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Background: Olfactory dysfunction is a non-motor symptom and an important biomarker of Parkinson's disease (PD) because of its high prevalence (> 90%). Whether hyposmia correlates with motor symptoms is unclear. In the present study, we aim to investigate the relationship between olfactory impairment with both motor and non-motor features and disease variables (disease duration, stage, and severity). Methods: One-hundred fifty-four PD patients were evaluated. Odor identification ability was tested using Italian Olfactory Identification Test (IOIT). A comprehensive spectrum of motor and non-motor features was assessed. Cognitive function was investigated through MMSE. Patients were divided into 3 different clinical phenotypes using UPDRS-III: tremor-dominant type (TDT), akinetic-rigid type (ART), and mixed type (MXT). Results: Three of the 33 IOIT items were most frequently misidentified: basil (74.3%), coffee (66.9%), and mushroom (59.6%). Hyposmia was found in 93%. Hyposmic patients were older than controls (p = 0.01). Hoehn & Yahr (H&Y) score of 2 or greater was associated with higher probability of being hyposmic (OR = 5.2, p = 0.01). IOIT score did not significantly differ between TDT, ART, and MXT of analyzed PD patients. Performance to IOIT inversely correlated with age (p < 0.01), disease duration (p = 0.01), and H&Y score of 2 or higher (p < 0.01). Clinical features that associated with higher IOIT score were freezing of gait (FOG) (p < 0.001) and camptocormia (p < 0.05). Conclusions: In our cohort, IOIT scores showed a positive correlation with axial motor signs, but not with non-motor symptoms. IOIT may be a useful tool not only for supporting PD diagnosis but also for providing prognostic information about motor function. [ABSTRACT FROM AUTHOR]

The present study investigated the clinical utility of ultrasound imaging (USI) for assessing changes in an individual's quadriceps muscle and subcutaneous fat (SF) thickness of the anterior thigh and their relative proportions. A patient was studied prior to and after anterior cruciate ligament reconstruction (ACLR) surgery and during rehabilitation. This case study involved an 18-year-old female recreational athlete with a complete tear of the anterior cruciate ligament (ACL). Tissue thickness (SF and quadriceps muscle) was measured from transverse USI of the anterior thigh before surgery, at weekly intervals during 12 weeks of postsurgery, and then every 2 weeks for the following 12 weeks (total of 21 measurement sets). Statistically significant differences presurgery to postrehabilitation were found for muscle thickness (p = 0.04) and SF tissue thickness (p = 0.04) measurements. There was no difference in muscle to fat ratio (p = 0.08). Changes in measurements greater than the reported minimal detectable change (MDC) demonstrate the sensitivity of the USI technique as an objective tool to assess clinically useful changes in an individual's anterior thigh muscle thickness post-ACLR surgery and during rehabilitation. [ABSTRACT FROM AUTHOR]

Background: The R2 component of blink reflex recovery cycle (R2BRrc) is a simple neurophysiological tool to detect the brainstem hyperexcitability commonly occurring in several neurological diseases such as Parkinson's disease and atypical parkinsonisms. In our study, we investigated for the first time the usefulness of R2BRrc to assess brainstem excitability in patients with idiopathic Normal Pressure Hydrocephalus (iNPH) in comparison with healthy subjects. Methods: Eighteen iNPH patients and 25 age-matched control subjects were enrolled. R2BRrc was bilaterally evaluated at interstimulus intervals (ISIs) of 100, 150, 200, 300, 400, 500 and 750 ms in all participants. We investigated the diagnostic performance of R2BRrc in differentiating iNPH patients from control subjects using ROC analysis. Midbrain area and Magnetic Resonance Hydrocephalic Index (MRHI), an MRI biomarker for the diagnosis of iNPH, were measured on T1-weighted MR images, and correlations between R2BRrc values and MRI measurements were investigated. Results: Fourteen (78%) of 18 iNPH patients showed an enhanced R2BRrc at ISIs 100–150–200 ms, while no control subjects had abnormal R2BRrc. The mean amplitude of bilateral R2BRrc at the shortest ISIs (100–150–200 ms) showed high accuracy in differentiating iNPH patients from controls (AUC = 0.89). R2BRrc values significantly correlated with midbrain area and MRHI values. Conclusions: This study represents the first evidence of brainstem hyperexcitability in iNPH patients. Given its low cost and wide availability, R2BRrc could be a useful tool for selecting elderly subjects with mild gait and urinary dysfunction who should undergo an extensive diagnostic workup for the diagnosis of NPH. [ABSTRACT FROM AUTHOR]

In this contribution we propose and rigorously analyze new variants of adaptive Trust-Region methods for parameter optimization with PDE constraints and bilateral parameter constraints. The approach employs successively enriched Reduced Basis surrogate models that are constructed during the outer optimization loop and used as model function for the Trust-Region method. Each Trust-Region sub-problem is solved with the projected BFGS method. Moreover, we propose a non-conforming dual (NCD) approach to improve the standard RB approximation of the optimality system. Rigorous improved a posteriori error bounds are derived and used to prove convergence of the resulting NCD-corrected adaptive Trust-Region Reduced Basis algorithm. Numerical experiments demonstrate that this approach enables to reduce the computational demand for large scale or multi-scale PDE constrained optimization problems significantly. [ABSTRACT FROM AUTHOR]

Background: Outcomes in people at clinical high risk for psychosis (CHRP) have usually been defined in terms of psychosis onset. However, within the subgroup of individuals who do not develop psychosis, some have persistent symptoms; while in others, symptoms resolve and functioning is restored. Currently, little is known about what predicts a good outcome (GO) in CHR-P individuals, partly because there is no consensus on how this should be defined.Method: The Delphi method was used to elicit the opinions of 46 experts to reach a consensus on factors that together could define GO in the CHR-P population. Three online surveys were implemented. The panel rated each survey item according to how important they thought it was as a measure of GO. Participants also answered open-ended questions on how GO should be determined, their responses were subject to content analysis.Results: Ninety-eight items were endorsed by 80% of the panel as essential or important for a GO; these fell into 4 domains: Functioning; Symptoms; Distress/Suicidality; and Subjective Wellbeing. The individual item that was rated as the most important, was daily functioning. Themes emerged from the qualitative data, which corresponded to the Delphi domains, including 'functioning'; 'clinical factors; and 'user-defined outcomes'.Conclusions: A GO in CHR-P subjects can be defined by using a combination of measures from domains that reflect level of functioning; symptoms; distress/suicidality; and subjective wellbeing. These results provide a basis for a standardised definition of good outcome in people at clinical high risk of psychosis. [ABSTRACT FROM AUTHOR]

Early identification and timely intervention are crucial issues in contemporary psychiatry, both in terms of improved outcome and optimal treatment delivery as well as service reform. Although the field has advanced substantially in the last 25 years, there is a constant need to revise and ponder the core constructs that have been developed and field-tested. This is even more important given that early identification relies on the timely discernment and recognition of a variety of symptomatic presentations which are typically subclinical in terms of intensity or frequency of signs and symptoms. This overview will offer an updated conceptual map of the field. [ABSTRACT FROM AUTHOR]

