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Find video protocols related to scientific articles indexed in Pubmed.
Fronto-striatal Dysfunction During Reward Processing in Unaffected Siblings of Schizophrenia Patients.
Schizophr Bull
PUBLISHED: 11-05-2014
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Schizophrenia is a psychiatric disorder that is associated with impaired functioning of the fronto-striatal network, in particular during reward processing. However, it is unclear whether this dysfunction is related to the illness itself or whether it reflects a genetic vulnerability to develop schizophrenia. Here, we examined reward processing in unaffected siblings of schizophrenia patients using functional magnetic resonance imaging. Brain activity was measured during reward anticipation and reward outcome in 27 unaffected siblings of schizophrenia patients and 29 healthy volunteers using a modified monetary incentive delay task. Task performance was manipulated online so that all subjects won the same amount of money. Despite equal performance, siblings showed reduced activation in the ventral striatum, insula, and supplementary motor area (SMA) during reward anticipation compared to controls. Decreased ventral striatal activation in siblings was correlated with sub-clinical negative symptoms. During the outcome of reward, siblings showed increased activation in the ventral striatum and orbitofrontal cortex compared to controls. Our finding of decreased activity in the ventral striatum during reward anticipation and increased activity in this region during receiving reward may indicate impaired cue processing in siblings. This is consistent with the notion of dopamine dysfunction typically associated with schizophrenia. Since unaffected siblings share on average 50% of their genes with their ill relatives, these deficits may be related to the genetic vulnerability for schizophrenia.
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An edge-centric perspective on the human connectome: link communities in the brain.
Philos. Trans. R. Soc. Lond., B, Biol. Sci.
PUBLISHED: 09-03-2014
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Brain function depends on efficient processing and integration of information within a complex network of neural interactions, known as the connectome. An important aspect of connectome architecture is the existence of community structure, providing an anatomical basis for the occurrence of functional specialization. Typically, communities are defined as groups of densely connected network nodes, representing clusters of brain regions. Looking at the connectome from a different perspective, instead focusing on the interconnecting links or edges, we find that the white matter pathways between brain regions also exhibit community structure. Eleven link communities were identified: five spanning through the midline fissure, three through the left hemisphere and three through the right hemisphere. We show that these link communities are consistently identifiable and investigate the network characteristics of their underlying white matter pathways. Furthermore, examination of the relationship between link communities and brain regions revealed that the majority of brain regions participate in multiple link communities. In particular, the highly connected and central hub regions showed a rich level of community participation, supporting the notion that these hubs play a pivotal role as confluence zones in which neural information from different domains merges.
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Delayed school progression and mental health problems in adolescence: a population-based study in 10,803 adolescents.
BMC Psychiatry
PUBLISHED: 08-19-2014
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Accumulating evidence suggests that several adult mental disorders, particularly psychoses, are preceded by impairments in cognitive function, reflected in scholastic underachievement. This study investigates the association between scholastic underachievement and general mental health problems in adolescence, using delay in school progression as a marker of poor scholastic performance.
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Resting state functional connectivity of the anterior cingulate cortex in veterans with and without post-traumatic stress disorder.
Hum Brain Mapp
PUBLISHED: 08-19-2014
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Post-traumatic stress disorder (PTSD) is an anxiety disorder that is associated with structural and functional alterations in several brain areas, including the anterior cingulate cortex (ACC). Here, we examine resting state functional connectivity of ACC subdivisions in PTSD, using a seed-based approach. Resting state magnetic resonance images were obtained from male veterans with (n?=?31) and without (n?=?25) PTSD, and healthy male civilian controls (n?=?25). Veterans with and without PTSD (combat controls) had reduced functional connectivity compared to healthy controls between the caudal ACC and the precentral gyrus, and between the perigenual ACC and the superior medial gyrus and middle temporal gyrus. Combat controls had increased connectivity between the rostral ACC and precentral/middle frontal gyrus compared to PTSD patients and healthy civilian controls. The resting state functional connectivity differences in the perigenual ACC network reported here indicate that veterans differ from healthy controls, potentially due to military training, deployment, and/or trauma exposure. In addition, specific alterations in the combat controls may potentially be related to resilience. These results underline the importance of distinguishing trauma-exposed (combat) controls from healthy civilian controls when studying PTSD. Hum Brain Mapp, 2014. © 2014 Wiley Periodicals, Inc.
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Association between olfactory identification and parkinsonism in patients with non-affective psychosis.
Early Interv Psychiatry
PUBLISHED: 07-22-2014
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Olfactory identification deficits (OIDs) are seen in schizophrenia patients and individuals at increased risk for psychosis but its pathophysiology remains unclear. Although dopaminergic imbalance is known to lie at the core of schizophrenia symptomatology, its role in the development of OIDs has not been elucidated yet. This study investigated the association between OIDs and symptoms of parkinsonism as a derivative of dopaminergic functioning.
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Extrapyramidal symptoms during treatment of first schizophrenia episode: results from EUFEST.
Eur Neuropsychopharmacol
PUBLISHED: 06-29-2014
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The European First Episode Schizophrenia Trial (EUFEST) included first-episode schizophrenia patients, assessing the efficacy of five antipsychotic drugs (haloperidol, amisulpride, olanzapine, quetiapine and ziprasidone) over one year. Baseline frequency of extrapyramidal symptoms (EPS) in this group of patients (n=490) was as follows: parkinsonism 10.8%, akathisia 10.0%, dystonia 1.8%, and dyskinesia 0.6%. The frequency of parkinsonism at baseline was greater in patients with a brief prior exposure to antipsychotics (?2 weeks) compared with antipsychotic-naïve ones, and was positively correlated with the intensity of negative symptoms and negatively with depressive symptoms. After one month of treatment, the increase of parkinsonism was highest in patients receiving haloperidol (+13%), that of akathisia in patients treated with ziprasidone (+14%), and 10.1% of the patients were taking anticholinergic drugs, most frequently in the haloperidol group (24%). In 291 patients remaining on treatment after one year, both parkinsonism and akathisia had decreased: the frequency of parkinsonism was 3%, highest in the haloperidol group (9.1%), that of akathisia was 3%, highest in the quetiapine group (7.5%), and 4% of patients were taking anticholinergic drugs, most frequently those receiving haloperidol (10.5%). The results obtained suggest that in first-episode schizophrenia patients during the first year of antipsychotic treatment (in this case amisulpride, haloperidol in low doses, olanzapine, quetiapine and ziprasidone), EPS were present as manageable clinical problems.
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Frontal-subcortical circuits involved in reactive control and monitoring of gaze.
J. Neurosci.
PUBLISHED: 06-27-2014
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Rapid and reactive control of movement is essential in a dynamic environment and is disrupted in several neuropsychiatric disorders. Nonhuman primate neurophysiology studies have made significant contributions to our understanding of how saccadic eye movements can be rapidly inhibited, changed, and monitored. These results highlight a frontostriatal network involved in gaze control and provide a strong basis for understanding how cognitive control of action is implemented in the human brain. The goal of the present study was to bridge human and nonhuman primate studies by investigating reactive control of eye movements during fMRI using a task that has been used in neurophysiology studies: the search-step task. This task requires a speeded response to a visual target (no-step trial). On a minority (40%) of trials, the target jumps to a new location and participants are instructed to inhibit the initially planned saccade and redirect gaze toward the new location (redirect trial). Compared with no-step trials, greater activation in a frontal oculomotor network, including frontal and supplementary eye fields (SEFs), and the striatum was observed during correctly executed redirect trials. Individual differences in stopping efficiency were related to striatal activation. Further, greater activation in SEF was in a region anterior to that activated during visually guided saccades and scaled positively with error magnitude, suggesting a prominent role in response monitoring. Combined, these data lend new evidence for a role of the striatum in reactive saccade control and further clarify the role of SEF in action inhibition and performance monitoring.
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Cortical thickness in individuals with non-clinical and clinical psychotic symptoms.
Brain
PUBLISHED: 06-20-2014
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Symptoms that are linked to psychosis are also experienced by individuals who are not in need of care. In the present study, cortical thickness was investigated in these individuals. Fifty individuals with non-clinical auditory verbal hallucinations (most of them also experienced other non-clinical psychotic symptoms), 50 patients with a psychotic disorder and auditory verbal hallucinations, and 50 healthy control subjects underwent structural magnetic resonance imaging. Data were analysed using FreeSurfer. Cortical thickness in the pars orbitalis, paracentral lobule, fusiform gyrus and inferior temporal gyrus was lowest in patients, intermediate in the non-clinical hallucinating group, and highest in control subjects. The patients also showed thinning in widespread additional areas compared to the two other groups, whereas both hallucinating groups showed similar levels of thinning in the insula. Ranking the levels of cortical thickness per brain region across groups revealed that for 88% of brain regions, cortical thickness was lowest in patients, intermediate in the non-clinical hallucinating group, and highest in controls. These findings show that individuals with non-clinical psychotic symptoms show a similar but less pronounced pattern of cortical thinning as patients with a psychotic disorder, which is suggestive of a similar, but milder underlying pathophysiology in this group compared to the psychosis group.
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Impaired right inferior frontal gyrus response to contextual cues in male veterans with PTSD during response inhibition.
J Psychiatry Neurosci
PUBLISHED: 06-03-2014
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Posttraumatic stress disorder (PTSD) is often associated with impaired fear inhibition and decreased safety cue processing; however, studies capturing the cognitive aspect of inhibition and contextual cue processing are limited. In this fMRI study, the role of contextual cues in response inhibition was investigated.
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The Neonatal Connectome During Preterm Brain Development.
Cereb. Cortex
PUBLISHED: 05-17-2014
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The human connectome is the result of an elaborate developmental trajectory. Acquiring diffusion-weighted imaging and resting-state fMRI, we studied connectome formation during the preterm phase of macroscopic connectome genesis. In total, 27 neonates were scanned at week 30 and/or week 40 gestational age (GA). Examining the architecture of the neonatal anatomical brain network revealed a clear presence of a small-world modular organization before term birth. Analysis of neonatal functional connectivity (FC) showed the early formation of resting-state networks, suggesting that functional networks are present in the preterm brain, albeit being in an immature state. Moreover, structural and FC patterns of the neonatal brain network showed strong overlap with connectome architecture of the adult brain (85 and 81%, respectively). Analysis of brain development between week 30 and week 40 GA revealed clear developmental effects in neonatal connectome architecture, including a significant increase in white matter microstructure (P < 0.01), small-world topology (P < 0.01) and interhemispheric FC (P < 0.01). Computational analysis further showed that developmental changes involved an increase in integration capacity of the connectivity network as a whole. Taken together, we conclude that hallmark organizational structures of the human connectome are present before term birth and subject to early development.
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Heritability of structural brain network topology: a DTI study of 156 twins.
