Debra L. Mills

Bridging cognition, the brain and molecular genetics: evidence from Williams syndrome

Williams syndrome (WMS) is a rare sporadic disorder that yields a distinctive profile of medical, cognitive, neurophysiological, neuroanatomical and genetic characteristics. The cognitive hallmark of WMS is a dissociation between language and face processing (relative strengths) and spatial cognition (profound impairment). Individuals with WMS also tend to be overly social, behavior that is opposite to that seen in autism. A genetic hallmark of WMS is a deletion on chromosome band 7q11.23. Williams syndrome is also associated with specific neuromorphological and neurophysiological profiles: proportional sparing of frontal, limbic and neocerebellar structures is seen using MRI; and abnormal functional organization of the neural systems that underlie both language and face processing is revealed through studies using event-related potentials. The non-uniformity in the cognitive, neuromorphological and neurophysiological domains of WMS make it a compelling model for elucidating the relationships between cognition, the brain and, ultimately, the genes.

Abnormal Cortical Complexity and Thickness Profiles Mapped in Williams Syndrome

We identified and mapped an anatomically localized failure of cortical maturation in Williams syndrome (WS), a genetic condition associated with deletion of ∼20 contiguous genes on chromosome 7. Detailed three-dimensional (3D) maps of cortical thickness, based on magnetic resonance imaging (MRI) scans of 164 brain hemispheres, identified a delimited zone of right hemisphere perisylvian cortex that was thicker in WS than in matched controls, despite pervasive gray and white matter deficits and reduced total cerebral volumes. 3D cortical surface models were extracted from 82 T1-weighted brain MRI scans (256 × 192 × 124 volumes) of 42 subjects with genetically confirmed WS (mean ± SD, 29.2 ± 9.0 years of age; 19 males, 23 females) and 40 age-matched healthy controls (27.5 ± 7.4 years of age; 16 males, 24 females). A cortical pattern-matching technique used 72 sulcal landmarks traced on each brain as anchors to align cortical thickness maps across subjects, build group average maps, and identify regions with altered cortical thickness in WS. Cortical models were remeshed in frequency space to compute their fractal dimension (surface complexity) for each hemisphere and lobe. Surface complexity was significantly increased in WS (p < 0.0015 and p < 0.0014 for left and right hemispheres, respectively) and correlated with temporoparietal gyrification differences, classified via Steinmetz criteria. In WS, cortical thickness was increased by 5-10% in a circumscribed right hemisphere perisylvian and inferior temporal zone (p < 0.002). Spatially extended cortical regions were identified with increased complexity and thickness; cortical thickness and complexity were also positively correlated in controls (p < 0.03). These findings visualize cortical zones with altered anatomy in WS, which merit additional study with techniques to assess function and connectivity.

Language comprehension and cerebral specialization from 13 to 20 months

The purpose of this study was to examine developmental changes in the organization of brain activity linked to comprehension of single words in 13‐ to 20‐month‐old infants. Event‐related potentials (ERPs) were recorded as children listened to a series of words whose meanings were understood by the child, words whose meanings the child did not understand, and backward words. The results were consistent with a previous study suggesting that ERPs differed as a function of word meaning within 200 ms after word onset. At 13 to 17 months, ERP differences between comprehended and unknown words were bilateral and broadly distributed over anterior and posterior regions. In contrast, at 20 months of age these effects were limited to temporal and parietal regions of the left hemisphere. The results are discussed in relation to the general effects of maturation, the maturation of language‐relevant brain systems, and the development of brain systems linked to level of ability independent of chronological age. We offer...

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.

Language acquisition and cerebral specialization in 20-month-old infants

The purpose of the present study was to examine patterns of neural activity relevant to language processing in 20-month-old infants, and to determine whether or not changes in cerebral organization occur as a function of specific changes in language development. Event-related potentials (ERPs) were recorded as children listened to a series of words whose meaning was understood by the child, words whose meaning the child did not understand, and backward words. The results showed that specific and different ERP components discriminated comprehended words from unknown and from backward words. Distinct lateral and anterior-posterior specializations were apparent in EW responsiveness to the different types of words. Moreover, the results suggested that increasing language abilities were associated with increasing cerebral specialization for language processing over the temporal and parietal regions of the left hemisphere.

3D pattern of brain abnormalities in Williams syndrome visualized using tensor-based morphometry.