Machine learning is becoming an increasingly popular approach for investigating spatially distributed and subtle neuroanatomical alterations in brain‐based disorders. However, some machine learning models have been criticized for requiring a large number of cases in each experimental group, and for resembling a "black box" that provides little or no insight into the nature of the data. In this article, we propose an alternative conceptual and practical approach for investigating brain‐based disorders which aim to overcome these limitations. We used an artificial neural network known as "deep autoencoder" to create a normative model using structural magnetic resonance imaging data from 1,113 healthy people. We then used this model to estimate total and regional neuroanatomical deviation in individual patients with schizophrenia and autism spectrum disorder using two independent data sets (n = 263). We report that the model was able to generate different values of total neuroanatomical deviation for each disease under investigation relative to their control group (p < .005). Furthermore, the model revealed distinct patterns of neuroanatomical deviations for the two diseases, consistent with the existing neuroimaging literature. We conclude that the deep autoencoder provides a flexible and promising framework for assessing total and regional neuroanatomical deviations in neuropsychiatric populations. [ABSTRACT FROM AUTHOR]

Recent studies have reported an association between psychopathology and subsequent clinical and functional outcomes in people at ultra-high risk (UHR) for psychosis. This has led to the suggestion that psychopathological information could be used to make prognostic predictions in this population. However, because the current literature is based on inferences at group level, the translational value of the findings for everyday clinical practice is unclear. Here we examined whether psychopathological information could be used to make individualized predictions about clinical and functional outcomes in people at UHR. Participants included 416 people at UHR followed prospectively at the Personal Assessment and Crisis Evaluation (PACE) Clinic in Melbourne, Australia. The data were analysed using Support Vector Machine (SVM), a supervised machine learning technique that allows inferences at the individual level. SVM predicted transition to psychosis with a specificity of 60.6%, a sensitivity of 68.6% and an accuracy of 64.6% (p<0.001). In addition, SVM predicted functioning with a specificity of 62.5%, a sensitivity of 62.5% and an accuracy of 62.5% (p=0.008). Prediction of transition was driven by disorder of thought content, attenuated positive symptoms and functioning, whereas functioning was best predicted by attention disturbances, anhedonia-asociality and disorder of thought content. These results indicate that psychopathological information allows individualized prognostic predictions with statistically significant accuracy. However, this level of accuracy may not be sufficient for clinical translation in real-world clinical practice. Accuracy might be improved by combining psychopathological information with other types of data using a multivariate machine learning framework. [ABSTRACT FROM AUTHOR]

This paper discusses the National School Feeding Program (PNAE) in the municipality of Alegre, Espírito Santo State, Brazil, in order to characterize the process of buying food from family farmers to serve this market, focusing on the evolution of this process from 2013 to 2015. The sources of the data used were as follows: Public Notices and the respective reports, available on the website of The City Council of Alegre; sales projects of rural associations provided by the Rural Workers' Union; and FNDE (National Education Development Fund) documents available on their website. It was found that the compulsory minimum purchase percentage was not met in 2013 (it was 15.52%), but it amounted to 116.68% of FNDE's fund transfer in 2014. The number of farmers of Alegre participating of PNAE grew 2.8 times, from 2013 to 2015, reaching 39 farmers. There was a 54% increase in food diversity, from 22 in 2013 to 34 different foods purchased in 2015. It was concluded that the PNAE of Alegre, even in the face of the challenges posed, is fulfilling its role to link family agriculture with school feeding, helping to promote sustainable rural development while bringing food and nutritional security to children and adolescents who study in public schools. [ABSTRACT FROM AUTHOR]

People at ultra-high risk (UHR) of psychosis have ∼30% chance of developing the illness within two years. A range of pharmacological and psychosocial interventions are now available but there is great individual variation in clinical response. Here we examine the evidence for clinically applicable predictors of clinical response in people at UHR of psychosis. We report that currently there are no reliable predictive markers that can be used to optimise treatment. We argue that there is an urgent need for a better understanding of why some people at UHR of psychosis benefit from a certain treatment whereas others do not. This information will help clinicians make more-effective treatment decisions, and improve long-term clinical outcomes in this population. [ABSTRACT FROM AUTHOR]

Several immunomodulatory treatments are currently available for relapsing-remitting forms of multiple sclerosis (RRMS). Interferon beta (IFN) was the first therapeutic intervention able to modify the course of the disease and it is still the most used first-line treatment in RRMS. Though two decades have passed since IFN-β was introduced in the management of MS, it remains a valid approach because of its good benefit/risk profile. This is witnessed by new efforts of pharmaceutical industry to improve this line: a PEGylated form of subcutaneous IFN-β 1a, (Plegridy ® ) with a longer half-life, has been recently approved in RRMS. This review will survey the various stages of the use of type I IFN in MS, with special attention to the effect of the treatment on the supposed viral etiologic factors associated to the disease. The antiviral activities of IFN (that initially prompted its use as immunomodulatory agent in MS), and the mounting evidences in favor of a viral etiology in MS, allowed us to outline a re-appraisal from etiology to therapy and back. [ABSTRACT FROM AUTHOR]

Despite five decades of search for clinically meaningful 'biomarkers' in schizophrenia there are still no common tests to inform diagnosis or treatment. Our aim was to understand why it has been so difficult to convert biological findings into clinical tests. We categorized all PubMed-indexed articles investigating psychosis-related biomarkers to date (over 3200). Studies showed an evident publication bias, a confusing array of terminology, and few systematic efforts at longitudinal evaluation or external validation. Fewer than 200 studies investigated biomarkers, longitudinally, for prediction of illness course and treatment response. These biomarkers were then evaluated in terms of their statistical reliability and clinical effect size. Only one passed our a priori threshold for clinical applicability. This is a modest record. In order to promote real progress, the field needs: (a) consistent use of terminology so that studies can be compared; (b) a system of standardized universal reporting to overcome the existing publication bias; and (c) practical criteria [a prototype is suggested here] for assessing the clinical applicability of the findings. [ABSTRACT FROM AUTHOR]

See Sprons (doi:10.1093/brain/awu148) for a scientific commentary on this article.Brain networks contain a minority of highly connected hub nodes with high topological value and biological cost. Using network analysis of DTI data from healthy volunteers, and meta-analyses of published MRI studies in 26 brain disorders, Crossley et al. show that lesions across disorders tend to be concentrated at hubs.Brain networks or ‘connectomes’ include a minority of highly connected hub nodes that are functionally valuable, because their topological centrality supports integrative processing and adaptive behaviours. Recent studies also suggest that hubs have higher metabolic demands and longer-distance connections than other brain regions, and therefore could be considered biologically costly. Assuming that hubs thus normally combine both high topological value and high biological cost, we predicted that pathological brain lesions would be concentrated in hub regions. To test this general hypothesis, we first identified the hubs of brain anatomical networks estimated from diffusion tensor imaging data on healthy volunteers (n = 56), and showed that computational attacks targeted on hubs disproportionally degraded the efficiency of brain networks compared to random attacks. We then prepared grey matter lesion maps, based on meta-analyses of published magnetic resonance imaging data on more than 20 000 subjects and 26 different brain disorders. Magnetic resonance imaging lesions that were common across all brain disorders were more likely to be located in hubs of the normal brain connectome (P < 10−4, permutation test). Specifically, nine brain disorders had lesions that were significantly more likely to be located in hubs (P < 0.05, permutation test), including schizophrenia and Alzheimer’s disease. Both these disorders had significantly hub-concentrated lesion distributions, although (almost completely) distinct subsets of cortical hubs were lesioned in each disorder: temporal lobe hubs specifically were associated with higher lesion probability in Alzheimer’s disease, whereas in schizophrenia lesions were concentrated in both frontal and temporal cortical hubs. These results linking pathological lesions to the topological centrality of nodes in the normal diffusion tensor imaging connectome were generally replicated when hubs were defined instead by the meta-analysis of more than 1500 task-related functional neuroimaging studies of healthy volunteers to create a normative functional co-activation network. We conclude that the high cost/high value hubs of human brain networks are more likely to be anatomically abnormal than non-hubs in many (if not all) brain disorders. [ABSTRACT FROM AUTHOR]

