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1.
  • Lycke Brandt, Christine, et al. (author)
  • Working memory networks and activation patterns in schizophrenia and bipolar disorder : comparison with healthy controls
  • 2014
  • In: British Journal of Psychiatry. - 0007-1250 .- 1472-1465. ; 204:4, s. 290-298
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Schizophrenia and bipolar disorder are severe mental disorders with overlapping genetic and clinical characteristics, including cognitive impairments. An important question is whether these disorders also have overlapping neuronal deficits.AIMS: To determine whether large-scale brain networks associated with working memory, as measured with functional magnetic resonance imaging (fMRI), are the same in both schizophrenia and bipolar disorder, and how they differ from those in healthy individuals.METHOD: Patients with schizophrenia (n = 100) and bipolar disorder (n = 100) and a healthy control group (n = 100) performed a 2-back working memory task while fMRI data were acquired. The imaging data were analysed using independent component analysis to extract large-scale networks of task-related activations.RESULTS: Similar working memory networks were activated in all groups. However, in three out of nine networks related to the experimental task there was a graded response difference in fMRI signal amplitudes, where patients with schizophrenia showed greater activation than those with bipolar disorder, who in turn showed more activation than healthy controls. Secondary analysis of the patient groups showed that these activation patterns were associated with history of psychosis and current elevated mood in bipolar disorder.CONCLUSIONS: The same brain networks were related to working memory in schizophrenia, bipolar disorder and controls. However, some key networks showed a graded hyperactivation in the two patient groups, in line with a continuum of neuronal abnormalities across psychotic disorders.
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2.
  • Van Schijndel, Jessica E., et al. (author)
  • Dual association of a TRKA polymorphism with schizophrenia
  • 2011
  • In: Psychiatric Genetics. - : Lippincott Williams & Wilkins. - 0955-8829 .- 1473-5873. ; 21:3, s. 125-131
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: An interaction between predisposing genes and environmental stressors is thought to underlie the neurodevelopmental disorder schizophrenia. In a targeted gene screening, we previously found that the minor allele of the single nucleotide polymorphism (SNP) rs6336 in the neurotrophic tyrosine kinase receptor 1 (NTRK1/TRKA) gene is associated with schizophrenia as a risk factor.METHODS: We genotyped the TRKA SNP in a total of eight independent Caucasian schizophrenia case-control groups.RESULT: Remarkably, although in five of the groups a higher frequency of the risk allele was indeed found in the patients compared with the controls, in the three other groups the SNP acted as a protective factor.CONCLUSION: An intriguing possibility is that this dual character of the TRKA SNP is caused by its interaction with endophenotypic and/or epistatic factors.
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3.
  • Welander-Vatn, Audun, et al. (author)
  • The neural correlates of cognitive control in bipolar I disorder : an fMRI study of medial frontal cortex activation during a Go/No-go task
  • 2013
  • In: Neuroscience Letters. - 0304-3940 .- 1872-7972. ; 549, s. 51-56
  • Journal article (peer-reviewed)abstract
    • In addition to dysregulation of mood, bipolar I disorder (BD I) is characterized by abnormalities in the execution of cognitive control. Hypoactivation of a specific sub-region in the cognitive control network, located in the medial frontal cortex, has been described among BD I patients. The aim of this study was to investigate whether patients with BD I showed decreased activation in this brain region as compared to healthy controls when performing a cognitive control task. Twenty-four BD I patients and 24 healthy controls performed a Go/No-go task during a functional magnetic resonance imaging (fMRI) session. Performance and response times were recorded. The BD I subjects had significantly slower response times and more patients made errors of omission compared to the healthy controls during the task. Both BD I subjects and healthy controls demonstrated activations in the brain region of interest during the task, but analyses revealed no statistically significant differences between groups. Although the patients display some deviances in behavioural measures, this study reveals no significant differences between BD I subjects and healthy controls in recruitment of the medial frontal cortex during a Go/No-go task.
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4.
  • Aminoff, Sofie Ragnhild, et al. (author)
  • An association between affective lability and executive functioning in bipolar disorder.
  • 2012
  • In: Psychiatry Research. - 0165-1781 .- 1872-7123. ; 198:1, s. 58-61
  • Journal article (peer-reviewed)abstract
    • Studies suggest altered affect regulation manifested by affective lability in manic/mixed and euthymic states in patients with bipolar disorder (BD). Altered affect regulation may arise from disturbances in interactions between the cognitive and the emotional brain networks. However, the relationship between affective lability and executive function has not previously been studied. Our aim was to investigate affective lability, as measured with the Affective Lability Scale (ALS) in patients with BD (N=32) compared to healthy controls (HC) (N=60), and its relationship to executive functioning. We found significantly higher ALS scores in the BD than in the HC group, indicating a higher degree of affective lability in patients with BD. Sub-sample analysis revealed a significant positive relationship between affective lability and semantic set shifting abilities in BD only. These findings suggest that higher levels of affective lability compared with controls are a trait as well as state dependent in BD, and that disturbed affective lability may arise from an aberrant interaction between cognitive and emotional brain networks.
