A human neurodevelopmental model for Williams syndrome.

Williams syndrome is a genetic neurodevelopmental disorder characterized by an uncommon hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. Nearly all clinically diagnosed individuals with Williams syndrome lack precisely the same set of genes, with breakpoints in chromosome band 7q11.23 (refs 1-5). The contribution of specific genes to the neuroanatomical and functional alterations, leading to behavioural pathologies in humans, remains largely unexplored. Here we investigate neural progenitor cells and cortical neurons derived from Williams syndrome and typically developing induced pluripotent stem cells. Neural progenitor cells in Williams syndrome have an increased doubling time and apoptosis compared with typically developing neural progenitor cells. Using an individual with atypical Williams syndrome, we narrowed this cellular phenotype to a single gene candidate, frizzled 9 (FZD9). At the neuronal stage, layer V/VI cortical neurons derived from Williams syndrome were characterized by longer total dendrites, increased numbers of spines and synapses, aberrant calcium oscillation and altered network connectivity. Morphometric alterations observed in neurons from Williams syndrome were validated after Golgi staining of post-mortem layer V/VI cortical neurons. This model of human induced pluripotent stem cells fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain.

Abnormalities in early visual processes are linked to hypersociability and atypical evaluation of facial trustworthiness: An ERP study with Williams syndrome.

Accurate assessment of trustworthiness is fundamental to successful and adaptive social behavior. Initially, people assess trustworthiness from facial appearance alone. These assessments then inform critical approach or avoid decisions. Individuals with Williams syndrome (WS) exhibit a heightened social drive, especially toward strangers. This study investigated the temporal dynamics of facial trustworthiness evaluation in neurotypic adults (TD) and individuals with WS. We examined whether differences in neural activity during trustworthiness evaluation may explain increased approach motivation in WS compared to TD individuals. Event-related potentials were recorded while participants appraised faces previously rated as trustworthy or untrustworthy. TD participants showed increased sensitivity to untrustworthy faces within the first 65-90 ms, indexed by the negative-going rise of the P1 onset (oP1). The amplitude of the oP1 difference to untrustworthy minus trustworthy faces was correlated with lower approachability scores. In contrast, participants with WS showed increased N170 amplitudes to trustworthy faces. The N170 difference to low-high-trust faces was correlated with low approachability in TD and high approachability in WS. The findings suggest that hypersociability associated with WS may arise from abnormalities in the timing and organization of early visual brain activity during trustworthiness evaluation. More generally, the study provides support for the hypothesis that impairments in low-level perceptual processes can have a cascading effect on social cognition.

Social functioning and autonomic nervous system sensitivity across vocal and musical emotion in Williams syndrome and autism spectrum disorder.

Both Williams syndrome (WS) and autism spectrum disorders (ASD) are associated with unusual auditory phenotypes with respect to processing vocal and musical stimuli, which may be shaped by the atypical social profiles that characterize the syndromes. Autonomic nervous system (ANS) reactivity to vocal and musical emotional stimuli was examined in 12 children with WS, 17 children with ASD, and 20 typically developing (TD) children, and related to their level of social functioning. The results of this small-scale study showed that after controlling for between-group differences in cognitive ability, all groups showed similar emotion identification performance across conditions. Additionally, in ASD, lower autonomic reactivity to human voice, and in TD, to musical emotion, was related to more normal social functioning. Compared to TD, both clinical groups showed increased arousal to vocalizations. A further result highlighted uniquely increased arousal to music in WS, contrasted with a decrease in arousal in ASD and TD. The ASD and WS groups exhibited arousal patterns suggestive of diminished habituation to the auditory stimuli. The results are discussed in the context of the clinical presentation of WS and ASD.

Parental report of cognitive and social-emotionality traits in school-age children with autism and Williams syndrome.