There is growing interest in the complex topology of human brain functional networks, often measured using resting-state functional MRI (fMRI). Here, we used a meta-analysis of the large primary literature that used fMRI or PET to measure task-related activation (>1,600 studies; 1985-2010). We estimated the similarity (Jaccard index) of the activation patterns across experimental tasks between each pair of 638 brain regions. This continuous coactivation matrix was used to build a weighted graph to characterize network topology. The coactivation network was modular, with occipital, central, and default-mode modules predominantly coactivated by specific cognitive domains (perception, action, and emotion, respectively). It also included a rich club of hub nodes, located in parietal and prefrontal cortex and often connected over long distances, which were coactivated by a diverse range of experimental tasks. Investigating the topological role of edges between a deactivated and an activated node, we found that such competitive interactions were most frequent between nodes in different modules or between an activated rich-club node and a deactivated peripheral node. Many aspects of the coactivation network were convergent with a connectivity network derived from resting state fMRI data (n = 27, healthy volunteers); although the connectivity network was more parsimoniously connected and differed in the anatomical locations of some hubs. We conclude that the community structure of human brain networks is relevant to cognitive function. Deactivations may play a role in flexible reconfiguration of the network according to cognitive demand, varying the integration between modules, and between the periphery and a central rich club. [ABSTRACT FROM AUTHOR]

Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a “candidate interactome” (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms. [ABSTRACT FROM AUTHOR]

Background: Compared with quantitative observations, the search for qualitative changes that may characterize the immune response to Epstein–Barr virus (EBV) in multiple sclerosis (MS) has been less intense.Objective: To examine the B-cell epitopes of antibodies against the Epstein–Barr nuclear antigen-1 (EBNA-1) and their relevance for MS, through a study in disease-discordant identical twins.Methods: We evaluated the antibodies to all unique, maximally overlapping octapeptides of EBNA-1 in 12 pairs of monozygotic (MZ) twins (9 MS-discordant, 3 healthy), 3 non-twin patients and 2 healthy subjects. All except one of the patients were untreated. The EBV serology of these individuals had been assessed in advance using commercially available and in-house enzyme-linked immunosorbent assay (ELISA) kits, including assays for antibodies against select peptides of EBNA-1: EBNA-72 (GAGGGAGAGG) and EBNA-206 (EADYFEYHQEGGPDGE).Results: The glycine–alanine rich domain of EBNA-1 was immunodominant in all subjects. Compared with healthy individuals, and similarly to what has been described in infectious mononucleosis (IM) patients, affected co-twins and non-twin patients had a significantly increased response to another EBNA-1 epitope (aa. 401–411).Conclusion: In a study that controls for confounders, our data focus an EBNA-1 specificity that may be associated with MS pathogenesis. [ABSTRACT FROM AUTHOR]

On the basis of findings in normative samples that different cortical brain regions covary in gray matter volume, most likely as a result of mutually trophic influences during cortical development, we aimed to study whether patterns of covariation in regional gray matter, i.e., structural covariance, differed between adolescents who were born very preterm and full-term controls. Optimized voxel-based morphometry was used to study structural magnetic resonance imaging scans from 218 very preterm adolescents (gestational age <33 weeks) and 127 controls at 14-15 years of age. Local gray matter volumes were obtained for 18 regions of interest involved in sensorimotor and higher-order cognitive functions. These were then used to predict local volumes in the remaining areas of the cortex, with total gray matter volume, age and gender used as confounding variables. Very preterm adolescents compared with controls demonstrated differential (i.e., both increased and decreased) structural covariance between medial, frontal and cingulate gyri, caudate nucleus, thalamus, primary visual cortex, cerebellum and several other cortical and subcortical regions of the cortex. These findings support previous research indicating that preterm birth is associated with altered cortical development, and suggest that developmental changes in one brain region may result in a cascade of alterations in multiple regions. Hum Brain Mapp, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

de Castro-Manglano P, Mechelli A, Soutullo C, Landecho I, Gimenez-Amaya JM, Ortuño F, McGuire P. Structural brain abnormalities in first-episode psychosis: differences between affective psychoses and schizophrenia and relationship to clinical outcome. Bipolar Disord 2011: 13: 545-555. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S. Objectives: Several studies have described volumetric brain abnormalities in first-episode psychosis. The extent to which these differ in patients with schizophrenia and affective psychoses, or are related to subsequent clinical outcome, is unclear. We examined volumetric magnetic resonance imaging (MRI) abnormalities in young patients with a first episode of psychosis, and compared these volumetric abnormalities in patients with schizophrenia versus affective psychosis. We then assessed whether baseline MRI abnormalities in the entire sample predicted subsequent clinical outcome. Methods: A total of 28 adolescent patients with first-episode psychosis and 20 age-matched healthy volunteers were scanned using a 1.5 T scanner. MRI data were processed and analysed using voxel-based morphometry (VBM). We assessed clinical outcome three years after the initial scan. Results: Patients had smaller grey matter (GM) volumes than controls in frontal, insular, parietal, and cerebellar cortex. Patients with an affective psychosis had greater GM volume in the right posterior cingulate than both controls and patients with schizophrenia, but less GM volume in the left cerebellum and insula. In the sample as a whole, smaller right hippocampus GM volume was associated with poor clinical outcome at three-year follow-up. Conclusions: Volumetric brain abnormalities are evident in young adults presenting with a first episode of both affective psychoses and schizophrenia, but there are also significant differences between these two patient groups. Clinical outcome after the first episode may be related to the severity of volumetric abnormalities at presentation. [ABSTRACT FROM AUTHOR]

Abstract: Individuals born very preterm (VPT) are at risk of neurodevelopmental damage and of adverse educational outcomes in childhood and adolescence. The present study used voxel-based morphometry to investigate the association between grey matter and white matter volume and measures of language and executive functioning in VPT born adolescents and term-born controls by gender. VPT individuals (N =218) and controls (N =127) underwent neuropsychological assessment and MRI at age 14–15 as part of a longitudinal study. Differential associations were found between spelling scores and frontal regional grey matter volume when group (VPT and control) and gender (males and females) were investigated. A main effect of group demonstrated a weaker association in VPT adolescents relative to controls between grey matter volume in the left medial and right superior frontal gyri and spelling scores. A main effect of gender revealed spelling scores to be correlated with grey matter volume in the right superior frontal gyrus in females to a greater extent than in males. Furthermore, a significant interaction between group and gender was detected in two regions. Spelling scores showed a stronger association with grey matter volume in a cluster with local maxima in the left medial frontal cortex extending to the caudate nucleus in VPT females than in control females and a weaker association in VPT males compared to control males. In addition, spelling scores showed a stronger association with grey matter volume in left middle frontal gyrus in VPT males compared to control males and a weaker association in VPT females than in control females. When group and gender were investigated, there were no statistically different correlations between structural brain volumes and performance on reading and executive function tests. These data demonstrate that the typical structure–function relationship in respect to spelling abilities appears to be altered in individuals born preterm and the processes underpinning this divergence may be subject to gender-specific influences. [Copyright &y& Elsevier]