Hum Brain Mapp
PUBLISHED: 03-31-2014
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Individual variation in structural brain network topology has been associated with heritable behavioral phenotypes such as intelligence and schizophrenia, making it a candidate endophenotype. However, little is known about the genetic influences on individual variation in structural brain network topology. Moreover, the extent to which structural brain network topology overlaps with heritability for integrity and volume of white matter remains unknown. In this study, structural network topology was examined using diffusion tensor imaging at 3T. Binary connections between 82 structurally defined brain regions per subject were traced, allowing for estimation of individual topological network properties. Heritability of normalized characteristic path length (?), normalized clustering coefficient (?), microstructural integrity (FA), and volume of the white matter were estimated using a twin design, including 156 adult twins from the newly acquired U-TWIN cohort. Both ? and ? were estimated to be under substantial genetic influence. The heritability of ? was estimated to be 68%, the heritability estimate for ? was estimated to be 57%. Genetic influences on network measures were found to be partly overlapping with volumetric and microstructural properties of white matter, but the largest component of genetic variance was unique to both network traits. Normalized clustering coefficient and normalized characteristic path length are substantially heritable, and influenced by independent genetic factors that are largely unique to network measures, but partly also implicated in white matter directionality and volume. Thus, network measures provide information about genetic influence on brain structure, independent of global white matter characteristics such as volume and microstructural directionality.
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Genetic liability for schizophrenia predicts risk of immune disorders.
Schizophr. Res.
PUBLISHED: 02-22-2014
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Schizophrenia patients and their parents have an increased risk of immune disorders compared to population controls and their parents. This may be explained by genetic overlap in the pathogenesis of both types of disorders. The purpose of this study was to investigate the genetic overlap between schizophrenia and three immune disorders and to compare with the overlap between schizophrenia and two disorders not primarily characterized by immune dysregulation: bipolar disorder and type 2 diabetes.
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Multi-site study of additive genetic effects on fractional anisotropy of cerebral white matter: Comparing meta and megaanalytical approaches for data pooling.
Neuroimage
PUBLISHED: 02-21-2014
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Combining datasets across independent studies can boost statistical power by increasing the numbers of observations and can achieve more accurate estimates of effect sizes. This is especially important for genetic studies where a large number of observations are required to obtain sufficient power to detect and replicate genetic effects. There is a need to develop and evaluate methods for joint-analytical analyses of rich datasets collected in imaging genetics studies. The ENIGMA-DTI consortium is developing and evaluating approaches for obtaining pooled estimates of heritability through meta-and mega-genetic analytical approaches, to estimate the general additive genetic contributions to the intersubject variance in fractional anisotropy (FA) measured from diffusion tensor imaging (DTI). We used the ENIGMA-DTI data harmonization protocol for uniform processing of DTI data from multiple sites. We evaluated this protocol in five family-based cohorts providing data from a total of 2248 children and adults (ages: 9-85) collected with various imaging protocols. We used the imaging genetics analysis tool, SOLAR-Eclipse, to combine twin and family data from Dutch, Australian and Mexican-American cohorts into one large "mega-family". We showed that heritability estimates may vary from one cohort to another. We used two meta-analytical (the sample-size and standard-error weighted) approaches and a mega-genetic analysis to calculate heritability estimates across-population. We performed leave-one-out analysis of the joint estimates of heritability, removing a different cohort each time to understand the estimate variability. Overall, meta- and mega-genetic analyses of heritability produced robust estimates of heritability.
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Heritability of brain volume change and its relation to intelligence.
Neuroimage
PUBLISHED: 02-12-2014
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Human brain volumes change throughout life, are highly heritable, and have been associated with general cognitive functioning. Cross-sectionally, this association between volume and cognition can largely be attributed to the same genes influencing both traits. We address the question whether longitudinal changes in brain volume or in surface area in young adults are under genetic control and whether these changes are also related to general cognitive functioning. We measured change in brain volume and surface area over a 5-year interval in 176 monozygotic and dizygotic twins and their non-twin siblings aged 19 to 56, using magnetic resonance imaging. Results show that changes in volumes of total brain (mean = -6.4 ml; 0.5% loss), cerebellum (1.4 ml, 1.0% increase), cerebral white matter (4.4 ml, 0.9% increase), lateral ventricles (0.6 ml; 4.8% increase) and in surface area (-19.7 cm(2),1.1% contraction) are heritable (h(2) = 43%; 52%; 29%; 31%; and 33%, respectively). An association between IQ (available for 91 participants) and brain volume change was observed, which was attributed to genes involved in both the variation in change in brain volume and in intelligence. Thus, dynamic changes in brain structure are heritable and may have cognitive significance in adulthood.
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Cytokine alterations in first-episode schizophrenia patients before and after antipsychotic treatment.
Schizophr. Res.
PUBLISHED: 01-23-2014
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Schizophrenia has been associated with central nervous system and peripheral immune system imbalances. However, most studies have not yielded conclusive results due to limitations such as small sample size, dissimilarities in the clinical status of patients and the high variability of cytokine levels within the normal human population. Here, we have attempted to account for these limitations by carrying out standardised multiplex immunoassay analyses of 9 cytokines in serum from 180 antipsychotic-naïve first-episode schizophrenia patients and 350 matched controls across 5 clinical cohorts. All subjects were matched for potential confounding factors including age, gender, smoking and body mass index. We found that the levels of interleukin (IL)-1RA, IL-10 and IL-15 were increased significantly in patients across the cohorts. We also found that the levels of IL-1RA and IL-10 were decreased in 32 patients who had been followed up and treated for 6 weeks with atypical antipsychotics. Interestingly, we found that the changes in IL-10 levels were significantly correlated with the improvements in negative, general and total symptom scores. These results indicate that mixed pro- and anti-inflammatory responses may be altered in first onset patients, suggesting a role in the aetiology of schizophrenia. The finding that only the anti-inflammatory cytokine IL-10 responded to treatment in parallel with symptom improvement suggests that this could be used as a potential treatment response biomarker in future studies of schizophrenia.
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Frontostriatal activity and connectivity increase during proactive inhibition across adolescence and early adulthood.
Hum Brain Mapp
PUBLISHED: 01-21-2014
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During adolescence, functional and structural changes in the brain facilitate the transition from childhood to adulthood. Because the cortex and the striatum mature at different rates, temporary imbalances in the frontostriatal network occur. Here, we investigate the development of the subcortical and cortical components of the frontostriatal network from early adolescence to early adulthood in 60 subjects in a cross-sectional design, using functional MRI and a stop-signal task measuring two forms of inhibitory control: reactive inhibition (outright stopping) and proactive inhibition (anticipation of stopping). During development, reactive inhibition improved: older subjects were faster in reactive inhibition. In the brain, this was paralleled by an increase in motor cortex suppression. The level of proactive inhibition increased, with older subjects slowing down responding more than younger subjects when anticipating a stop-signal. Activation increased in the right striatum, right ventral and dorsal inferior frontal gyrus, and supplementary motor area. Moreover, functional connectivity during proactive inhibition increased between striatum and frontal regions with age. In conclusion, we demonstrate that developmental improvements in proactive inhibition are paralleled by increases in activation and functional connectivity of the frontostriatal network. These data serve as a stepping stone to investigate abnormal development of the frontostriatal network in disorders such as schizophrenia and attention-deficit hyperactivity disorder.
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Functional differences in emotion processing during adolescence and early adulthood.
Neuroimage
PUBLISHED: 01-21-2014
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Adolescence is a transitional period between childhood and adulthood and is characterized by emotional instability. Underlying this behavior may be an imbalance between the limbic subcortical areas and the prefrontal cortex. Here, we investigated differences in these regions during adolescence and young adulthood. Fifty subjects aged 10 to 24 viewed and rated neutral, negative, and positive pictures (IAPS: International Affective Picture System), while being scanned with functional MRI. Only those trials in which there was a match between the subject's response and the IAPS rating were included in the analyses. Task performance (matching accuracy, reaction times) did not differ across age. Activity in the amygdala and hippocampus decreased with age when processing emotional salient stimuli versus neutral stimuli. In contrast, activation in the ventrolateral prefrontal cortex increased with age. Importantly, we show for the first time that these age-related changes are paralleled by an increase in functional coupling of the amygdala and hippocampus with the orbitofrontal cortex and ventrolateral prefrontal cortex. These findings are in line with the general notion that brain development from childhood to adulthood is characterized by a gradual increase in frontal control over subcortical regions. Understanding these developmental changes is important as these may underlie typical adolescent behavior.
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Open, randomized trial of the effects of aripiprazole versus risperidone on social cognition in schizophrenia.
Eur Neuropsychopharmacol
PUBLISHED: 01-15-2014
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To date, only few studies have examined the impact of medication on social cognition and none have examined the effects of aripiprazole in this respect. The goal of this 8-week, randomized, multicenter, open-label study was to examine the effects of aripiprazole and risperidone on social cognition and neurocognition in individuals with schizophrenia. Eighty schizophrenia patients (DSM-IV-TR) aged 16-50 years were administered multiple computerized measures of social cognition and neurocognition including reaction times at baseline and the end of week 8. Social functioning was mapped with the Social Functioning scale and Quality of Life scale. The study ran from June 2005 to March 2011. Scores on social cognitive and neurocognitive tests improved with both treatments, as did reaction time. There were few differences between the two antipsychotics on (social) cognitive test-scores. The aripiprazole group performed better (more correct items) on symbol substitution (P=.003). Aripiprazole was also superior to risperidone on reaction time for emotional working memory and working memory (P=.006 and P=.023, respectively). Improvements on these tests were correlated with social functioning. In conclusion, aripiprazole and risperidone showed a similar impact on social cognitive test-scores. However, aripiprazole treatment produced a greater effect on patients' processing speed compared to risperidone, with these improvements being associated with concurrent improvements in social functioning. Further research on the long-term effects of aripiprazole on cognition is warranted.
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Stress exposure across the life span cumulatively increases depression risk and is moderated by neuroticism.
Depress Anxiety
PUBLISHED: 01-14-2014
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Even though traumatic stress is a major risk factor for depression, most people do not develop a depression. The effects of stress may particularly emerge after repeated exposure in vulnerable individuals. Therefore, we hypothesized that (1) increased exposure to stress across the life span is associated with an increased depression risk and (2) this effect is the most pronounced in individuals with high levels of neuroticism.
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Changes in Thickness and Surface Area of the Human Cortex and Their Relationship with Intelligence.
Cereb. Cortex
PUBLISHED: 01-11-2014
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Changes in cortical thickness over time have been related to intelligence, but whether changes in cortical surface area are related to general cognitive functioning is unknown. We therefore examined the relationship between intelligence quotient (IQ) and changes in cortical thickness and surface over time in 504 healthy subjects. At 10 years of age, more intelligent children have a slightly thinner cortex than children with a lower IQ. This relationship becomes more pronounced with increasing age: with higher IQ, a faster thinning of the cortex is found over time. In the more intelligent young adults, this relationship reverses so that by the age of 42 a thicker cortex is associated with higher intelligence. In contrast, cortical surface is larger in more intelligent children at the age of 10. The cortical surface is still expanding, reaching its maximum area during adolescence. With higher IQ, cortical expansion is completed at a younger age; and once completed, surface area decreases at a higher rate. These findings suggest that intelligence may be more related to the magnitude and timing of changes in brain structure during development than to brain structure per se, and that the cortex is never completed but shows continuing intelligence-dependent development.
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The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data.