The majority of the research examining children with Autism Spectrum Disorder (ASD) and Williams Syndrome (WS) focus on the social domain while few have examined cognitive style and emotionality. Accordingly, this current study assessed the day-to-day cognitive and behavioral functioning of school-age children with ASD, WS, and neurotypical development (ND) through caregiver-report inventories to further delineate commonalities and disparities in cognitive and social-emotional traits. Two caregiver-report inventories, the Children's Behavior Questionnaire and the Multidimensional Personality Questionnaire were employed to assess the day-to-day functioning of children ages 7-14 years. Participants included 64 caregivers of children, of these, 25 were caregivers of children with high functioning autism (HFA), 14 with WS, and 25 with ND. Multivariate analysis of covariance was computed to assess between-group differences for each subscale within a questionnaire. Covariates included age and full-scale IQ. For cognitive traits, group differences were observed across two categories while seven were present within the social-emotional categories. The majority of the group effects reflected differences in social-emotional traits between ND and both neurodevelopmental groups, while limited distinctions were found between the two clinical groups. This brief report provides additional evidence that HFA and WS may show similarities in cognitive traits but more divergent social-emotional tendencies, despite controlling for age and intellect. This study highlights the large social-emotional differences that supports prior phenotypic descriptions of both neurodevelopmental groups. Future research in these domains are needed to determine focused interventions to address social impairment.

The fusiform face area is enlarged in Williams syndrome.

Williams syndrome (WS) is a genetic condition characterized by atypical brain structure, cognitive deficits, and a life-long fascination with faces. Face recognition is relatively spared in WS, despite abnormalities in aspects of face processing and structural alterations in the fusiform gyrus, part of the ventral visual stream. Thus, face recognition in WS may be subserved by abnormal neural substrates in the ventral stream. To test this hypothesis, we used functional magnetic resonance imaging and examined the fusiform face area (FFA), which is implicated in face recognition in typically developed (TD) individuals, but its role in WS is not well understood. We found that the FFA was approximately two times larger among WS than TD participants (both absolutely and relative to the fusiform gyrus), despite apparently normal levels of face recognition performance on a Benton face recognition test. Thus, a larger FFA may play a role in face recognition proficiency among WS.

Parents' perspective on the social traits observed in school-age children with autism and children with Williams syndrome.

Individuals with autism spectrum disorders and those with Williams syndrome often have impairments in social behaviors. These two neurodevelopmental disorders are often reputed to be on the opposite ends of the social spectrum, with autistic individuals being socially avoidant and those with Williams syndrome highly social. Most research on children with autism and Williams syndrome has focused on preschool and younger school-age children. The current study assessed school-age children between the ages of 7-14 years with high-functioning autism, Williams syndrome, and neurotypical developing peers. Parents completed the Salk Institute Sociability Questionnaire and the Social Responsiveness Scale, to provide unique insights into social functioning and tap into different behavioral areas, social approach behaviors, and social responsiveness. This study provides additional evidence that young children with autism and Williams syndrome continue to show divergent social-behavioral tendencies at school-age, despite controlling for age and intellect. Results of this study better elucidate disparities as well as commonalities across school-age children with neurodevelopmental disorders and their typically developing peers, providing insight into everyday social functioning.

Genetic influences on sociability: heightened amygdala reactivity and event-related responses to positive social stimuli in Williams syndrome.

Williams syndrome (WS) is a genetic disorder caused by a hemizygous microdeletion on chromosome 7q11.23. WS is associated with a compelling neurocognitive profile characterized by relative deficits in visuospatial function, relative strengths in face and language processing, and enhanced drive toward social engagement. We used a combined functional magnetic resonance imaging (fMRI) and event-related potential (ERP) approach to examine the neural basis of social responsiveness in WS participants to two types of social stimuli, negative (fearful) and positive (happy) emotional facial expressions. Here, we report a double dissociation consistent across both methods such that WS participants exhibited heightened amygdala reactivity to positive (happy) social stimuli and absent or attenuated amygdala reactivity to negative (fearful) social stimuli, compared with controls. The fMRI findings indicate that atypical social processing in WS may be rooted in altered development of disparate amygdalar nuclei that subserve different social functions. The ERP findings suggest that abnormal amygdala reactivity in WS may possibly function to increase attention to and encoding of happy expressions and to decrease arousal to fearful expressions. This study provides the first evidence that the genetic deletion associated with WS influences the function of the amygdala to be particularly responsive to socially appetitive stimuli.

