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Terms modified by Hum Selected AbstractsQuantification of Chlamydia pneumoniae in cultured human macrophages and HL cells: comparison of real-time PCR, immunofluorescence and ELISA methodsAPMIS, Issue 1 2010KARI POIKONEN Poikonen K, Lajunen T, Silvennoinen-Kassinen S, Leinonen M, Saikku P. Quantification of Chlamydia pneumoniae in cultured human macrophages and HL cells: comparison of real-time PCR, immunofluorescence and ELISA methods. APMIS 2010; 118: 45,8. Chlamydia pneumoniae is an intracellular gram-negative bacterium, which replicates only in eukaryotic cells. Quantification of C. pneumoniae in cell culture is needed when studying e.g. the effect of drugs or host cell factors on infectivity and replication. Conventionally, this has been performed by immunofluorescence staining and microscopic counting of chlamydial inclusions. However, this method is usable only if the cell numbers do not fluctuate in cell culture vials and the inclusions are uniform. In macrophages, inclusions are often aberrant, their sizes vary, and multiple inclusions are also seen. Therefore, methods are needed to quantify exact amounts of C. pneumoniae in cells. Here, we describe a new method based on the real-time PCR quantification of chlamydial genomes adjusted to the number of human genomes in cultures. In human epithelial (HL) cell cultures, the C. pneumoniae inclusion numbers and the ratio of C. pneumonia genomes/human genome (Cpn/Hum) correlated significantly (r = 0.978, p < 0.001); thus with HL cells, both methods are usable. However, in macrophage cultures, the correlation was weaker (r = 0.133, p = 0.036) and we recommend PCR quantification for exact measurements. [source] Striatal modulation of cAMP-response-element-binding protein (CREB) after excitotoxic lesions: implications with neuronal vulnerability in Huntington's diseaseEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2006Carmela Giampą Abstract Recent evidence has shown that the activity of cAMP responsive element-binding protein (CREB) and of CREB-binding protein (CBP) is decreased in Huntington's disease (HD) [Steffan et al. (2000)Proc. Natl Acad. Sci. USA, 97, 6763,6768; Gines et al. (2003)Hum. Mol. Genet., 12, 497,508; Rouaux et al. (2004) Biochem. Pharmacol., 68, 1157,1164; Sugars et al. (2004)J. Biol. Chem., 279, 4988,4999]. Such decrease is thought to reflect the impaired energy metabolism observed in a HD mouse model, where a decline in striatum cAMP levels has been observed [Gines et al. (2003)Hum. Mol. Genet., 12, 497,508]. Increased levels of CREB have also been demonstrated to exert neuroprotective functions [Lonze & Ginty (2002)Neuron, 35, 605,623; Lonze et al. (2002)Neuron, 34, 371,385]. Our study aimed to investigate the distribution of CREB in the neuronal subpopulations of the striatum in normal rats compared to the HD model of quinolinic acid lesion. Twenty-five Wistar rats were administered quinolinic acid 100 mm into the right striatum, and killed after 24 h, 48 h, 1 week, 2 weeks, and six weeks, respectively. The contralateral striata were used as controls. Dual-label immunofluorescence was employed using antibodies against phosphorylated CREB and each of the different neuronal subpopulations markers. Our results show that activated CREB levels decrease progressively in projection neurons and parvalbumin (PARV) and calretinin (CALR) interneurons, whereas such levels remain stable in cholinergic and somatostatin interneurons. Thus, we speculate that the ability of cholinergic interneurons to maintain their levels of CREB after excitotoxic lesions is one of the factors determining their protection in Huntington's disease. [source] Using evidence for population stratification bias in combined individual- and family-level genetic association analyses of quantitative traitsGENETIC EPIDEMIOLOGY, Issue 5 2010Lucia Mirea Abstract Genetic association studies are generally performed either by examining differences in the genotype distribution between individuals or by testing for preferential allele transmission within families. In the absence of population stratification bias (PSB), integrated analyses of individual and family data can increase power to identify susceptibility loci [Abecasis et al., 2000. Am. J. Hum. Genet. 66:279,292; Chen and Lin, 2008. Genet. Epidemiol. 32:520,527; Epstein et al., 2005. Am. J. Hum. Genet. 76:592,608]. In existing methods, the presence of PSB is initially assessed by comparing results from between-individual and within-family analyses, and then combined analyses are performed only if no significant PSB is detected. However, this strategy requires specification of an arbitrary testing level ,PSB, typically 5%, to declare PSB significance. As a novel alternative, we propose to directly use the PSB evidence in weights that combine results from between-individual and within-family analyses. The weighted approach generalizes previous methods by using a continuous weighting function that depends only on the observed P -value instead of a binary weight that depends on ,PSB. Using simulations, we demonstrate that for quantitative trait analysis, the weighted approach provides a good compromise between type I error control and power to detect association in studies with few genotyped markers and limited information regarding population structure. Genet. Epidemiol. 34: 502,511, 2010. © 2010 Wiley-Liss, Inc. [source] Association tests using kernel-based measures of multi-locus genotype similarity between individualsGENETIC EPIDEMIOLOGY, Issue 3 2010Indranil Mukhopadhyay Abstract In a genetic association study, it is often desirable to perform an overall test of whether any or all single-nucleotide polymorphisms (SNPs) in a gene are associated with a phenotype. Several such tests exist, but most of them are powerful only under very specific assumptions about the genetic effects of the individual SNPs. In addition, some of the existing tests assume that the direction of the effect of each SNP is known, which is a highly unlikely scenario. Here, we propose a new kernel-based association test of joint association of several SNPs. Our test is non-parametric and robust, and does not make any assumption about the directions of individual SNP effects. It can be used to test multiple correlated SNPs within a gene and can also be used to test independent SNPs or genes in a biological pathway. Our test uses an analysis of variance paradigm to compare variation between cases and controls to the variation within the groups. The variation is measured using kernel functions for each marker, and then a composite statistic is constructed to combine the markers into a single test. We present simulation results comparing our statistic to the U -statistic-based method by Schaid et al. ([2005] Am. J. Hum. Genet. 