Paul M Thompson, Jason L Stein, Sarah E Medland, Derrek P Hibar, Alejandro Arias Vasquez, Miguel E Rentería, Roberto Toro, Neda Jahanshad, Gunter Schumann, Barbara Franke, Margaret J Wright, Nicholas G Martin, Ingrid Agartz, Martin Alda, Saud Alhusaini, Laura Almasy, Jorge Almeida, Kathryn Alpert, Nancy C Andreasen, Ole A Andreassen, Liana G Apostolova, Katja Appel, Nicola J Armstrong, Benjamin Aribisala, Mark E Bastin, Michael Bauer, Carrie E Bearden, Orjan Bergmann, Elisabeth B Binder, John Blangero, Henry J Bockholt, Erlend Bøen, Catherine Bois, Dorret I Boomsma, Tom Booth, Ian J Bowman, Janita Bralten, Rachel M Brouwer, Han G Brunner, David G Brohawn, Randy L Buckner, Jan Buitelaar, Kazima Bulayeva, Juan R Bustillo, Vince D Calhoun, Dara M Cannon, Rita M Cantor, Melanie A Carless, Xavier Caseras, Gianpiero L Cavalleri, M Mallar Chakravarty, Kiki D Chang, Christopher R K Ching, Andrea Christoforou, Sven Cichon, Vincent P Clark, Patricia Conrod, Giovanni Coppola, Benedicto Crespo-Facorro, Joanne E Curran, Michael Czisch, Ian J Deary, Eco J C de Geus, Anouk den Braber, Giuseppe Delvecchio, Chantal Depondt, Lieuwe de Haan, Greig I de Zubicaray, Danai Dima, Rali Dimitrova, Srdjan Djurovic, Hongwei Dong, Gary Donohoe, Ravindranath Duggirala, Thomas D Dyer, Stefan Ehrlich, Carl Johan Ekman, Torbjørn Elvsåshagen, Louise Emsell, Susanne Erk, Thomas Espeseth, Jesen Fagerness, Scott Fears, Iryna Fedko, Guillén Fernández, Simon E Fisher, Tatiana Foroud, Peter T Fox, Clyde Francks, Sophia Frangou, Eva Maria Frey, Thomas Frodl, Vincent Frouin, Hugh Garavan, Sudheer Giddaluru, David C Glahn, Beata Godlewska, Rita Z Goldstein, Randy L Gollub, Hans J Grabe, Oliver Grimm, Oliver Gruber, Tulio Guadalupe, Raquel E Gur, Ruben C Gur, Harald H H Göring, Saskia Hagenaars, Tomáš Hájek, Geoffrey B Hall, Jeremy Hall, John Hardy, Catharina A Hartman, Johanna Hass, Sean N Hatton, Unn K Haukvik, Katrin Hegenscheid, Andreas Heinz, Ian B Hickie, Beng-Choon Ho, David Hoehn, Pieter J Hoekstra, Marisa Hollinshead, Avram J Holmes, Georg Homuth, Martine Hoogman, L Elliot Hong, Norbert Hosten, Jouke-Jan Hottenga, Hilleke E Hulshoff Pol, Kristy S Hwang, Clifford R Jack, Mark Jenkinson, Caroline Johnston, Erik G Jönsson, René S Kahn, Dalia Kasperaviciute, Sinead Kelly, Sungeun Kim, Peter Kochunov, Laura Koenders, Bernd Krämer, John B J Kwok, Jim Lagopoulos, Gonzalo Laje, Mikael Landén, Bennett A Landman, John Lauriello, Stephen M Lawrie, Phil H Lee, Stephanie Le Hellard, Herve Lemaitre, Cassandra D Leonardo, Chiang-Shan Li, Benny Liberg, David C Liewald, Xinmin Liu, Lorna M Lopez, Eva Loth, Anbarasu Lourdusamy, Michelle Luciano, Fabio Macciardi, Marise W J Machielsen, Glenda M Macqueen, Ulrik F Malt, René Mandl, Dara S Manoach, Jean-Luc Martinot, Mar Matarin, Karen A Mather, Manuel Mattheisen, Morten Mattingsdal, Andreas Meyer-Lindenberg, Colm McDonald, Andrew M McIntosh, Francis J McMahon, Katie L McMahon, Eva Meisenzahl, Ingrid Melle, Yuri Milaneschi, Sebastian Mohnke, Grant W Montgomery, Derek W Morris, Eric K Moses, Bryon A Mueller, Susana Muñoz Maniega, Thomas W Mühleisen, Bertram Müller-Myhsok, Benson Mwangi, Matthias Nauck, Kwangsik Nho, Thomas E Nichols, Lars-Göran Nilsson, Allison C Nugent, Lars Nyberg, Rene L Olvera, Jaap Oosterlaan, Roel A Ophoff, Massimo Pandolfo, Melina Papalampropoulou-Tsiridou, Martina Papmeyer, Tomas Paus, Zdenka Pausova, Godfrey D Pearlson, Brenda W Penninx, Charles P Peterson, Andrea Pfennig, Mary Phillips, G Bruce Pike, Jean-Baptiste Poline, Steven G Potkin, Benno Pütz, Adaikalavan Ramasamy, Jerod Rasmussen, Marcella Rietschel, Mark Rijpkema, Shannon L Risacher, Joshua L Roffman, Roberto Roiz-Santiañez, Nina Romanczuk-Seiferth, Emma J Rose, Natalie A Royle, Dan Rujescu, Mina Ryten, Perminder S Sachdev, Alireza Salami, Theodore D Satterthwaite, Jonathan Savitz, Andrew J Saykin, Cathy Scanlon, Lianne Schmaal, Hugo G Schnack, Andrew J Schork, S Charles Schulz, Remmelt Schür, Larry Seidman, Li Shen, Jody M Shoemaker, Andrew Simmons, Sanjay M Sisodiya, Colin Smith, Jordan W Smoller, Jair C Soares, Scott R Sponheim, Emma Sprooten, John M Starr, Vidar M Steen, Stephen Strakowski, Lachlan Strike, Jessika Sussmann, Philipp G Sämann, Alexander Teumer, Arthur W Toga, Diana Tordesillas-Gutierrez, Daniah Trabzuni, Sarah Trost, Jessica Turner, Martijn van den Heuvel, Nic J van der Wee, Kristel van Eijk, Theo G M van Erp, Neeltje E M van Haren, Dennis van 't Ent, Marie-José van Tol, Maria C Valdés Hernández, Dick J Veltman, Amelia Versace, Henry Völzke, Robert Walker, Henrik Walter, Lei Wang, Joanna M Wardlaw, Michael E Weale, Michael W Weiner, Wei Wen, Lars T Westlye, Heather C Whalley, Christopher D Whelan, Tonya White, Anderson M Winkler, Katharina Wittfeld, Girma Woldehawariat, Christiane Wolf, David Zilles, Marcel P Zwiers, Anbupalam Thalamuthu, Peter R Schofield, Nelson B Freimer, Natalia S Lawrence, Wayne Drevets, .
Brain Imaging Behav
PUBLISHED: 01-09-2014
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The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
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Seasonal changes in gene expression represent cell-type composition in whole blood.
Hum. Mol. Genet.
PUBLISHED: 01-07-2014
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Seasonal patterns in behavior and biological parameters are widespread. Here, we examined seasonal changes in whole blood gene expression profiles of 233 healthy subjects. Using weighted gene co-expression network analysis, we identified three co-expression modules showing circannual patterns. Enrichment analysis suggested that this signal stems primarily from red blood cells and blood platelets. Indeed, a large clinical database with 51 142 observations of blood cell counts over 3 years confirmed a corresponding seasonal pattern of counts of red blood cells, reticulocytes and platelets. We found no direct evidence that these changes are linked to genes known to be key players in regulating immune function or circadian rhythm. It is likely, however, that these seasonal changes in cell counts and gene expression profiles in whole blood represent biological and clinical relevant phenomena. Moreover, our findings highlight possible confounding factors relevant to the study of gene expression profiles in subjects collected at geographical locations with disparaging seasonality patterns.
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Genetic associations between intelligence and cortical thickness emerge at the start of puberty.
Hum Brain Mapp
PUBLISHED: 01-03-2014
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Cognitive abilities are related to (changes in) brain structure during adolescence and adulthood. Previous studies suggest that associations between cortical thickness and intelligence may be different at different ages. As both intelligence and cortical thickness are heritable traits, the question arises whether the association between cortical thickness development and intelligence is due to genes influencing both traits. We study this association in a longitudinal sample of young twins. Intelligence was assessed by standard IQ tests at age 9 in 224 twins, 190 of whom also underwent structural magnetic resonance imaging (MRI). Three years later at age 12, 177/125 twins returned for a follow-up measurement of intelligence/MRI scanning, respectively. We investigated whether cortical thickness was associated with intelligence and if so, whether this association was driven by genes. At age 9, there were no associations between cortical thickness and intelligence. At age 12, a negative relationship emerged. This association was mainly driven by verbal intelligence, and manifested itself most prominently in the left hemisphere. Cortical thickness and intelligence were explained by the same genes. As a post hoc analysis, we tested whether a specific allele (rs6265; Val66Met in the BDNF gene) contributed to this association. Met carriers showed lower intelligence and a thicker cortex, but only the association between the BDNF genotype and cortical thickness in the left superior parietal gyrus reached significance. In conclusion, it seems that brain areas contributing to (verbal) intellectual performance are specializing under the influence of genes around the onset of puberty.
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GABA and glutamate in schizophrenia: A 7 T (1)H-MRS study.
Neuroimage Clin
PUBLISHED: 01-01-2014
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Schizophrenia is characterized by loss of brain volume, which may represent an ongoing pathophysiological process. This loss of brain volume may be explained by reduced neuropil rather than neuronal loss, suggesting abnormal synaptic plasticity and cortical microcircuitry. A possible mechanism is hypofunction of the NMDA-type of glutamate receptor, which reduces the excitation of inhibitory GABAergic interneurons, resulting in a disinhibition of glutamatergic pyramidal neurons. Disinhibition of pyramidal cells may result in excessive stimulation by glutamate, which in turn could cause neuronal damage or death through excitotoxicity. In this study, GABA/creatine ratios, and glutamate, NAA, creatine and choline concentrations in the prefrontal and parieto-occipital cortices were measured in 17 patients with schizophrenia and 23 healthy controls using proton magnetic resonance spectroscopy at an ultra-high magnetic field strength of 7 T. Significantly lower GABA/Cr ratios were found in patients with schizophrenia in the prefrontal cortex as compared to healthy controls, with GABA/Cr ratios inversely correlated with cognitive functioning in the patients. No significant change in the GABA/Cr ratio was found between patients and controls in the parieto-occipital cortex, nor were levels of glutamate, NAA, creatine, and choline differed in patients and controls in the prefrontal and parieto-occipital cortices. Our findings support a mechanism involving altered GABA levels distinguished from glutamate levels in the medial prefrontal cortex in schizophrenia, particularly in high functioning patients. A (compensatory) role for GABA through altered inhibitory neurotransmission in the prefrontal cortex may be ongoing in (higher functioning) patients with schizophrenia.
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Characterization of genome-methylome interactions in 22 nuclear pedigrees.