Effects of age on American Sign Language sentence repetition.

The study of deaf users of signed languages, who often experience delays in primary language (L1) acquisition, permits a unique opportunity to examine the effects of aging on the processing of an L1 acquired under delayed or protracted development. A cohort of 107 congenitally deaf adult signers ages 45-85 years who were exposed to American Sign Language (ASL) either in infancy, early childhood, or late childhood were tested using an ASL sentence repetition test. Participants repeated 20 sentences that gradually increased in length and complexity. Logistic mixed-effects regression with the variables of chronological age (CA) and age of acquisition (AoA) was used to assess sentence repetition accuracy. Results showed that CA was a significant predictor, with increased age being associated with decreased likelihood to reproduce a sentence correctly (odds ratio [OR] = 0.56, p = .010). In addition, effects of AoA were observed. Relative to native deaf signers, those who acquired ASL in early childhood were less likely to successfully reproduce a sentence (OR = 0.42, p = .003), as were subjects who learned ASL in late childhood (OR = 0.27, p < .001). These data show that aging affects verbatim recall in deaf users of ASL and that the age of sign language acquisition has a significant and lasting effect on repetition ability, even after decades of sign language use. These data show evidence for life-span continuity of early life effects. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Decreased density of cholinergic interneurons in striatal territories in Williams syndrome.

Williams syndrome (WS) is a rare neurodevelopmental disorder caused by the hemideletion of approximately 25-28 genes at 7q11.23. Its unusual social and cognitive phenotype is most strikingly characterized by the disinhibition of social behavior, in addition to reduced global IQ, with a relative sparing of language ability. Hypersociality and increased social approach behavior in WS may represent a unique inability to inhibit responses to specific social stimuli, which is likely associated with abnormalities of frontostriatal circuitry. The striatum is characterized by a diversity of interneuron subtypes, including inhibitory parvalbumin-positive interneurons (PV+) and excitatory cholinergic interneurons (Ch+). Animal model research has identified an important role for these specialized cells in regulating social approach behavior. Previous research in humans identified a depletion of interneuron subtypes associated with neuropsychiatric disorders. Here, we examined the density of PV+ and Ch+ interneurons in the striatum of 13 WS and neurotypical (NT) subjects. We found a significant reduction in the density of Ch+ interneurons in the medial caudate nucleus and nucleus accumbens, important regions receiving cortical afferents from the orbitofrontal and ventromedial prefrontal cortex, and circuitry involved in language and reward systems. No significant difference in the distribution of PV+ interneurons was found. The pattern of decreased Ch+ interneuron densities in WS differs from patterns of interneuron depletion found in other disorders.

Neural dissociation in the production of lexical versus classifier signs in ASL: distinct patterns of hemispheric asymmetry.

We examine the hemispheric organization for the production of two classes of ASL signs, lexical signs and classifier signs. Previous work has found strong left hemisphere dominance for the production of lexical signs, but several authors have speculated that classifier signs may involve the right hemisphere to a greater degree because they can represent spatial information in a topographic, non-categorical manner. Twenty-one unilaterally brain damaged signers (13 left hemisphere damaged, 8 right hemisphere damaged) were presented with a story narration task designed to elicit both lexical and classifier signs. Relative frequencies of the two types of errors were tabulated. Left hemisphere damaged signers produced significantly more lexical errors than did right hemisphere damaged signers, whereas the reverse pattern held for classifier signs. Our findings argue for different patterns of hemispheric asymmetry for these two classes of ASL signs. We suggest that the requirement to encode analogue spatial information in the production of classifier signs results in the increased involvement of the right hemisphere systems.

