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The influence of response bias on segregation and linkage analysis.

Response bias in epidemiologic studies can occur if affected individuals are more (or less) likely to participate in a survey than their unaffected counterparts. To examine the effect of response bias in the context of a family study, we conducted segregation and linkage analysis in all 1,000 individuals in the Problem 2 data set, and in two different 65% samples: one sample consisting of 648 randomly selected individuals, and the other sample nonrandomly constructed so that individuals with high levels of Q1 were oversampled. In this simulation the ability to detect major genes for Q1-Q4 in segregation analysis and to link these putative major genes to genetic markers in linkage analysis was not markedly different between the 65% random and the 65% enriched samples.

Alleles↗

Meta-analyses of object naming: effect of baseline.

The neural systems sustaining object naming were examined using the activation likelihood estimation (ALE) meta-analysis approach on the results of 16 previously published studies. The activation task in each study required subjects to name pictures of objects or animals, but the baseline tasks varied. Separate meta-analyses were carried out on studies that used: (1) high-level baselines to control for speech processing and visual input; and (2) low-level baselines that did not control for speech or complex visual processing. The results of the two meta-analyses were then compared directly, revealing a double dissociation in the activation pattern for studies using high and low baselines. To interpret the differential activations, we report two new functional imaging experiments. The aim of the first was to characterize activation differences associated with visual stimuli that are typically used in baseline conditions (complex visual features, simple structures, or fixation). The aim of the second was to classify object-naming regions in terms of whether they were engaged preferentially by semantic or phonological processes. The results reveal a remarkably precise correspondence between the areas identified by the meta-analyses as affected differentially by baseline and the areas that are affected differentially by non-object structure, semantics or phonology. As expected, high-level baselines reduced object-naming activation in areas associated with the processing of complex visual features and speech production. In addition, high-level baselines increased sensitivity to activation in areas associated with semantic processing, visual-speech integration and response selection. For example, activation in the anterior temporal areas that neuropsychological studies have associated with semantic processing was more strongly activated in the context of high-level baselines. These results therefore have implications for understanding the convergence of functional imaging and neuropsychological findings.

Brain↗

Neuroanatomical correlates of phonological processing of Chinese characters and alphabetic words: a meta-analysis.

We used the activation likelihood estimation (ALE) method to quantitatively synthesize data from 19 published brain mapping studies of phonological processing in reading, six with Chinese and 13 with alphabetic languages. It demonstrated high concordance of cortical activity across multiple studies in each written language system as well as significant differences of activation likelihood between languages. Four neural systems for the phonological processing of Chinese characters included: (1) a left dorsal lateral frontal system at Brodmann area (BA) 9; (2) the dorsal aspect of left inferior parietal system; (3) a bilateral ventral-occipitotemporal system including portions of fusiform gyrus and middle occipital gyrus; and (4) a left ventral prefrontal system covering the superior aspect of inferior frontal gyrus. For phonological processing of written alphabetic words, cortical areas identified here are consistent with the three neural systems proposed previously in the literature: (1) a ventral prefrontal system involving superior portions of left inferior frontal gyrus; (2) a left dorsal temporoparietal system including mid-superior temporal gyri and the ventral aspect of inferior parietal cortex (supramarginal region); and (3) a left ventral occipitotemporal system. Contributions of each of these systems to phonological processing in reading were discussed, and a covariant learning hypothesis is offered to account for the findings that left middle frontal gyrus is responsible for addressed phonology in Chinese whereas left temporoparietal regions mediate assembled phonology in alphabetic languages. Language form, cognitive process, and learning strategy drive the development of functional neuroanatomy.

Brain↗

BrainMap taxonomy of experimental design: description and evaluation.

