Attentional rather than sensory differences characterize auditory processing in Williams syndrome.

Individuals with Williams Syndrome (WS) exhibit an atypical auditory profile. Across two experiments, we used event-related potentials (ERPs) in a three-stimulus auditory oddball task to examine early sensory (P1, N1, P2) and later cognitive (P3a, P3b) stages of cortical auditory processing in adults with WS and age-matched typical peers. In Study 1, piano chords served as standard, target, and novel stimuli; whereas, in Study 2, a variety of non-piano sounds comprised the novel stimuli. Across both experiments, there were no group differences in the earliest stages of sensory encoding (P1, N1), along with evidence for atypically large P2 responses in participants with WS. Persons with WS exhibited larger than typical P3a responses when the novel stimuli were perceptually distinct from the standard and the target stimuli (Study 2), but not when task-relevant and -irrelevant stimuli were perceptually similar (Study 1). Further, the WS group demonstrated reduced goal-directed attention (attenuated P3b response). These group differences in ERPs were not directly related to IQ. Our results in the context of an active discrimination task point to a more complex profile of auditory processing in persons with WS than previously reported, with group differences emerging during the later stages of stimulus categorization and evaluation, but not within early stimulus detection and feature encoding.

Anxiety and autonomic response to social-affective stimuli in individuals with Williams syndrome.

BACKGROUND: Williams syndrome (WS) is a genetic condition characterized by an unusual "hypersocial" personality juxtaposed by high anxiety. Recent evidence suggests that autonomic reactivity to affective face stimuli is disorganised in WS, which may contribute to emotion dysregulation and/or social disinhibition. METHODS: Electrodermal activity (EDA) and mean interbeat interval (IBI) of 25 participants with WS (19 - 57 years old) and 16 typically developing (TD; 17-43 years old) adults were measured during a passive presentation of affective face and voice stimuli. The Beck Anxiety Inventory was administered to examine associations between autonomic reactivity to social-affective stimuli and anxiety symptomatology. RESULTS: The WS group was characterized by higher overall anxiety symptomatology, and poorer anger recognition in social visual and aural stimuli relative to the TD group. No between-group differences emerged in autonomic response patterns. Notably, for participants with WS, increased anxiety was uniquely associated with diminished arousal to angry faces and voices. In contrast, for the TD group, no associations emerged between anxiety and physiological responsivity to social-emotional stimuli. CONCLUSIONS: The anxiety associated with WS appears to be intimately related to reduced autonomic arousal to angry social stimuli, which may also be linked to the characteristic social disinhibition.

Vascular disease modeling using induced pluripotent stem cells: Focus in Hutchinson-Gilford Progeria Syndrome.

Induced pluripotent stem cells (iPSCs) represent today an invaluable tool to create disease cell models for modeling and drug screening. Several lines of iPSCs have been generated in the last 7 years that changed the paradigm for studying diseases and the discovery of new drugs to treat them. In this article we focus our attention to vascular diseases in particular Hutchinson-Gilford Progeria Syndrome (HGPS), a devastating premature aging disease caused by a mutation in the lamin A gene. In general, patients die because of myocardial infarction or stroke. Because the patients are fragile the isolation of a particular type of cells is very difficult. Therefore in the last 5 years, researchers have used cells derived from iPSCs to model aspects of the HGPS and to screen libraries of chemicals to retard or treat the disease.

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.

Hyperactive auditory processing in Williams syndrome: Evidence from auditory evoked potentials.

The neurophysiologic aberrations underlying the auditory hypersensitivity in Williams syndrome (WS) are not well defined. The P1-N1-P2 obligatory complex and mismatch negativity (MMN) response were investigated in 18 participants with WS, and the results were compared with those of 18 age- and gender-matched typically developing (TD) controls. Results revealed significantly higher amplitudes of both the P1-N1-P2 obligatory complex and the MMN response in the WS participants than in the TD controls. The P1-N1-P2 complex showed an age-dependent reduction in the TD but not in the WS participants. Moreover, high P1-N1-P2 complex was associated with low verbal comprehension scores in WS. This investigation demonstrates that central auditory processing is hyperactive in WS. The increase in auditory brain responses of both the obligatory complex and MMN response suggests aberrant processes of auditory encoding and discrimination in WS. Results also imply that auditory processing may be subjected to a delayed or diverse maturation and may affect the development of high cognitive functioning in WS.