Abstract: Recent studies have identified DAAO as a probable susceptibility gene for schizophrenia and bipolar disorder. However, little is known about how this gene affects brain function to increase vulnerability to these disorders. We examined the impact of DAAO genotype (rs3918346) on brain function in patients with schizophrenia, patients with bipolar I disorder and healthy controls. We tested the hypothesis that a variation in DAAO genotype would be associated with altered prefrontal function and altered functional connectivity in schizophrenia and bipolar disorder. We used functional magnetic resonance imaging to measure brain responses during a verbal fluency task in a total of 121 subjects comprising 40 patients with schizophrenia, 33 patients with bipolar disorder and 48 healthy volunteers. We then used statistical parametric mapping (SPM) and psycho-physiological interaction (PPI) analyses to estimate the main effects of diagnostic group, the main effect of genotype, and their interaction on brain activation and on functional connectivity. Inferences were made at p<0.05, after correction for multiple comparisons across the whole brain. In the schizophrenia group relative to the control group, patients with one or two copies of the T allele showed lower deactivation in the left precuneus and greater activation in the right posterior cingulate gyrus than patients with two copies of the C allele. This diagnosis×genotype interaction was associated with differences in the functional connectivity of these two regions with other cortical and subcortical areas. In contrast, there were no significant effects of diagnosis or of genotype in comparisons involving bipolar patients. Our results suggest that genetic variation in DAAO has a significant impact on both regional activation and functional connectivity, and provide evidence for a diagnosis-dependent pattern of gene action. [Copyright &y& Elsevier]

Abstract: Both schizophrenia and bipolar disorder have been associated with progressive changes in grey matter (GM) volume. However, the temporal trajectories of these changes are poorly understood. The aim of this study was to assess longitudinal changes in grey matter volume subsequent to the first episode of schizophrenia and of affective psychoses. Adolescent patients with a first episode psychosis (n =26) were scanned twice using magnetic resonance imaging, at first presentation and after a 3-year follow-up period. An age-matched group of healthy volunteers (n =17) was scanned at the same time points. Within-group and between-group changes in regional grey matter volume were examined using voxel-based morphometry. There were significant group by time interactions (p FDRcorr <0.05) in the frontal, temporal, parietal, cerebellar cortex, and in the thalamus, mainly reflecting longitudinal reductions in the controls but not in the patients. Subdivision of the patient group revealed that there were similar longitudinal reductions in patients with affective psychoses as in the controls but no volumetric changes in patients with schizophrenia. Psychosis with onset in adolescence or early adulthood may be associated with a delay or a loss of longitudinal reductions in regional grey matter volume that normally occur at this stage of development. These changes may be specific to schizophrenia. [Copyright &y& Elsevier]

Background. Schizotypy is conceptualized as a subclinical manifestation of the same underlying biological factors that give rise to schizophrenia and other schizophrenia spectrum disorders. Individuals with psychometric schizotypy (PS) experience subthreshold psychotic signs and can be psychometrically identified among the general population. Previous research using magnetic resonance imaging (MRI) has shown gray-matter volume (GMV) abnormalities in chronic schizophrenia, in subjects with an at-risk mental state (ARMS) and in individuals with schizotypal personality disorder (SPD). However, to date, no studies have investigated the neuroanatomical correlates of PS. Method. Six hundred first- and second-year university students completed the Community Assessment of Psychic Experiences (CAPE), a self-report instrument on psychosis proneness measuring attenuated positive psychotic experiences. A total of 38 subjects with high and low PS were identified and subsequently scanned with MRI. Voxel-based morphometry (VBM) was applied to examine GMV differences between subjects with high and low positive PS. Results. Subjects with high positive PS showed larger global volumes compared to subjects with low PS, and larger regional volumes in the medial posterior cingulate cortex (PCC) and the precuneus. There were no regions where GMV was greater in low than in high positive PS subjects. Conclusions. These regions, the PCC and precuneus, have also been sites of volumetric differences in MRI studies of ARMS subjects and schizophrenia, suggesting that psychotic or psychotic-like experiences may have common neuroanatomical correlates across schizophrenia spectrum disorders. [ABSTRACT FROM AUTHOR]

Adult psychopathology is often rooted early in life and first emerges during childhood and adolescence. However, as most imaging genetic research to date has involved adult participants, little is known about how risk genes affect brain function to influence biological vulnerability in childhood. We examined the impact of neuregulin1 (NRG1), a probable susceptibility gene for schizophrenia and bipolar disorder, on brain function in a sample of 102 healthy 10–12 year old boys including 18 pairs of monozygotic twins, 24 pairs of dizygotic twins and 18 singletons. Each participant performed a perceptual matching task, while brain responses were measured using functional magnetic resonance imaging. Response accuracy and reaction times did not differ as a function of NRG1 genotype; however, individuals with two high-risk alleles showed relatively increased brain activation in a distributed network comprising the precuneus bilaterally, and the left cuneus, middle occipital gyrus, angular gyrus and caudate nucleus. These results indicate that genetic variation in NRG1 significantly affects cortical function during perceptual and monitoring processes in healthy children as young as 10–12 years of age. [ABSTRACT FROM AUTHOR]

Abstract: Schizophrenia is a neurodevelopmental disorder, and risk genes are thought to act through disruption of brain development. Several genetic studies have identified dystrobrevin binding protein 1 (DTNBP1, also known as dysbindin) as a potential susceptibility gene for schizophrenia, but its impact on brain function is poorly understood. It has been proposed that DTNBP1 may be associated with differences in visual processing. To test this, we examined the impact on visual processing in 61 healthy children aged 10–12 years of a genetic variant in DTNBP1 (rs2619538) that was common to all schizophrenia associated haplotypes in an earlier UK-Irish study. We tested the hypothesis that carriers of the risk allele would show altered occipital cortical function relative to noncarriers. Functional Magnetic Resonance Imaging (fMRI) was used to measure brain responses during a visual matching task. The data were analysed using statistical parametric mapping and statistical inferences were made at p <0.05 (corrected for multiple comparisons). Relative to noncarriers, carriers of the risk allele had greater activation in the lingual, fusiform gyrus and inferior occipital gyri. In these regions DTNBP1 genotype accounted for 19%, 20% and 14% of the inter-individual variance, respectively. Our results suggest that that genetic variation in DTNBP1 is associated with differences in the function of brain areas that mediate visual processing, and that these effects are evident in young children. These findings are consistent with the notion that the DTNBP1 gene influences brain development and can thereby modulate vulnerability to schizophrenia. [Copyright &y& Elsevier]