Coordinate-based, voxel-wise meta-analysis is an exciting recent addition to the human functional brain mapping literature. In view of the critical importance of selection criteria for any valid meta-analysis, a taxonomy of experimental design should be an important tool for aiding in the design of rigorous meta-analyses. The coding scheme of experimental designs developed for and implemented within the BrainMap database provides a candidate taxonomy. In this study, the BrainMap experimental-design taxonomy is described and evaluated by comparing taxonomy fields to data-filtering choices made by subject-matter experts carrying out meta-analyses of the functional imaging literature. Fifteen publications reporting a total of 46 voxel-wise meta-analyses were included in this assessment. Collectively these 46 meta-analyses pooled data from 351 publications, selected for experimental similarity within each meta-analysis. Filter implementations within BrainMap were graded by ease-of-use (A-C) and by stage-of-use (1-3). Quality filters and content filters were tabulated separately. Quality filters required for data entry into BrainMap were classed as mandatory (five filters), being above the use grading system. All authors spontaneously adopted the five mandatory filters in constructing their meta-analysis, indicating excellent agreement on data quality among authors and between authors and the BrainMap development team. Two non-mandatory quality filters (group size and imaging modality) were applied by all authors; both were Stage 1, Grade A filters. Field-of-view filters were the least-accessible quality filters (Stage 3, Grade C); two field-of-view filters were applied by six and four authors, respectively. Authors made a total of 115 content-filter choices. Of these, 78 (68%) were Stage 1, Grade A filters; 16 (14%) were Stage 2, Grade A; and 21 (18%) were Stage 2, Grade C. No author-applied filter was absent from the taxonomy.

Brain Mapping↗

Comparison of two screening methods, modified Hb H preparation and the osmotic fragility test, for alpha-thalassemic traits on the basis of gene mapping.

We evaluated 61 patients with two screening tests for alpha-thalassemia traits on the basis of endonuclease gene mapping. Comparing these two methods--the osmotic fragility test of the red cell and modified hemoglobin H inclusion staining for the sensitivity--we found that the latter was much superior to the former with 100% sensitivity in detecting heterozygous alpha-1 thalassemia and it was also specific as a confirmatory test for thalassemia traits. Red cell indices are still the basic screening tool and can be used together with modified Hb H inclusion staining. The osmotic fragility test was not better than the red cell indices and was not confirmatory. Besides the MCV, RBC, and discrimination functions, we found that RBC distribution width-standard deviation (RDW-SD) was consistently low in heterozygous alpha-1 thalassemia but not in heterozygous alpha-2 thalassemia. None of the above tests was shown to be really helpful in screening in the latter situation. We conclude that the modified Hb H inclusion staining is superior to the osmotic fragility test in screening of alpha-1 thalassemia.

Chromosome Deletion↗

Human BAC ends quality assessment and sequence analyses.

End sequences from bacterial artificial chromosomes (BACs) provide highly specific sequence markers in large-scale sequencing projects. To date, we have generated >300,000 end sequences from >186,000 human BAC clones with an average read length of >460 bp for a total of 141 Mb covering approximately 4.7% of the genome. Over 60% of the clones have BAC end sequences (BESs) from both ends representing more than fivefold coverage of the human genome by the paired-end clones. Our quality assessments and sequence analyses indicate that BESs from human BAC libraries developed at The California Institute of Technology (CalTech) and Roswell Park Cancer Institute have similar properties. The analyses have highlighted differences in insert size for different segments of the CalTech library. Problems with the fidelity of tracking of sequence data back to physical clones have been observed in some subsets of the overall BES dataset. The annotation results of BESs for the contents of available genomic sequences, sequence tagged sites, expressed sequence tags, protein encoding regions, and repeats indicate that this resource will be valuable in many areas of genome research.

Chromosome Mapping↗

Database challenges and solutions in neuroscientific applications.

In the scientific community, the quality and progress of various endeavors depend in part on the ability of researchers to share and exchange large quantities of heterogeneous data with one another efficiently. This requires controlled sharing and exchange of information among autonomous, distributed, and heterogeneous databases. In this paper, we focus on a neuroscience application, Neuroanatomical Rat Brain Viewer (NeuART Viewer) to demonstrate alternative database concepts that allow neuroscientists to manage and exchange data. Requirements for the NeuART application, in combination with an underlying network-aware database, are described at a conceptual level. Emphasis is placed on functionality from the user's perspective and on requirements that the database must fulfill. The most important functionality required by neuroscientists is the ability to construct brain models using information from different repositories. To accomplish such a task, users need to browse remote and local sources and summaries of data and capture relevant information to be used in building and extending the brain models. Other functionalities are also required, including posing queries related to brain models, augmenting and customizing brain models, and sharing brain models in a collaborative environment. An extensible object-oriented data model is presented to capture the many data types expected in this application. After presenting conceptual level design issues, we describe several known database solutions that support these requirements and discuss requirements that demand further research. Data integration for heterogeneous databases is discussed in terms of reducing or eliminating semantic heterogeneity when translations are made from one system to another. Performance enhancement mechanisms such as materialized views and spatial indexing for three-dimensional objects are explained and evaluated in the context of browsing, incorporating, and sharing. Policies for providing the system with fault tolerance and avoiding possible intellectual property abuses are presented. Finally, two existing systems are evaluated and compared using the identified requirements.