76:780,793) and another statistic by Wessel and Schork ([2006] Am. J. Hum. Genet. 79:792,806). We consider a variety of different disease models and assumptions about how many SNPs within the gene are actually associated with disease. Our results indicate that our statistic has higher power than other statistics under most realistic conditions. Genet. Epidemiol. 34: 213,221, 2010. © 2009 Wiley-Liss, Inc. [source] Asymptotic tests of association with multiple SNPs in linkage disequilibriumGENETIC EPIDEMIOLOGY, Issue 6 2009Wei Pan Abstract We consider detecting associations between a trait and multiple single nucleotide polymorphisms (SNPs) in linkage disequilibrium (LD). To maximize the use of information contained in multiple SNPs while minimizing the cost of large degrees of freedom (DF) in testing multiple parameters, we first theoretically explore the sum test derived under a working assumption of a common association strength between the trait and each SNP, testing on the corresponding parameter with only one DF. Under the scenarios that the association strengths between the trait and the SNPs are close to each other (and in the same direction), as considered by Wang and Elston [Am. J. Hum. Genet. [2007] 80:353,360], we show with simulated data that the sum test was powerful as compared to several existing tests; otherwise, the sum test might have much reduced power. To overcome the limitation of the sum test, based on our theoretical analysis of the sum test, we propose five new tests that are closely related to each other and are shown to consistently perform similarly well across a wide range of scenarios. We point out the close connection of the proposed tests to the Goeman test. Furthermore, we derive the asymptotic distributions of the proposed tests so that P -values can be easily calculated, in contrast to the use of computationally demanding permutations or simulations for the Goeman test. A distinguishing feature of the five new tests is their use of a diagonal working covariance matrix, rather than a full covariance matrix as used in the usual Wald or score test. We recommend the routine use of two of the new tests, along with several other tests, to detect disease associations with multiple linked SNPs. Genet. Epidemiol. 33:497,507, 2009. © 2009 Wiley-Liss, Inc. [source] Genetic association tests in the presence of epistasis or gene-environment interactionGENETIC EPIDEMIOLOGY, Issue 7 2008Kai WangArticle first published online: 24 APR 200 Abstract A genetic variant is very likely to manifest its effect on disease through its main effect as well as through its interaction with other genetic variants or environmental factors. Power to detect genetic variants can be greatly improved by modeling their main effects and their interaction effects through a common set of parameters or "generalized association parameters" (Chatterjee et al. [2006] Am. J. Hum. Genet. 79:1002,1016) because of the reduced number of degrees of freedom. Following this idea, I propose two models that extend the work by Chatterjee and colleagues. Particularly, I consider not only the case of relatively weak interaction effect compared to the main effect but also the case of relatively weak main effect. This latter case is perhaps more relevant to genetic association studies. The proposed methods are invariant to the choice of the allele for scoring genotypes or the choice of the reference genotype score. For each model, the asymptotic distribution of the likelihood ratio statistic is derived. Simulation studies suggest that the proposed methods are more powerful than existing ones under certain circumstances. Genet. Epidemiol. 2008. © 2008 Wiley-Liss, Inc. [source] Informative-Transmission Disequilibrium Test (i-TDT): combined linkage and association mapping that includes unaffected offspring as well as affected offspringGENETIC EPIDEMIOLOGY, Issue 2 2007Chao-Yu Guo Abstract To date, there is no test valid for the composite null hypothesis of no linkage or no association that utilizes transmission information from heterozygous parents to their unaffected offspring as well as the affected offspring from ascertained nuclear families. Since the unaffected siblings also provide information about linkage and association, we introduce a new strategy called the informative-transmission disequilibrium test (i-TDT), which uses transmission information from heterozygous parents to all of the affected and unaffected offspring in ascertained nuclear families and provides a valid chi-square test for both linkage and association. The i-TDT can be used in various study designs and can accommodate all types of independent nuclear families with at least one affected offspring. We show that the transmission/disequilibrium test (TDT) (Spielman et al. [1993] Am. J. Hum. Genet. 52:506,516) is a special case of the i-TDT, if the study sample contains only case-parent trios. If the sample contains only affected and unaffected offspring without parental genotypes, the i-TDT is equivalent to the sibship disequilibrium test (SDT) (Horvath and Laird [1998] Am. J. Hum. Genet. 