Fronto-parietal and cerebellar contributions to motor dysfunction in Williams syndrome: a review and future directions

Williams syndrome (WS) is a rare genetically based neurodevelopmental disorder which is associated with mental retardation and a distinctive cognitive and behavioural profile, including weaknesses in visuospatial processing but preserved language abilities and face recognition. Relative to the cognitive characteristics of WS, there is a dearth of research into the movement problems associated with this syndrome. This is despite the evidence from clinical and experimental studies that indicate disordered movement may be an important neuromotor characteristic of WS. This article reviews the current neuroanatomical and behavioural literature on visuomotor deficits in WS, and examines the differential role of fronto-parietal and cerebellar regions in motor dysfunction. The role of these brain regions in disturbances of visuomotor control is discussed in the context of the important interaction with attention, executive and planning deficits in WS. Finally, directions are provided for future research emphasising the need to examine developmental changes in motor functioning across a range of movement parameters and to investigate the functional correlates of abnormal neural connectivity in WS. It is concluded that further investigation of motor dysfunction in WS may provide us with a greater understanding of how important movement-related brain regions develop and operate.     

Epidemiological and clinical studies of West syndrome in Nagasaki Prefecture, Japan.

Recent advances in diagnostic and therapeutic techniques may have changed incidence and etiologies of West syndrome (WS). We performed a retrospective epidemiological study of WS that occurred in 47 children in Nagasaki Prefecture during a recent 10-year period from 1989 to 1998. The incidence of WS was 3.1/10,000 live births. Thirty-nine patients (83%) had symptomatic WS, in which the prenatal causes were most frequent, followed by low-birth weight (LBW) infants, perinatal and postnatal. Such high frequency of LBW may have been due to a relative increase in survivors of premature babies because of recent advances in perinatal care. The brain computerized tomography/magnetic resonance imaging performed in 41 patients revealed congenital brain malformation (10 patients), destructive brain disorders (13 patients), and no structural abnormalities (18 patients). The seizure outcome was worse in the symptomatic WS than in the cryptogenic WS. The developmental outcome was very poor in both symptomatic and cryptogenic WS. The mean developmental quotient (DQ) in all patients was 25, and only four patients (11%) had a normal DQ (>70). DQ was lower in patients with developmental delay before the onset of WS, symptomatic group, relapse and/or persistence of seizure. Developmental delay seen in WS patients seems to be related to the two major factors, that is, underlying brain abnormalities and the persistent seizures as a result of the former. Therefore, every effort should be made to control seizures, including medical and early surgical treatment, as well as prevention of brain damage through perinatal care.     

Linguistic heterogeneity in Williams syndrome

Williams syndrome (WS) is a rare genetic disorder resulting from a deletion on chromosome 7. A number of studies have shown that individuals with WS have a superior linguistic profile compared to their non-verbal abilities, however the evidence has been inconclusive, as many studies have disputed such a profile. The vast majority of studies on WS have assumed a single, homogeneous WS linguistic profile in order to support various theoretical viewpoints. The present study investigated the linguistic profiles of 5 individuals with WS on a number of standardized verbal measures and in conversational settings. The results indicated substantially variable performance in all aspects of the verbal domain, which supports the view that WS, linguistically, is a rather heterogeneous condition and this should be taken into consideration when referring to it in theoretical accounts of language acquisition and debates on modularity.     

Linguistic heterogeneity in Williams syndrome

Williams syndrome (WS) is a rare genetic disorder resulting from a deletion on chromosome 7. A number of studies have shown that individuals with WS have a superior linguistic profile compared to their non‐verbal abilities, however the evidence has been inconclusive, as many studies have disputed such a profile. The vast majority of studies on WS have assumed a single, homogeneous WS linguistic profile in order to support various theoretical viewpoints. The present study investigated the linguistic profiles of 5 individuals with WS on a number of standardized verbal measures and in conversational settings. The results indicated substantially variable performance in all aspects of the verbal domain, which supports the view that WS, linguistically, is a rather heterogeneous condition and this should be taken into consideration when referring to it in theoretical accounts of language acquisition and debates on modularity.     