Animals↗

Structural group analysis of functional activation maps.

We present here a new method for cerebral activation detection over a group of subjects. This method is performed using individual activation maps of any sort. It aims at processing a group analysis while preserving individual information and at overcoming as far as possible limitations of the spatial normalization used to compare different subjects. We designed it such that it provides the individual occurrence of the activations detected at a group level. The localization can then be performed on the individual anatomy of each subject. The analysis starts with a hierarchical multiscale object-based description of each individual map. These descriptions are then compared, rather than comparing the images directly. The analysis is thus performed at an object level instead of voxel by voxel. It is made using a comparison graph, on which a labeling process is performed. The label field on the graph is modeled by a Markov random field, which allows us to introduce high-level rules of interrogation of the data. The process has been evaluated on simulated data and real data from a PET protocol.

Brain↗

Lectin localization in human nerve by biochemically defined lectin-binding glycoproteins, neoglycoprotein and lectin-specific antibody.

Molecular recognition can be mediated by protein (lectin)-carbohydrate interaction, explaining the interest in this topic. Plant lectins and, more recently, chemically glycosylated neoglycoproteins principally allow to map the occurrence of components of this putative recognition system. Labelled endogenous lectins and the lectin-binding ligands can add to the panel of glycohistochemical tools. They may be helpful to derive physiologically valid conclusions in this field for mammalian tissues. Consequently, experiments were prompted to employ the abundant beta-galactoside-specific lectin of human nerves in affinity chromatography and in histochemistry to purify and to localize its specific glycoprotein ligands. In comparison to the beta-galactoside-specific plant lectins from Ricinus communis and Erythrina cristagalli, notable similarities were especially detectable in the respective profiles of the mammalian and the Erythrina lectin. They appear to account for rather indistinguishable staining patterns in fixed tissue sections. Inhibitory controls within affinity chromatography, within solid-phase assays for each fraction of lectin-binding glycoproteins and within histochemistry as well as the demonstration of crossreactivity of the three fractions of lectin-binding glycoproteins with the biotinylated Erythrina lectin in blotting ascertained the specificity of the lectin-glycoprotein interaction. In addition to monitoring the accessible cellular ligand part by the endogenous lectin as probe, the comparison of immunohistochemical and glycohistochemical detection of the lectin in serial sections proved these methods for receptor analysis to be rather equally effective. The observation that the biotinylated lectin-binding glycoproteins are also appropriate ligands in glycohistochemical analysis warrants emphasis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Inter- and intra-individual probability maps in EEG cartography by use of nonparametric Fisher tests.

The three types of non-parametric permutation Fisher tests have been applied to inter-individual group studies and further to intra-individual multiple EEG recording sequences, providing computations of EEG probability maps testing two ordinal hypotheses. Two examples of previous group studies with "EEG local cerebral activation" are given: mental computation in a group of 20 controls and caffeine effects versus placebo in a group of 10 controls. For the intra-individual study, two successive recordings of 2.3 min eyes closed (EC1 and EC2), obtained at 50 min intervals, were compared by paired exact permutation Fisher tests (over 15 or 42 synchronous EEG sequences). These tests were applied to descriptive spectral parameters: RMS and % amplitudes, mean frequencies, resonance coefficient, for raw unfiltered EEG and delta, theta, alpha, alpha 1, alpha 2, beta 1, beta 2 frequency bands. Two hypotheses were tested for each of the computed 31 parameters, providing two probability maps indicating if the parameter was greater or lower in the first EEG recording or in the second. The second EEG sequence, EC2, was "EEG activated" compared to the first sequence EC1 if the following were present: decreased amplitudes mainly in raw EEG, low activity and alpha bands; increased frequencies mainly, in raw EEG, delta and beta 1 fast activities; increased fast activity percentages; decreased coefficient of resonance. The effect of choice of reference was also evaluated: probability maps for a frontal reference were different than other probability maps obtained after computation of average reference or source derivation.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain Mapping↗

Topographic mapping of the EEG: an examination of accuracy and precision.