PLoS ONE
PUBLISHED: 01-01-2014
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Genetic polymorphisms can shape the global landscape of DNA methylation, by either changing substrates for DNA methyltransferases or altering the DNA binding affinity of cis-regulatory proteins. The interactions between CpG methylation and genetic polymorphisms have been previously investigated by methylation quantitative trait loci (mQTL) and allele-specific methylation (ASM) analysis. However, it remains unclear whether these approaches can effectively and comprehensively identify all genetic variants that contribute to the inter-individual variation of DNA methylation levels. Here we used three independent approaches to systematically investigate the influence of genetic polymorphisms on variability in DNA methylation by characterizing the methylation state of 96 whole blood samples in 52 parent-child trios from 22 nuclear pedigrees. We performed targeted bisulfite sequencing with padlock probes to quantify the absolute DNA methylation levels at a set of 411,800 CpG sites in the human genome. With mid-parent offspring analysis (MPO), we identified 10,593 CpG sites that exhibited heritable methylation patterns, among which 70.1% were SNPs directly present in methylated CpG dinucleotides. We determined the mQTL analysis identified 49.9% of heritable CpG sites for which regulation occurred in a distal cis-regulatory manner, and that ASM analysis was only able to identify 5%. Finally, we identified hundreds of clusters in the human genome for which the degree of variation of CpG methylation, as opposed to whether or not CpG sites were methylated, was associated with genetic polymorphisms, supporting a recent hypothesis on the genetic influence of phenotypic plasticity. These results show that cis-regulatory SNPs identified by mQTL do not comprise the full extent of heritable CpG methylation, and that ASM appears overall unreliable. Overall, the extent of genome-methylome interactions is well beyond what is detectible with the commonly used mQTL and ASM approaches, and is likely to include effects on plasticity.
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Impaired Rich Club Connectivity in Unaffected Siblings of Schizophrenia Patients.
Schizophr Bull
PUBLISHED: 12-02-2013
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Schizophrenia has been conceptualized as a disorder of brain connectivity. Recent studies suggest that brain connectivity may be disproportionally impaired among the so-called rich club. This small core of densely interconnected hub regions has been hypothesized to form an important infrastructure for global brain communication and integration of information across different systems of the brain. Given the heritable nature of the illness, we hypothesized that connectivity disturbances, including abnormal rich club connectivity, may be related to familial vulnerability for schizophrenia. To test this hypothesis, both schizophrenia patients and unaffected siblings of patients were investigated. Rich club organization was examined in networks derived from diffusion-weighted imaging in 40 schizophrenia patients, 54 unaffected siblings of patients, and 51 healthy control subjects. Connectivity between rich club hubs was differentially reduced across groups (P = .014), such that it was highest in controls, intermediate in siblings (7.9% reduced relative to controls), and lowest in patients (19.6% reduced compared to controls). Furthermore, in patients, lower levels of rich club connectivity were found to be related to longer duration of illness and worse overall functioning. Together, these findings suggest that impaired rich club connectivity is related to familial, possibly reflecting genetic, vulnerability for schizophrenia. Our findings support a central role for abnormal rich club organization in the etiology of schizophrenia.
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Efficacy of Anti-inflammatory Agents to Improve Symptoms in Patients With Schizophrenia: An Update.
Schizophr Bull
PUBLISHED: 10-08-2013
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Background: The inflammatory hypothesis of schizophrenia is not new, but recently it has regained interest because more data suggest a role of the immune system in the pathogenesis of schizophrenia. If increased inflammation of the brain contributes to the symptoms of schizophrenia, reduction of the inflammatory status could improve the clinical picture. Lately, several trials have been conducted investigating the potential of anti-inflammatory agents to improve symptoms of schizophrenia. This study provides an update regarding the efficacy of anti-inflammatory agents on schizophrenic symptoms in clinical studies performed so far. Methods: An electronic search was performed using PubMed, Embase, the National Institutes of Health web site http://www.clinicaltrials.gov, Cochrane Schizophrenia Group entries in PsiTri, and the Cochrane Database of Systematic Reviews. Only randomized, double-blind, placebo-controlled studies that investigated clinical outcome were included. Results: Our search yielded 26 double-blind randomized controlled trials that provided information on the efficacy on symptom severity of the following components: aspirin, celecoxib, davunetide, fatty acids such as eicosapentaenoic acids and docosahexaenoic acids, estrogens, minocycline, and N-acetylcysteine (NAC). Of these components, aspirin (mean weighted effect size [ES]: 0.3, n = 270, 95% CI: 0.06-0.537, I(2) = 0), estrogens (ES: 0.51, n = 262, 95% CI: 0.043-0.972, I(2) = 69%), and NAC (ES: 0.45, n = 140, 95% CI: 0.112-0.779) showed significant effects. Celecoxib, minocycline, davunetide, and fatty acids showed no significant effect. Conclusion: The results of aspirin addition to antipsychotic treatment seem promising, as does the addition of NAC and estrogens. These 3 agents are all very broadly active substances, and it has to be investigated if the beneficial effects on symptom severity are indeed mediated by their anti-inflammatory aspects.
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Schizophrenia is a cognitive illness: time for a change in focus.
JAMA Psychiatry
PUBLISHED: 08-09-2013
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Schizophrenia is currently classified as a psychotic disorder. This article posits that this emphasis on psychosis is a conceptual fallacy that has greatly contributed to the lack of progress in our understanding of this illness and hence has hampered the development of adequate treatments. Not only have cognitive and intellectual underperformance consistently been shown to be risk factors for schizophrenia, several studies have found that a decline in cognitive functioning precedes the onset of psychosis by almost a decade. Although the question of whether cognitive function continues to decline after psychosis onset is still debated, it is clear that cognitive function in schizophrenia is related to outcome and little influenced by antipsychotic treatment. Thus, our focus on defining (and preventing) the disorder on the basis of psychotic symptoms may be too narrow. Not only should cognition be recognized as the core component of the disorder, our diagnostic efforts should emphasize the changes in cognitive function that occur earlier in development. Putting the focus back on cognition may facilitate finding treatments for the illness before psychosis ever emerges.
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Working memory and default mode network abnormalities in unaffected siblings of schizophrenia patients.
Schizophr. Res.
PUBLISHED: 08-06-2013
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Impaired working memory (WM) is a hallmark of schizophrenia. In addition to classical WM regions such as the dorsolateral prefrontal cortex (DLPFC) and the striatum, dysfunctions in the default-mode network (DMN) contribute to these WM deficits. Unaffected siblings of patients also show WM impairments. However, the nature of the functional deficits underlying these impairments is unclear, mainly because of impaired performance confounding neuroimaging results.
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Genome-wide association analysis identifies 13 new risk loci for schizophrenia.
Stephan Ripke, Colm O'Dushlaine, Kimberly Chambert, Jennifer L Moran, Anna K Kähler, Susanne Akterin, Sarah E Bergen, Ann L Collins, James J Crowley, Menachem Fromer, Yunjung Kim, Sang Hong Lee, Patrik K E Magnusson, Nick Sanchez, Eli A Stahl, Stephanie Williams, Naomi R Wray, Kai Xia, Francesco Bettella, Anders D Borglum, Brendan K Bulik-Sullivan, Paul Cormican, Nick Craddock, Christiaan de Leeuw, Naser Durmishi, Michael Gill, Vera Golimbet, Marian L Hamshere, Peter Holmans, David M Hougaard, Kenneth S Kendler, Kuang Lin, Derek W Morris, Ole Mors, Preben B Mortensen, Benjamin M Neale, Francis A O'Neill, Michael J Owen, Milica Pejović Milovančević, Danielle Posthuma, John Powell, Alexander L Richards, Brien P Riley, Douglas Ruderfer, Dan Rujescu, Engilbert Sigurdsson, Teimuraz Silagadze, August B Smit, Hreinn Stefansson, Stacy Steinberg, Jaana Suvisaari, Sarah Tosato, Matthijs Verhage, James T Walters, , Douglas F Levinson, Pablo V Gejman, Claudine Laurent, Bryan J Mowry, Michael C O'Donovan, Ann E Pulver, Sibylle G Schwab, Dieter B Wildenauer, Frank Dudbridge, Jianxin Shi, Margot Albus, Madeline Alexander, Dominique Campion, David Cohen, Dimitris Dikeos, Jubao Duan, Peter Eichhammer, Stephanie Godard, Mark Hansen, F Bernard Lerer, Kung-Yee Liang, Wolfgang Maier, Jacques Mallet, Deborah A Nertney, Gerald Nestadt, Nadine Norton, George N Papadimitriou, Robert Ribble, Alan R Sanders, Jeremy M Silverman, Dermot Walsh, Nigel M Williams, Brandon Wormley, Maria J Arranz, Steven Bakker, Stephan Bender, Elvira Bramon, David Collier, Benedicto Crespo-Facorro, Jeremy Hall, Conrad Iyegbe, Assen Jablensky, René S Kahn, Luba Kalaydjieva, Stephen Lawrie, Cathryn M Lewis, Don H Linszen, Ignacio Mata, Andrew McIntosh, Robin M Murray, Roel A Ophoff, Jim van Os, Muriel Walshe, Matthias Weisbrod, Durk Wiersma, Peter Donnelly, Inês Barroso, Jenefer M Blackwell, Matthew A Brown, Juan P Casas, Aiden P Corvin, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S Markus, Christopher G Mathew, Colin N A Palmer, Robert Plomin, Anna Rautanen, Stephen J Sawcer, Richard C Trembath, Ananth C Viswanathan, Nicholas W Wood, Chris C A Spencer, Gavin Band, Celine Bellenguez, Colin Freeman, Garrett Hellenthal, Eleni Giannoulatou, Matti Pirinen, Richard D Pearson, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia Langford, Sarah E Hunt, Sarah Edkins, Rhian Gwilliam, Hannah Blackburn, Suzannah J Bumpstead, Serge Dronov, Matthew Gillman, Emma Gray, Naomi Hammond, Alagurevathi Jayakumar, Owen T McCann, Jennifer Liddle, Simon C Potter, Radhi Ravindrarajah, Michelle Ricketts, Avazeh Tashakkori-Ghanbaria, Matthew J Waller, Paul Weston, Sara Widaa, Pamela Whittaker, Mark I McCarthy, Kari Stefansson, Edward Scolnick, Shaun Purcell, Steven A McCarroll, Pamela Sklar, Christina M Hultman, Patrick F Sullivan.
Nat. Genet.
PUBLISHED: 08-01-2013
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Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.
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Abnormal rich club organization and functional brain dynamics in schizophrenia.
JAMA Psychiatry
PUBLISHED: 06-07-2013
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The human brain forms a large-scale structural network of regions and interregional pathways. Recent studies have reported the existence of a selective set of highly central and interconnected hub regions that may play a crucial role in the brains integrative processes, together forming a central backbone for global brain communication. Abnormal brain connectivity may have a key role in the pathophysiology of schizophrenia.
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The endocannabinoid system and emotional processing: a pharmacological fMRI study with ?9-tetrahydrocannabinol.
Eur Neuropsychopharmacol
PUBLISHED: 06-05-2013
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Various psychiatric disorders such as major depression are associated with abnormalities in emotional processing. Evidence indicating involvement of the endocannabinoid system in emotional processing, and thus potentially in related abnormalities, is increasing. In the present study, we examined the role of the endocannabinoid system in processing of stimuli with a positive and negative emotional content in healthy volunteers. A pharmacological functional magnetic resonance imaging (fMRI) study was conducted with a placebo-controlled, cross-over design, investigating effects of the endocannabinoid agonist ?9-tetrahydrocannabinol (THC) on brain function related to emotional processing in 11 healthy subjects. Performance and brain activity during matching of stimuli with a negative (fearful faces) or a positive content (happy faces) were assessed after placebo and THC administration. After THC administration, performance accuracy was decreased for stimuli with a negative but not for stimuli with a positive emotional content. Our task activated a network of brain regions including amygdala, orbital frontal gyrus, hippocampus, parietal gyrus, prefrontal cortex, and regions in the occipital cortex. THC interacted with emotional content, as activity in this network was reduced for negative content, while activity for positive content was increased. These results indicate that THC administration reduces the negative bias in emotional processing. This adds human evidence to support the hypothesis that the endocannabinoid system is involved in modulation of emotional processing. Our findings also suggest a possible role for the endocannabinoid system in abnormal emotional processing, and may thus be relevant for psychiatric disorders such as major depression.