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5.
  • Aminoff, Sofie R, et al. (author)
  • Decreased self-reported arousal in schizophrenia during aversive picture viewing compared to bipolar disorder and healthy controls.
  • 2011
  • In: Psychiatry Research. - 0165-1781 .- 1872-7123. ; 185:3, s. 309-314
  • Journal article (peer-reviewed)abstract
    • Both schizophrenia (SCZ) and bipolar disorder (BD) are associated with disturbances in emotion processing. Previous studies suggest that patients with SCZ assess unpleasant pictures as less arousing than healthy controls (HC), while patients with BD assess neutral pictures as more arousing than HC. No previous studies have investigated whether there is a difference in emotional response across all three groups. Our aim was to explore whether there was a difference in the evaluation of valence and in arousal between SCZ, BD and HC for aversive and neutral pictures. We showed 72 pictures (neutral, non-socially aversive and socially aversive) from the International Affective Picture System (IAPS) to 347 subjects. There was a clear interaction effect between the diagnostic group and increasing picture aversiveness for both valence and arousal. There were no significant differences in valence ratings between the different groups or in arousal ratings on any type of stimuli between BD patients and HC. However, SCZ patients reported significantly lower arousal for aversive stimuli, particularly with a social content, when compared to BD patients and HC. This was more pronounced in females. The presence of lifetime psychotic symptoms did not influence emotional responses.
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6.
  • Andreou, Dimitrios, et al. (author)
  • d-amino acid oxidase activator gene (DAOA) variation affects cerebrospinal fluid homovanillic acid concentrations in healthy Caucasians
  • 2012
  • In: European Archives of Psychiatry and Clinical Neuroscience. - : Springer Science and Business Media LLC. - 0940-1334 .- 1433-8491. ; 262:7, s. 549-556
  • Journal article (peer-reviewed)abstract
    • The d-amino acid oxidase activator (DAOA) protein regulates the function of d-amino oxidase (DAO), an enzyme that catalyzes the oxidative deamination of d-3,4-dihydroxyphenylalanine (D-DOPA) and d-serine. D-DOPA is converted to l-3,4-DOPA, a precursor of dopamine, whereas d-serine participates in glutamatergic transmission. We hypothesized that DAOA polymorphisms are associated with dopamine, serotonin and noradrenaline turnover in the human brain. Four single-nucleotide polymorphisms, previously reported to be associated with schizophrenia, were genotyped. Cerebrospinal fluid (CSF) samples were drawn by lumbar puncture, and the concentrations of the major dopamine metabolite homovanillic acid (HVA), the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) and the major noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured. Two of the investigated polymorphisms, rs3918342 and rs1421292, were significantly associated with CSF HVA concentrations. Rs3918342 was found to be nominally associated with CSF 5-HIAA concentrations. None of the polymorphisms were significantly associated with MHPG concentrations. Our results indicate that DAOA gene variation affects dopamine turnover in healthy individuals, suggesting that disturbed dopamine turnover is a possible mechanism behind the observed associations between genetic variation in DAOA and behavioral phenotypes in humans.
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7.
  • Andreou, Dimitrios, et al. (author)
  • Dystrobrevin-binding protein 1 gene (DTNBP1) variants associated with cerebrospinal fluid homovanillic acid and 5-hydroxyindoleacetic acid concentrations in healthy volunteers
  • 2011
  • In: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X .- 1873-7862. ; 21:9, s. 700-704
  • Journal article (peer-reviewed)abstract
    • The dystrobrevin binding protein-1 (DTNBP1) gene encodes dysbindin-1, a protein involved in neurodevelopmental and neurochemical processes related mainly to the monoamine dopamine. We investigated possible associations between eleven DTNBP1 polymorphisms and cerebrospinal fluid (CSF) concentrations of the major dopamine metabolite homovanillic acid (HVA), the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), and the major noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy human subjects (n=132). Two polymorphisms, rs2619538 and rs760666, were nominally associated with CSF HVA and 5-HIAA concentrations, whereas a third polymorphism, rs909706, showed association only with HVA. After correction for multiple testing only the associations between rs2619538 and HVA and 5-HIAA concentrations remained significant. No significant association was found between any of the investigated DTNBP1 polymorphisms and CSF MHPG concentrations. The results suggest that genetic variation in DTNBP1 gene affects the regulation of dopamine and serotonin turnover in the central nervous system of healthy volunteers.