The accuracy and precision of topographic maps depicting scalp potentials and scalp potentials squared have been examined. Electrode placement was that specified by the International 10-20 System and the methods of interpolation bilinear and bicubic spines. The results indicate that, for these interpolation methods, the maximum error expected between the measured scalp quantities and those predicted by interpolation is positively correlated to the root-mean-square value of the measured quantity. Both interpolation methods produce accurate estimates of the interelectrode quantities. Both methods produce precise estimates of the scalp potential in the delta, theta and alpha frequency bands but only poor estimates in the beta band. The precision of the estimates of the scalp potentials squared is poor in all frequency bands. This result indicates that another look at the now common practice of topographically mapping the power-spectral components of the EEG is in order. In general, the bilinear and bicubic spline methods of interpolation perform about equally. This result is used to suggest that because of its additional computational complexity, use of the bicubic method for potential mapping may not be warranted. Advantages of the bicubic method, particularly in radial-current mapping, are however discussed.

Adult↗

Human cerebral circulation: positron emission tomography studies.

We reviewed the literature on human cerebral circulation and oxygen metabolism, as measured by positron emission tomography (PET), with respect to normal values and of regulation of cerebral circulation. A multicenter study in Japan showed that between-center variations in cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) values were not considerably larger than the corresponding within-center variations. Overall mean +/- SD values in cerebral cortical regions of normal human subjects were as follows: CBF = 44.4 +/- 6.5 ml/100 ml/min; CBV = 3.8 +/- 0.7 ml/100 ml; OEF = 0.44 +/- 0.06; CMRO2 = 3.3 +/- 0.5 ml/100 ml/min (11 PET centers, 70 subjects). Intrinsic regulation of cerebral circulation involves several factors. Autoregulation maintains CBF in response to changes in cerebral perfusion pressure; chemical factors such as PaCO2 affect cerebral vascular tone and alter CBF; changes in neural activity cause changes in cerebral energy metabolism and CBF; neurogenic control of CBF occurs by sympathetic innervation. Regional differences in vascular response to changes in PaCO2 have been reported, indicating regional differences in cerebral vascular tone. Relations between CBF and CBV during changes in PaCO2 and during changes in neural activity were in good agreement with Poiseuille's law. The mechanisms of vascular response to neural activation and deactivation were independent on those of responses to PaCO2 changes. CBV in a brain region is the sum of three components: arterial, capillary and venous blood volumes. It has been reported that the arterial blood volume fraction is approximately 30% in humans and that changes in human CBV during changes in PaCO2 are caused by changes in arterial blood volume without changes in venous blood volume. These findings should be considered in future studies of the pathophysiology of cerebrovascular diseases.

Brain↗

[Neural correlates of working memory deficits in schizophrenic patients. Ways to establish neurocognitive endophenotypes of psychiatric disorders].

This article briefly reviews some methodological limitations of functional neuroimaging studies in psychiatric patients. We argue that the investigation of the neural substrates of cognitive deficits in psychiatric disorders requires a combination of functional neuroimaging studies in healthy subjects with corresponding behavioral experiments in patients. In order to exemplify this methodological approach we review recent findings regarding the functional neuroanatomy of distinct components of human working memory and provide evidence for selective dysfunctions of cortical networks that underlie specific working memory deficits in schizophrenia. This identification of subgroups of schizophrenic patients according to neurocognitive parameters may facilitate the establishment of behavioral and neurophysiological endophenotypes and the development of a neurobiological classification of psychiatric disorders.

Brain Mapping↗

[Working memory in healthy subjects and schizophrenics: studies using BOLD fMRT].

Functional magnetic resonance imaging uses the blood oxygen level-dependent effect (BOLD MRI) for noninvasive display of cerebral correlatives of cognitive function. The importance for the understanding of physiological and pathological processes is demonstrated by investigations of working memory in schizophrenics and healthy controls. Working memory is involved in processing rather than storage of information and therefore is linked to complex processes such as learning and problem solving. In schizophrenic psychosis, these functions are clearly restricted. Training effects in the working memory task follow an inverse U-shape function, suggesting that cerebral activation reaches a peak before economics of the brain find a more efficient method and activation decreases.

Brain↗