63:1886,1897. In addition, the test statistic of i-TDT is simple, explicit and can be implemented easily without intensive computing. Through computer simulations, we demonstrate that power of the i-TDT can be higher in many circumstances compared to a method that uses affected offspring only. Applying the i-TDT to the Framingham Heart Study data, we found that the apolipoprotein E (APOE) gene is significantly linked and associated with cross-sectional measures and longitudinal changes in total cholesterol. Genet. Epidemiol. © 2006 Wiley-Liss, Inc. [source] Perils and pitfalls of permutation tests for distinguishing the effects of neighbouring polymorphismsGENETIC EPIDEMIOLOGY, Issue 7 2006Joanna M. Biernacka Abstract In a small region several marker loci may be associated with a trait, either because they directly influence the trait or because they are in linkage disequilibrium (LD) with a causal variant. Having established a potentially causal effect at a primary variant, we may ask if any other variants in the region appear to further contribute to the trait, indicating that the additional variant is either causal or is in LD with another causal locus. Methods of approaching this problem using case-parent trio data include the stepwise conditional logistic regression approach described by Cordell and Clayton ([2002] Am. J. Hum. Genet. 70:124,141), and a constrained-permutation method recently proposed by Spijker et al. ([2005] Ann. Hum. Genet. 69:90,101). Through simulation we demonstrate that the procedure described by Spijker et al. [2005], as well as unconditional logistic regression with "affected family-based controls" (AFBACs), can lead to inflated type 1 errors in situations when haplotypes are not inferable for all trios, whereas the conditional logistic regression approach gives correct significance levels. We propose an alternative to the permutation method of Spijker et al. [2005], which does not rely on haplotyping, and results in correct type 1 errors and potentially high power when assumptions of random mating, Hardy-Weinberg Equilibrium, and multiplicative effects of disease alleles are satisfied. Genet. Epidemiol. 2006. © 2006 Wiley-Liss, Inc. [source] Simultaneous localization of two linked disease susceptibility genesGENETIC EPIDEMIOLOGY, Issue 1 2005Joanna M. Biernacka Abstract For diseases with complex genetic etiology, more than one susceptibility gene may exist in a single chromosomal region. Extending the work of Liang et al. ([2001] Hum. Hered. 51:64,78), we developed a method for simultaneous localization of two susceptibility genes in one region. We derived an expression for expected allele sharing of an affected sib pair (ASP) at each point across a chromosomal segment containing two susceptibility genes. Using generalized estimating equations (GEE), we developed an algorithm that uses marker identical-by-descent (IBD) sharing in affected sib pairs to simultaneously estimate the locations of the two genes and the mean IBD sharing in ASPs at these two disease loci. Confidence intervals for gene locations can be constructed based on large sample approximations. Application of the described methods to data from a genome scan for type 1 diabetes (Mein et al. [1998] Nat. Genet. 19:297,300) yielded estimates of two putative disease gene locations on chromosome 6, approximately 20 cM apart. Properties of the estimators, including bias, precision, and confidence interval coverage, were studied by simulation for a range of genetic models. The simulations demonstrated that the proposed method can improve disease gene localization and aid in resolving large peaks when two disease genes are present in one chromosomal region. Joint localization of two disease genes improves with increased excess allele sharing at the disease gene loci, increased distance between the disease genes, and increased number of affected sib pairs in the sample. Genet. Epidemiol. © 2004 Wiley-Liss, Inc. [source] Method for using complete and incomplete trios to identify genes related to a quantitative trait,GENETIC EPIDEMIOLOGY, Issue 1 2004Emily O. Kistner Abstract A number of tests for linkage and association with qualitative traits have been developed, with the most well-known being the transmission/disequilibrium test (TDT). For quantitative traits, varying extensions of the TDT have been suggested. The quantitative trait approach we propose is based on extending the log-linear model for case-parent trio data (Weinberg et al. [1998] Am. J. Hum. Genet. 62:969,978). Like the log-linear approach for qualitative traits, our proposed polytomous logistic approach for quantitative traits allows for population admixture by conditioning on parental genotypes. Compared to other methods, simulations demonstrate good power and robustness of the proposed test under various scenarios of the genotype effect, distribution of the quantitative trait, and population stratification. In addition, missing parental genotype data can be accommodated through an expectation-maximization (EM) algorithm approach. The EM approach allows recovery of most of the lost power due to incomplete trios. Published 2004 Wiley-Liss, Inc. [source] Quantitative trait linkage analysis by generalized estimating equations: Unification of variance components and Haseman-Elston regressionGENETIC EPIDEMIOLOGY, Issue 4 2004Wei-Min Chen Two of the major approaches for linkage analysis with quantitative traits in humans include variance components and Haseman-Elston regression. Previously, these were viewed as quite separate methods. We describe a general model, fit by use of generalized estimating equations (GEE), for which the variance components and Haseman-Elston methods (including many of the extensions to the original Haseman-Elston method) are special cases, corresponding to different choices for a working covariance matrix. We also show that the regression-based test of Sham et al. ([2002] Am. J. Hum. Genet. 71:238,253) is equivalent to a robust score statistic derived from our GEE approach. These results have several important implications. First, this work provides new insight regarding the connection between these methods. Second, asymptotic approximations for power and sample size allow clear comparisons regarding the relative efficiency of the different methods. Third, our general framework suggests important extensions to the Haseman-Elston approach which make more complete use of the data in extended pedigrees and allow a natural incorporation of environmental and other covariates. © 2004 Wiley-Liss, Inc. [source] Gamma regression improves Haseman-Elston and variance components linkage analysis for sib-pairsGENETIC EPIDEMIOLOGY, Issue 2 2004Mathew J. Barber Abstract Existing standard methods of linkage analysis for quantitative phenotypes rest on the assumptions of either ordinary least squares (Haseman and Elston [1972] Behav. Genet. 