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8.
  • Andreou, Dimitrios, et al. (author)
  • Tryptophan hydroxylase gene 1 (TPH1) variants associated with cerebrospinal fluid 5-hydroxyindole acetic acid and homovanillic acid concentrations in healthy volunteers
  • 2010
  • In: Psychiatry Research. - : Elsevier BV. - 0165-1781 .- 1872-7123. ; 180:2-3, s. 63-67
  • Journal article (peer-reviewed)abstract
    • Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin synthesis. We investigated possible relationships between five TPH1 gene polymorphisms and cerebrospinal fluid (CSF) concentrations of the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the major dopamine metabolite homovanillic acid (HVA), and the major norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers (n = 132). The G-allele of the TPH1 rs4537731 (A-6526G) polymorphism was associated with 5-HIM and HVA, but not MHPG concentrations. None of the other four TPH1 polymorphisms (rs211105, rs1800532, rs1799913 and rs7933505) were significantly associated with any of the monoamine metabolite concentrations. Two (rs4537731G/rs211105T/rs1800532C/rs1799913C/rs7933505G and rs4537731A/rs211105T/rs1800532C/rs1799913C/rs7933505G) of five common TPH1 five-allele haplotypes were associated with 5-HIAA and HVA concentrations in opposite directions. None of the common haplotypes was associated with MHPG concentrations in the CSF. The results suggest that TPH1 gene variation participates in the regulation of serotonin and dopamine turnover rates in the central nervous system of healthy human subjects.
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9.
  • Bolstad, Ingeborg, et al. (author)
  • Aversive event anticipation affects connectivity between the ventral striatum and the orbitofrontal cortex in an fMRI avoidance task
  • 2013
  • In: PLOS ONE. - 1932-6203. ; 8:6, s. e68494-
  • Journal article (peer-reviewed)abstract
    • Ability to anticipate aversive events is important for avoiding dangerous or unpleasant situations. The motivation to avoid an event is influenced by the incentive salience of an event-predicting cue. In an avoidance fMRI task we used tone intensities to manipulate salience in order to study the involvement of the orbitofrontal cortex in processing of incentive salience. In the task, cues predicting either aversive or neutral avoidable tones were presented. Ventral striatum, amygdala and anterior insula activations were significantly stronger during presentation of cues for aversive than neutral tones. A psychophysiological interaction analysis showed stronger connectivity between the ventral striatum and the orbitofrontal cortex during aversive than neutral conditions. The present study shows an interaction between the ventral striatum, a structure previously linked to negative incentive salience, and the orbitofrontal cortex supporting a role for this region in processing salience. In addition, this study replicates previous findings suggesting that the task is robust.
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10.
  • Bolstad, Ingeborg, et al. (author)
  • Aversive event anticipation affects connectivity between the ventral striatum and the orbitofrontal cortex in an fMRI avoidance task
  • 2013
  • In: PLoS ONE. - : Public Library of Science. - 1932-6203. ; 8:6
  • Journal article (peer-reviewed)abstract
    • Ability to anticipate aversive events is important for avoiding dangerous or unpleasant situations. The motivation to avoid an event is influenced by the incentive salience of an event-predicting cue. In an avoidance fMRI task we used tone intensities to manipulate salience in order to study the involvement of the orbitofrontal cortex in processing of incentive salience. In the task, cues predicting either aversive or neutral avoidable tones were presented. Ventral striatum, amygdala and anterior insula activations were significantly stronger during presentation of cues for aversive than neutral tones. A psychophysiological interaction analysis showed stronger connectivity between the ventral striatum and the orbitofrontal cortex during aversive than neutral conditions. The present study shows an interaction between the ventral striatum, a structure previously linked to negative incentive salience, and the orbitofrontal cortex supporting a role for this region in processing salience. In addition, this study replicates previous findings suggesting that the task is robust.
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13.
  • Desikan, Rahul S, et al. (author)
  • The role of clusterin in amyloid-β-associated neurodegeneration.
  • 2014
  • In: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 71:2, s. 180-7
  • Journal article (peer-reviewed)abstract
    • Converging evidence indicates that clusterin, a chaperone glycoprotein, influences Alzheimer disease neurodegeneration. However, the precise role of clusterin in Alzheimer disease pathogenesis is still not well understood.
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16.