William's syndrome: gene expression is related to parental origin and regional coordinate control.

William's syndrome (WS) features a spectrum of neurocognitive and behavioral abnormalities due to a rare 1.5 MB deletion that includes about 24-28 genes on chromosome band 7q11.23. Study of the expression of these genes from the single normal copy provides an opportunity to elucidate the genetic and epigenetic controls on these genes as well as their roles in both WS and normal brain development and function. We used quantitative RT-PCR to determine the transcriptional level of 14 WS gene markers in a cohort of 77 persons with WS and 48 normal controls. Results reported here: (1) show that the expression of the genes deleted in WS is decreased in some but not all cases, (2) demonstrate that the parental origin of the deletion contributes to the level of expression of GTF2I independently of age and gender and (3) indicate that the correlation of expression between GTF2I and some other genes in the WS region differs in WS subjects and normal controls, which in turn points toward a regulatory role for this gene. Interspecies comparisons suggest GTF2I may play a key role in normal brain development.

More is not always better: increased fractional anisotropy of superior longitudinal fasciculus associated with poor visuospatial abilities in Williams syndrome.

We used diffusion tensor imaging to examine white matter integrity in the dorsal and ventral streams among individuals with Williams syndrome (WS) compared with two control groups (typically developing and developmentally delayed) and using three separate analysis methods (whole brain, region of interest, and fiber tractography). All analysis methods consistently showed that fractional anisotropy (FA; a measure of microstructural integrity) was higher in the right superior longitudinal fasciculus (SLF) in WS compared with both control groups. There was a significant association with deficits in visuospatial construction and higher FA in WS individuals. Comparable increases in FA across analytic methods were not observed in the left SLF or the bilateral inferior longitudinal fasciculus in WS subjects. Together, these findings suggest a specific role of right SLF abnormality in visuospatial construction deficits in WS.

Association between cerebral shape and social use of language in Williams syndrome.

Williams syndrome (WS) is a neurogenetic disorder resulting from a hemizygous microdeletion at band 7q11.23. It is characterized by aberrant development of the brain and a unique profile of cognitive and behavioral features. We sought to identify the neuroanatomical abnormalities that are most strongly associated with WS employing signal detection methodology. Once identified with a Quality Receiver Operating Characteristic Curve (QROC), we hypothesized those brain regions distinguishing subjects with WS from controls would be linked to the social phenotype of individuals with this disorder. Thirty-nine adolescents and young adults with WS and 40 typically developing controls matched for age and gender were studied. The QROC identified a combination of an enlarged ventral anterior prefrontal cortex and large bending angle of the corpus callosum to distinguish between WS and controls with a sensitivity of 85.4% and specificity of 75.0%. Within the WS group, bending angle significantly correlated with ventral anterior prefrontal cortex size but not with other morphometric brain measures. Ventral anterior prefrontal size in subjects with WS was positively associated with the use of social engagement devices in a narrative task assessing the use of social and affective language. Our findings suggest that aberrant morphology of the ventral anterior prefrontal cortex is a pivotal contributing factor to the abnormal size and shape of the cerebral cortex and to the social-affective language use typical of individuals with WS.

Decreased Neuron Density and Increased Glia Density in the Ventromedial Prefrontal Cortex (Brodmann Area 25) in Williams Syndrome.

Williams Syndrome (WS) is a neurodevelopmental disorder caused by a deletion of 25⁻28 genes on chromosome 7 and characterized by a specific behavioral phenotype, which includes hypersociability and anxiety. Here, we examined the density of neurons and glia in fourteen human brains in Brodmann area 25 (BA 25), in the ventromedial prefrontal cortex (vmPFC), using a postmortem sample of five adult and two infant WS brains and seven age-, sex- and hemisphere-matched typically developing control (TD) brains. We found decreased neuron density, which reached statistical significance in the supragranular layers, and increased glia density and glia to neuron ratio, which reached statistical significance in both supra- and infragranular layers. Combined with our previous findings in the amygdala, caudate nucleus and frontal pole (BA 10), these results in the vmPFC suggest that abnormalities in frontostriatal and frontoamygdala circuitry may contribute to the anxiety and atypical social behavior observed in WS.

