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 having a well characterized hemideletion containing some 20 contiguous genes on chromosome 7, and having well characterized cognitive and social phenotypes allows us to closely examine: 1) genetic determinants of the function, structure, and organization of neural systems relevant to cognition and behavior, in general; 2) the neural basis of genetically-determined of visuospatial constructive abilities; and 3) the neural mechanism by which genetic factors influence social cognition and behavior. Each of our studies compares high functioning groups of people with WS 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 to address specific concerns of analyzing brain images from special populations. Over the past year, we have made significant progress in characterizing 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 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 that is 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. It is also noted that activation and interactions of prefrontal brain regions linked to amygdala were abnormal and that 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 MRI studies showed profound reduction in resting cerebral blood flow (rCBF) which is indicative of disorders having an impact on hippocampal integrity and neural function. Measures of N-acetyl aspirate, the biological marker for synaptic activity were reduced indicating reduced excitation of the glutamatergic transporters and receptors. In contrast to these marked functional deficits, structural abnormalities of the HF in Williams syndrome were subtle and consisted of a change in the anterior-posterior distribution of HF volume. These data implicate LIMK1 and CYLN2 in human hippocampal function as was demonstrated in the mouse model and suggests that hippocampal abnormalities may contribute to neurocognitive abnormalities described in WS. We also explored the genetic contributions to human cerebral 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. Most recently, we reviewed the current advances for examining the functional and structural neural mechanisms specifically altered in WS. We have identified specific neural mechanisms that are more than likely associated to the unique behavioral phenotype of this condition. Data have consistently shown that WS is the result of complex interplay between these altered neural systems most likely during brain development. Our continued research will delve into a more detailed mechanistic inquiry of specific mechanisms for executive and social cognition by examining individual genes and gene-gene interactions using animal models and special populations. In addition, we hope to pursue developmental studies which investigate the time course for the emergence of WS and modifications of altered neural circuitry. Because this rare condition offers an unprecedented view into the genetic mechanisms underlying complex behavior, the potential research and clinical impact will extend beyond those with 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 |