  • Haukvik, Unn Kristin, et al. (author)
  • An exploratory model for G x E interaction on hippocampal volume in schizophrenia; obstetric complications and hypoxia-related genes
  • 2010
  • In: Progress in Neuro-Psychopharmacology and Biological Psychiatry. - : Elsevier BV. - 0278-5846 .- 1878-4216. ; 34:7, s. 1259-1265
  • Research review (peer-reviewed)abstract
    • Background Smaller hippocampal volume has repeatedly been reported in schizophrenia patients Obstetric complications (OCs) and single nucleotide polymorphism (SNP) variation in schizophrenia susceptibility genes have independently been related to hippocampal volume We investigated putative independent and interaction effects of severe hypoxia-related OCs and variation in four hypoxia-regulated schizophrenia susceptibility genes (BDNF, DTNBP1, GRM3 and NRG1) on hippocampal volume in schizophrenia patients and healthy controls. Methods Clinical assessment, structural MRI scans, and blood samples for genotyping of 32 SNPs were obtained from 54 schizophrenia patients and 53 control subjects Information on obstetric complications was collected from original birth records Results Severe OCs were related to hippocampal volume in both patients with schizophrenia and healthy control subjects Of the 32 SNPs studied, effects of severe OCs on hippocampal volume were associated with allele variation in GRM3 rs13242038, but the interaction effect was not specific for schizophrenia. SNP variation in any of the four investigated genes alone did not significantly affect hippocampal volume. Conclusions. The findings suggest a gene-environment (G x E) interaction between GRM3 gene variants and severe obstetric complications on hippocampus volume, independent of a diagnosis of schizophrenia Due to the modest sample size, the results must be considered preliminary and require replication in independent samples. (C) 2010 Elsevier Inc All rights reserved
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17.
  • Humphreys, Keith, et al. (author)
  • The Genetic Structure of the Swedish Population
  • 2011
  • In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:8, s. e22547-
  • Journal article (peer-reviewed)abstract
    • Patterns of genetic diversity have previously been shown to mirror geography on a global scale and within continents and individual countries. Using genome-wide SNP data on 5174 Swedes with extensive geographical coverage, we analyzed the genetic structure of the Swedish population. We observed strong differences between the far northern counties and the remaining counties. The population of Dalarna county, in north middle Sweden, which borders southern Norway, also appears to differ markedly from other counties, possibly due to this county having more individuals with remote Finnish or Norwegian ancestry than other counties. An analysis of genetic differentiation (based on pairwise F(st)) indicated that the population of Sweden's southernmost counties are genetically closer to the HapMap CEU samples of Northern European ancestry than to the populations of Sweden's northernmost counties. In a comparison of extended homozygous segments, we detected a clear divide between southern and northern Sweden with small differences between the southern counties and considerably more segments in northern Sweden. Both the increased degree of homozygosity in the north and the large genetic differences between the south and the north may have arisen due to a small population in the north and the vast geographical distances between towns and villages in the north, in contrast to the more densely settled southern parts of Sweden. Our findings have implications for future genome-wide association studies (GWAS) with respect to the matching of cases and controls and the need for within-county matching. We have shown that genetic differences within a single country may be substantial, even when viewed on a European scale. Thus, population stratification needs to be accounted for, even within a country like Sweden, which is often perceived to be relatively homogenous and a favourable resource for genetic mapping, otherwise inferences based on genetic data may lead to false conclusions.
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18.
  • Liu, Jimmy Z, et al. (author)
  • Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis.
  • 2013
  • In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:6, s. 670-5
  • Journal article (peer-reviewed)abstract
    • Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.
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19.
  • Mattingsdal, Morten, et al. (author)
  • Pathway analysis of genetic markers associated with a functional MRI faces paradigm implicates polymorphisms in calcium responsive pathways
  • 2013
  • In: NeuroImage. - 1053-8119 .- 1095-9572. ; 70, s. 143-149
  • Journal article (peer-reviewed)abstract
    • Several lines of evidence suggest that common polygenic variation influences brain function in humans. Combining high-density genetic markers with brain imaging techniques is constricted by the practicalities of collecting sufficiently large brain imaging samples. Pathway analysis promises to leverage knowledge on function of genes to detect recurring signals of moderate effect. We adapt this approach, exploiting the deep information collected on brain function by fMRI methods, to identify molecular pathways containing genetic variants which influence brain activation during a commonly applied experiment based on a face matching task (n=246) which was developed to study neural processing of faces displaying negative emotions. Genetic markers moderately associated (p<10(-4)) with whole brain activation phenotypes constructed by applying principal components to contrast maps, were tested for pathway enrichment using permutation based methods. The most significant pathways are related to post NMDA receptor activation events, driven by genetic variants in calcium/calmodulin-dependent protein kinase II (CAMK2G, CAMK2D) and a calcium-regulated nucleotide exchange factor (RASGRF2) in which all are activated by intracellular calcium/calmodulin. The most significant effect of the combined polygenic model were localized to the left inferior frontal gyrus (p=1.03 × 10(-9)), a region primarily involved in semantic processing but also involved in processing negative emotions. These findings suggest that pathway analysis of GWAS results derived from principal component analysis of fMRI data is a promising method, to our knowledge, not previously described.