A postmortem stereological study of the amygdala in Williams syndrome.

Perturbations to the amygdala have been observed in neurological disorders characterized by abnormalities in social behavior, such as autism and schizophrenia. Here, we quantitatively examined the amygdala in the postmortem human brains of male and female individuals diagnosed with Williams Syndrome (WS), a neurodevelopmental disorder caused by a well-defined deletion of ~ 26 genes, and accompanied by a consistent behavioral profile that includes profound hypersociability. Using unbiased stereological sampling, we estimated nucleus volume, number of neurons, neuron density, and neuron soma area in four major amygdaloid nuclei- the lateral nucleus, basal nucleus, accessory basal nucleus, and central nucleus- in a sample of five adult and two infant WS brains and seven age-, sex- and hemisphere-matched typically developing control (TD) brains. Boundaries of the four nuclei examined were drawn on Nissl-stained coronal sections as four separate regions of interest for data collection. We found that the lateral nucleus contains significantly more neurons in WS compared to TD. WS and TD do not demonstrate significant differences in neuron number in the basal, accessory basal, or central nuclei, and there are no significant differences between WS and TD in nuclei volume, neuron density, and neuron soma area in any of the four nuclei. A similarly designed study reported a decrease in lateral nucleus neuron number in autism, mirroring the opposing extremes of the two disorders in the social domain. These results suggest that the number of neurons in the lateral nucleus may contribute to pathological disturbances in amygdala function and sociobehavioral phenotype.

Neuroanatomical correlates of emotion-processing in children with unilateral brain lesion: A preliminary study of limbic system organization.

In this study, MRI and DTI were employed to examine subcortical volume and microstructural properties (FA, MD) of the limbic network, and their relationships with affect discrimination in 13 FL (6 right FL, M = 10.17 years; 7 left FL; M = 10.09) and 13 typically-developing children (TD; M = 10.16). Subcortical volume of the amygdala, hippocampus and thalamus and FA and MD of the fornix and anterior thalamic radiation (ATR) were examined. Results revealed no group differences across emotion-perception tasks or amygdalar volume. However, contrasting neuroanatomical patterns were observed in right versus left FL youth. Right FL participants showed increased left hippocampal and thalamic volume relative to left FL participants; whereas, the latter group showed increased right thalamic volume. DTI findings also indicated right FL children show greater MD of right fornix than other groups, whereas, left FL youth showed greater MD of left fornix. Right FL youth also showed lower FA of right fornix than left FL children, whereby the latter showed greater FA of left fornix and ATR. Differential associations between DTI indices and auditory/visual emotion-perception were observed across FL groups. Findings indicate diverging brain-behavioral relationships for emotion-perception among right and left FL children.

Increased glia density in the caudate nucleus in williams syndrome: Implications for frontostriatal dysfunction in autism.

Williams syndrome (WS) is a rare neurodevelopmental disorder with a well-described, known genetic etiology. In contrast to Autism Spectrum Disorders (ASD), WS has a unique phenotype characterized by global reductions in IQ and visuospatial ability, with relatively preserved language function, enhanced reactivity to social stimuli and music, and an unusual eagerness to interact socially with strangers. A duplication of the deleted region in WS has been implicated in a subset of ASD cases, defining a spectrum of genetic and behavioral variation at this locus defined by these opposite extremes in social behavior. The hypersociability characteristic of WS may be linked to abnormalities of frontostriatal circuitry that manifest as deficits in inhibitory control of behavior. Here, we examined the density of neurons and glia in associative and limbic territories of the striatum including the caudate, putamen, and nucleus accumbens regions in Nissl stained sections in five pairs of age, sex, and hemisphere-matched WS and typically-developing control (TD) subjects. In contrast to what is reported in ASD, no significant increase in overall neuron density was observed in this study. However, we found a significant increase in the density of glia in the dorsal caudate nucleus, and in the ratio of glia to neurons in the dorsal and medial caudate nucleus in WS, accompanied by a significant increase in density of oligodendrocytes in the medial caudate nucleus. These cellular abnormalities may underlie reduced frontostriatal activity observed in WS, with implications for understanding altered connectivity and function in ASD. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 531-545, 2018.