2:3,19; Sham and Purcell [2001] Am. J. Hum. Genet. 68:1527,1532) or phenotypic normality (Almasy and Blangero [1998] Am. J. Hum. Genet. 68:1198,1199; Kruglyak and Lander [1995] Am. J. Hum. Genet. 57:439,454). The limitations of both these methods lie in the specification of the error distribution in the respective regression analyses. In ordinary least squares regression, the residual distribution is misspecified as being independent of the mean level. Using variance components and assuming phenotypic normality, the dependency on the mean level is correctly specified, but the remaining residual coefficient of variation is constrained a priori. Here it is shown that these limitations can be addressed (for a sample of unselected sib-pairs) using a generalized linear model based on the gamma distribution, which can be readily implemented in any standard statistical software package. The generalized linear model approach can emulate variance components when phenotypic multivariate normality is assumed (Almasy and Blangero [1998] Am. J. Hum Genet. 68: 1198,1211) and is therefore more powerful than ordinary least squares, but has the added advantage of being robust to deviations from multivariate normality and provides (often overlooked) model-fit diagnostics for linkage analysis. Genet Epidemiol 26:97,107, 2004. © 2004 Wiley-Liss, Inc. [source] A score for Bayesian genome screeningGENETIC EPIDEMIOLOGY, Issue 3 2003E. Warwick Daw Abstract Bayesian Monte Carlo Markov chain (MCMC) techniques have shown promise in dissecting complex genetic traits. The methods introduced by Heath ([1997], Am. J. Hum. Genet. 61:748,760), and implemented in the program Loki, have been able to localize genes for complex traits in both real and simulated data sets. Loki estimates the posterior probability of quantitative trait loci (QTL) at locations on a chromosome in an iterative MCMC process. Unfortunately, interpretation of the results and assessment of their significance have been difficult. Here, we introduce a score, the log of the posterior placement probability ratio (LOP), for assessing oligogenic QTL detection and localization. The LOP is the log of the posterior probability of linkage to the real chromosome divided by the posterior probability of linkage to an unlinked pseudochromosome, with marker informativeness similar to the marker data on the real chromosome. Since the LOP cannot be calculated exactly, we estimate it in simultaneous MCMC on both real and pseudochromosomes. We investigate empirically the distributional properties of the LOP in the presence and absence of trait genes. The LOP is not subject to trait model misspecification in the way a lod score may be, and we show that the LOP can detect linkage for loci of small effect when the lod score cannot. We show how, in the absence of linkage, an empirical distribution of the LOP may be estimated by simulation and used to provide an assessment of linkage detection significance. Genet Epidemiol 24:181,190, 2003. © 2003 Wiley-Liss, Inc. [source] Multipoint affected sibpair linkage methods for localizing susceptibility genes of complex diseasesGENETIC EPIDEMIOLOGY, Issue 2 2003David V. Glidden Abstract Recently, Liang et al. ([2001] Hum. Hered. 51:64,78) proposed a general multipoint linkage method for estimating the chromosomal position of a putative susceptibility locus. Their technique is computationally simple and does not require specification of penetrance or a mode of inheritance. In complex genetic diseases, covariate data may be available which reflect etiologic or locus heterogeneity. We developed approaches to incorporating covariates into the method of Liang et al. ([2001] Hum. Hered. 51:64,78) with particular attention to exploiting age-at-onset information. The results of simulation studies, and a worked data example using a family data set ascertained through probands with schizophrenia, suggest that utilizing covariate information can yield substantial efficiency gains in localizing susceptibility genes. Genet Epidemiol 24: 107,117, 2003. © 2003 Wiley-Liss, Inc. [source] Frontoparietal cortical activity of methamphetamine-dependent and comparison subjects performing a delay discounting taskHUMAN BRAIN MAPPING, Issue 5 2007John R. Monterosso Abstract Relative to individuals who do not have addictive disorders, drug abusers exhibit greater devaluation of rewards as a function of their delay ("delay discounting"). The present study sought to extend this finding to methamphetamine (MA) abusers and to help understand its neural basis. MA abusers (n = 12) and control subjects who did not use illicit drugs (n = 17) participated in tests of delay discounting with hypothetical money rewards. We then used a derived estimate of each individual's delay discounting to generate a functional magnetic resonance imaging probe task consisting of three conditions: "hard choices," requiring selections between "smaller, sooner" and "larger, later" alternatives that were similarly valued given the individual's delay discounting; "easy choices," in which alternatives differed dramatically in value; and a "no choice" control condition. MA abusers exhibited more delay discounting than control subjects (P < 0.05). Across groups, the "hard choice > no choice" contrast revealed significant effects in the ventrolateral prefrontal cortex, dorsolateral prefrontal cortex (DLPFC), dorsal anterior cingulate cortex, and areas surrounding the intraparietal sulcus (IPS). With group comparisons limited to these clusters, the "hard choice > easy choice" contrast indicated significant group differences in task-related activity within the left DLPFC and right IPS; qualitatively similar nonsignificant effects were present in the other clusters tested. Whereas control subjects showed less recruitment