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20.
  • Nesvag, Ragnar, et al. (author)
  • The use of screening instruments for detecting alcohol and other drug use disorders in first-episode psychosis
  • 2010
  • In: PSYCHIATRY RESEARCH. - : Elsevier Science B.V., Amsterdam.. - 0165-1781. ; 177:1-2, s. 228-234
  • Journal article (peer-reviewed)abstract
    • The high rate of drug abuse among patients with psychosis represents a challenge to clinicians in their treatment of the patients. Powerful screening tools to detect problematic drug use in an early phase of psychotic illness are needed. The aim of the present study was to investigate prevalence of drug use disorders and psychometric properties of the Alcohol Use Disorder Identification Test (AUDIT) and the Drug Use Disorder Identification Test (DUDIT) in 205 first-episode psychosis patients in Oslo, Norway. Internal consistency of the instruments and criterion-based validity as compared to a current DSM-IV diagnosis of abuse or dependence of alcohol or other drugs were analyzed. Fifteen percent of the men and 11% of the women had a DSM-IV diagnosis of alcohol use disorders while 33% of the men and 16% of the women had non-alcohol drug use disorders. The instruments were reliable (Cronbachs alpha above 0.90) and valid (Area under the curve above 0.83). Suitable cut-off scores (sensitivity andgt;0.80 and specificity andgt;0.70) were ten for men and eight for women on AUDIT and three for men and one for women on DUDIT. The results of this study suggest that AUDIT and DUDIT are powerful screening instruments for detecting alcohol and other drug use disorders in patients with first-episode psychosis.
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21.
  • Ousdal, Olga Therese, et al. (author)
  • Associations between variants near a monoaminergic pathways gene (PHOX2B) and amygdala reactivity : a genome-wide functional imaging study.
  • 2012
  • In: Twin Research and Human Genetics. - 1832-4274 .- 1839-2628. ; 15:3, s. 273-285
  • Journal article (peer-reviewed)abstract
    • As the amygdala is part of the phylogenetic old brain, and its anatomical and functional properties are conserved across species, it is reasonable to assume genetic influence on its activity. A large corpus of candidate gene studies indicate that individual differences in amygdala activity may be caused by genetic variants within monoaminergic signaling pathways such as dopamine, serotonin, and norepinephrine. However, to our knowledge, the use of genome-wide data to discover genetic variants underlying individual differences in adult amygdala activity is novel. In the present study, the combination of genome-wide data and functional imaging phenotypes from an emotional faces task yielded a significant association between rs10014254 and the amygdala using a region of interest approach. This single nucleotide polymorphism is located in a regulatory region upstream of the Paired-like homeobox 2b (PHOX2B) gene; therefore it could affect the expression of this gene. PHOX2B regulates the expression of enzymes necessary for the synthesis of several monoamines and is essential for the development of the autonomic nervous system. However, an attempt to replicate the finding in an independent sample from North America did not succeed. The synthesis of functional magnetic resonance imaging (fMRI) and genome-wide data takes a hypothesis-free approach as to which genetic variants are of interest. Therefore, we believe that an undirected finding within such a plausible region is of interest, and that our results add further support to the hypothesis that monoaminergic signaling pathways play a central role in regulating amygdala activity.
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22.
  • Ousdal, Olga Therese, et al. (author)
  • Effect of relevance on amygdala activation and association with the ventral striatum.