Frontostriatal dysfunction during response inhibition in Williams syndrome.

BACKGROUND: Williams syndrome (WS) has provided researchers with an exciting opportunity to understand the complex interplay among genes, neurobiological and cognitive functions. However, despite a well-characterized cognitive and behavioral phenotype, little attention has been paid to the marked deficits in social and behavioral inhibition. Here we explore the neural systems that mediate response inhibition in WS. METHODS: We used functional MRI (fMRI) to obtain blood oxygenation level dependence (BOLD) signal maps during the performance of a Go/NoGo response inhibition task from 11 clinically and genetically diagnosed WS patients and 11 age- and gender-matched typically developing (TD) control subjects. Correlations between behavioral, neuropsychological measures, and BOLD signal were also conducted. RESULTS: Although TD control subjects showed significantly faster response times, no group differences in behavioral accuracy were observed. Compared with control subjects, WS participants demonstrated significantly reduced activity in the striatum, dorsolateral prefrontal, and dorsal anterior cingulate cortices. These findings support the hypothesis that persons with WS fail to activate critical cortical and subcortical structures involved in behavioral inhibition. CONCLUSIONS: Our results provide important evidence for reduced engagement of the frontostriatal circuits in WS and provide putative biological markers for the deficits in response inhibition and the unusual social phenotype.

Orientation and affective expression effects on face recognition in Williams syndrome and autism.

We sought to clarify the nature of the face processing strength commonly observed in individuals with Williams syndrome (WS) by comparing the face recognition ability of persons with WS to that of persons with autism and to healthy controls under three conditions: Upright faces with neutral expressions, upright faces with varying affective expressions, and inverted faces with neutral expressions. No differences were observed under the upright/neutral expression condition. However, the WS group was more accurate than the autism group when discriminating upright faces with varying affective expressions, whereas the opposite pattern emerged when discriminating inverted faces. We interpret these differences as a reflection of the contrasting social features of the two syndromes.

Neuron density is decreased in the prefrontal cortex in Williams syndrome.

Williams Syndrome (WS) is a rare neurodevelopmental disorder associated with a hemideletion in chromosome 7, which manifests a distinct behavioral phenotype characterized by a hyperaffiliative social drive, in striking contrast to the social avoidance behaviors that are common in Autism Spectrum Disorder (ASD). MRI studies have observed structural and functional abnormalities in WS cortex, including the prefrontal cortex (PFC), a region implicated in social cognition. This study utilizes the Bellugi Williams Syndrome Brain Collection, a unique resource that comprises the largest WS postmortem brain collection in existence, and is the first to quantitatively examine WS PFC cytoarchitecture. We measured neuron density in layers II/III and V/VI of five cortical areas: PFC areas BA 10 and BA 11, primary motor BA 4, primary somatosensory BA 3, and visual area BA 18 in six matched pairs of WS and typically developing (TD) controls. Neuron density in PFC was lower in WS relative to TD, with layers V/VI demonstrating the largest decrease in density, reaching statistical significance in BA 10. In contrast, BA 3 and BA 18 demonstrated a higher density in WS compared to TD, although this difference was not statistically significant. Neuron density in BA 4 was similar in WS and TD. While other cortical areas were altered in WS, prefrontal areas appeared to be most affected. Neuron density is also altered in the PFC of individuals with ASD. Together these findings suggest that the PFC is targeted in neurodevelopmental disorders associated with sociobehavioral alterations. Autism Res 2017, 10: 99-112. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.