associated with easy than with hard choices, MA abusers generally did not. Correlational analysis did not indicate a relationship between this anomaly in frontoparietal recruitment and greater degree of delay discounting exhibited by MA abusers. Therefore, while apparent inefficiency of cortical processing related to decision-making in MA abusers may contribute to the neural basis of enhanced delay discounting by this population, other factors remain to be identified. Hum. Brain Mapp, 2007. © 2006 Wiley-Liss, Inc. [source] Odor processing in multiple chemical sensitivityHUMAN BRAIN MAPPING, Issue 3 2007Lena Hillert Abstract Multiple chemical sensitivity (MCS) is characterized by somatic distress upon exposure to odors. As in other idiopathic environmental intolerances, the mechanisms behind the reported hypersensitivity are unknown. Using the advantage of the well-defined trigger (odor), we investigated whether subjects with MCS could have an increased odor-signal response in the odor-processing neuronal circuits. Positron emission tomography (PET) activation studies with several different odorants were carried out in 12 MCS females and 12 female controls. Activation was defined as a significant increase in regional cerebral blood flow (rCBF) during smelling of the respective odorant compared to smelling of odorless air. The study also included online measurements of respiratory frequency and amplitude and heart rate variations by recording of R wave intervals (RR) on the surface electrocardiogram. The MCS subjects activated odor-processing brain regions less than controls, despite the reported, and physiologically indicated (decreased RR interval) distress. In parallel, they showed an odorant-related increase in activation of the anterior cingulate cortex and cuneus-precuneus. Notably, the baseline rCBF was normal. Thus, the abnormal patterns were observed only in response to odor signals. Subjects with MCS process odors differently from controls, however, without signs of neuronal sensitization. One possible explanation for the observed pattern of activation in MCS is a top-down regulation of odor-response via cingulate cortex. Hum. Brain Mapp, 2007. © 2006 Wiley-Liss, Inc. [source] Neural basis of first and second language processing of sentence-level linguistic prosodyHUMAN BRAIN MAPPING, Issue 2 2007Jackson Gandour Abstract A fundamental question in multilingualism is whether the neural substrates are shared or segregated for the two or more languages spoken by polyglots. This study employs functional MRI to investigate the neural substrates underlying the perception of two sentence-level prosodic phenomena that occur in both Mandarin Chinese (L1) and English (L2): sentence focus (sentence-initial vs. -final position of contrastive stress) and sentence type (declarative vs. interrogative modality). Late-onset, medium proficiency Chinese-English bilinguals were asked to selectively attend to either sentence focus or sentence type in paired three-word sentences in both L1 and L2 and make speeded-response discrimination judgments. L1 and L2 elicited highly overlapping activations in frontal, temporal, and parietal lobes. Furthermore, region of interest analyses revealed that for both languages the sentence focus task elicited a leftward asymmetry in the supramarginal gyrus; both tasks elicited a rightward asymmetry in the mid-portion of the middle frontal gyrus. A direct comparison between L1 and L2 did not show any difference in brain activation in the sentence type task. In the sentence focus task, however, greater activation for L2 than L1 occurred in the bilateral anterior insula and superior frontal sulcus. The sentence focus task also elicited a leftward asymmetry in the posterior middle temporal gyrus for L1 only. Differential activation patterns are attributed primarily to disparities between L1 and L2 in the phonetic manifestation of sentence focus. Such phonetic divergences lead to increased computational demands for processing L2. These findings support the view that L1 and L2 are mediated by a unitary neural system despite late age of acquisition, although additional neural resources may be required in task-specific circumstances for unequal bilinguals. Hum. Brain Mapp, 2007. © 2006 Wiley-Liss, Inc. [source] Volitional control of attention and brain activation in dual task performanceHUMAN BRAIN MAPPING, Issue 2 2007Sharlene D. Newman Abstract This study used functional MRI (fMRI) to examine the neural effects of willfully allocating one's attention to one of two ongoing tasks. In a dual task paradigm, participants were instructed to focus either on auditory sentence comprehension, mental rotation, or both. One of the major findings is that the distribution of brain activation was amenable to strategic control, such that the amount of activation per task was systematically related to the attention-dividing instructions. The activation in language processing regions was lower when attending to mental rotation than when attending to the sentences, and the activation in visuospatial processing regions was lower when attending to sentences than when attending to mental rotations. Additionally, the activation was found to be underadditive, with the dual-task condition eliciting less activation than the sum of the attend sentence and attend rotation conditions. We also observed a laterality shift across conditions within language-processing regions, with the attend sentence condition showing bilateral activation, while the dual task condition showed a left hemispheric dominance. This shift suggests multiple language-processing modes and may explain the underadditivity in activation observed in the current and previous studies. Hum. Brain Mapp, 2007. © 2006 Wiley-Liss, Inc. [source] Neural systems connecting interoceptive awareness and feelingsHUMAN BRAIN MAPPING, Issue 1 2007Olga Pollatos Abstract In many theories of emotions the representations of bodily responses play an important role for subjective feelings. We tested the hypothesis that the perception of bodily states is positively related to the experienced intensity of feelings as well as to the activity of