Abstract: Emotional liability and mood dysregulation characterize bipolar disorder (BD), yet no study has examined effective connectivity between parahippocampal gyrus and prefrontal cortical regions in ventromedial and dorsal/lateral neural systems subserving mood regulation in BD. Participants comprised 46 individuals (age range: 18–56 years): 21 with a DSM-IV diagnosis of BD, type I currently remitted; and 25 age- and gender-matched healthy controls (HC). Participants performed an event-related functional magnetic resonance imaging paradigm, viewing mild and intense happy and neutral faces. We employed dynamic causal modeling (DCM) to identify significant alterations in effective connectivity between BD and HC. Bayes model selection was used to determine the best model. The right parahippocampal gyrus (PHG) and right subgenual cingulate gyrus (sgCG) were included as representative regions of the ventromedial neural system. The right dorsolateral prefrontal cortex (DLPFC) region was included as representative of the dorsal/lateral neural system. Right PHG–sgCG effective connectivity was significantly greater in BD than HC, reflecting more rapid, forward PHG–sgCG signaling in BD than HC. There was no between-group difference in sgCG–DLPFC effective connectivity. In BD, abnormally increased right PHG–sgCG effective connectivity and reduced right PHG activity to emotional stimuli suggest a dysfunctional ventromedial neural system implicated in early stimulus appraisal, encoding and automatic regulation of emotion that may represent a pathophysiological functional neural mechanism for mood dysregulation in BD. [Copyright &y& Elsevier]

Background: Superior temporal lobe dysfunction is a robust finding in functional neuroimaging studies of schizophrenia and is thought to be related to a disruption of fronto-temporal functional connectivity. However, the stage of the disorder at which these functional alterations occur is unclear. We addressed this issue by using functional MRI (fMRI) to study subjects in the prodromal and first episode phases of schizophrenia. Methods: Subjects with an at risk mental state (ARMS) for psychosis, a first psychotic episode (FEP), and controls were studied using fMRI while performing a working memory task. Activation in the superior temporal gyrus (STG) was assessed using statistical parametric mapping, and its relationship to frontal activation was examined using dynamic causal modeling. Results: The STG was differentially engaged across the three groups. There was deactivation of this region during the task in controls, whereas subjects with FEP showed activation and the response in subjects with ARMS was intermediately relative to the two other groups. There were corresponding differences in the effective connectivity between the STG and the middle frontal gyrus across the three groups, with a negative coupling between these areas in controls, a positive coupling in the FEP group, and an intermediate value in the ARMS group. Conclusions: A failure to deactivate the superior temporal lobe during tasks that engage prefrontal cortex is evident at the onset of schizophrenia and may reflect a disruption of fronto-temporal connectivity. Qualitatively similar alterations are evident in people with prodromal symptoms of the disorder. Hum Brain Mapp, 2009. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The majority of psychopathology is rooted early in life and first emerges during childhood and adolescence. However, little is known about how risk genes affect brain function to increase biological vulnerability to psychopathology in childhood, because most imaging genetic studies published so far have been conducted on adult participants. We examined the impact of neuregulin1 (NRG1), a probable susceptibility gene for schizophrenia and bipolar disorder, on brain function in a sample of 102 ten- to twelve-year-old children. Each participant performed a Go/Nogo task, whereas brain responses were measured using functional magnetic resonance imaging. Statistical parametric mapping was used to estimate the impact of genetic variation in NRG1 on brain activation. Response accuracy and reaction times did not differ as a function of NRG1 genotype. However, individuals with the high-risk variant expressed greater brain activation for both Go and Nogo stimuli in the right posterior orbital gyrus, where NRG1 genotype accounted for 11% of interindividual variance. There were no regions showing a significant interaction between NRG1 genotype and stimulus type even at trend level, suggesting that the impact of NRG1 on brain activation was not specific to either response inhibition or motor execution. These results suggest that that genetic variation in NRG1 is associated with different levels of prefrontal engagement in children as young as 10-12 years of age. Our investigation provides support to the idea that genetic factors may affect brain function to moderate vulnerability to psychopathology from childhood. Hum Brain Mapp, 2009. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Recent neuroimaging studies have reported deficits in functional integration between prefrontal cortex and the hippocampal formation in schizophrenia. It is unclear whether these alterations are a consequence of chronic illness or its treatment, and whether they are also evident in non-psychotic subjects at increased risk of the disorder. We addressed these issues by investigating prefrontal–hippocampal interactions in patients with first episode schizophrenia and subjects with an At Risk Mental State (ARMS). Using functional Magnetic Resonance Imaging, we measured brain responses from 16 individuals with an ARMS, 10 patients with first episode schizophrenia and 14 healthy controls during a delayed matching to sample task. Dynamic causal modelling was used to estimate the effective connectivity between prefrontal cortex and anterior and posterior hippocampal regions. The normal pattern of effective connectivity from the right posterior hippocampus to the right inferior frontal gyrus was significantly decreased in both first episode patients and subjects with an ARMS (ANOVA; F = 8.16, P = 0.01). Interactions between the inferior frontal gyrus and the anterior part of the hippocampus did not differ across the three groups. Perturbed hippocampal–prefrontal interactions are evident in individuals at high risk of developing psychosis and in patients who have just developed schizophrenia. This suggests that it may be a correlate of increased vulnerability to psychosis and that it is not attributable to an effect of chronic illness or its treatment. [ABSTRACT FROM PUBLISHER]

Dopamine has a crucial role in the modulation of neurocognitive function, and synaptic dopamine activity is normally regulated by the dopamine transporter (DAT) and catechol-O-methyltransferase (COMT). Perturbed dopamine function is a key pathophysiological feature of schizophrenia. Our objectives were (i) to examine epistasis between the DAT 3′ UTR variable number of tandem repeats (VNTR) and COMT Val158Met polymorphisms on brain activation during executive function, and (ii) to then determine the extent to which such interaction is altered in schizophrenia. Regional brain response was measured by using blood-oxygen-level-dependent fMRI during an overt verbal fluency task in 85 subjects (44 healthy volunteers and 41 patients with DSM-IV schizophrenia), and inferences were estimated by using an ANOVA in SPM5. There was a significant COMT × DAT nonadditive interaction effect on activation in the left supra-marginal gyrus, irrespective of diagnostic group (Z-score = 4.3; family-wise error (FWE) p = 0.03), and in healthy volunteers alone (Z-score = 4.7; FWEp = 0.006). In this region, relatively increased activation was detected only when COMT Met-158/Met-158 subjects also carried the 9-repeat DAT allele, or when, reversely, Val-158/Val-158 subjects carried the 10/10-repeat genotype. Also, there was a significant diagnosis × COMT × DAT nonadditive interaction in the right orbital gyrus (Z-score = 4.3; FWEp = 0.04), where, only within patients, greater activation was only associated with a 9-repeat allele and Val-158 conjunction, and with a 10-repeat and Met-158 conjunction (Z-score = 4.3; FWE p = 0.04). These data demonstrate that COMT and DAT genes interact nonadditively to modulate cortical function during executive processing, and also, that this effect is significantly altered in schizophrenia, which may reflect abnormal dopamine function in the disorder. [ABSTRACT FROM AUTHOR]