Epidemiological and clinical study of West syndrome in Nagasaki Prefecture, Japan

To determine the occurrence, outcome, and prognostic factors of West syndrome (WS), we performed a retrospective epidemiological study of WS occurred in 47 children (26 boys and 21 girls) in Nagasaki prefecture during a recent 10-year period from 1989 to 1998. The incidence of WS was 3.1/10,000 live births. The mean age at onset of spasm is 6.3 months (range: 2 to 12 months). Thirty-nine patients (83%) had symptomatic WS, in which the prenatal causes (patients) were most frequent, followed by low-birth weight infants (patients), perinatal (patients) and postnatal (patients). The brain CT was performed in 37 patients, and revealed congenital brain malformations (9 patients), destructive brain disorders (12 patients), and no structural abnormalities (16 patients). The seizure outcome was worse in the symptomatic WS than in the cryptogenic WS; seizure/disappeared in 39% of the former and in 75% of the latter/developmental delay before the onset of WS, relapse of WS and persistence of seizures were associated with poor seizure outcomes. Among the remaining seizures at the time of this surveillance, a tonic seizure was most frequently observed, followed by the partial seizures. Lennox-Gastaut syndrome was observed in 2 patients only. Epileptic discharge in the latest interictal EEG were diffuse in 4.3%, focal or multifocal in 60.7%, and absent in 35%, suggesting that many patients with WS had cortical epileptogenic foci. The developmental outcome was very poor in both the symptomatic and cryptogenic WS. The mean DQ in all the patients was 25, and only 4 patients (11%) had a normal DQ (> 75). DQ was lower in patients with congenital brain malformations than in those with destructive brain disorders.     

Williams syndrome hypersociability: a neuropsychological study of the amygdala and prefrontal cortex hypotheses

Individuals with Williams syndrome display indiscriminate approach towards strangers. Neuroimaging studies conducted so far have linked this social profile to structural and/or functional abnormalities in WS amygdala and prefrontal cortex. In this study, the neuropsychological hypotheses of amygdala and prefrontal cortex involvement in WS hypersociability was explored using three behavioral tasks - facial emotional recognition task, a social approach task and a go no/go task. Thus, a group 15 individuals with Williams syndrome was compared to two groups of normal developing individuals - a group of 15 individuals matched for chronological age (CA) and 15 individuals matched for mental age (MA), and sex. Individuals with WS present a specific impairment in recognizing negative facial expressions and do not display impairments in response inhibition when compared with typically developing groups. Although these findings partially support the amygdala contribution to WS hypersociability, we found that general cognitive functioning predicted this performance. Additionally, individuals with WS did not differ from both CA and MA groups in the recognition of angry facial expressions, a finding suggesting that they are actually able to identify stimuli associated with social threat. Overall, the results seem to indicate that this social profile must be understood within a developmental framework.     

Item and error analysis on Raven's Coloured Progressive Matrices in Williams Syndrome

Raven's Coloured Progressive Matrices (RCPM) is a standardised test that is commonly used to obtain a non-verbal reasoning score for children. As the RCPM involves the matching of a target to a pattern it is also considered to be a visuo-spatial perception task. RCPM is therefore frequently used in studies in Williams Syndrome (WS), in order to match WS participants to a control group or as a single measure to predict performance on a test-condition in developmental trajectory analyses. However, little is known about the performance of participants with WS on the RCPM. The current study compared the type of errors and the difficulty of each item for 53 participants with WS to 53 typically developing children who were individually matched on the total raw score for RCPM. Results showed that the participants with WS made the same proportion of error types and that the proportion of error types changed similarly to those of typically developing controls over development. Furthermore, the differential item difficulty between the two groups was highly similar. It is therefore argued that, although participants with WS are delayed on RCPM, their performance is not atypical which suggests that RCPM performance is supported by typical mechanisms. The RCPM is therefore a useful tool to match WS to control groups or to construct developmental trajectories.     

MR evidence of structural and metabolic changes in brains of patients with Werner’s syndrome

Abstract. Objective: To assess CNS abnormalities in patients with Werners syndrome (WS) using MR metrics specific for tissue damage. Background: WS is a rare autosomal recessive disorder that causes premature aging. The CNS involvement in this disease is still debated. Methods: Two siblings who showed signs of neurological involvement underwent MR spectroscopic imaging (MRSI) and magnetization transfer (MT) imaging. Also, on conventional T₁-weighted MR images, measurements of total brain volume were performed. Results: Conventional MR images of both WS patients did not show abnormalities on visual inspection. However, both WS patients showed significantly lower values of normalized total brain volume and MT ratio in the white matter than agematched normal controls. Also, proton MRSI showed significantly lower values of central brain NAA/Cr in WS patients than in normal controls. Conclusions: Our findings suggest that, despite normal appearance on conventional MRI, diffuse structural and metabolic tissue damage can be demonstrated in WS brains by means of sensitive MR methods even in patients with moderate or subclinical CNS involvement.     