  • 2012
  • In: NeuroImage. - 1053-8119 .- 1095-9572. ; 62:1, s. 95-101
  • Journal article (peer-reviewed)abstract
    • While the amygdala historically has been implicated in emotional stimuli processing, recent data suggest a general role in parceling out the relevance of stimuli, regardless of their emotional properties. Using functional magnetic resonance imaging, we tested the relevance hypothesis by investigating human amygdala responses to emotionally neutral stimuli while manipulating their relevance. The task was operationalized as highly relevant if a subsequent opportunity to respond for a reward depended on response accuracy of the task, and less relevant if the reward opportunity was independent of task performance. A region of interest analysis revealed bilateral amygdala activations in response to the high relevance condition compared to the low relevance condition. An exploratory whole-brain analysis yielded robust similar results in bilateral ventral striatum. A subsequent functional connectivity analysis demonstrated increased connectivity between amygdala and ventral striatum for the highly relevant stimuli compared to the less relevant stimuli. These findings suggest that the amygdala's processing profile goes beyond detection of emotions per se, and directly support the proposed role in relevance detection. In addition, the findings suggest a close relationship between amygdala and ventral striatal activity when processing relevant stimuli. Thus, the results may indicate that human amygdala modulates ventral striatum activity and subsequent behaviors beyond that observed for emotional cues, to encompass a broader range of relevant stimuli.
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23.
  • Ousdal, Olga T., et al. (author)
  • Increased amygdala and visual cortex activity and functional connectivity towards stimulus novelty is associated with state anxiety
  • 2014
  • In: PLOS ONE. - 1932-6203. ; 9:4, s. e96146-
  • Journal article (peer-reviewed)abstract
    • Novel stimuli often require a rapid reallocation of sensory processing resources to determine the significance of the event, and the appropriate behavioral response. Both the amygdala and the visual cortex are central elements of the neural circuitry responding to novelty, demonstrating increased activity to new as compared to highly familiarized stimuli. Further, these brain areas are intimately connected, and thus the amygdala may be a key region for directing sensory processing resources to novel events. Although knowledge regarding the neurocircuit of novelty detection is gradually increasing, we still lack a basic understanding of the conditions that are necessary and sufficient for novelty-specific responses in human amygdala and the visual cortices, and if these brain areas interact during detection of novelty. In the present study, we investigated the response of amygdala and the visual cortex to novelty, by comparing functional MRI activity between 1st and 2nd time presentation of a series of emotional faces in an event-related task. We observed a significant decrease in amygdala and visual cortex activity already after a single stimulus exposure. Interestingly, this decrease in responsiveness was less for subjects with a high score on state anxiety. Further, novel faces stimuli were associated with a relative increase in the functional coupling between the amygdala and the inferior occipital gyrus (BA 18). Thus, we suggest that amygdala is involved in fast sensory boosting that may be important for attention reallocation to novel events, and that the strength of this response depends on individual state anxiety.
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24.
  • Ousdal, Olga T., et al. (author)
  • Increased amygdala and visual cortex activity and functional connectivity towards stimulus novelty is associated with state anxiety
  • 2014
  • In: PLoS ONE. - : Public Library of Science. - 1932-6203. ; 9:4
  • Journal article (peer-reviewed)abstract
    • Novel stimuli often require a rapid reallocation of sensory processing resources to determine the significance of the event, and the appropriate behavioral response. Both the amygdala and the visual cortex are central elements of the neural circuitry responding to novelty, demonstrating increased activity to new as compared to highly familiarized stimuli. Further, these brain areas are intimately connected, and thus the amygdala may be a key region for directing sensory processing resources to novel events. Although knowledge regarding the neurocircuit of novelty detection is gradually increasing, we still lack a basic understanding of the conditions that are necessary and sufficient for novelty-specific responses in human amygdala and the visual cortices, and if these brain areas interact during detection of novelty. In the present study, we investigated the response of amygdala and the visual cortex to novelty, by comparing functional MRI activity between 1st and 2nd time presentation of a series of emotional faces in an event-related task. We observed a significant decrease in amygdala and visual cortex activity already after a single stimulus exposure. Interestingly, this decrease in responsiveness was less for subjects with a high score on state anxiety. Further, novel faces stimuli were associated with a relative increase in the functional coupling between the amygdala and the inferior occipital gyrus (BA 18). Thus, we suggest that amygdala is involved in fast sensory boosting that may be important for attention reallocation to novel events, and that the strength of this response depends on individual state anxiety.
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25.
  • Ousdal, Olga Therese, et al. (author)
  • The human amygdala encodes value and space during decision making
  • 2014
  • In: NeuroImage. - 1053-8119 .- 1095-9572. ; 101, s. 712-719
  • Journal article (peer-reviewed)abstract
    • Valuable stimuli are invariably localized in space. While our knowledge regarding the neural networks supporting value assignment and comparisons is considerable, we lack a basic understanding of how the human brain integrates motivational and spatial information. The amygdala is a key structure for learning and maintaining the value of sensory stimuli and a recent non-human primate study provided initial evidence that it also acts to integrate value with spatial location, a question we address here in a human setting. We measured hemodynamic responses (fMRI) in amygdala while manipulating the value and spatial configuration of stimuli in a simple stimulus-reward task. Subjects responded significantly faster and showed greater amygdala activation when a reward was dependent on a spatial specific response, compared to when a reward required less spatial specificity. Supplemental analysis supported this spatial specificity by demonstrating that the pattern of amygdala activity varied based on whether subjects responded to a motivational target presented in the ipsilateral or contralateral visual space. Our data show that the human amygdala integrates information about space and value, an integration of likely importance for assigning cognitive resources towards highly valuable stimuli in our environment.