Background: The majority of affective psychopathology is rooted early in life and first emerges during childhood and adolescence. However, little is known about how genetic vulnerability affects brain structure and function in childhood since the vast majority of studies published so far have been conducted on adult participants. The present investigation examined for the first time the effects of catechol-O-methyltransferase (COMT) valine (val) 158 methionine (met) (val158met) polymorphism, which has been shown to moderate predisposition to negative mood and affective disorders, on brain structure and function in children. Methods: Voxel-based morphometry and functional magnetic resonance imaging were used to measure gray matter volume and emotional reactivity in 50 children aged between 10 and 12 years. We tested the hypothesis that met158 allele affects structural brain development and confers heightened reactivity within the affective frontolimbic circuit in children. Results: The met158 allele was positively associated with gray matter volume in the left hippocampal head where genotype accounted for 59% of interindividual variance. In addition, the met158 allele was positively associated with neuronal responses to fearful relative to neutral facial expressions in the right parahippocampal gyrus where genotype accounted for 14% of the interindividual variance. Conclusions: These results indicate that the met158 allele is associated with increased gray matter volume and heightened reactivity during emotional processing within the limbic system in children as young as 10 to 12 years of age. These findings are consistent with the notion that genetic factors affect brain function to moderate vulnerability to affective psychopathology from childhood. [Copyright &y& Elsevier]

Background: Catechol-O-methyltransferase (COMT) is essential for dopamine metabolism in the brain, and normal variation in the COMT Val158Met polymorphism can influence regional brain function during cognitive tasks. How this is affected when central dopamine function is perturbed is unclear. We addressed this by comparing the effects of COMT Val158Met genotype on cortical activation during a task of executive functions in healthy and schizophrenic subjects. Methods: We studied 90 subjects comprising 48 healthy volunteers (15 Met158/Met158, 20 Val158/Met158, and 13 Val158/Val158) and 42 patients with DSM-IV schizophrenia (13 Met158/Met158, 17 Val158/Met158, and 12 Val158/Val158). Subjects were studied with functional magnetic resonance imaging while performing a verbal fluency task, with performance recorded online. Main effects of genotype and diagnosis and their interaction on cortical activation and functional connectivity were assessed using SPM5. Results: In the right peri-Sylvian cortex, the Met158 allele of the COMT Val158Met polymorphism was associated with greater activation than the Val158 allele in control subjects; the converse applied in patients (Z = 4.3; false discovery rate p = .04). There was also a strong trend for a group × genotype interaction on functional connectivity between this right peri-Sylvian region and the left anterior insula/operculum (Z = 3.4; p < .001, uncorrected). These findings were independent of between-group differences in task performance, medication, demographic factors, or IQ. Conclusions: Frontotemporal function during verbal generation is modulated by variation in COMT genotype. This effect is altered in schizophrenia, which may reflect the perturbation of central dopamine function associated with the disorder. [Copyright &y& Elsevier]

The Hayling Sentence Completion Task (HSCT) is known to activate left hemisphere frontal and temporal language regions. However, the effective connectivity between frontal and temporal language regions associated with the task has yet to be examined. The aims of the study were to examine activation and effective connectivity during the HSCT using a functional magnetic resonance imaging (fMRI) paradigm in which participants made ovett verbal responses. We predicted that proclucing an incongruent response (tesponse suppression), compared to a congruent one (response initiation), would be associated with greater activation in the left prefrontal cortex and an increase in the effective connectivity between temporal and frontal regions. Fifteen participants were scanned while completing 80 sentence stems. The congruency and constraint of sentences varied across trials. Dynamic Causal Modeling (DCM) and Bayesian Model Selection (BMS) were used to compare a set of alternative DCMs of fronto-temporal connectivity. The HSCT activated regions in the left temporal and prefrontal cortices, and the cuneus. Response suppression was associated with greater activation in the left middle and orbital frontal gyri and the bilateral precuneus than response initiation. Left middle temporal and frontal regions identified by the conventional IMRI analyses were entered into the DCM analysis. Using a systematic BMS procedure, the optimal DCM showed that the connection from the left middle temporal gyrus, which was driven by verbal stimuli per se was significantly increased in strength during response suppression compared to initiation. Greater effective connectivity between left temporal and prefrontal regions during response suppression may reflect the transfer of information from posterior temporal regions where semantic and lexical information is stored to prefrontal regions where it is manipulated in preparation for an appropriate response. [ABSTRACT FROM AUTHOR]

Abstract: Recent studies have identified neuregulin1 as a probable susceptibility gene for schizophrenia and bipolar disorder. However, little is known about how this gene may affect brain function to increase vulnerability to these disorders. The present investigation examined the impact of neuregulin1 genotype on brain function in patients with schizophrenia, patients with bipolar I disorder and healthy volunteers. We used functional magnetic resonance imaging to measure brain responses during a verbal fluency task in a total of 115 subjects comprising 41 patients with schizophrenia, 29 patients with bipolar disorder and 45 healthy volunteers. We then used statistical parametric mapping to estimate the main effects of diagnostic group, the main effect of genotype and their interaction. We tested the hypothesis that the high-risk variant of neuregulin1 would be associated with altered prefrontal function. In all three diagnostic groups, the high-risk variant of neuregulin1 was associated with greater deactivation in the left precuneus. In addition, there was an interaction between diagnosis and genotype in two regions of the prefrontal cortex. The right inferior frontal gyrus expressed increased activation in individuals with the high-risk variant, but only in patients with schizophrenia. Conversely, the right posterior orbital gyrus expressed increased activation in individuals with the high-risk variant, but only in patients with bipolar disorder. Our results suggest that genetic variation in neuregulin1 has a measurable impact on brain function and provide preliminary evidence for a disease-specific pattern of gene action in different regions of the prefrontal cortex. [Copyright &y& Elsevier]

We used high-resolution fMRI to investigate claims that learning to read results in greater left occipito-temporal (OT) activation for written words relative to pictures of objects. In the first experiment, 9/16 subjects performing a one-back task showed activation in ≥1 left OT voxel for words relative to pictures ( P < 0.05 uncorrected). In a second experiment, another 9/15 subjects performing a semantic decision task activated ≥1 left OT voxel for words relative to pictures. However, at this low statistical threshold false positives need to be excluded. The semantic decision paradigm was therefore repeated, within subject, in two different scanners (1.5 and 3 T). Both scanners consistently localised left OT activation for words relative to fixation and pictures relative to words, but there were no consistent effects for words relative to pictures. Finally, in a third experiment, we minimised the voxel size (1.5 × 1.5 × 1.5 mm3) and demonstrated a striking concordance between the voxels activated for words and pictures, irrespective of task (naming vs. one-back) or script (English vs. Hebrew). In summary, although we detected differential activation for words relative to pictures, these effects: (i) do not withstand statistical rigour; (ii) do not replicate within or between subjects; and (iii) are observed in voxels that also respond to pictures of objects. Our findings have implications for the role of left OT activation during reading. More generally, they show that studies using low statistical thresholds in single subject analyses should correct the statistical threshold for the number of comparisons made or replicate effects within subject. Hum Brain Mapp 2008. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Several studies report that patients with schizophrenia who experience auditory verbal hallucinations (AVH) tend to misidentify their own speech as that of somebody else. We tested the hypothesis that this tendency is associated with poor functional integration within the network of regions that mediate the evaluation of speech. Using functional magnetic resonance imaging, we measured brain responses from 11 schizophrenics with AVH, 10 schizophrenics without AVH, and 10 healthy controls. Stimuli comprised prerecorded words, which varied for their source (self, alien) and acoustic quality (undistorted, distorted). Participants had to indicate whether each word was spoken in their own or another person's voice via a button press. Using dynamic causal modeling, we estimated the impact of one region over another ('effective connectivity') and how this was modulated by source and distortion. In controls and in patients without AVH, the connectivity between left superior temporal and anterior cingulate cortex was significantly greater for alien- than for self-generated speech; in contrast, the reverse trend was found in schizophrenic patients with AVH. In conclusion, when patients with AVH appraise their own speech we find impaired functional integration between left superior temporal and anterior cingulate cortex. Although this finding is based on external rather than internal speech, the same mechanism may contribute to the faulty appraisal of inner speech that putatively underlies AVH. Hum Brain Mapp 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