Brain stem reflexes in patients with Wallenberg's syndrome: Correlation with clinical and magnetic resonance imaging (MRI) findings

In spite of the general clinical uniformity of Wallenberg's syndrome (WS), individual patients present with a slightly different clinical picture, and detailed studies with magnetic resonance imaging (MRI) show differences in the topography of the brain stem lesion. Neurophysiological characterization of the lesion in WS has been known for a long time, but there are no studies on the possible correlation between lesion topography and neurophysiological deficit. Assuming that afferents from the three branches of the trigeminal nerve reach different parts of the trigeminal nuclei, we examined the possible correlation between the lesion topography assessed by the MRI and the neurophysiological deficit, assessed by studying the brain stem reflexes in patients with WS within 2 weeks after stroke. Neurophysiological abnormalities were always located in the afferent branch of the reflexes examined, but not all patients exhibited abnormalities in all responses. The ophthalmic branch was involved in 92.8% of patients, and the mandibular branch in 57.1% of patients. The patients with MRI lesions located in the lower medulla had normal responses with infraorbital or mental nerve stimulation. The results of this neurophysiological study confirm the heterogeneity of WS. Whether the neurophysiological identification of different subgroups of patients is relevant for clinical outcome needs further studies. © 1996 John Wiley & Sons, Inc.     

Amygdala response to faces parallels social behavior in Williams syndrome

Individuals with Williams syndrome (WS), a genetically determined disorder, show relatively strong face-processing abilities despite poor visuospatial skills and depressed intellectual function. Interestingly, beginning early in childhood they also show an unusually high level of interest in face-to-face social interaction. We employed functional magnetic resonance imaging (fMRI) to investigate physiological responses in face-sensitive brain regions, including ventral occipito-temporal cortex and the amygdala, in this unique genetic disorder. Participants included 17 individuals with WS, 17 age- and gender-matched healthy adults (chronological age-matched controls, CA) and 17 typically developing 8- to 9-year-old children (developmental age controls, DA). While engaged in a face discrimination task, WS participants failed to recruit the amygdala, unlike both CA and DA controls. WS fMRI responses in ventral occipito-temporal cortex, however, were comparable to those of DA controls. Given the integral role of the amygdala in social behavior, the failure of WS participants to recruit this region during face processing may be a neural correlate of the abnormally high sociability that characterizes this disorder.     

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.     

Effect of musical experience on verbal memory in Williams syndrome: evidence from a novel word learning task

Williams syndrome (WS) is a neurogenetic developmental disorder characterized by an increased affinity for music, deficits in verbal memory, and atypical brain development. Music has been shown to improve verbal memory in typical individuals as well as those with learning difficulties, but no studies have examined this relationship in WS. The aim of our two studies was to examine whether music can enhance verbal memory in individuals with WS. In Study 1, we presented a memory task of eight spoken or sung sentences that described an animal and identified its group name to 38 individuals with WS. Study 2, involving another group of individuals with WS (n = 38), included six spoken or sung sentences that identified an animal group name. In both studies, those who had participated in formal music lessons scored significantly better on the verbal memory task when the sentences were sung than when they were spoken. Those who had not taken formal lessons showed no such benefit. We also found that increased enjoyment of music and heightened emotional reactions to music did not impact performance on the memory task. These compelling findings provide the first evidence that musical experience may enhance verbal memory in individuals with WS and shed more light on the complex relationship between aspects of cognition and altered neurodevelopment in this unique disorder.     

How do the many etiologies of West syndrome lead to excitability and seizures? The corticotropin releasing hormone excess hypothesis.