first-order and second-order brain structures involved in the processing of feelings. Using a heartbeat perception task, subjects were separated into groups with either high or poor interoceptive awareness. During emotional picture presentation we measured high-density EEG and used spatiotemporal current density reconstruction to identify regions involved in both interoceptive awareness and emotion processing. We observed a positive relation between interoceptive awareness and the experienced intensity of emotions. Furthermore, the P300 amplitudes to pleasant and unpleasant pictures were enhanced for subjects with high interoceptive awareness. The source reconstruction revealed that interoceptive awareness is related to an enhanced activation in both first-order structures (insula, somatosensory cortices) and second-order structures (anterior cingulate, prefrontal cortices). We conclude that the perception of bodily states is a crucial determinant for the processing and the subjective experience of feelings. Hum. Brain Mapping, 2007. © 2006 Wiley-Liss, Inc. [source] MEG reveals different contributions of somatomotor cortex and cerebellum to simple reaction time after temporally structured cuesHUMAN BRAIN MAPPING, Issue 7 2006Tim Martin Abstract Magnetoencephalography (MEG) was used to measure brain activity while participants performed a simple reaction to targets after either a random interval (uncued targets) or a series of isochronous warning stimuli with 200-ms intervals that acted as a countdown. Targets could arrive "on time" or "early" relative to the preceding warning stimuli. Cerebellar activity before any stimulus onset predicted uncued simple reaction time. Onset of activity in somatomotor cortex relative to the target predicted reaction time after two warning stimuli when the target arrived on time or early. After three warning stimuli, when the target arrived on time and was certain to occur, prestimulus cerebellar activity and somatomotor onset were significant predictors of reaction time. When the target arrived early after three warning stimuli, prestimulus cerebellar and cingulate activity were predictive. The cerebellar results may reflect a number of possible factors, including a role in timing, response readiness, prediction and attention. Hum. Brain Mapping 2005. © 2005 Wiley-Liss, Inc. [source] Vowel sound extraction in anterior superior temporal cortexHUMAN BRAIN MAPPING, Issue 7 2006Jonas Obleser Abstract We investigated the functional neuroanatomy of vowel processing. We compared attentive auditory perception of natural German vowels to perception of nonspeech band-passed noise stimuli using functional magnetic resonance imaging (fMRI). More specifically, the mapping in auditory cortex of first and second formants was considered, which spectrally characterize vowels and are linked closely to phonological features. Multiple exemplars of natural German vowels were presented in sequences alternating either mainly along the first formant (e.g., [u]-[o], [i]-[e]) or along the second formant (e.g., [u]-[i], [o]-[e]). In fixed-effects and random-effects analyses, vowel sequences elicited more activation than did nonspeech noise in the anterior superior temporal cortex (aST) bilaterally. Partial segregation of different vowel categories was observed within the activated regions, suggestive of a speech sound mapping across the cortical surface. Our results add to the growing evidence that speech sounds, as one of the behaviorally most relevant classes of auditory objects, are analyzed and categorized in aST. These findings also support the notion of an auditory "what" stream, with highly object-specialized areas anterior to primary auditory cortex. Hum. Brain Mapp, 2005. © 2005 Wiley-Liss, Inc. [source] Spatiotemporal mapping of cortical activity accompanying voluntary movements using an event-related beamforming approachHUMAN BRAIN MAPPING, Issue 3 2006Douglas Cheyne Abstract We describe a novel spatial filtering approach to the localization of cortical activity accompanying voluntary movements. The synthetic aperture magnetometry (SAM) minimum-variance beamformer algorithm was used to compute spatial filters three-dimensionally over the entire brain from single trial neuromagnetic recordings of subjects performing self-paced index finger movements. Images of instantaneous source power ("event-related SAM") computed at selected latencies revealed activation of multiple cortical motor areas prior to and following left and right index finger movements in individual subjects, even in the presence of low-frequency noise (e.g., eye movements). A slow premovement motor field (MF) reaching maximal amplitude ,50 ms prior to movement onset was localized to the hand area of contralateral precentral gyrus, followed by activity in the contralateral postcentral gyrus at 40 ms, corresponding to the first movement-evoked field (MEFI). A novel finding was a second activation of the precentral gyrus at a latency of ,150 ms, corresponding to the second movement-evoked field (MEFII). Group averaging of spatially normalized images indicated additional premovement activity in the ipsilateral precentral gyrus and the left inferior parietal cortex for both left and right finger movements. Weaker activations were also observed in bilateral premotor areas and the supplementary motor area. These results show that event-related beamforming provides a robust method for studying complex patterns of time-locked cortical activity accompanying voluntary movements, and offers a new approach for the localization of multiple cortical sources derived from neuromagnetic recordings in single subject and group data. Hum. Brain Mapping 2005. © 2005 Wiley-Liss, Inc. [source] Quantitative evaluation of automated skull-stripping methods applied to contemporary and legacy images: Effects of diagnosis, bias correction, and slice locationHUMAN BRAIN MAPPING, Issue 2 2006Christine Fennema-Notestine Abstract Performance of automated methods to isolate brain from nonbrain tissues in magnetic resonance (MR) structural images may be influenced by MR signal inhomogeneities, type of MR image set, regional