UNLABELLED Williams syndrome (WS) is a neurodevelopmental disorder associated with deletion of approximately 20 contiguous genes in chromosome band 7q11.23. Individuals with WS exhibit mild to moderate mental retardation, but are relatively more proficient in specific language and musical abilities. We used tensor-based morphometry (TBM) to visualize the complex pattern of gray/white matter reductions in WS, based on fluid registration of structural brain images. METHODS 3D T1-weighted brain MRIs of 41 WS subjects (age [mean+/-SD]: 29.2+/-9.2 years; 23F/18M) and 39 age-matched healthy controls (age: 27.5+/-7.4 years; 23F/16M) were fluidly registered to a minimum deformation target. Fine-scale volumetric differences were mapped between diagnostic groups. Local regions were identified where regional structure volumes were associated with diagnosis, and with intelligence quotient (IQ) scores. Brain asymmetry was also mapped and compared between diagnostic groups. RESULTS WS subjects exhibited widely distributed brain volume reductions (approximately 10-15% reduction; P<0.0002, permutation test). After adjusting for total brain volume, the frontal lobes, anterior cingulate, superior temporal gyrus, amygdala, fusiform gyrus and cerebellum were found to be relatively preserved in WS, but parietal and occipital lobes, thalamus and basal ganglia, and midbrain were disproportionally decreased in volume (P<0.0002). These regional volumes also correlated positively with performance IQ in adult WS subjects (age > or = 30 years, P = 0.038). CONCLUSION TBM facilitates 3D visualization of brain volume reductions in WS. Reduced parietal/occipital volumes may be associated with visuospatial deficits in WS. By contrast, frontal lobes, amygdala, and cingulate gyrus are relatively preserved or even enlarged, consistent with unusual affect regulation and language production in WS.

Defining the Social Phenotype in Williams Syndrome: A Model for Linking Gene, the Brain, and Behavior

Research into phenotype-genotype correlations in neurodevelopmental disorders has greatly elucidated the contribution of genetic and neurobiological factors to variations in typical and atypical development. Etiologically relatively homogeneous disorders, such as Williams syndrome (WS), provide unique opportunities for elucidating gene-brain-behavior relationships. WS is a neurogenetic disorder caused by a hemizygous deletion of approximately 25 genes on chromosome 7q11.23. This results in a cascade of physical, cognitive-behavioral, affective, and neurobiological aberrations. WS is associated with a markedly uneven neurocognitive profile, and the mature state cognitive profile of WS is relatively well developed. Although anecdotally, individuals with WS have been frequently described as unusually friendly and sociable, personality remains a considerably less well studied area. This paper investigates genetic influences, cognitive-behavioral characteristics, aberrations in brain structure and function, and environmental and biological variables that influence the social outcomes of individuals with WS. We bring together a series of findings across multiple levels of scientific enquiry to examine the social phenotype in WS, reflecting the journey from gene to the brain to behavior. Understanding the complex multilevel scientific perspective in WS has implications for understanding typical social development by identifying important developmental events and markers, as well as helping to define the boundaries of psychopathology.

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.

Language Experience and the Organization of Brain Activity to Phonetically Similar Words: ERP Evidence from 14- and 20-Month-Olds

The ability to discriminate phonetically similar speech sounds is evident quite early in development. However, inexperienced word learners do not always use this information in processing word meanings Stager & Werker (1997). Nature, 388, 381382. The present study used event-related potentials (ERPs) to examine developmental changes from 14 to 20 months in brain activity important in processing phonetic detail in the context of meaningful words. ERPs were compared to three types of words: words whose meanings were known by the child (e.g., bear), nonsense words that differed by an initial phoneme (e.g., gare), and nonsense words that differed from the known words by more than one phoneme (e.g., kobe). These results supported the behavioral findings suggesting that inexperienced word learners do not use information about phonetic detail when processing word meanings. For the 14-month-olds, ERPs to known words (e.g., bear) differed from ERPs to phonetically dissimilar nonsense words (e.g., kobe), but did not differ from ERPs to phonetically similar nonsense words (e.g., gare), suggesting that known words and similar mispronunciations were processed as the same word. In contrast, for experienced word learners (i.e., 20-month-olds), ERPs to known words (e.g., bear) differed from those to both types of nonsense words (gare and kobe). Changes in the lateral distribution of ERP differences to known and unknown (nonce) words between 14 and 20 months replicated previous findings. The findings suggested that vocabulary development is an important factor in the organization of neural systems linked to processing phonetic detail within the context of word comprehension.

Evidence for superior parietal impairment in Williams syndrome

Parietal lobe impairment is hypothesized to contribute to the dramatic visual-spatial deficits in Williams syndrome (WS). The authors examined the superior and inferior parietal lobule in 17 patients with WS and 17 control female adults (CNLs). The right and left superior parietal lobule gray matter volumes were significantly smaller in patients with WS than in CNLs, even after controlling for total cerebral gray matter. Impaired superior parietal function could explain WS visual-spatial and visual-motor problems.