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Different developmental trajectories for anticipation and receipt of reward during adolescence.
Dev Cogn Neurosci
PUBLISHED: 05-22-2013
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Typical adolescent behaviour such as increased risk-taking and novelty-seeking is probably related to developmental changes in the brain reward system. This functional MRI study investigated how brain activation related to two components of reward processing (Reward Anticipation and Reward Outcome) changes with age in a sample of 39 children, adolescents and young adults aged 10-25. Our data revealed age-related changes in brain activity during both components of reward processing. Activation related to Reward Anticipation increased with age, while activation related to Reward Outcome decreased in various regions of the reward network. This shift from outcome to anticipation was confirmed by subsequent analyses showing positive correlations between age and the difference in activation between Reward Anticipation and Reward Outcome. The shift was predominantly present in striatal regions and was accompanied by a significant effect of age on behaviour, with older participants showing more response speeding on potentially rewarding trials than younger participants. This study provides evidence for functional changes in the reward system which may underlie typical adolescent behaviour.
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Can structural MRI aid in clinical classification? A machine learning study in two independent samples of patients with schizophrenia, bipolar disorder and healthy subjects.
Neuroimage
PUBLISHED: 05-10-2013
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Although structural magnetic resonance imaging (MRI) has revealed partly non-overlapping brain abnormalities in schizophrenia and bipolar disorder, it is unknown whether structural MRI scans can be used to separate individuals with schizophrenia from those with bipolar disorder. An algorithm capable of discriminating between these two disorders could become a diagnostic aid for psychiatrists. Here, we scanned 66 schizophrenia patients, 66 patients with bipolar disorder and 66 healthy subjects on a 1.5T MRI scanner. Three support vector machines were trained to separate patients with schizophrenia from healthy subjects, patients with schizophrenia from those with bipolar disorder, and patients with bipolar disorder from healthy subjects, respectively, based on their gray matter density images. The predictive power of the models was tested using cross-validation and in an independent validation set of 46 schizophrenia patients, 47 patients with bipolar disorder and 43 healthy subjects scanned on a 3T MRI scanner. Schizophrenia patients could be separated from healthy subjects with an average accuracy of 90%. Additionally, schizophrenia patients and patients with bipolar disorder could be distinguished with an average accuracy of 88%.The model delineating bipolar patients from healthy subjects was less accurate, correctly classifying 67% of the healthy subjects and only 53% of the patients with bipolar disorder. In the latter group, lithium and antipsychotics use had no influence on the classification results. Application of the 1.5T models on the 3T validation set yielded average classification accuracies of 76% (healthy vs schizophrenia), 66% (bipolar vs schizophrenia) and 61% (healthy vs bipolar). In conclusion, the accurate separation of schizophrenia from bipolar patients on the basis of structural MRI scans, as demonstrated here, could be of added value in the differential diagnosis of these two disorders. The results also suggest that gray matter pathology in schizophrenia and bipolar disorder differs to such an extent that they can be reliably differentiated using machine learning paradigms.
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NMDA-receptor coagonists in serum, plasma, and cerebrospinal fluid of schizophrenia patients: a meta-analysis of case-control studies.
Neurosci Biobehav Rev
PUBLISHED: 04-02-2013
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Serine and other amino acids that function as coagonists at the N-methyl-d-aspartate receptor (NMDAR) have been extensively investigated in schizophrenia (SCZ). However, studies comparing amino acid levels in body fluids of SCZ patients with healthy controls have yielded inconsistent results. We therefore conducted a meta-analysis (search: May 9, 2013) of serine, l-serine, d-serine, glycine, alanine, proline, and aspartate levels in blood and cerebrospinal fluid (CSF) obtained from adult SCZ patients and healthy controls. Standardized differences of means (SDMs) were computed, and heterogeneity, subgroup, sensitivity, and publication bias analyses were conducted. Blood serine levels were found to be significantly higher in SCZ patients compared to healthy controls (SDM=0.280 (0.021-0.540), p=0.034; N=1671 subjects), whereas CSF serine, l-serine, d-serine, glycine, alanine, proline, and aspartate levels did not differ. Stratification by sex suggested that the case-control difference in blood serine levels particularly applies to male subjects. These results provide support for blood serine level aberrations in SCZ patients and warrant further research to disentangle the involvement of serine with SCZ in both sexes.
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A Genome-Wide Association Analysis of a Broad Psychosis Phenotype Identifies Three Loci for Further Investigation.
Biol. Psychiatry
PUBLISHED: 03-27-2013
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Genome-wide association studies (GWAS) have identified several loci associated with schizophrenia and/or bipolar disorder. We performed a GWAS of psychosis as a broad syndrome rather than within specific diagnostic categories.
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The effect of childhood maltreatment and cannabis use on adult psychotic symptoms is modified by the COMT Val¹??Met polymorphism.
Schizophr. Res.
PUBLISHED: 03-20-2013
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Cannabis use and childhood maltreatment are independent risk factors for the development of psychotic symptoms. These factors have been found to interact in some but not all studies. One of the reasons may be that childhood maltreatment and cannabis primarily induce psychotic symptoms in genetically susceptible individuals. In this context, an extensively studied psychosis vulnerability gene is catechol-methyl-transferase (COMT). Therefore, we aimed to examine whether the COMT Val(158)Met polymorphism (rs4680) moderates the interaction between childhood maltreatment and cannabis use on psychotic symptoms in the general population.
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Issues and perspectives in designing clinical trials for negative symptoms in schizophrenia.
Schizophr. Res.
PUBLISHED: 03-11-2013
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A number of pharmacological agents for treating negative symptoms in schizophrenia are currently in development. Unresolved questions regarding the design of clinical trials in this area were discussed at an international meeting in Florence, Italy in April 2012. Participants included representatives from academia, the pharmaceutical industry, and the European Medicines Agency (EMA). Prior to the meeting, participants submitted key questions for debate and discussion. Responses to the questions guided the discussion during the meeting. The group reached agreement on a number of issues: (1) study subjects should be under the age of 65; (2) subjects should be excluded for symptoms of depression that do not overlap with negative symptoms; (3) functional measures should not be required as a co-primary in negative symptom trials; (4) information from informants should be included for ratings when available; (5) Phase 2 negative symptom trials should be 12weeks and 26weeks is preferred for Phase 3 trials; (6) prior to entry into a negative symptom study, subjects should demonstrate clinical stability for a period of 4 to 6months by collection of retrospective information; and (7) prior to entry, the stability of negative and positive symptoms should be confirmed prospectively for four weeks or longer. The participants could not reach agreement on whether predominant or prominent negative symptoms should be required for study subjects.
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Family-wise automatic classification in schizophrenia.
Schizophr. Res.
PUBLISHED: 03-06-2013
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Automatic classification of individuals at increased risk for schizophrenia can become an important screening method that allows for early intervention based on disease markers, if proven to be sufficiently accurate. Conventional classification methods typically consider information from single subjects, thereby ignoring (heritable) features of the persons relatives. In this paper we show that the inclusion of these features can lead to an increase in classification accuracy from 0.54 to 0.72 using a support vector machine model. This inclusion of contextual information is especially useful in diseases where the classification features carry a heritable component.
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Genes contributing to subcortical volumes and intellectual ability implicate the thalamus.
Hum Brain Mapp
PUBLISHED: 02-12-2013
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It has been shown that brain volume and general intellectual ability are to a significant extent influenced by the same genetic factors. Several cortical regions of the brain also show a genetic correlation with intellectual ability, demonstrating that intellectual functioning is probably represented in a heritable distributed network of cortical regions throughout the brain. This study is the first to investigate a genetic association between subcortical volumes and intellectual ability, taking into account the thalamus, caudate nucleus, putamen, globus pallidus, hippocampus, amygdala, and nucleus accumbens using an extended twin design. Genetic modeling was performed on a healthy adult twin sample consisting of 106 twin pairs and 30 of their siblings, IQ data was obtained from 132 subjects. Our results demonstrate that of all subcortical volumes measured, only thalamus volume is significantly correlated with intellectual functioning. Importantly, the association found between thalamus volume and intellectual ability is significantly influenced by a common genetic factor. This genetic factor is also implicated in cerebral brain volume. The thalamus, with its widespread cortical connections, may thus play a key role in human intelligence. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc.
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Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.