anatomy, and age and diagnosis of subjects studied. The present study compared the performance of four methods: Brain Extraction Tool (BET; Smith [2002]: Hum Brain Mapp 17:143,155); 3dIntracranial (Ward [1999] Milwaukee: Biophysics Research Institute, Medical College of Wisconsin; in AFNI); a Hybrid Watershed algorithm (HWA, Segonne et al. [2004] Neuroimage 22:1060,1075; in FreeSurfer); and Brain Surface Extractor (BSE, Sandor and Leahy [1997] IEEE Trans Med Imag 16:41,54; Shattuck et al. [2001] Neuroimage 13:856,876) to manually stripped images. The methods were applied to uncorrected and bias-corrected datasets; Legacy and Contemporary T1 -weighted image sets; and four diagnostic groups (depressed, Alzheimer's, young and elderly control). To provide a criterion for outcome assessment, two experts manually stripped six sagittal sections for each dataset in locations where brain and nonbrain tissue are difficult to distinguish. Methods were compared on Jaccard similarity coefficients, Hausdorff distances, and an Expectation-Maximization algorithm. Methods tended to perform better on contemporary datasets; bias correction did not significantly improve method performance. Mesial sections were most difficult for all methods. Although AD image sets were most difficult to strip, HWA and BSE were more robust across diagnostic groups compared with 3dIntracranial and BET. With respect to specificity, BSE tended to perform best across all groups, whereas HWA was more sensitive than other methods. The results of this study may direct users towards a method appropriate to their T1 -weighted datasets and improve the efficiency of processing for large, multisite neuroimaging studies. Hum. Brain Mapping, 2005. © 2005 Wiley-Liss, Inc. [source] Difference in somatosensory evoked fields elicited by mechanical and electrical stimulations: Elucidation of the human homunculus by a noninvasive methodHUMAN BRAIN MAPPING, Issue 4 2005Ken Inoue Abstract We recently recorded somatosensory evoked fields (SEFs) elicited by compressing the glabrous skin of the finger and decompressing it by using a photosensor trigger. In that study, the equivalent current dipoles (ECDs) for these evoked fields appeared to be physiologically similar to the ECDs of P30m in median nerve stimulation. We sought to determine the relations of evoked fields elicited by mechanically stimulating the glabrous skin of the great toe and those of electrically produced P40m. We studied SEFs elicited by mechanical and electrical stimulations from the median and tibial nerves. The orientations of dipoles from the mechanical stimulations were from anterior-to-posterior, similar to the orientations of dipoles for P30m. The direction of the dipole around the peak of N20m from median nerve electrical stimulation was opposite to these directions. The orientations of dipoles around the peak of P40m by tibial nerve stimulation were transverse, whereas those by the compression and decompression stimulation of the toe were directed from anterior-to-posterior. The concordance of the orientations in ECDs for evoked fields elicited by mechanical and electrical stimulations suggests that the ECDs of P40m are physiologically similar to those of P30m but not to those of N20m. The discrepancy in orientations in ECDs for evoked field elicited by these stimulations in the lower extremity suggests that electrical and compression stimulations elicit evoked fields responding to fast surface rubbing stimuli and/or stimuli to the muscle and joint. Hum. Brain Mapping 24:274,283, 2005. © 2005 Wiley-Liss, Inc. [source] Brief breath holding may confound functional magnetic resonance imaging studiesHUMAN BRAIN MAPPING, Issue 4 2005David F. Abbott Abstract We demonstrate that breath holding of short durations may confound functional magnetic resonance imaging (fMRI) studies. Some subjects may hold their breath for a short time during task performance, especially if the task is challenging. Breath holding may therefore need to be considered specifically when interpreting fMRI experiments. We studied the temporal and spatial characteristics of cerebral T2*-weighted signal during short periods of breath holding by seven individuals in a 3-tesla MR scanner. We demonstrate that breath-holds as short as 3 s can result in regions of significant cerebral activation. More interestingly, we show that focal activation remains present when the data is analysed in a number of different ways, including analyses that correct for motion and model the task epoch as if it were 10 times longer than the actual breath-hold length. These findings have potential relevance for many researchers carrying out fMRI studies. Hum. Brain Mapping 24:284,290, 2005. © 2005 Wiley-Liss, Inc. [source] Temporal dynamics of ipsilateral and contralateral motor activity during voluntary finger movementHUMAN BRAIN MAPPING, Issue 1 2004Ming-Xiong Huang Abstract The role of motor activity ipsilateral to movement remains a matter of debate, due in part to discrepancies among studies in the localization of this activity, when observed, and uncertainty about its time course. The present study used magnetoencephalography (MEG) to investigate the spatial localization and temporal dynamics of contralateral and ipsilateral motor activity during the preparation of unilateral finger movements. Eight right-handed normal subjects carried out self-paced finger-lifting movements with either their dominant or nondominant hand during MEG recordings. The Multi-Start Spatial Temporal multi-dipole method was used to analyze MEG responses recorded during the movement preparation and early execution stage (,800 msec to +30 msec) of movement. Three sources were localized consistently, including a source in the contralateral primary motor area (M1) and in the supplementary motor area (SMA). A third source ipsilateral to movement was located significantly anterior, inferior, and lateral to M1, in the premotor area (PMA) (Brodmann area [BA] 6). Peak latency of the SMA and the ipsilateral PMA sources significantly preceded the peak latency of the contralateral M1 source by 60 msec and 52 msec, respectively. Peak dipole strengths