MRI amygdala volume in Williams syndrome

One of the most intriguing characteristics of Williams Syndrome individuals is their hypersociability. The amygdala has been consistently implicated in the etiology of this social profile, particularly given its role in emotional and social behavior. This study examined amygdala volume and symmetry in WS individuals and in age and sex matched controls. Magnetic resonance imaging scans were obtained on a GE 1.5-T magnet with 1.5- mm contiguous slices and were used to measure whole gray matter, white matter and cerebrospinal fluid volumes, as well as amygdala volume (right and left). Results revealed significantly reduced intracranial volume in individuals with WS, compared with controls. There were no differences between groups in absolute amygdalae volume, although there was a relative increase in amygdalae volumes, when adjusted for total intracranial content. There were no inter-hemispheric differences in amygdalae volumes in both groups. These results suggest a relative increase in amygdala volume in WS compared with healthy controls that likely reflects abnormal neurodevelopmental processes of midline brain structures.This research was supported by the grants PIC/IC/83290/2007 from Fundac¸a˜o para a Cieˆncia e Tecnologia (Portugal) and Fundacio´n Alicia Koplowitz. (V convocatoria de 2009. Ayudas a la investigacio´n en psiquiatrı´a de la infancia y adolescencia enfermedades neurodegenerativas tempranas

Regional Brain Differences in Cortical Thickness, Surface Area and Subcortical Volume in Individuals with Williams Syndrome

Williams syndrome (WS) is a rare genetic neurodevelopmental disorder characterized by increased non-social anxiety, sensitivity to sounds and hypersociability. Previous studies have reported contradictory findings with regard to regional brain variation in WS, relying on only one type of morphological measure (usually volume) in each study. The present study aims to contribute to this body of literature and perhaps elucidate some of these discrepancies by examining concurrent measures of cortical thickness, surface area and subcortical volume between WS subjects and typically-developing (TD) controls. High resolution MRI scans were obtained on 31 WS subjects and 50 typically developing control subjects. We derived quantitative regional estimates of cortical thickness, cortical surface area, and subcortical volume using FreeSurfer software. We evaluated between-group ROI differences while controlling for total intracranial volume. In post-hoc exploratory analyses within the WS group, we tested for correlations between regional brain variation and Beck Anxiety Inventory scores. Consistent with our hypothesis, we detected complex patterns of between-group cortical variation, which included lower surface area in combination with greater thickness in the following cortical regions: post central gyrus, cuneus, lateral orbitofrontal cortex and lingual gyrus. Additional cortical regions showed between-group differences in one (but not both) morphological measures. Subcortical volume was lower in the basal ganglia and the hippocampus in WS versus TD controls. Exploratory correlations revealed that anxiety scores were negatively correlated with gray matter surface area in insula, OFC, rostral middle frontal, superior temporal and lingual gyrus. Our results were consistent with previous reports showing structural alterations in regions supporting the socio-affective and visuospatial impairments in WS. However, we also were able to effectively capture novel and complex patterns of cortical differences using both surface area and thickness. In addition, correlation results implicate specific brain regions in levels of anxiety in WS, consistent with previous reports investigating general anxiety disorders in the general population

Learning by observation: insights from Williams syndrome.

Observing another person performing a complex action accelerates the observer's acquisition of the same action and limits the time-consuming process of learning by trial and error. Observational learning makes an interesting and potentially important topic in the developmental domain, especially when disorders are considered. The implications of studies aimed at clarifying whether and how this form of learning is spared by pathology are manifold. We focused on a specific population with learning and intellectual disabilities, the individuals with Williams syndrome. The performance of twenty-eight individuals with Williams syndrome was compared with that of mental age- and gender-matched thirty-two typically developing children on tasks of learning of a visuo-motor sequence by observation or by trial and error. Regardless of the learning modality, acquiring the correct sequence involved three main phases: a detection phase, in which participants discovered the correct sequence and learned how to perform the task; an exercise phase, in which they reproduced the sequence until performance was error-free; an automatization phase, in which by repeating the error-free sequence they became accurate and speedy. Participants with Williams syndrome beneficiated of observational training (in which they observed an actor detecting the visuo-motor sequence) in the detection phase, while they performed worse than typically developing children in the exercise and automatization phases. Thus, by exploiting competencies learned by observation, individuals with Williams syndrome detected the visuo-motor sequence, putting into action the appropriate procedural strategies. Conversely, their impaired performances in the exercise phases appeared linked to impaired spatial working memory, while their deficits in automatization phases to deficits in processes increasing efficiency and speed of the response. Overall, observational experience was advantageous for acquiring competencies, since it primed subjects' interest in the actions to be performed and functioned as a catalyst for executed action

Leftward Lateralization of Auditory Cortex Underlies Holistic Sound Perception in Williams Syndrome

BACKGROUND: Individuals with the rare genetic disorder Williams-Beuren syndrome (WS) are known for their characteristic auditory phenotype including strong affinity to music and sounds. In this work we attempted to pinpoint a neural substrate for the characteristic musicality in WS individuals by studying the structure-function relationship of their auditory cortex. Since WS subjects had only minor musical training due to psychomotor constraints we hypothesized that any changes compared to the control group would reflect the contribution of genetic factors to auditory processing and musicality. METHODOLOGY/PRINCIPAL FINDINGS: Using psychoacoustics, magnetoencephalography and magnetic resonance imaging, we show that WS individuals exhibit extreme and almost exclusive holistic sound perception, which stands in marked contrast to the even distribution of this trait in the general population. Functionally, this was reflected by increased amplitudes of left auditory evoked fields. On the structural level, volume of the left auditory cortex was 2.2-fold increased in WS subjects as compared to control subjects. Equivalent volumes of the auditory cortex have been previously reported for professional musicians. CONCLUSIONS/SIGNIFICANCE: There has been an ongoing debate in the neuroscience community as to whether increased gray matter of the auditory cortex in musicians is attributable to the amount of training or innate disposition. In this study musical education of WS subjects was negligible and control subjects were carefully matched for this parameter. Therefore our results not only unravel the neural substrate for this particular auditory phenotype, but in addition propose WS as a unique genetic model for training-independent auditory system properties