, S Hong Lee, Stephan Ripke, Benjamin M Neale, Stephen V Faraone, Shaun M Purcell, Roy H Perlis, Bryan J Mowry, Anita Thapar, Michael E Goddard, John S Witte, Devin Absher, Ingrid Agartz, Huda Akil, Farooq Amin, Ole A Andreassen, Adebayo Anjorin, Richard Anney, Verneri Anttila, Dan E Arking, Philip Asherson, Maria H Azevedo, Lena Backlund, Judith A Badner, Anthony J Bailey, Tobias Banaschewski, Jack D Barchas, Michael R Barnes, Thomas B Barrett, Nicholas Bass, Agatino Battaglia, Michael Bauer, Mònica Bayés, Frank Bellivier, Sarah E Bergen, Wade Berrettini, Catalina Betancur, Thomas Bettecken, Joseph Biederman, Elisabeth B Binder, Donald W Black, Douglas H R Blackwood, Cinnamon S Bloss, Michael Boehnke, Dorret I Boomsma, Gerome Breen, René Breuer, Richard Bruggeman, Paul Cormican, Nancy G Buccola, Jan K Buitelaar, William E Bunney, Joseph D Buxbaum, William F Byerley, Enda M Byrne, Sian Caesar, Wiepke Cahn, Rita M Cantor, Miguel Casas, Aravinda Chakravarti, Kimberly Chambert, Khalid Choudhury, Sven Cichon, C Robert Cloninger, David A Collier, Edwin H Cook, Hilary Coon, Bru Cormand, Aiden Corvin, William H Coryell, David W Craig, Ian W Craig, Jennifer Crosbie, Michael L Cuccaro, David Curtis, Darina Czamara, Susmita Datta, Geraldine Dawson, Richard Day, Eco J De Geus, Franziska Degenhardt, Srdjan Djurovic, Gary J Donohoe, Alysa E Doyle, Jubao Duan, Frank Dudbridge, Eftichia Duketis, Richard P Ebstein, Howard J Edenberg, Josephine Elia, Sean Ennis, Bruno Etain, Ayman Fanous, Anne E Farmer, I Nicol Ferrier, Matthew Flickinger, Eric Fombonne, Tatiana Foroud, Josef Frank, Barbara Franke, Christine Fraser, Robert Freedman, Nelson B Freimer, Christine M Freitag, Marion Friedl, Louise Frisén, Louise Gallagher, Pablo V Gejman, Lyudmila Georgieva, Elliot S Gershon, Daniel H Geschwind, Ina Giegling, Michael Gill, Scott D Gordon, Katherine Gordon-Smith, Elaine K Green, Tiffany A Greenwood, Dorothy E Grice, Magdalena Gross, Detelina Grozeva, Weihua Guan, Hugh Gurling, Lieuwe de Haan, Jonathan L Haines, Hakon Hakonarson, Joachim Hallmayer, Steven P Hamilton, Marian L Hamshere, Thomas F Hansen, Annette M Hartmann, Martin Hautzinger, Andrew C Heath, Anjali K Henders, Stefan Herms, Ian B Hickie, Maria Hipolito, Susanne Hoefels, Peter A Holmans, Florian Holsboer, Witte J Hoogendijk, Jouke-Jan Hottenga, Christina M Hultman, Vanessa Hus, Andrés Ingason, Marcus Ising, Stéphane Jamain, Edward G Jones, Ian Jones, Lisa Jones, Jung-Ying Tzeng, Anna K Kähler, René S Kahn, Radhika Kandaswamy, Matthew C Keller, James L Kennedy, Elaine Kenny, Lindsey Kent, Yunjung Kim, George K Kirov, Sabine M Klauck, Lambertus Klei, James A Knowles, Martin A Kohli, Daniel L Koller, Bettina Konte, Ania Korszun, Lydia Krabbendam, Robert Krasucki, Jonna Kuntsi, Phoenix Kwan, Mikael Landén, Niklas Långström, Mark Lathrop, Jacob Lawrence, William B Lawson, Marion Leboyer, David H Ledbetter, Phil H Lee, Todd Lencz, Klaus-Peter Lesch, Douglas F Levinson, Cathryn M Lewis, Jun Li, Paul Lichtenstein, Jeffrey A Lieberman, Dan-Yu Lin, Don H Linszen, Chunyu Liu, Falk W Lohoff, Sandra K Loo, Catherine Lord, Jennifer K Lowe, Susanne Lucae, Donald J MacIntyre, Pamela A F Madden, Elena Maestrini, Patrik K E Magnusson, Pamela B Mahon, Wolfgang Maier, Anil K Malhotra, Shrikant M Mane, Christa L Martin, Nicholas G Martin, Manuel Mattheisen, Keith Matthews, Morten Mattingsdal, Steven A McCarroll, Kevin A McGhee, James J McGough, Patrick J McGrath, Peter McGuffin, Melvin G McInnis, Andrew McIntosh, Rebecca McKinney, Alan W McLean, Francis J McMahon, William M McMahon, Andrew McQuillin, Helena Medeiros, Sarah E Medland, Sandra Meier, Ingrid Melle, Fan Meng, Jobst Meyer, Christel M Middeldorp, Lefkos Middleton, Vihra Milanova, Ana Miranda, Anthony P Monaco, Grant W Montgomery, Jennifer L Moran, Daniel Moreno-De-Luca, Gunnar Morken, Derek W Morris, Eric M Morrow, Valentina Moskvina, Pierandrea Muglia, Thomas W Mühleisen, Walter J Muir, Bertram Müller-Myhsok, Michael Murtha, Richard M Myers, Inez Myin-Germeys, Michael C Neale, Stan F Nelson, Caroline M Nievergelt, Ivan Nikolov, Vishwajit Nimgaonkar, Willem A Nolen, Markus M Nöthen, John I Nurnberger, Evaristus A Nwulia, Dale R Nyholt, Colm O'Dushlaine, Robert D Oades, Ann Olincy, Guiomar Oliveira, Line Olsen, Roel A Ophoff, Urban Osby, Michael J Owen, Aarno Palotie, Jeremy R Parr, Andrew D Paterson, Carlos N Pato, Michele T Pato, Brenda W Penninx, Michele L Pergadia, Margaret A Pericak-Vance, Benjamin S Pickard, Jonathan Pimm, Joseph Piven, Danielle Posthuma, James B Potash, Fritz Poustka, Peter Propping, Vinay Puri, Digby J Quested, Emma M Quinn, Josep Antoni Ramos-Quiroga, Henrik B Rasmussen, Soumya Raychaudhuri, Karola Rehnström, Andreas Reif, Marta Ribasés, John P Rice, Marcella Rietschel, Kathryn Roeder, Herbert Roeyers, Lizzy Rossin, Aribert Rothenberger, Guy Rouleau, Douglas Ruderfer, Dan Rujescu, Alan R Sanders, Stephan J Sanders, Susan L Santangelo, Joseph A Sergeant, Russell Schachar, Martin Schalling, Alan F Schatzberg, William A Scheftner, Gerard D Schellenberg, Stephen W Scherer, Nicholas J Schork, Thomas G Schulze, Johannes Schumacher, Markus Schwarz, Edward Scolnick, Laura J Scott, Jianxin Shi, Paul D Shilling, Stanley I Shyn, Jeremy M Silverman, Susan L Slager, Susan L Smalley, Johannes H Smit, Erin N Smith, Edmund J S Sonuga-Barke, David St Clair, Matthew State, Michael Steffens, Hans-Christoph Steinhausen, John S Strauss, Jana Strohmaier, T Scott Stroup, James S Sutcliffe, Peter Szatmari, Szabocls Szelinger, Srinivasa Thirumalai, Robert C Thompson, Alexandre A Todorov, Federica Tozzi, Jens Treutlein, Manfred Uhr, Edwin J C G van den Oord, Gerard van Grootheest, Jim van Os, Astrid M Vicente, Veronica J Vieland, John B Vincent, Peter M Visscher, Christopher A Walsh, Thomas H Wassink, Stanley J Watson, Myrna M Weissman, Thomas Werge, Thomas F Wienker, Ellen M Wijsman, Gonneke Willemsen, Nigel Williams, A Jeremy Willsey, Stephanie H Witt, Wei Xu, Allan H Young, Timothy W Yu, Stanley Zammit, Peter P Zandi, Peng Zhang, Frans G Zitman, Sebastian Zöllner, Bernie Devlin, John R Kelsoe, Pamela Sklar, Mark J Daly, Michael C O'Donovan, Nicholas Craddock, Patrick F Sullivan, Jordan W Smoller, Kenneth S Kendler, Naomi R Wray.
Nat. Genet.
PUBLISHED: 02-10-2013
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Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohns disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
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D-amino acid aberrations in cerebrospinal fluid and plasma of smokers.
Neuropsychopharmacology
PUBLISHED: 02-06-2013
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The glutamatergic neurotransmission system and the N-methyl-D-aspartate receptor (NMDAR) have been implicated in smoking and alcohol consumption behavior. Preclinical studies have demonstrated that nicotine and ethanol influence NMDAR functionality, which may have a role in tendencies to consume these substances. Nonetheless, little is known about concentrations of NMDAR coagonists in the cerebrospinal fluid (CSF) and plasma of individuals who smoke or consume alcohol. Glycine and L- and D-stereoisomers of alanine, serine, and proline were therefore measured using ultra-high-performance liquid chromatography-tandem mass spectrometry in 403 healthy subjects. Nicotine and alcohol consumption were quantified using questionnaires. Possible differences in NMDAR coagonist concentrations in plasma and CSF were investigated using ANCOVA with age, body mass index, and storage duration as covariates. The significance threshold was Bonferroni corrected (?=0.00625). Compared with non-smokers, smokers displayed lower levels of D-proline in plasma (p=0.0027, Cohens d=-0.41) and D-proline in CSF (p=0.0026, Cohens d=-0.43). D-Serine in CSF was higher in smokers than in non-smokers (p=0.0052, Cohens d=0.41). After subdividing participants based on smoking quantity, dose-dependent decreases were demonstrated in smokers for D-proline in plasma (F=5.65, p=0.0039) and D-proline in CSF (F=5.20, p=0.0060). No differences in NMDAR coagonist levels between alcohol consumption groups were detected. To our knowledge, this is the first report to implicate D-amino acids in smoking behavior of humans. Whether such concentration differences lie at the root of or result from smoking habits may be addressed in prospective studies.
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Time-dependent changes in altruistic punishment following stress.
Psychoneuroendocrinology
PUBLISHED: 02-01-2013
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Decisions are rarely made in social isolation. One phenomenon often observed in social interactions is altruistic punishment, i.e. the punishment of unfair behavior by others at a personal cost. The tendency for altruistic punishment is altered by affective states including those induced by stress exposure. Stress is thought to exert bi-directional effects on behavior: immediately after stress, reflex-like and habitual behavior is promoted while later on more far-sighted, flexible and goal-directed behavior is enhanced. We hypothesized that such time-dependent effects of stress would also be present in the context of altruistic punishment behavior. Healthy male participants (N=80) were exposed to either a grouped stress test or a control condition. Participants were tested in prosocial decision making tasks either directly after stress or 75 min later. Altruistic punishment was assessed using the Ultimatum Game. General altruism was assessed with a one-shot version of the Dictator Game in which an anonymous donation could be offered to a charitable organization. We found that stress caused a bi-directional effect on altruistic punishment, with decreased rejection rates in the late aftermath of stress in response to ambiguous 30% offers. In the Dictator Game, stressed participants were less generous than controls, but no time-dependent effect was observed, indicating that the general reward sensitivity remained unchanged at various time-points after stress. Overall, during the late aftermath after acute stress exposure (i.e. 75 min later), participants acted more consistent with their own material self-interest, and had a lower propensity for altruistic punishment, possibly through upregulation of cognitive self-control mechanisms. Thus, our findings underscore the importance of time as a factor in simple, real-life economic decisions in a stressful social context.
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The effects of physical exercise in schizophrenia and affective disorders.
Eur Arch Psychiatry Clin Neurosci
PUBLISHED: 01-28-2013
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Affective and non-affective psychoses are severe and frequent psychiatric disorders. Amongst others, they not only have a profound impact on affected individuals through their symptomatology, but also regarding cognition, brain structure and function. Cognitive impairment influences patients quality of life as well as their ability to work and being employed. While exercise therapy has been implemented in the treatment of psychiatric conditions since the days of Kraepelin and Bleuler, the underlying mechanisms have never been systematically studied. Since the early 1990s, studies emerged examining the effect of physical exercise in animal models, revealing stimulation of neurogenesis, synaptogenesis and neurotransmission. Based on that body of work, clinical studies have been carried out in both healthy humans and in patient populations. These studies differ with regard to homogenous study samples, sample size, type and duration of exercise, outcome variables and measurement techniques. Based on their review, we draw conclusions regarding recommendations for future research strategies showing that modern therapeutic approaches should include physical exercise as part of a multimodal intervention programme to improve psychopathology and cognitive symptoms in schizophrenia and affective disorders.
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Fibroblast growth factors in neurodevelopment and psychopathology.
Neuroscientist
PUBLISHED: 01-23-2013
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In psychiatric disorders, the effect of genetic and environmental factors may converge on molecular pathways and brain circuits related to growth factor functioning. In this review, we describe how disturbances in fibroblast growth factors (FGFs) and their receptors influence behavior by affecting brain development. Recently, several studies reported associations of members of the FGF family with psychiatric disorders. FGFs are key candidates to modulate the impact of environmental factors, such as stress. Mutant mice for FGF receptor 1 show schizophrenia-like behaviors that are related to general loss of neurons and postnatal glia dysfunction. Mice lacking FGF2, a FGFR1 ligand, show similar reductions in brain volume and hyperactivity, as well as increased anxiety behaviors. FGFR2 and FGF17 are involved in the development of frontal brain regions and impairments in cognitive and social behaviors, respectively. Moreover, treatment with FGF2 was beneficial for depressive and cognitive measures in several animal studies and one human study. These findings indicate the importance of the FGF system with respect to developing novel etiology-directed treatments for psychopathology.
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The auditory dorsal stream plays a crucial role in projecting hallucinated voices into external space.
