Methods for analysis of data representing concentration profiles of platelet analogues in blood flow

Methods for the estimation of particle concentration profiles from numerical data are presented. The estimation techniques described, which involve the use of Fourier transforms, make more efficient use of data than do simple histogram techniques. Additionally, Fourier methods of analysis have been used to test theoretical models of experimental data

Optimization and evaluation of a neural network classifier for PET scans of memory disorder subjects

Back-propagation neural networks were used to classify PET scans as either normal or abnormal, with abnormal subjects defined as subjects who had previously been clinically diagnosed with memory disorders. Numerous neural network experiments were performed in order to achieve optimization with respect to number of hidden units and training duration. Optimizations and performance evaluations were based on ROC analysis, in which the area under the ROC curve was the figure of merit. The neural network's performance was better than that of dlscrlminant analysis, and comparable to the expert's performance, despite the low resolution image data, which consisted of one value per brain lobe, provided to the network

Evaluation of a neural-network classifier for PET scans of normal and Alzheimer's disease subjects

The value of PET as an objective diagnostic tool for dementia may depend on the degree to which abnormal metabolic patterns can be detected by quantitative classification methods. In these studies, a neural-network classifier based on coarse region of interest analyses was used to classify normal and abnormal FDG-PET scans. The performance of neural networks and of an expert reader were evaluated by cross validation testing. When the "abnormal" class was represented by subjects with clinical diagnoses of "Probable Alzheimer's," the areas under the relative-operating-characteristic (ROC) curves were 0.85 and 0.89 for the neural network and the expert reader, respectively. When testing with abnormal subjects represented by "Possible AD" cases, ROC areas for both the network and the expert were 0.81. The neural network out-performed discriminant analysis. It is concluded that PET has potential for the detection of abnormal brain function in dementing diseases, and that the combination of neural networks and PET is a useful diagnostic tool. Despite the low-resolution "view" afforded the neural network, its performance was nearly equivalent to that of an expert reader

Contrasting neurofunctional correlates of face- and visuospatial-processing in children and adolescents with Williams syndrome: convergent results from four fMRI paradigms.

Funder: National Institute of Mental Health (NIMH)Understanding neurogenetic mechanisms underlying neuropsychiatric disorders such as schizophrenia and autism is complicated by their inherent clinical and genetic heterogeneity. Williams syndrome (WS), a rare neurodevelopmental condition in which both the genetic alteration (hemideletion of ~ twenty-six 7q11.23 genes) and the cognitive/behavioral profile are well-defined, offers an invaluable opportunity to delineate gene-brain-behavior relationships. People with WS are characterized by increased social drive, including particular interest in faces, together with hallmark difficulty in visuospatial processing. Prior work, primarily in adults with WS, has searched for neural correlates of these characteristics, with reports of altered fusiform gyrus function while viewing socioemotional stimuli such as faces, along with hypoactivation of the intraparietal sulcus during visuospatial processing. Here, we investigated neural function in children and adolescents with WS by using four separate fMRI paradigms, two that probe each of these two cognitive/behavioral domains. During the two visuospatial tasks, but not during the two face processing tasks, we found bilateral intraparietal sulcus hypoactivation in WS. In contrast, during both face processing tasks, but not during the visuospatial tasks, we found fusiform hyperactivation. These data not only demonstrate that previous findings in adults with WS are also present in childhood and adolescence, but also provide a clear example that genetic mechanisms can bias neural circuit function, thereby affecting behavioral traits

Functional, structural, and metabolic abnormalities of the hippocampal formation in Williams syndrome

Williams syndrome (WS), caused by microdeletion of some 21 genes on chromosome 7q11.23, is characterized by dysmorphic features, mental retardation or learning difficulties, elastin arteriopathy, and striking neurocognitive and social-behavioral abnormalities. Recent studies of murine knockouts of key genes in the microdeleted region, LIM kinase 1 (LIMK1) and cytoplasmatic linker protein 2 (CYLN2), demonstrated significant functional and metabolic abnormalities, but grossly normal structure, in the hippocampal formation (HF). Furthermore, deficits in spatial navigation and long-term memory, major cognitive domains dependent on hippocampal function, have been described in WS. We used multimodal neuroimaging to characterize hippocampal structure, function, and metabolic integrity in 12 participants with WS and 12 age-, sex-, and IQ-matched healthy controls. PET and functional MRI studies showed profound reduction in resting blood flow and absent differential response to visual stimuli in the anterior HF in WS. Spectroscopic measures of N-acetyl aspartate, considered a marker of synaptic activity, were reduced. Hippocampal size was preserved, but subtle alterations in shape were present. These data demonstrate abnormalities in HF in WS in agreement with murine models, implicate LIMK1 and CYLN2 in human hippocampal function, and suggest that hippocampal dysfunction may contribute to neurocognitive abnormalities in WS

Dorsal visual stream and LIMK1: hemideletion, haplotype, and enduring effects in children with Williams syndrome

Abstract Background Williams syndrome (WS), a rare neurodevelopmental disorder caused by hemizygous deletion of ~ 25 genes from chromosomal band 7q11.23, affords an exceptional opportunity to study associations between a well-delineated genetic abnormality and a well-characterized neurobehavioral profile. Clinically, WS is typified by increased social drive (often termed “hypersociability”) and severe visuospatial construction deficits. Previous studies have linked visuospatial problems in WS with alterations in the dorsal visual processing stream. We investigated the impacts of hemideletion and haplotype variation of LIMK1, a gene hemideleted in WS and linked to neuronal maturation and migration, on the structure and function of the dorsal stream, specifically the intraparietal sulcus (IPS), a region known to be altered in adults with WS. Methods We tested for IPS structural and functional changes using longitudinal MRI in a developing cohort of children with WS (76 visits from 33 participants, compared to 280 visits from 94 typically developing age- and sex-matched participants) over the age range of 5–22. We also performed MRI studies of 12 individuals with rare, shorter hemideletions at 7q11.23, all of which included LIMK1. Finally, we tested for effects of LIMK1 variation on IPS structure and imputed LIMK1 expression in two independent cohorts of healthy individuals from the general population. Results IPS structural (p < 10−4 FDR corrected) and functional (p < .05 FDR corrected) anomalies previously reported in adults were confirmed in children with WS, and, consistent with an enduring genetic mechanism, were stable from early childhood into adulthood. In the short hemideletion cohort, IPS deficits similar to those in WS were found, although effect sizes were smaller than those found in WS for both structural and functional findings. Finally, in each of the two general population cohorts stratified by LIMK1 haplotype, IPS gray matter volume (p discovery < 0.05 SVC, p replication = 0.0015) and imputed LIMK1 expression (p discovery = 10−15, p replication = 10−23) varied according to LIMK1 haplotype. Conclusions This work offers insight into neurobiological and genetic mechanisms responsible for the WS phenotype and also more generally provides a striking example of the mechanisms by which genetic variation, acting by means of molecular effects on a neural intermediary, can influence human cognition and, in some cases, lead to neurocognitive disorders

Midbrain dopamine and prefrontal function in humans: Interaction and modulation by COMT genotype

Using multimodal neuroimaging in humans, we demonstrate specific interactions between prefrontal activity and midbrain dopaminergic synthesis. A common V(108/158)M substitution in the gene for catecholamine-O-methyltransferase (COMT), an important enzyme regulating prefrontal dopamine turnover, predicted reduced dopamine synthesis in midbrain and qualitatively affected the interaction with prefrontal cortex. These data implicate a dopaminergic tuning mechanism in prefrontal cortex and suggest a systems-level mechanism for cognitive and neuropsychiatric associations with COMT