Sleep EEG fingerprints reveal accelerated thalamocortical oscillatory dynamics in Williams syndrome.

Sleep EEG alterations are emerging features of several developmental disabilities, but detailed quantitative EEG data on the sleep phenotype of patients with Williams syndrome (WS, 7q11.23 microdeletion) is still lacking. Based on laboratory (Study I) and home sleep records (Study II) here we report WS-related features of the patterns of antero-posterior 8-16 Hz non-rapid-eye-movement (NREM) sleep EEG power distributions. Participants in Study I were 9 WS and 9 typically developing (TD) controls matched for age (14-29 years) and sex, and sleeping for two consecutive nights in the laboratory. WS participants were characterized by region-independent decreases in 10.50-12.50 Hz and central increases in 14.75-15.75 Hz EEG power. Region-independent decreases and increases in z-scores of the spectra were observed in the 10.25-12.25 Hz and 14-16 Hz ranges, respectively. Moreover, in the EEG spectra of participants with WS a lower probability for the emergence of a frontally dominant peak was observed. Parietal fast sigma peaks and the antero-posterior shifts in power distributions were of higher frequencies in WS (~1 Hz difference). A 1 year follow-up of 9 WS and 3 TD participants, as well as their inclusion into larger samples (20 WS and 20 TD, age: 6-29 years) of a two-night ambulatory home polysomnography study confirmed the WS-specific decrease in alpha/low sigma power (8-11.75 Hz) and the pattern of z-score differences (decreases: 8.50-11.25 Hz; increases: 13.5-14 Hz), including the antero-posterior shifts in power distribution (0.5 Hz) and some features of the spectral peaks. Altogether these data suggest a decrease in alpha/low sigma power, as well as a redistribution of NREM sleep 8-16 Hz EEG power toward the higher frequencies and/or a higher frequency of NREM sleep thalamocortical oscillations in WS.

Cochlear active mechanisms in young normal-hearing subjects affected by Williams syndrome: time-frequency analysis of otoacoustic emissions.

The aim of this study was to investigate the functionality of cochlear active mechanisms in normal-hearing subjects affected by Williams syndrome (WS). Transient evoked otoacoustic emissions (TEOAEs) were recorded in a group of young WS subjects and a group of typically developing control subjects, all having normal-hearing thresholds and normal middle-ear functionality. We also analysed the narrow-band frequency components of TEOAEs, extracted from the broad-band TEOAE recordings by using a time-frequency analysis algorithm based on the Wavelet transform. We observed that TEOAEs and the frequency components extracted from TEOAEs measured in WS subjects had significantly lower energy compared to the controls. Also, the narrow-band frequency components of TEOAEs measured in WS subjects had slightly increased latency compared to the controls. Overall, results would suggest a subtle (i.e., sub-clinical) dysfunction of the cochlear active mechanisms in WS subjects with otherwise normal hearing. Also, results point out the relevance of using otoacoustic emissions in the audiological evaluation and monitoring of WS subjects to early identify possible subtle auditory dysfunctions, before the onset of mild or moderate hearing loss that could exacerbate language or cognitive impairments associated with WS.

Abnormal processing of emotional prosody in Williams syndrome: an event-related potentials study.