Schizophr. Res.
PUBLISHED: 01-20-2013
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Verbal auditory hallucinations (VAHs) are experienced as spoken voices which seem to originate in the extracorporeal environment or inside the head. Animal and human research has identified a where pathway for sound processing comprising the planum temporale, the middle frontal gyrus and the inferior parietal lobule. We hypothesize that increased activity of that where pathway mediates the exteriorization of VAHs.
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Dosing frequency and adherence in chronic psychiatric disease: systematic review and meta-analysis.
Neuropsychiatr Dis Treat
PUBLISHED: 01-16-2013
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The purpose of this study was to investigate the impact of dosing frequency on adherence in severe chronic psychiatric and neurological diseases.
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Increased paternal age and the influence on burden of genomic copy number variation in the general population.
Hum. Genet.
PUBLISHED: 01-13-2013
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Genomic copy number variations (CNVs) and increased parental age are both associated with the risk to develop a variety of clinical neuropsychiatric disorders such as autism, schizophrenia and bipolar disorder. At the same time, it has been shown that the rate of transmitted de novo single nucleotide mutations is increased with paternal age. To address whether paternal age also affects the burden of structural genomic deletions and duplications, we examined various types of CNV burden in a large population sample from the Netherlands. Healthy participants with parental age information (n = 6,773) were collected at different University Medical Centers. CNVs were called with the PennCNV algorithm using Illumina genome-wide SNP array data. We observed no evidence in support of a paternal age effect on CNV load in the offspring. Our results were negative for global measures as well as several proxies for de novo CNV events in this unique sample. While recent studies suggest de novo single nucleotide mutation rate to be dominated by the age of the father at conception, our results strongly suggest that at the level of global CNV burden there is no influence of increased paternal age. While it remains possible that local genomic effects may exist for specific phenotypes, this study indicates that global CNV burden and increased fathers age may be independent disease risk factors.
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Heritability of subcortical brain measures: a perspective for future genome-wide association studies.
Neuroimage
PUBLISHED: 01-10-2013
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Several large imaging-genetics consortia aim to identify genetic variants influencing subcortical brain volumes. We investigated the extent to which genetic variation accounts for the variation in subcortical volumes, including thalamus, amygdala, putamen, caudate nucleus, globus pallidus and nucleus accumbens and obtained the stability of these brain volumes over a five-year period. The heritability estimates for all subcortical regions were high, with the highest heritability estimates observed for the thalamus (.80) and caudate nucleus (.88) and lowest for the left nucleus accumbens (.44). Five-year stability was substantial and higher for larger [e.g., thalamus (.88), putamen (.86), caudate nucleus (.87)] compared to smaller [nucleus accumbens (.45)] subcortical structures. These results provide additional evidence that subcortical structures are promising starting points for identifying genetic variants that influence brain structure.
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IQ change over time in schizophrenia and healthy individuals: a meta-analysis.
Schizophr. Res.
PUBLISHED: 01-08-2013
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Cognitive deficits have been recognized as a key feature of schizophrenia, since the first description by Kraepelin. Specifically, lower intelligence is considered a core feature of the disorder and may represent a risk factor for its development. However, whether global intelligence decreases over time in schizophrenia is not known. The aims of this quantitative meta-analysis are to gather, integrate and estimate the overall mean effect size of IQ change over time in schizophrenia as compared to healthy individuals.
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fMRI Guided rTMS Evidence for Reduced Left Prefrontal Involvement after Task Practice.
PLoS ONE
PUBLISHED: 01-01-2013
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Cognitive tasks that do not change the required response for a stimulus over time (consistent mapping) show dramatically improved performance after relative short periods of practice. This improvement is associated with reduced brain activity in a large network of brain regions, including left prefrontal and parietal cortex. The present study used fMRI-guided repetitive transcranial magnetic stimulation (rTMS), which has been shown to reduce processing efficacy, to examine if the reduced activity in these regions also reflects reduced involvement, or possibly increased efficiency.
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Evidence That Transition from Health to Psychotic Disorder Can Be Traced to Semi-Ubiquitous Environmental Effects Operating against Background Genetic Risk.
PLoS ONE
PUBLISHED: 01-01-2013
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In order to assess the importance of environmental and genetic risk on transition from health to psychotic disorder, a prospective study of individuals at average (n?=?462) and high genetic risk (n?=?810) was conducted.
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Default mode network in the effects of ?9-Tetrahydrocannabinol (THC) on human executive function.
PLoS ONE
PUBLISHED: 01-01-2013
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Evidence is increasing for involvement of the endocannabinoid system in cognitive functions including attention and executive function, as well as in psychiatric disorders characterized by cognitive deficits, such as schizophrenia. Executive function appears to be associated with both modulation of active networks and inhibition of activity in the default mode network. In the present study, we examined the role of the endocannabinoid system in executive function, focusing on both the associated brain network and the default mode network. A pharmacological functional magnetic resonance imaging (fMRI) study was conducted with a placebo-controlled, cross-over design, investigating effects of the endocannabinoid agonist ?9-tetrahydrocannabinol (THC) on executive function in 20 healthy volunteers, using a continuous performance task with identical pairs. Task performance was impaired after THC administration, reflected in both an increase in false alarms and a reduction in detected targets. This was associated with reduced deactivation in a set of brain regions linked to the default mode network, including posterior cingulate cortex and angular gyrus. Less deactivation was significantly correlated with lower performance after THC. Regions that were activated by the continuous performance task, notably bilateral prefrontal and parietal cortex, did not show effects of THC. These findings suggest an important role for the endocannabinoid system in both default mode modulation and executive function. This may be relevant for psychiatric disorders associated with executive function deficits, such as schizophrenia and ADHD.
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Assumptions and properties of limiting pathway models for analysis of epistasis in complex traits.
PLoS ONE
PUBLISHED: 01-01-2013
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For most complex traits, results from genome-wide association studies show that the proportion of the phenotypic variance attributable to the additive effects of individual SNPs, that is, the heritability explained by the SNPs, is substantially less than the estimate of heritability obtained by standard methods using correlations between relatives. This difference has been called the "missing heritability". One explanation is that heritability estimates from family (including twin) studies are biased upwards. Zuk et al. revisited overestimation of narrow sense heritability from twin studies as a result of confounding with non-additive genetic variance. They propose a limiting pathway (LP) model that generates significant epistatic variation and its simple parametrization provides a convenient way to explore implications of epistasis. They conclude that over-estimation of narrow sense heritability from family data (phantom heritability) may explain an important proportion of missing heritability. We show that for highly heritable quantitative traits large phantom heritability estimates from twin studies are possible only if a large contribution of common environment is assumed. The LP model is underpinned by strong assumptions that are unlikely to hold, including that all contributing pathways have the same mean and variance and are uncorrelated. Here, we relax the assumptions that underlie the LP model to be more biologically plausible. Together with theoretical, empirical, and pragmatic arguments we conclude that in outbred populations the contribution of additive genetic variance is likely to be much more important than the contribution of non-additive variance.
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Effects of ?9-tetrahydrocannabinol administration on human encoding and recall memory function: a pharmacological FMRI study.
J Cogn Neurosci
PUBLISHED: 11-08-2011
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Deficits in memory function are an incapacitating aspect of various psychiatric and neurological disorders. Animal studies have recently provided strong evidence for involvement of the endocannabinoid (eCB) system in memory function. Neuropsychological studies in humans have shown less convincing evidence but suggest that administration of cannabinoid substances affects encoding rather than recall of information. In this study, we examined the effects of perturbation of the eCB system on memory function during both encoding and recall. We performed a pharmacological MRI study with a placebo-controlled, crossover design, investigating the effects of ?9-tetrahydrocannabinol (THC) inhalation on associative memory-related brain function in 13 healthy volunteers. Performance and brain activation during associative memory were assessed using a pictorial memory task, consisting of separate encoding and recall conditions. Administration of THC caused reductions in activity during encoding in the right insula, the right inferior frontal gyrus, and the left middle occipital gyrus and a network-wide increase in activity during recall, which was most prominent in bilateral cuneus and precuneus. THC administration did not affect task performance, but while during placebo recall activity significantly explained variance in performance, this effect disappeared after THC. These findings suggest eCB involvement in encoding of pictorial information. Increased precuneus activity could reflect impaired recall function, but the absence of THC effects on task performance suggests a compensatory mechanism. These results further emphasize the eCB system as a potential novel target for treatment of memory disorders and a promising target for development of new therapies to reduce memory deficits in humans.
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Cannabis use and subclinical positive psychotic experiences in early adolescence: findings from a Dutch survey.
Addiction
PUBLISHED: 11-01-2011
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To investigate the association between early cannabis use and subclinical psychotic experiences, distinguishing between five levels of use: never used, discontinued use (life-time users who did not use in the preceding year), experimental use, regular use and heavy use.
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Translational neuroscience of schizophrenia: seeking a meeting of minds between mouse and man.
Sci Transl Med
PUBLISHED: 09-30-2011
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Understanding the etiology of developmental brain disorders such as schizophrenia is critical for achieving advances in treatment and requires new research strategies that control for individual variation in genetic background, environmental challenges, and expression of phenotype. SYSGENET, a European systems genetics network for the study of complex genetic human diseases with mouse genetic reference populations, brought together in Helsinki a cross-disciplinary group of clinical and basic scientists and mouse geneticists to debate, formulate, and prioritize a strategy for future research based on mouse models. The main conclusions of this meeting are summarized here.
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Impaired cerebellar functional connectivity in schizophrenia patients and their healthy siblings.
Front Psychiatry
PUBLISHED: 09-14-2011
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The long-standing notion of schizophrenia as a disorder of connectivity is supported by emerging evidence from recent neuroimaging studies, suggesting impairments of both structural and functional connectivity in schizophrenia. However, investigations are generally restricted to supratentorial brain regions, thereby excluding the cerebellum. As increasing evidence suggests that the cerebellum contributes to cognitive and affective processing, aberrant connectivity in schizophrenia may include cerebellar dysconnectivity. Moreover, as schizophrenia is highly heritable, unaffected family members of schizophrenia patients may exhibit similar connectivity profiles. The present study applies resting-state functional magnetic resonance imaging to determine cerebellar functional connectivity profiles, and the familial component of cerebellar connectivity profiles, in 62 schizophrenia patients and 67 siblings of schizophrenia patients. Compared to healthy control subjects, schizophrenia patients showed impaired functional connectivity between the cerebellum and several left-sided cerebral regions, including the hippocampus, thalamus, middle cingulate gyrus, triangular part of the inferior frontal gyrus, supplementary motor area, and lingual gyrus (all p?
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Changes in cortical thickness during the course of illness in schizophrenia.
Arch. Gen. Psychiatry
PUBLISHED: 09-07-2011
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Whether cortical thickness changes in schizophrenia over time are more pronounced relative to the changes that can be attributed to normal aging has not been studied.
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Efficacy of antipsychotic drugs against hostility in the European First-Episode Schizophrenia Trial (EUFEST).
J Clin Psychiatry
PUBLISHED: 08-10-2011
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To compare the effects of haloperidol, amisulpride, olanzapine, quetiapine, and ziprasidone on hostility in first-episode schizophrenia, schizoaffective disorder, or schizophreniform disorder.
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Differences in craving for cannabis between schizophrenia patients using risperidone, olanzapine or clozapine.