West syndrome (WS) is associated with diverse etiological factors. This fact has suggested that there must be a 'final common pathway' for these etiologies, which operates on the immature brain to result in WS only at the maturational state present during infancy. Any theory for the pathogenesis of WS has to account for the unique features of this disorder. For example, how can a single entity have so many etiologies? Why does WS arise only in infancy, even when a known insult had occurred prenatally, and why does it disappear? Why is WS associated with lasting cognitive dysfunction? And, importantly, why do these seizures--unlike most others--respond to treatment by a hormone, ACTH? The established hormonal role of ACTH in human physiology is to function in the neuroendocrine cascade of the responses to all stressful stimuli, including insults to the brain. As part of this function, ACTH is known to suppress the production of corticotropin releasing hormone (CRH), a peptide that is produced in response to diverse insults and stressors.The many etiologies of WS all lead to activation of the stress response, including increased production and secretion of the stress-neurohormone CRH. CRH has been shown, in infant animal models, to cause severe seizures and death of neurons in areas involved with learning and memory. These effects of CRH are restricted to the infancy period because the receptors for CRH, which mediate its action on neurons, are most abundant during this developmental period. ACTH administration is known to inhibit production and release of CRH via a negative feedback mechanism. Therefore, the efficacy of ACTH for WS may depend on its ability to decrease the levels of the seizure-promoting stress-neurohormone CRH.This CRH-excess theory for the pathophysiology of WS is consistent not only with the profile of ACTH effects, but also with the many different 'causes' of WS, with the abnormal ACTH levels in the cerebrospinal fluid of affected infants and with the spontaneous disappearance of the seizures. Furthermore, if CRH is responsible for the seizures, and CRH-mediated neuronal injury contributes to the worsened cognitive outcome of individuals with WS, then drugs which block the actions of CRH on its receptors may provide a better therapy for this disorder.     

The neuroanatomy of the autistic phenotype

The autism phenotype is associated with an excess of brain volume due in part to decreased pruning during development. Here we aimed at assessing brain volume early in development to further elucidate previous findings in autism and determine whether this pattern is restricted to idiopathic autism or shared within the autistic phenotype (fragile X syndrome [FXS]). We investigated brain volume in 37 participants, using the fully automated Civet pipeline anatomical magnetic resonance imaging. 3 groups with intellectual deficiency: autism (AUT); its most associated FXS; and its most opposite Williams syndrome (WS) were compared with each other and with normal controls (NC). We report increased total and regional gray and white matter brain volume in AUT and FXS relative to WS and NC. These findings are discussed in light of the possibilities leading for the enlarged brain volume in children with the AUT phenotype. We speculate that this excess suggests reduced regression of neuronal processes “pruning” in cortical and subcortical regions in AUT/FXS, which may be due to a mutation in specific genes involved in pruning and/or a lack of socio-emotional environmental experience during a critical developmental period.     

What have we learned about cognitive development from neuroimaging?

Changes in many domains of cognition occur with development. In this paper, we discuss neuroimaging approaches to understanding these changes at a neural level. We highlight how modern imaging methods such as functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) are being used to examine how cognitive development is supported by the maturation of the brain. Some reports suggest developmental changes in patterns of brain activity appear to involve a shift from diffuse to more focal activation, likely representing a fine-tuning of relevant neural systems with experience. One of the challenges in investigating the interplay between cognitive development and maturation of the brain is to separate the contributions of neural changes specific to development and learning. Examples are given from the developmental neuroimaging literature. The focus is on the development of cognitive control, as the protracted developmental course of this ability into adolescence raises key issues. Finally, the relevance of normative studies for understanding neural and cognitive changes in developmental disorders is discussed.     

Morphological differences in the mirror neuron system in Williams syndrome

Williams syndrome (WS) is a genetic condition characterized by an overly gregarious personality, including high empathetic concern for others. Although seemingly disparate from the profile of autism spectrum disorder (ASD), both are associated with deficits in social communication/cognition. Notably, the mirror neuron system (MNS) has been implicated in social dysfunction for ASD; yet, the integrity of this network and its association with social functioning in WS remains unknown. Magnetic resonance imaging (MRI) methods were used to examine the structural integrity of the MNS of adults with WS versus typically developing (TD) individuals. The Social Responsiveness Scale (SRS), a tool typically used to screen for social features of ASD, was also employed to assess the relationships between social functioning with the MNS morphology in WS participants. WS individuals showed reduced cortical surface area of MNS substrates yet relatively preserved cortical thickness as compared to TD adults. Increased cortical thickness of the inferior parietal lobule (IPL) was associated with increased deficits in social communication, social awareness, social cognition, and autistic mannerisms. However, social motivation was not related to anatomical features of the MNS. Our findings indicate that social deficits typical to both ASD and WS may be attributed to an aberrant MNS, whereas the unusual social drive marked in WS is subserved by substrates distinct from this network.     