This functional magnetic resonance imaging study compared the neuronal implementation of word and pseudoword processing during two commonly used word recognition tasks: lexical decision and reading aloud. In the lexical decision task, participants made a finger-press response to indicate whether a visually presented letter string is a word or a pseudoword (e.g., ‘paple’). In the reading-aloud task, participants read aloud visually presented words and pseudowords. The same sets of words and pseudowords were used for both tasks. This enabled us to look for the effects of task (lexical decision vs. reading aloud), lexicality (words vs. nonwords), and the interaction of lexicality with task. We found very similar patterns of activation for lexical decision and reading aloud in areas associated with word recognition and lexical retrieval (e.g., left fusiform gyrus, posterior temporal cortex, pars opercularis, and bilateral insulae), but task differences were observed bilaterally in sensorimotor areas. Lexical decision increased activation in areas associated with decision making and finger tapping (bilateral postcentral gyri, supplementary motor area, and right cerebellum), whereas reading aloud increased activation in areas associated with articulation and hearing the sound of the spoken response (bilateral precentral gyri, superior temporal gyri, and posterior cerebellum). The effect of lexicality (pseudoword vs. words) was also remarkably consistent across tasks. Nevertheless, increased activation for pseudowords relative to words was greater in the left precentral cortex for reading than lexical decision, and greater in the right inferior frontal cortex for lexical decision than reading. We attribute these effects to differences in the demands on speech production and decision-making processes, respectively. [ABSTRACT FROM AUTHOR]

The aim of the present study was to dissociate the neural correlates of semantic and phonological processes during word reading and picture naming. Previous studies have addressed this issue by contrasting tasks involving semantic and phonological decisions. However, these tasks engage verbal short-term memory and executive functions that are not required for reading and naming. Here, 20 subjects were instructed to overtly name written words and pictures of objects while their neuronal responses were measured using functional magnetic resonance imaging (fMRI). Each trial consisted of a pair of successive stimuli that were either semantically related (e.g., 'ROBIN-nest'), phonologically related (e.g., 'BELL-belt'), unrelated (e.g., 'KITE-lobster'), or semantically and phonologically identical (e.g., 'FRIDGE-fridge'). In addition, a pair of stimuli could be presented in either the same modality (word-word or picture-picture) or a different modality (word-picture or picture-word). We report that semantically related pairs modulate neuronal responses in a left-lateralized network, including the pars orbitalis of the inferior frontal gyrus, the middle temporal gyrus, the angular gyrus, and the superior frontal gyrus. We propose that these areas are involved in stimulus-driven semantic processes. In contrast, phonologically related pairs modulate neuronal responses in bilateral insula. This region is therefore implicated in the discrimination of similar, competing phonological and articulatory codes. The above effects were detected with both words and pictures and did not differ between the two modalities even with a less conservative statistical threshold. In conclusion, this study dissociates the effects of semantic and phonological relatedness between successive items during reading and naming aloud. Hum Brain Mapp, 2007. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

This functional MRI (fMRI) study investigated the effect of lexical and syllable frequency on visual word processing during lexical decision and reading aloud. Previous research has shown a dissociation of syllable and word frequency effects in Spanish using behavioral and electrophysiological measures, suggesting that sublexical (syllabic) representations are computed and mediate the firing of lexical candidates. Here, we characterize the neuroanatomical basis of these lexical and sublexical manipulations and their dependence on task. During lexical decision, words with low vs. high lexical frequency increased activation in left frontal, anterior cingulate, supplemental motor area (SMA), and pre-SMA regions; while words with high vs. low syllable frequency increased activation in a left anterior inferior temporal region. In contrast, when the words were read aloud those with low vs. high syllable frequency increased activation in the left anterior insula, with no other significant effects. On the basis of the neuroanatomy, we propose that the contrasting effects of syllable frequency during lexical decision and reading aloud reflect two different cognitive processes in visual word processing. Specifically, words with high-frequency syllables may increase lexical competition in the inferior temporal lobe while facilitating articulatory planning in the left anterior insula. Hum Brain Mapp, 2006. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Human adults can assess the number of objects in a set (numerosity) by approximate estimation or by exact counting. There is evidence suggesting that numerosity estimation depends on a dedicated mechanism that is a-modal and non-verbal. By contrast, counting requires the coordination between the pre-existing numerosity estimation abilities with language and one-to-one correspondence principles. In this paper we investigate with fMRI the neural correlates of numerosity estimation and counting in human adults, using both visual and auditory stimuli. Results show that attending to approximate numerosity correlates with increased activity of a right lateralized fronto-parietal cortical network, and that this activity is independent of the stimuli presentation''s modality. Counting activates additional left prefrontal, parietal, and bilateral premotor areas, again independently from stimulus modality. These results dissociate two neuronal systems that underlie different numerosity judgements. [Copyright &y& Elsevier]

Abstract: We used functional Magnetic Resonance Imaging to explore the neural correlates of semantic relevance in 12 healthy participants performing a picture-naming task. In addition, we tested the hypothesis that category effects typically found in functional imaging can be partly explained in terms of different semantic relevance for animals and artefacts. We report that semantic relevance modulates neuronal responses in the medial fusiform gyrus bilaterally. As predicted, category effects in this region are strongly modulated by the semantic relevance of the items. Specifically, the effect of artefacts > animals is greatly reduced when the two categories are matched for semantic relevance. Thus, the present study demonstrates that neuronal responses during concept retrieval are modulated by the semantic relevance of the features. It also suggests that increased activation in the medial fusiform gyrus typically found for artefacts > animals can be explained by different semantic relevance for animal and artefact items. [Copyright &y& Elsevier]

Previous studies of patients with phonological and surface alexia have demonstrated a double dissociation between the reading of pseudo words and words with atypical spelling-to-sound relationships. A corresponding double dissociation in the neuronal activation patterns for pseudo words and exception words has not, however, been consistently demonstrated in normal subjects. Motivated by the literature on acquired alexia, the present study contrasted pseudo words to exception words and explored how neuronal interactions within the reading system are inf luenced by word type. Functional magnetic resonance imaging was used to measure neuronal responses during reading in 22 healthy volunteers. The direct comparison of reading pseudo words and exception words revealed a double dissociation within the left frontal cortex. Pseudo words preferentially increased left dorsal premotor activation, whereas exception words preferentially increased left pars triangularis activation. Critically, these areas correspond to those previously associated with phonological and semantic processing, respectively. Word-type dependent interactions between brain areas were then investigated using dynamic causal modeling. This revealed that increased activation in the dorsal premotor cortex for pseudo words was associated with a selective increase in effective connectivity from the posterior fusiform gyrus. In contrast, increased activation in the pars triangularis for exception words was associated with a selective increase in effective connectivity from the anterior fusiform gyrus. The present investigation is the first to identify distinct neuronal mechanisms for semantic and phonological contributions to reading. [ABSTRACT FROM AUTHOR]