J. Psychopharmacol. (Oxford)
PUBLISHED: 07-18-2011
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Substance abuse and psychotic disorders have a high rate of comorbidity. Both disorders are associated with changes in the dopaminergic transmission in the mesocorticolimbic pathways of the brain. Since antipsychotic medications interact with the dopamine receptors in these pathways, these medications could affect craving for substances. In the current study, the effect of clozapine (n = 27, mean dosage 350 mg), risperidone (n = 54, mean dosage 3.46 mg) and olanzapine (n = 60, mean dosage 13.78 mg) on subjective craving for cannabis was compared in 123 patients with cannabis dependence and psychotic disorder. Patients treated with risperidone reported significantly more craving compared with patients treated with clozapine (Z = -3.19, p = .001) or olanzapine (Z = -2.24, p = .025). No significant differences in craving between clozapine and olanzapine were found. These results are in concordance with findings in the literature on this subject and could be explained by differences in three dopamine mediated mechanisms of these compounds: 1) occupancy rate of dopamine D(2) receptors, 2) dissociation rate of dopamine D(2) receptors, 3) D(1)/D(2) occupancy ratio. Risperidone and clozapine show a maximal difference in D(2) receptor occupancy rate, dissociation rate and D(1)/D(2) ratio. Olanzapine is intermediate between risperidone and clozapine in these characteristics.
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Glutamate in schizophrenia: a focused review and meta-analysis of ¹H-MRS studies.
Schizophr Bull
PUBLISHED: 07-11-2011
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Schizophrenia is a severe chronic psychiatric illness, characterized by hallucinations and delusions. Decreased brain volumes have been observed in the disease, although the origin of these changes is unknown. Changes in the n-methyl-d-aspartate (NMDA)-receptor mediated glutamatergic neurotransmission are implicated, since it is hypothesized that NMDA-receptor dysfunction in schizophrenia leads to increased glutamate release, which can have excitotoxic effects. However, the magnitude and extent of changes in glutamatergic metabolites in schizophrenia are not clear. With (1)H magnetic resonance spectroscopy ((1)H-MRS), in vivo information about glutamate and glutamine concentrations can be obtained in the brain. A systematic search through the MEDLINE database was conducted to identify relevant (1)H-MRS studies that examined differences in glutamate and glutamine concentrations between patients with schizophrenia and healthy control subjects. Twenty-eight studies were identified and included a total of 647 patients with schizophrenia and 608 healthy-control subjects. For each study, Cohens d was calculated and main effects for group analyses were performed using the random-effects model. Medial frontal region glutamate was decreased and glutamine was increased in patients with schizophrenia as compared with healthy individuals. Group-by-age associations revealed that in patients with schizophrenia, glutamate and glutamine concentrations decreased at a faster rate with age as compared with healthy controls. This could reflect aberrant processes in schizophrenia, such as altered synaptic activity, changed glutamate receptor functioning, abnormal glutamine-glutamate cycling, or dysfunctional glutamate transport.
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Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI.
Soc Cogn Affect Neurosci
PUBLISHED: 07-06-2011
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Klinefelter syndrome (KS) is a chromosomal condition (47, XXY) that may help us to unravel gene-brain behavior pathways to psychopathology. The phenotype includes social cognitive impairments and increased risk for autism traits. We used functional MRI to study neural mechanisms underlying social information processing. Eighteen nonclinical controls and thirteen men with XXY were scanned during judgments of faces with regard to trustworthiness and age. While judging faces as untrustworthy in comparison to trustworthy, men with XXY displayed less activation than controls in (i) the amygdala, which plays a key role in screening information for socio-emotional significance, (ii) the insula, which plays a role in subjective emotional experience, as well as (iii) the fusiform gyrus and (iv) the superior temporal sulcus, which are both involved in the perceptual processing of faces and which were also less involved during age judgments in men with XXY. This is the first study showing that KS can be associated with reduced involvement of the neural network subserving social cognition. Studying KS may increase our understanding of the genetic and hormonal basis of neural dysfunctions contributing to abnormalities in social cognition and behavior, which are considered core abnormalities in psychiatric disorders such as autism and schizophrenia.
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Predictive validity of a culturally informed diagnosis of schizophrenia: a 30 month follow-up study with first episode psychosis.
Schizophr. Res.
PUBLISHED: 07-05-2011
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Previous research has shown discrepancies between a standard diagnostic interview for schizophrenia (CASH) and a culture sensitive version of this instrument (CASH-CS) in Moroccan patients. More specifically we showed that among Moroccan immigrants the CASH-CS resulted in fewer patients with a diagnosis of schizophrenia compared with diagnoses based on the CASH, whereas for Native Dutch patients there was no difference between the CASH and the CASH-CS. The aim of the current study was to compare the predictive validity of a diagnosis of schizophrenia according to the CASH and CASH-CS.
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Hypothalamus and pituitary volume in schizophrenia: a structural MRI study.
Int. J. Neuropsychopharmacol.
PUBLISHED: 05-20-2011
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Volumetric differences of the hypothalamus and/or the pituitary gland tend to support involvement of the HPA axis in psychotic disorders. These structures were manually outlined in 154 schizophrenia patients and 156 matched healthy comparison subjects by MRI brain images. Linear regression analyses were performed to investigate differences in volume between groups. Moreover, the effects of illness duration and type of medication were investigated. No significant differences were found between patients and healthy controls in volumes of the hypothalamus and pituitary gland. In addition, there were no differences in volumes between patients with short and long illness duration. There was a trend towards patients receiving typical antipsychotic medication at the time of scanning having larger pituitary volumes than patients receiving atypical medication. These findings indicate that volume decreases in brain structures important for the normal functioning of the HPA axis are not present, either in recent-onset or chronically ill patients.
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Aberrations in the arcuate fasciculus are associated with auditory verbal hallucinations in psychotic and in non-psychotic individuals.
Hum Brain Mapp
PUBLISHED: 05-17-2011
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The pathophysiology of auditory verbal hallucinations (AVH) is still unclear. Cognitive as well as electrophysiological studies indicate that a defect in sensory feedback (corollary discharge) may contribute to the experience of AVH. This could result from disruption of the arcuate fasciculus, the major tract connecting frontal and temporo-parietal language areas. Previous diffusion tensor imaging studies indeed demonstrated abnormalities of this tract in schizophrenia patients with AVH. It is, however, difficult to disentangle specific associations with AVH in this patient group as many other factors, such as other positive and negative symptoms, medication or halted education could likewise have affected tract integrity. We therefore investigated AVH in relative isolation and studied a group of non-psychotic individuals with AVH as well as patients with AVH and non-hallucinating matched controls. We compared tract integrity of the arcuate fasiculus and of three other control tracts, between 35 non-psychotic individuals with AVH, 35 schizophrenia patients with AVH, and 36 controls using diffusion tensor imaging and magnetization transfer imaging. Both groups with AVH showed an increase in magnetization transfer ratio (MTR) in the arcuate fasciculus, but not in the other control tracts. In addition, a general decrease in fractional anisotropy (FA) for almost all bundles was observed in the patient group, but not in the non-psychotic individuals with AVH. As increased MTR in the arcuate fasciculus was present in both hallucinating groups, a specific association with AVH seems plausible. Decreases in FA, on the other hand, seem to be related to other disease processes of schizophrenia.
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Methods of the pharmacological imaging of the cannabinoid system (PhICS) study: towards understanding the role of the brain endocannabinoid system in human cognition.
Int J Methods Psychiatr Res
PUBLISHED: 05-17-2011
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Various lines of (pre)clinical research indicate that cannabinoid agents carry the potential for therapeutic application to reduce symptoms in several psychiatric disorders. However, direct testing of the involvement of cannabinoid brain systems in psychiatric syndromes is essential for further development. In the Pharmacological Imaging of the Cannabinoid System (PhICS) study, the involvement of the endocannabinoid system in cognitive brain function is assessed by comparing acute effects of the cannabinoid agonist ?9-tetrahydrocannabinol (THC) on brain function between healthy controls and groups of psychiatric patients showing cognitive dysfunction. This article describes the objectives and methods of the PhICS study and presents preliminary results of the administration procedure on subjective and neurophysiological parameters. Core elements in the methodology of PhICS are the administration method (THC is administered by inhalation using a vaporizing device) and a comprehensive use of pharmacological magnetic resonance imaging (phMRI) combining several types of MRI scans including functional MRI (fMRI), Arterial Spin Labeling (ASL) to measure brain perfusion, and resting-state fMRI. Additional methods like neuropsychological testing further specify the exact role of the endocannabinoid system in regulating cognition. Preliminary results presented in this paper indicate robust behavioral and subjective effects of THC. In addition, fMRI paradigms demonstrate activation of expected networks of brain regions in the cognitive domains of interest. The presented administration and assessment protocol provides a basis for further research on the involvement of the endocannabionoid systems in behavior and in psychopathology, which in turn may lead to development of therapeutic opportunities of cannabinoid ligands.
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Underestimated effect sizes in GWAS: fundamental limitations of single SNP analysis for dichotomous phenotypes.
PLoS ONE
PUBLISHED: 05-09-2011
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Complex diseases are often highly heritable. However, for many complex traits only a small proportion of the heritability can be explained by observed genetic variants in traditional genome-wide association (GWA) studies. Moreover, for some of those traits few significant SNPs have been identified. Single SNP association methods test for association at a single SNP, ignoring the effect of other SNPs. We show using a simple multi-locus odds model of complex disease that moderate to large effect sizes of causal variants may be estimated as relatively small effect sizes in single SNP association testing. This underestimation effect is most severe for diseases influenced by numerous risk variants. We relate the underestimation effect to the concept of non-collapsibility found in the statistics literature. As described, continuous phenotypes generated with linear genetic models are not affected by this underestimation effect. Since many GWA studies apply single SNP analysis to dichotomous phenotypes, previously reported results potentially underestimate true effect sizes, thereby impeding identification of true effect SNPs. Therefore, when a multi-locus model of disease risk is assumed, a multi SNP analysis may be more appropriate.
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Auditory hallucinations elicit similar brain activation in psychotic and nonpsychotic individuals.
Schizophr Bull
PUBLISHED: 04-28-2011
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While auditory verbal hallucinations (AVH) are most characteristic for schizophrenia, they also occur in nonpsychotic individuals in the absence of a psychiatric or neurological disorder and in the absence of substance abuse. At present, it is unclear if AVH in these nonpsychotic individuals constitute the same phenomenon as AVH in psychotic patients. Comparing brain activation during AVH between nonpsychotic and psychotic individuals could provide important clues regarding this question. 21 nonpsychotic subjects with AVH and 21 matched psychotic patients indicated the presence of AVH during 3T functional magnetic resonance imaging (fMRI) scanning. To identify common areas of activation during the experience of AVH in both groups, a conjunction analysis was performed. In addition, a 2-sample t-test was employed to discover possible differences in AVH-related activation between the groups. Several common areas of activation were observed for the psychotic and nonpsychotic subjects during the experience of AVH, consisting of the bilateral inferior frontal gyri, insula, superior temporal gyri, supramarginal gyri and postcentral gyri, left precentral gyrus, inferior parietal lobule, superior temporal pole, and right cerebellum. No significant differences in AVH-related brain activation were present between the groups. The presence of multiple common areas of AVH-related activation in psychotic and nonpsychotic individuals, in the absence of significant differences, implicates the involvement of the same cortical network in the experience of AVH in both groups.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.