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26.
  • Ousdal, Olga Therese, et al. (author)
  • The human amygdala encodes value and space during decision making
  • 2014
  • In: NeuroImage. - : Academic Press Inc.. - 1053-8119 .- 1095-9572. ; 101, s. 712-719
  • Journal article (peer-reviewed)abstract
    • Valuable stimuli are invariably localized in space. While our knowledge regarding the neural networks supporting value assignment and comparisons is considerable, we lack a basic understanding of how the human brain integrates motivational and spatial information. The amygdala is a key structure for learning and maintaining the value of sensory stimuli and a recent non-human primate study provided initial evidence that it also acts to integrate value with spatial location, a question we address here in a human setting. We measured hemodynamic responses (fMRI) in amygdala while manipulating the value and spatial configuration of stimuli in a simple stimulus-reward task. Subjects responded significantly faster and showed greater amygdala activation when a reward was dependent on a spatial specific response, compared to when a reward required less spatial specificity. Supplemental analysis supported this spatial specificity by demonstrating that the pattern of amygdala activity varied based on whether subjects responded to a motivational target presented in the ipsilateral or contralateral visual space. Our data show that the human amygdala integrates information about space and value, an integration of likely importance for assigning cognitive resources towards highly valuable stimuli in our environment.
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27.
  • Reckless, Greg E., et al. (author)
  • Motivation alters response bias and neural activation patterns in a perceptual decision-making task.
  • 2013
  • In: Neuroscience. - 0306-4522 .- 1873-7544. ; 238, s. 135-147
  • Journal article (peer-reviewed)abstract
    • Motivation has been demonstrated to affect individuals' response strategies in economic decision-making, however, little is known about how motivation influences perceptual decision-making behavior or its related neural activity. Given the important role motivation plays in shaping our behavior, a better understanding of this relationship is needed. A block-design, continuous performance, perceptual decision-making task where participants were asked to detect a picture of an animal among distractors was used during functional magnetic resonance imaging (fMRI). The effect of positive and negative motivation on sustained activity within regions of the brain thought to underlie decision-making was examined by altering the monetary contingency associated with the task. In addition, signal detection theory was used to investigate the effect of motivation on detection sensitivity, response bias and response time. While both positive and negative motivation resulted in increased sustained activation in the ventral striatum, fusiform gyrus, left dorsolateral prefrontal cortex (DLPFC) and ventromedial prefrontal cortex, only negative motivation resulted in the adoption of a more liberal, closer to optimal response bias. This shift toward a liberal response bias correlated with increased activation in the left DLPFC, but did not result in improved task performance. The present findings suggest that motivation alters aspects of the way perceptual decisions are made. Further, this altered response behavior is reflected in a change in left DLPFC activation, a region involved in the computation of perceptual decisions.
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28.
  • Reckless, Greg E., et al. (author)
  • The left inferior frontal gyrus is involved in adjusting response bias during a perceptual decision-making task
  • 2014
  • In: Brain and Behavior. - 2162-3279 .- 2162-3279. ; 4:3, s. 398-407
  • Journal article (peer-reviewed)abstract
    • IntroductionChanging the way we make decisions from one environment to another allows us to maintain optimal decision-making. One way decision-making may change is how biased one is toward one option or another. Identifying the regions of the brain that underlie the change in bias will allow for a better understanding of flexible decision-making.MethodsAn event-related, perceptual decision-making task where participants had to detect a picture of an animal amongst distractors was used during functional magnetic resonance imaging. Positive and negative financial motivation were used to affect a change in response bias, and changes in decision-making behavior were quantified using signal detection theory.ResultsResponse bias became relatively more liberal during both positive and negative motivated trials compared to neutral trials. For both motivational conditions, the larger the liberal shift in bias, the greater the left inferior frontal gyrus (IFG) activity. There was no relationship between individuals' belief that they used a different strategy and their actual change in response bias.ConclusionsThe present findings suggest that the left IFG plays a role in adjusting response bias across different decision environments. This suggests a potential role for the left IFG in flexible decision-making.
  •  
29.