The morphology of the human cortex varies remarkably across individuals, regardless of overall brain size. It is currently unclear whether related cortical regions covary in gray matter density, as a result of mutually trophic influences or common experience-related plasticity. We acquired a structural magnetic resonance imaging scan from 172 subjects and extracted the regional gray matter densities from 12 readily identifiable regions of interest involved in sensorimotor or higher-order cognitive functions. We then used these values to predict regional densities in the remaining areas of the cortex, using voxel-based morphometry. This revealed patterns of positive and negative covariance that provide insight into the topographical organization of multiple cortical regions. We report that the gray matter density of a region is a good predictor of the density of the homotopic region in the contralateral hemisphere, with the striking exception of primary visual cortex. Whereas some regions express patterns of regional covariance that are mirror symmetrical relative to the interhemispheric fissure, other regions express asymmetric patterns of regional covariance. Finally, patterns of covariance are remarkably consistent between males and females, with the exception of the left amygdala, which is positively associated with the left and right anterior inferior temporal cortex in males and with the right angular gyrus in females. Our study establishes that the density of different cortical regions is coordinated within an individual. The coordinated variations we report are likely to be determined by both genetic and environmental factors and may be the basis for differences in individual behavior. [ABSTRACT FROM AUTHOR]

Recent functional neuroimaging studies are generating novel insights into our knowledge of skilled and disturbed reading. In neurologically normal subjects, a double dissociation in neural activation in response to reading words and pseudowords has been revealed that corresponds to that observed in the comparison of semantic and phonological tasks. In patients with acquired dyslexia, functional imaging is demonstrating re-organisation within the reading system; in developmental dyslexia, functional imaging is being used to identify the impact of rehabilitation. Together, these findings have implications for cognitive models of reading that have previously relied on input from behavioural data. [Copyright &y& Elsevier]

Telomeric chromatin has peculiar features with respect to bulk chromatin, which are not fully clarified to date. Nucleosomal arrays, reconstituted on fragments of human telomeric DNA and on tandemly repeated tetramers of 5S rDNA, have been investigated at single-molecule level by atomic force microscopy and Monte Carlo simulations. A satisfactory correlation emerges between experimental and theoretical internucleosomal distance distributions. However, in the case of telomeric nucleosomal arrays containing two nucleosomes, we found significant differences. Our results show that sequence features of DNA are significant in the basic chromatin organization, but are not the only determinant. [Copyright &y& Elsevier]

In this study, we combined functional magnetic resonance imaging (fMRI) and dynamic causal modeling (DCM) to investigate whether object category effects in the occipital and temporal cortex are mediated by inputs from early visual cortex or parietal regions. Resolving this issue may provide anatomical constraints on theories of category specificity— which make different assumptions about the underlying neurophysiology. The data were acquired by Ishai, Ungerleider, Martin, Schouten, and Haxby (1999, 2000) and provided by the National fMRI Data Center (http://www.fmridc.org). The original authors used a conventional analysis to estimate differential effects in the occipital and temporal cortex in response to pictures of chairs, faces, and houses. We extended this approach by estimating neuronal interactions that mediate category effects using DCM. DCM uses a Bayesian framework to estimate and make inferences about the influence that one region exerts over another and how this is affected by experimental changes. DCM differs from previous approaches to brain connectivity, such as multivariate autoregressive models and structural equation modeling, as it assumes that the observed hemodynamic responses are driven by experimental changes rather than endogenous noise. DCM therefore brings the analysis of brain connectivity much closer to the analysis of regionally specific effects usually applied to functional imaging data. We used DCM to estimate the influence that V3 and the superior/inferior parietal cortex exerted over category-responsive regions and how this was affected by the presentation of houses, faces, and chairs. We found that category effects in occipital and temporal cortex were mediated by inputs from early visual cortex. In contrast, the connectivity from the superior/inferior parietal area to the category-responsive areas was unaffected by the presentation of chairs, faces, or houses. These findings indicate that category effects in the occipital and temporal cortex can be mediated by bottom–up mechanisms—a finding that needs to be embraced by models of category specificity. [ABSTRACT FROM AUTHOR]

This technical note deals with a priori estimation of efficiency of functional magnetic resonance imaging (fMRI) designs. The efficiency of an estimator is a measure of how reliable it is and depends on error variance (the variance not modeled by explanatory variables in the design matrix) and the design variance (a function of the explanatory variables and the contrast tested). Changes in the experimental design can induce changes in the variance of estimated responses. This translates into changes in the standard error of the response estimate or equivalently into changes in efficiency. One consequence is that statistics, testing for the same activation in different contexts (i.e., experimental designs), can change substantially even if the activation and error variance are exactly the same. We demonstrate this effect using an event-related fMRI study of single word reading during blocked and randomized trial presentations. Furthermore, we show that the error variance can change with the experimental design. This highlights a problem with a priori comparison of efficiency for two or more experimental designs, which usually assumes identical error variance. [Copyright &y& Elsevier]

In this study we demonstrate that, even in blocked design fMRI, an event-related analysis may provide a more accurate model of the hemodynamic responses than an epoch-related analysis. This is because the temporal shape of the predicted response differs between the event-related and the epoch model, with the former reaching its peak sooner and returning to baseline later than the latter. We present data from a blocked design fMRI study of single word reading alternated with rest. Conventionally, such a design would be analyzed using an epoch analysis with boxcar regressors. However, here we used a combined model in which trials were modeled as both single events and epochs. This allowed us to estimate the variance in the BOLD signal that was explained by either the event-related or the epoch regressors having discounted the effect of the other. We found that, in a number of language regions, the event-related model explained changes in activity that were not accounted for by the epoch model. In addition, we show that the advantage of the event-related over epoch model was engendered by its early onset rather than its late offset, relative to the epoch model. [Copyright &y& Elsevier]

Several functional neuroimaging studies have compared words and pseudowords to test different cognitive models of reading. There are difficulties with this approach, however, because cognitive models do not make clear-cut predictions at the neural level. Therefore, results can only be interpreted on the basis of prior knowledge of cognitive anatomy. Furthermore, studies comparing words and pseudowords have produced inconsistent results. The inconsistencies could reflect false-positive results due to the low statistical thresholds applied or confounds from nonlexical aspects of the stimuli. Alternatively, they may reflect true effects that are inconsistent across subjects; dependent on experimental parameters such as stimulus rate or duration; or not replicated across studies because of insufficient statistical power. In this fMRI study, we investigate consistent and inconsistent differences between word and pseudoword reading in 20 subjects, and distinguish between effects associated with increases and decreases in activity relative to fixation. In addition, the interaction of word type with stimulus duration is explored. We find that words and pseudowords activate the same set of regions relative to fixation, and within this system, there is greater activation for pseudowords than words in the left frontal operculum, left posterior inferior temporal gyrus, and the right cerebellum. The only effects of words relative to pseudowords consistent over subjects are due to decreases in activity for pseudowords relative to fixation; and there are no significant interactions between word type and stimulus duration. Finally, we observe inconsistent but highly significant effects of word type at the individual subject level. These results (i) illustrate that pseudowords place increased demands on areas that have previously been linked to lexical retrieval, and (ii) highlight the importance of including one or more baselines to qualify word type effects. Furthermore, (iii) they suggest that inconsistencies observed in the previous literature may result from effects arising from a small number of subjects only. [ABSTRACT FROM AUTHOR]