Williams syndrome (WS), a neurodevelopmental genetic disorder due to a microdeletion in chromosome 7, is described as displaying an intriguing socio-cognitive phenotype. Deficits in prosody production and comprehension have been consistently reported in behavioral studies. It remains, however, to be clarified the neurobiological processes underlying prosody processing in WS. This study aimed at characterizing the electrophysiological response to neutral, happy, and angry prosody in WS, and examining if this response was dependent on the semantic content of the utterance. A group of 12 participants (5 female and 7 male), diagnosed with WS, with age range between 9 and 31 years, was compared with a group of typically developing participants, individually matched for chronological age, gender and laterality. After inspection of EEG artifacts, data from 9 participants with WS and 10 controls were included in ERP analyses. Participants were presented with neutral, positive and negative sentences, in two conditions: (1) with intelligible semantic and syntactic information; (2) with unintelligible semantic and syntactic information ('pure prosody' condition). They were asked to decide which emotion was underlying the auditory sentence. Atypical event-related potentials (ERP) components were related with prosodic processing (N100, P200, N300) in WS. In particular, reduced N100 was observed for prosody sentences with semantic content; more positive P200 for sentences with semantic content, in particular for happy and angry intonations; and reduced N300 for both types of sentence conditions. These findings suggest abnormalities in early auditory processing, indicating a bottom-up contribution to the impairment in emotional prosody processing and comprehension. Also, at least for N100 and P200, they suggest the top-down contributions of semantic processes in the sensory processing of speech. This study showed, for the first time, that abnormalities in ERP measures of early auditory processing in WS are also present during the processing of emotional vocal information. This may represent a physiological signature of underlying impaired on-line language and socio-emotional processing.

Discovering structure in auditory input: evidence from Williams syndrome.

We examined auditory perception in Williams syndrome by investigating strategies used in organizing sound patterns into coherent units. In Experiment 1, we investigated the streaming of sound sequences into perceptual units, on the basis of pitch cues, in a group of children and adults with Williams syndrome compared to typical controls. We showed that individuals with Williams syndrome were sensitive to the same pitch cues as typical children and adults when streaming these patterns. In Experiment 2, we evaluated differences in reliance on pitch and contour cues in unfamiliar melody perception in a group of adults with Williams syndrome relative to typical control children and adults. Unlike controls who demonstrated greater proficiency when contour cues were available, adults with Williams syndrome showed no such advantage.

Auditory attraction: activation of visual cortex by music and sound in Williams syndrome.

Williams syndrome is a genetic neurodevelopmental disorder with a distinctive phenotype, including cognitive-linguistic features, nonsocial anxiety, and a strong attraction to music. we preformed functional MRI studies examining brain responses to musical and other types of stimuli in young adults with Williams syndrome and typically developing controls. In Study 1, the Williams syndrome group exhibited unforeseen activations of the visual cortex to musical stimuli, and it was this novel finding that became the focus of two subsequent studies. Using retinotopy, color localizers, and additional sound conditions, we identified specific visual areas in subjects with Williams syndrome that were activated by both musical and nonmusical auditory stimuli. The results, similar to synthetic-like experiences, have implications for cross-modal sensory processing in typical and atypical neurodevelopment.

Auditory cortical volumes and musical ability in Williams syndrome.

Individuals with Williams syndrome (WS) have been shown to have atypical morphology in the auditory cortex, an area associated with aspects of musicality. Some individuals with WS have demonstrated specific musical abilities, despite intellectual delays. Primary auditory cortex and planum temporale volumes were manually segmented in 25 individuals with WS and 25 control participants, and the participants also underwent testing of musical abilities. Left and right planum temporale volumes were significantly larger in the participants with WS than in controls, with no significant difference noted between groups in planum temporale asymmetry or primary auditory cortical volumes. Left planum temporale volume was significantly increased in a subgroup of the participants with WS who demonstrated specific musical strengths, as compared to the remaining WS participants, and was highly correlated with scores on a musical task. These findings suggest that differences in musical ability within WS may be in part associated with variability in the left auditory cortical region, providing further evidence of cognitive and neuroanatomical heterogeneity within this syndrome.

Atypical hemispheric asymmetry in the perception of negative human vocalizations in individuals with Williams syndrome.

Williams syndrome is a neurological condition associated with high levels of auditory reactivity and emotional expression combined with impaired perception of prosody. Yet, little is currently known about the neural organization of affective auditory processing in individuals with this disorder. The current study examines auditory emotion processing in individuals with Williams syndrome. Hemispheric organization for positive and negative human non-linguistic sound processing was compared in participants with and without the disorder using a dichotic listening paradigm. While controls exhibited an expected right cerebral hemisphere advantage for processing negative sounds, those with Williams syndrome showed the opposite pattern. No differences between the groups emerged for the positive stimuli. The results suggest aberrant processing of negative auditory information in Williams syndrome.