Heterozygous deletion of the Williams-Beuren syndrome critical interval in mice recapitulates most features of the human disorder

Williams-Beuren syndrome is a developmental multisystemic disorder caused by a recurrent 1.55-1.83 Mb heterozygous deletion on human chromosome band 7q11.23. Through chromosomal engineering with the cre-loxP system, we have generated mice with an almost complete deletion (CD) of the conserved syntenic region on chromosome 5G2. Heterozygous CD mice were viable, fertile and had a normal lifespan, while homozygotes were early embryonic lethal. Transcript levels of most deleted genes were reduced 50% in several tissues, consistent with gene dosage. Heterozygous mutant mice showed postnatal growth delay with reduced body weight and craniofacial abnormalities such as small mandible. The cardiovascular phenotype was only manifested with borderline hypertension, mildly increased arterial wall thickness and cardiac hypertrophy. The neurobehavioral phenotype revealed impairments in motor coordination, increased startle response to acoustic stimuli and hypersociability. Mutant mice showed a general reduction in brain weight. Cellular and histological abnormalities were present in the amygdala, cortex and hippocampus, including increased proportion of immature neurons. In summary, these mice recapitulate most crucial phenotypes of the human disorder, provide novel insights into the pathophysiological mechanisms of the disease such as the neural substrates of the behavioral manifestations, and will be valuable to evaluate novel therapeutic approaches.This work was supported by the Spanish Ministry of Ecomomy and Competitivity to V.C. (grant SAF2012-40036) and to L.P.J. (FIS PM002512 and SAF2004-06382), the European AnEuploidy project to L.P.J., M.D. and Y.H. The Rare Diseases CIBER (CIBERER) Fellowship supported M.S-P. and C.B

Genomic sister-disorders of neurodevelopment: an evolutionary approach

Genomic sister-disorders are defined here as diseases mediated by duplications versus deletions of the same region. Such disorders can provide unique information concerning the genomic underpinnings of human neurodevelopment because effects of diametric variation in gene copy number on cognitive and behavioral phenotypes can be inferred. We describe evidence from the literature on deletions versus duplications for the regions underlying the best-known human neurogenetic sister-disorders, including Williams syndrome, Velocardiofacial syndrome, and Smith–Magenis syndrome, as well as the X-chromosomal conditions Klinefelter and Turner syndromes. These data suggest that diametric copy-number alterations can, like diametric alterations to imprinted genes, generate contrasting phenotypes associated with autistic-spectrum and psychotic-spectrum conditions. Genomically based perturbations to the development of the human social brain are thus apparently mediated to a notable degree by effects of variation in gene copy number. We also conducted the first analyses of positive selection for genes in the regions affected by these disorders. We found evidence consistent with adaptive evolution of protein-coding genes, or selective sweeps, for three of the four sets of sister-syndromes analyzed. These studies of selection facilitate identification of candidate genes for the phenotypes observed and lend a novel evolutionary dimension to the analysis of human cognitive architecture and neurogenetic disorders

Developmental malformation of the corpus callosum: a review of typical callosal development and examples of developmental disorders with callosal involvement

This review provides an overview of the involvement of the corpus callosum (CC) in a variety of developmental disorders that are currently defined exclusively by genetics, developmental insult, and/or behavior. I begin with a general review of CC development, connectivity, and function, followed by discussion of the research methods typically utilized to study the callosum. The bulk of the review concentrates on specific developmental disorders, beginning with agenesis of the corpus callosum (AgCC)—the only condition diagnosed exclusively by callosal anatomy. This is followed by a review of several genetic disorders that commonly result in social impairments and/or psychopathology similar to AgCC (neurofibromatosis-1, Turner syndrome, 22q11.2 deletion syndrome, Williams yndrome, and fragile X) and two forms of prenatal injury (premature birth, fetal alcohol syndrome) known to impact callosal development. Finally, I examine callosal involvement in several common developmental disorders defined exclusively by behavioral patterns (developmental language delay, dyslexia, attention-deficit hyperactive disorder, autism spectrum disorders, and Tourette syndrome)

Williams Syndrome and Music: A Systematic Integrative Review

Background: Researchers and clinicians have often cited a strong relationship between individuals with Williams syndrome (WS) and music. This review systematically identified, analyzed, and synthesized research findings related to WS and music.Methods: Thirty-one articles were identified that examined this relationship and were divided into seven areas. This process covered a diverse array of methodologies, with aims to: (1) report current findings; (2) assess methodological quality; and (3) discuss the potential implications and considerations for the clinical use of music with this population.Results: Results indicate that individuals with WS demonstrate a high degree of variability in skill and engagement in music, presenting with musical skills that are more in line with their cognitive abilities than chronological age (CA). Musical strengths for this population appear to be based more in musicality and expressivity than formal musical skills, which are expressed through a heightened interest in music, a greater propensity toward musical activities, and a heightened emotional responsiveness to music. Individuals with WS seem to conserve the overall structure of musical phrases better than they can discriminate or reproduce them exactly. The affinity for music often found in this population may be rooted in atypical auditory processing, autonomic irregularities, and differential neurobiology.Conclusions: More studies are needed to explore how this affinity for music can be harnessed in clinical and educational interventions