of both the SMA and ipsilateral PMA sources were significantly weaker than was the contralateral M1 source, but did not differ from each other. Altogether, the results indicated that the ipsilateral motor activity was associated with premotor function, rather than activity in M1. The time courses of activation in SMA and ipsilateral PMA were consistent with their purported roles in planning movements. Hum. Brain Mapp. 23:26,39, 2004. © 2004 Wiley-Liss, Inc. [source] Monocular visual activation patterns in albinism as revealed by functional magnetic resonance imagingHUMAN BRAIN MAPPING, Issue 1 2004Bernd Schmitz Abstract Human albinism is characterized by a disturbance of the chiasmatic projection system leading to predominant representation of just one eye in the contralateral hemisphere. Patients show congenital nystagmus without perceiving oscillopsia. The purpose of the present study was to demonstrate the consequences of atypical chiasmatic crossing with monocular visual stimulation using functional magnetic resonance imaging (fMRI). Sixteen patients with albinism and fifteen normally pigmented controls were stimulated with a monocular visual activation paradigm using flickering checkerboards. In patients, we observed contralaterally dominated activation of visual cortices correlating to clinical albinism parameters. This confirms albinism as a continuous range of hypopigmentation disorders. Additionally, albinos showed activation of the superior colliculus and of visual motion areas although the stimulus was stationary. Activation of visual motion areas is due probably to congenital nystagmus without a conscious correlate like oscillopsia. Hum. Brain Mapping 23:40,52, 2004. © 2004 Wiley-Liss, Inc. [source] A split,merge-based region-growing method for fMRI activation detectionHUMAN BRAIN MAPPING, Issue 4 2004Yingli Lu Abstract We introduce a hybrid method for functional magnetic resonance imaging (fMRI) activation detection based on the well-developed split,merge and region-growing techniques. The proposed method includes conjoining both of the spatio-temporal priors inherent in split,merge and the prior information afforded by the hypothesis-led component of region selection. Compared to the fuzzy c-means clustering analysis, this method avoids making assumptions about the number of clusters and the computation complexity is reduced markedly. We evaluated the effectiveness of the proposed method in comparison with the general linear model and the fuzzy c-means clustering method conducted on simulated and in vivo datasets. Experimental results show that our method successfully detected expected activated regions and has advantages over the other two methods. Hum. Brain Mapping 22:271,279, 2004. © 2004 Wiley-Liss, Inc. [source] Cross-modal temporal order memory for auditory digits and visual locations: An fMRI studyHUMAN BRAIN MAPPING, Issue 4 2004Daren Zhang Abstract A function of working memory is to remember the temporal sequence of events, often occurring across different sensory modalities. To study the neural correlates of this function, we conducted an event-related functional magnetic resonance imaging (fMRI) experiment with a cross-modal memory task. Subjects were required to recall auditory digits and visual locations either in mixed order (cross-modality) or in separate order (within-modality). To identify the brain regions involved in the memory of cross-modal temporal order, we compared the blood oxygenation level-dependent (BOLD) response between the mixed and the separate order tasks. As a control, cortical areas sensitive to the memory load were mapped by comparing the 10-item condition with the 6-item condition in the separate order task. Results show that the bilateral prefrontal, right premotor, temporo-parietal junction (TPJ) and left superior parietal cortices had significantly more activation in the mixed task than in the separate task. Some of these areas were also sensitive to the memory load, whereas the right prefrontal cortex and TPJ were relatively more sensitive to the cross-modal order but not the memory load. Our study provides potential neural correlates for the episodic buffer, a key component of working memory as proposed previously [Baddeley. Trends Cogn Sci 2000;4:417,423]. Hum. Brain Mapping 22:280,289, 2004. © 2004 Wiley-Liss, Inc. [source] EEG-fMRI of focal epileptic spikes: Analysis with multiple haemodynamic functions and comparison with gadolinium-enhanced MR angiogramsHUMAN BRAIN MAPPING, Issue 3 2004Andrew P. Bagshaw Abstract Combined EEG-fMRI has recently been used to explore the BOLD responses to interictal epileptiform discharges. This study examines whether misspecification of the form of the haemodynamic response function (HRF) results in significant fMRI responses being missed in the statistical analysis. EEG-fMRI data from 31 patients with focal epilepsy were analysed with four HRFs peaking from 3 to 9 sec after each interictal event, in addition to a standard HRF that peaked after 5.4 sec. In four patients, fMRI responses were correlated with gadolinium-enhanced MR angiograms and with EEG data from intracranial electrodes. In an attempt to understand the absence of BOLD responses in a significant group of patients, the degree of signal loss occurring as a result of magnetic field inhomogeneities was compared with the detected fMRI responses in ten patients with temporal lobe spikes. Using multiple HRFs resulted in an increased percentage of data sets with significant fMRI activations, from 45% when using the standard HRF alone, to 62.5%. The standard HRF was good at detecting positive BOLD responses, but less appropriate for negative BOLD responses, the majority of which were more accurately modelled by an HRF that peaked later than the standard. Co-registration of statistical maps with gadolinium-enhanced MRIs suggested that the detected fMRI responses were not in general related to large veins. Signal loss in the temporal lobes seemed to be an important factor in 7 of 12 patients who did not show fMRI activations with any of the HRFs. Hum. Brain Mapp. 22:179,192, 2004. © 2004 Wiley-Liss, Inc. [source] | ||||||||||