Cross-modal influences of affect across social and non-social domains in individuals with Williams syndrome.

The Williams syndrome (WS) cognitive profile is characterized by relative strengths in face processing, an attentional bias towards social stimuli, and an increased affinity and emotional reactivity to music. An audio-visual integration study examined the effects of auditory emotion on visual (social/non-social) affect identification in individuals with WS and typically developing (TD) and developmentally delayed (DD) controls. The social bias in WS was hypothesized to manifest as an increased ability to process social than non-social affect, and a reduced auditory influence in social contexts. The control groups were hypothesized to perform similarly across conditions. The results showed that while participants with WS exhibited indistinguishable performance to TD controls in identifying facial affect, DD controls performed significantly more poorly. The TD group outperformed the WS and DD groups in identifying non-social affect. The results suggest that emotionally evocative music facilitated the ability of participants with WS to process emotional facial expressions. These surprisingly strong facial-processing skills in individuals with WS may have been due to the effects of combining social and music stimuli and to a reduction in anxiety due to the music in particular. Several directions for future research are suggested.

Hyperactive auditory efferent system and lack of acoustic reflexes in Williams syndrome.

The auditory efferent system and acoustic reflexes have been investigated in patients with Williams syndrome (WS). Twenty-one patients aged 6-26 years with a genetically confirmed diagnosis of WS and with reported hyperacusis were compared with 21 normally developing age-matched subjects. The medial olivocochlear (MOC) efferent system was tested by stimulation of the contralateral ear with increasing levels of white noise, while recording transient evoked otoacoustic emissions (TEOAE) in the ipsilateral ear. The suppression effect on the amplitudes of the TEOAE was computed for each contralateral stimulus level. This measure reflects the strength of the MOC efferent system. In addition, the thresholds of ipsilateral and contralateral acoustic reflexes in response to 1, 2 and 4 kHz tones as well as to broadband stimuli were also recorded. Results showed that patients with WS had a significantly higher suppression effect of the MOC reflex on TEOAE. Ipsilateral and contralateral acoustic reflexes to tonal and broadband stimuli presented at maximum stimulus intensities were absent in 62-86% of the patients with WS. In the remainder, acoustic reflexes were elicited at lower auditory sensation thresholds than in controls. Hyperexcitability of the MOC efferent system coupled with absence of acoustic reflexes may contribute to the hyperacusis in WS and the consequent high-tone hearing loss induced by environmental noise. Both measures can be used for objective detection and thus, intervention of hyperacusis in the early stages of life.

Reduced parietal and visual cortical activation during global processing in Williams syndrome.

Several lines of investigation suggest that individuals with Williams syndrome (WS), a neurodevelopmental disorder of well-characterized genetic etiology, have selective impairments in integrating local image elements into global configurations. We compared global processing abilities in 10 clinically and genetically diagnosed participants with WS (eight females, two males; mean age 31y 10mo [SD 9y 7mo], range 15y 5mo-48y 4mo) with a typically developed (TD) age- and sex-matched comparison group (seven females, one male; mean age 35y 2mo [SD 10y 10mo], range 24y-54y 7mo) using functional magnetic resonance imaging (fMRI). Behavioral data showed participants with WS to be significantly less accurate (p<0.042) together with a non-significant trend to be slower than the TD comparison group while performing the global processing task. fMRI data showed participants with WS to possess reduced activation in the visual and parietal cortices. Participants with WS also showed relatively normal activation in the ventral occipitotemporal cortex, but elevated activation in several posterior thalamic nuclei. These preliminary results largely confirm previous research findings and neural models implicating neurodevelopmental abnormalities in extended subcortical and cortical visual systems in WS, most notably dorsal-stream pathways.

Global and local music perception in children with Williams syndrome.

Musical processing can be decomposed into the appreciation of global and local elements. This global/local dissociation was investigated with the processing of contour-violated and interval-violated melodies. Performance of a group of 16 children with Williams syndrome and a group of 16 control children were compared in a same-different task. Control participants were more accurate in detecting differences in the contour-violated than in the interval-violated condition while Williams syndrome individuals performed equally well in both conditions. This finding suggests that global precedence may occur at an early perceptual stage in normally developing children. In contrast, no such global precedence is observed in the Williams syndrome population. These data are discussed in the context of atypical cognitive profiles of individuals with Williams syndrome.

