The Section on Integrative Neuroimaging of the Clinical Brain Disorders Branch employs multimodal neuroimaging methodologies, functional magnetic resonance imaging (fMRI), structural magnetic resonance imaging (MRI), and positron emission tomography (PET) to help characterize the specific neurocognitive deficits that are seen in people with Williams syndrome (WS). Studying this rare genetically based neurodevelopmental disorder, which has a well characterized hemideletion containing some 20 contiguous genes on chromosome 7 in addition to well-characterized cognitive and social phenotypes, allows us to closely examine: 1) the function, structure, and organization of cognitive systems; 2) various genetic determinants of visuospatial constructive function; and 3) the genetic factors that may influence social cognition and behavior. Each of our studies compares high functioning groups of people with Williams syndrome with healthy normal controls. These comparison groups are matched for age, sex, handedness, and IQ scores. By controlling these variables, we eliminate the possibility that factors such as mental retardation or developmental level would influence interpretation of results. Our multimodal neuroimaging approach incorporates various methodologies that are noted for their rigor and sensitivity and that address specific concerns of analyzing brain images from special populations. Over the past year, we have begun to characterize intermediate brain phenotypes that are unique to WS patients when compared to normal healthy controls. In a study aimed at exploring the neural basis for a genetically determined visuospatial construction deficit, our findings have demonstrated effects of a localized abnormality on visual information processing pathway in WS. By having our participants perform a series of fMRI experiments designed to access visual system function at several levels of processing hierarchy followed by examining the morphology of the brain, we were able to link abnormalities in a localized structural and functional parietal region of the dorsal stream, giving rise to a neural systems-level phenotype for WS which may be used as a model for determination of the molecular mechanism of the visuospatial construction deficit. In another study, we examined the role of the amygdala (the brain region that processes emotions) and its connections in abnormal social behavior commonly observed in those with WS. The amygdala's response and regulation are thought to be central to socially protective neural processing through monitoring environmental events such as danger. It has been reported that lesions of the amygdala and associated regions, such as the orbitofrontal cortex (OFC), impair social function and therefore can cause disinhibition. Our fMRI analyses demonstrate reduced amygdala activation in persons with WS for threatening faces, but showed increased activation for threatening scenes. Activation and interactions of prefrontal brain regions linked to amygdala were abnormal; these regions (dorsolateral prefrontal cortex (DLPFC), medial prefrontal cortex (MPFC), and OFC) may exert indirect influence suggesting a genetically controlled neural circuitry for regulating human social behavior. To further characterize WS intermediate phenotypes, we examined the functional, structural, and metabolic abnormalities of hippocampal formation (HF) in our special population. Deficits in spatial navigation, long-term memory, and major cognitive domains depend on hippocampal function suggesting involvement of the HF in the pathophysiology of WS. Recent studies of mice lacking the LIM Kinase 1 (LIMK1) and cytoplasmic linker protein 2 (CYLN2) genes demonstrated significant functional and metabolic abnormalities in the hippocampus while structural integrity of the HF was grossly maintained while only showing subtly altered shape. Our PET and fMRI studies showed profound reduction in resting cerebral blood flow (rCBF) which is indicative of disorders having an impact on hippocampal integrity and neural function as seen with early Alzheimers disease. Measures of N-acetyl aspirate, the biological marker for synaptic activity were reduced indicating reduced excitation of the glutamatergic transporters and receptors. These data implicate LIMK1 and CYLN2 in human hippocampal function as demonstrated in the mouse model and suggests that hippocampal dysfunction may contribute to neurocognitive abnormalities described in WS. We also explored the genetic contributions to human gyrification by examining sulcal morphology in our subjects with WS. To date, very little is known about the genetics or abnormal gyrification or the resulting functional consequences. Using our two matched study groups, participants with WS and normal healthy controls we compared group differences with those obtained from a voxel-based morphometry analysis (VBM). Our findings revealed significant reductions in depth in the intraparietal/occipitoparietal sulcus (PS), orbitofrontal region and the left collateral sulcus. We have also demonstrated locally high variance in structure of the left PS region in WS participants as compared with controls. These morphological changes may be attributed to pathological processes consistent with the visuoconstructive deficit that is the unique neuropsychological feature of WS.
| Marenco, Stefano; Siuta, Michael A; Kippenhan, J Shane et al. (2007) Genetic contributions to white matter architecture revealed by diffusion tensor imaging in Williams syndrome. Proc Natl Acad Sci U S A 104:15117-22 |
| Meyer-Lindenberg, Andreas; Hariri, Ahmad R; Munoz, Karen E et al. (2005) Neural correlates of genetically abnormal social cognition in Williams syndrome. Nat Neurosci 8:991-3 |
| Meyer-Lindenberg, Andreas; Mervis, Carolyn B; Sarpal, Deepak et al. (2005) Functional, structural, and metabolic abnormalities of the hippocampal formation in Williams syndrome. J Clin Invest 115:1888-95 |
| Kippenhan, J Shane; Olsen, Rosanna K; Mervis, Carolyn B et al. (2005) Genetic contributions to human gyrification: sulcal morphometry in Williams syndrome. J Neurosci 25:7840-6 |
| Meyer-Lindenberg, Andreas; Kohn, Philip; Mervis, Carolyn B et al. (2004) Neural basis of genetically determined visuospatial construction deficit in Williams syndrome. Neuron 43:623-31 |