Interpretation of Ambiguous Situations: Evidence for a Dissociation Between Social and Physical Threat in Williams Syndrome

Williams syndrome (WS) is associated with an unusual profile of anxiety, characterised by increased rates of non-social anxiety but not social anxiety (Dodd and Porter, J Ment Health Res Intellect Disabil 2(2):89–109, 2009). The present research examines whether this profile of anxiety is associated with an interpretation bias for ambiguous physical, but not social, situations. Sixteen participants with WS, aged 13–34 years, and two groups of typically developing controls matched to the WS group on chronological age (CA) and mental age (MA), participated. Consistent with the profile of anxiety reported in WS, the WS group were significantly more likely to interpret an ambiguous physical situation as threatening than both control groups. However, no between-group differences were found on the ambiguous social situations.     

The cross‐sectional interplay between neurochemical profile and brain connectivity

Neurochemical profile and brain connectivity are both critical aspects of brain function. However, our knowledge of their interplay across development is currently poor. We combined single‐voxel magnetic resonance spectroscopy and resting functional magnetic resonance imaging in a cross‐sectional sample spanning from childhood to adulthood which was reassessed in ~1.5 years (N = 293). We revealed the developmental trajectories of 20 neurochemicals in two key developmental brain regions (the intraparietal sulcus, IPS, and the middle frontal gyrus, MFG). We found that certain neurochemicals exhibited similar developmental trajectories across the two regions, while other trajectories were region‐specific. Crucially, we mapped the connectivity of the brain regions IPS and MFG to the rest of the brain across development as a function of regional glutamate and GABA concentration. We demonstrated that glutamate concentration within the IPS is modulated by age in explaining IPS connectivity with frontal, temporal and parietal regions. In mature participants, higher glutamate within the IPS was related to more negative connectivity while the opposite pattern was found for younger participants. Our findings offer specific developmental insights on the interplay between the brain''s resting activity and the glutamatergic system both of which are crucial for regulating normal functioning and are dysregulated in several clinical conditions.     

Texture segmentation in Williams syndrome

Williams syndrome (WS) is a developmental disorder in which visuo-spatial cognition is poor relative to verbal ability. At the level of visuo-spatial perception, individuals with WS can perceive both the local and global aspects of an image. However, the manner in which local elements are integrated into a global whole is atypical, with relative strengths in integration by luminance, closure, and alignment compared to shape, orientation and proximity. The present study investigated the manner in which global images are segmented into local parts. Segmentation by seven gestalt principles was investigated: proximity, shape, luminance, orientation, closure, size (and alignment: Experiment 1 only). Participants were presented with uniform texture squares and asked to detect the presence of a discrepant patch (Experiment 1) or to identify the form of a discrepant patch as a capital E or H (Experiment 2). In Experiment 1, the pattern and level of performance of the WS group did not differ from that of typically developing controls, and was commensurate with the general level of non-verbal ability observed in WS. These results were replicated in Experiment 2, with the exception of segmentation by proximity, where individuals with WS demonstrated superior performance relative to the remaining segmentation types. Overall, the results suggest that, despite some atypical aspects of visuo-spatial perception in WS, the ability to segment a global form into parts is broadly typical in this population. In turn, this informs predictions of brain function in WS, particularly areas V1 and V4.     

Toddlers with Williams Syndrome Process Upright but not Inverted Faces Holistically

Holistic processing of upright, but not inverted, faces is a marker of perceptual expertise for faces. This pattern is shown by typically developing individuals beginning at age 7 months. Williams syndrome (WS) is a rare neurogenetic developmental disorder characterized by extreme interest in faces from a very young age. Research on the effects of inversion on holistic processing of faces by older children and adults with WS has produced mixed results. Younger children with WS were not included in these previous studies. Using the habituation switch paradigm, we demonstrated that 15–35-month-olds with WS process upright, but not inverted, faces holistically. This study provides evidence of perceptual expertise for faces in individuals with WS early in life.