Growth hormone deficiency in a child with Williams-Beuren syndrome. The response to growth hormone therapy.

Pre- and postnatal growth retardation of unknown pathogenesis is a common clinical feature in patients with Williams-Beuren syndrome (WBS). However, growth hormone deficiency (GHD) has not been considered a major cause of growth retardation. There is only one patient in the literature with confirmed GHD who responded well to human growth hormone (hGH) therapy. We report a female infant with confirmed WBS who, through provocative testing, was found to have GHD and who responded satisfactorily to hGH therapy. Height SDS was -4.2 at the age of 12 months when hGH was initiated and increased to -0.8 at the age of 4.25 years. The pathogenesis of GHD in our patient is unclear. Nevertheless, the elevated levels of prolactin and the response of hGH to growth hormone releasing hormone (GHRH) administration are indicative of a hypothalamic rather than pituitary defect. In conclusion, GH deficiency might contribute to the growth failure in a number of patients with WBS and in such cases hGH therapy will most likely improve final height.

Multisystem study of 20 older adults with Williams syndrome.

To address the natural history of Williams syndrome (WS), we performed multisystem assessments on 20 adults with WS over 30 years of age and documented a high frequency of problems in multiple organ systems. The most striking and consistent findings were: abnormal body habitus; mild-moderate high frequency sensorineural hearing loss; cardiovascular disease and hypertension; gastrointestinal symptoms including diverticular disease; diabetes and abnormal glucose tolerance on standard oral glucose tolerance testing; subclinical hypothyroidism; decreased bone mineral density on DEXA scanning; and a high frequency of psychiatric symptoms, most notably anxiety, often requiring multimodal therapy. Review of brain MRI scans did not demonstrate consistent pathology. The adults in our cohort were not living independently and the vast majority were not competitively employed. Our preliminary findings raise concern about the occurrence of mild accelerated aging, which may additionally complicate the long-term natural history of older adults with WS. We provide monitoring guidelines to assist in the comprehensive care of adults with WS.

Brain biochemistry in Williams syndrome: evidence for a role of the cerebellum in cognition?

OBJECTIVE: To determine what biochemical changes may occur in the brain in Williams syndrome (WS) and whether these changes may be related to the cognitive deficits. BACKGROUND: WS is a rare, congenital disorder with a characteristic physical, linguistic, and behavioral phenotype with known cognitive deficits. METHODS: We obtained 31P magnetic resonance spectra (MRS) from a region consisting of mostly frontal and parietal lobe of 14 patients with WS (age, 8 to 37 years) and 48 similarly-aged controls. 1H MRS (27 cm3) localized to the left cerebellum obtained from the WS cohort were compared with those from 16 chronological age- and sex-matched normal controls. A battery of cognitive tests were administered to all subjects undergoing 1H MRS. RESULTS: WS brains exhibited significant biochemical abnormalities. All 31P MRS ratios containing the phosphomonoester (PME) peak were significantly altered in WS, suggesting that PME is significantly decreased. Ratios of choline-containing compounds and creatine-containing compounds to N-acetylaspartate (Cho/NA and Cre/NA) were significantly elevated in the cerebellum in WS cf. controls, whereas the ratio of Cho/Cre was not altered. This suggests a decrease in the neuronal marker N-acetylaspartate in the cerebellum. Significant correlations were found between the cerebellar ratios Cho/NA and Cre/NA and the ability of all subjects at various neuropsychological tests, including Verbal and Performance IQ, British Picture Vocabulary Scale, Ravens Progressive Matrices, and Inspection Time. CONCLUSIONS: The correlations can be interpreted in two ways: 1) Our sampling of cerebellar biochemistry reflects a measure of "global" cerebral biochemistry and is unrelated to cerebellar function, or 2) The relations indicate that cerebellar neuronal integrity is a requirement (on a developmental time scale or in real-time) for ability on a variety of cognitive tests.