthy controls (HC) using functional magnetic resonance imaging (fMRI). Participants completed computerized versions of the Stroop and Go/No-Go task. We found that during the conflict monitoring and response inhibition condition in the Go/No-Go task, individuals with HD had significantly greater activity than controls in the anterior cingulate cortex (ACC) and right dorsolateral prefrontal cortex (DLPFC). HD also exhibited significantly greater right DLPFC activity than OCD. We also observed significant differences in activity between HD and HC and between HD and OCD in regions (ACC, anterior insula, orbitofrontal cortex, and striatum) involved in evaluating stimulus-response-reward associations, or the personal and task-relevant value of stimuli and behavioral responses to stimuli. These results support the hypothesis that individuals with HD have difficulty deciding on the value or task relevance of stimuli, and may perceive an abnormally high risk of negative feedback for difficult or erroneous cognitive behavior.

Delayed Match Retrieval: a novel anticipation-based visual working memory paradigm.

We tested 8- and 10-month-old infants' visual working memory (VWM) for object-location bindings - what is where - with a novel paradigm, Delayed Match Retrieval, that measured infants' anticipatory gaze responses (using a Tobii T120 eye tracker). In an inversion of Delayed-Match-to-Sample tasks and with inspiration from the game Memory, in test trials, three face-down virtual 'cards' were presented. Two flipped over sequentially (revealing, e.g. a swirl pattern and then a star), and then flipped back face-down. Next, the third card was flipped to reveal a match (e.g. a star) to one of the previously seen, now face-down cards. If infants looked to the location where the (now face-down) matching card had been shown, this was coded as a correct response. To encourage anticipatory looks, infants subsequently received a reward (a brief, engaging animation) presented at that location. Ten-month-old infants performed significantly above chance, showing that their VWM could hold object-location information for the two cards. Overall, 8-month-olds' performance was at chance, but they showed a robust learning trend. These results corroborate previous findings (Kaldy & Leslie, 2005; Oakes, Ross-Sheehy & Luck, 2006) and point to rapid development of VWM for object-location bindings. However, compared to previous paradigms that measure passive gaze responses to novelty, this paradigm presents a more challenging, ecologically relevant test of VWM, as it measures the ability to make online predictions and actively localize objects based on VWM. In addition, this paradigm can be readily scaled up to test toddlers or older children without significant modification.

Attention-modulated alpha-band oscillations protect against intrusion of irrelevant information.

Combining high-density scalp EEG recordings with a sensitive analog measure of STM's fidelity, we characterized the temporal dynamics of intentional ignoring and related those dynamics to the intrusion of task-irrelevant information. On each trial of the task, two study Gabors were briefly presented in succession. A green or red disc preceding each Gabor signified whether that Gabor should be remembered or ignored, respectively. With cue-stimulus intervals of 300, 600, or 900 msec presented in separate sessions, we found that the onset of posterior, prestimulus alpha oscillations varied with the length of the interval. Although stimulus onset time was entirely predictable, the longer the cue-stimulus interval, the earlier the increase in prestimulus alpha power. However, the alpha-band modulation was not simply locked to the cue offset. The temporal envelopes of posterior alpha-band modulation were strikingly similar for both cued attending and cued ignoring and differed only in magnitude. This similarity suggests that cued attending includes suppression of task-irrelevant, spatial processing. Supporting the view that alpha-band oscillations represent inhibition, our graded measure of recall revealed that, when the stimulus to be ignored appears second in the sequence, peristimulus alpha power predicted the degree to which that irrelevant stimulus distorted subsequent recall of the stimulus that was to be remembered. These results demonstrate that timely deployment of attention-related alpha-band oscillations can aid STM by filtering out task-irrelevant information.

Auditory dysfunction in traumatic brain injury.

Effective communication is essential for successful rehabilitation, especially in patients with traumatic brain injury (TBI). The authors examined the prevalence and characteristics of auditory dysfunction in patients with TBI who were admitted to a Department of Veterans Affairs TBI inpatient unit before and after the onset of Operation Iraqi Freedom (OIF). In order to delineate the characteristics of the auditory manifestations of patients who had sustained blast-related (BR) TBI, we reviewed the medical records of 252 patients with TBI and categorized them according to admission date, either before (Group I, n = 102) or after (Group II, n = 150) the onset of OIF. We subdivided Group II into non-blast-related (NBR) and BR TBI; no subjects in Group I had BR TBI. We found that admissions for TBI have increased 47% since the onset of OIF. In Group I, 28% of patients with TBI complained of hearing loss and 11% reported tinnitus. In Group II-NBR (n = 108), 44% complained of hearing loss and 18% reported tinnitus. In Group II-BR (n = 42), 62% complained of hearing loss and 38% reported tinnitus. Sensorineural loss was the most prevalent type of hearing loss in Group II-BR patients. In light of the high prevalence of hearing loss and tinnitus in this growing population of returning soldiers, we need to develop and implement strategies for diagnosis and management of these conditions.

Program development and defining characteristics of returning military in a VA Polytrauma Network Site.

The conflicts in Iraq and Afghanistan have resulted in a new generation of combat survivors with complex physical injuries and emotional trauma. This article reports the initial implementation of the Polytrauma Network Site (PNS) clinic, which is a key component of the Department of Veterans Affairs (VA) Polytrauma System of Care and serves military personnel returning from combat. The PNS clinic in Palo Alto, California, is described to demonstrate the VA healthcare system's evolving effort to meet the clinical needs of this population. We summarize the following features of this interdisciplinary program: (1) sequential assessment, from initial traumatic brain injury screening throughout our catchment area to evaluation by the PNS clinic team, and (2) clinical evaluation results for the first 62 clinic patients. In summary, this population shows a high prevalence of postconcussion symptoms, posttraumatic stress, poor cognitive performance, head and back pain, auditory and visual symptoms, and problems with dizziness or balance. An anonymous patient feedback survey, which we used to fine-tune the clinic process, reflected high satisfaction with this new program. We hope that the lessons learned at one site will enhance the identification and treatment of veterans with polytrauma across the country.