  • Reckless, Greg E., et al. (author)
  • The left inferior frontal gyrus is involved in adjusting response bias during a perceptual decision-making task
  • 2014
  • In: Brain and Behavior. - : John Wiley and Sons Inc.. - 2162-3279. ; 4:3, s. 398-407
  • Journal article (peer-reviewed)abstract
    • Introduction Changing the way we make decisions from one environment to another allows us to maintain optimal decision-making. One way decision-making may change is how biased one is toward one option or another. Identifying the regions of the brain that underlie the change in bias will allow for a better understanding of flexible decision-making. Methods An event-related, perceptual decision-making task where participants had to detect a picture of an animal amongst distractors was used during functional magnetic resonance imaging. Positive and negative financial motivation were used to affect a change in response bias, and changes in decision-making behavior were quantified using signal detection theory. Results Response bias became relatively more liberal during both positive and negative motivated trials compared to neutral trials. For both motivational conditions, the larger the liberal shift in bias, the greater the left inferior frontal gyrus (IFG) activity. There was no relationship between individuals' belief that they used a different strategy and their actual change in response bias. Conclusions The present findings suggest that the left IFG plays a role in adjusting response bias across different decision environments. This suggests a potential role for the left IFG in flexible decision-making.
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30.
  • Saetre, Peter, et al. (author)
  • Methylenetetrahydrofolate Reductase (MTHFR) C677T and A1298C Polymorphisms and Age of Onset in Schizophrenia : A Combined Analysis of Independent Samples
  • 2011
  • In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics. - : Wiley. - 1552-4841. ; 156B156:2, s. 215-224
  • Journal article (peer-reviewed)abstract
    • Methylenetetrahydrofolate reductase (MTHFR) is involved in the one-carbon cycle, which is of importance for nucleotide synthesis and methylation of DNA, membranes, proteins and lipids. The MTHFR gene includes two common polymorphisms (rs1801133 or C677T; rs1801131 or A1298C) which both alter enzyme activity. The T-allele of the C677T polymorphism has recently been associated with earlier age at onset of schizophrenia. In the present study we examined the association between the MTHFR C677T and A1298C polymorphisms and age at onset of schizophrenia in twelve samples consisting of 3,213 unrelated schizophrenia patients, including the original Scandinavian sample. There was no consistent relationship between MTHFR C677T, A1298C or combined 677T/1298C carriers and age of onset in schizophrenia when the results of each study were combined using meta-analysis. The present results suggest that the investigated MTHFR polymorphisms do not influence age of onset in schizophrenia.
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31.
  • Saetre, Peter, et al. (author)
  • The Tryptophan Hydroxylase 1 (TPH1) Gene, Schizophrenia Susceptibility, and Suicidal Behavior : A Multi-Centre Case-Control Study and Meta-Analysis
  • 2010
  • In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics. - : Wiley. - 1552-4841. ; 153B:2, s. 387-396
  • Journal article (peer-reviewed)abstract
    • Serotonin (5-hydroxytryptamin; 5-HT) alternations has since long been suspected in the pathophysiology of schizophrenia. Tryptophan hydroxylase (tryptophan 5-monooxygenase; TPH) is the rate-limiting enzyme in the biosynthesis of 5-HT, and sequence variation in intron 6 of the TPH1 gene has been associated with schizophrenia. The minor allele (A) of this polymorphism (A218C) is also more frequent in patients who have attempted suicide and individuals who died by suicide, than in healthy control individuals. In an attempt to replicate previous findings, five single nucleotide polymorphisms (SNPs) were genotyped in 837 Scandinavian schizophrenia patients and 1,473 controls. Three SNPs spanning intron 6 and 7, including the A218C and A779C polymorphisms, were associated with schizophrenia susceptibility (P = 0.019). However there were no differences in allele frequencies of these loci between affected individuals having attempted suicide at least once and patients with no history of suicide attempts (P=0.84). A systematic literature review and meta-analysis support the A218C polymorphism as a susceptibility locus for schizophrenia (odds ratio 1.17, 95% confidence interval 1.07-1.29). Association studies on suicide attempts are however conflicting (heterogeneity index I-2 = 0.54) and do not support the A218C/A779C polymorphisms being a susceptibility locus for suicidal behavior among individuals diagnosed with a psychiatric disorder (OR = 0.96 [0.80-1.16]). We conclude that the TPH1 A218/A779 locus increases the susceptibility of schizophrenia in Caucasian and Asian populations. In addition, the data at hand suggest that the locus contributes to the liability of psychiatric disorders characterized by elevated suicidal rates, rather than affecting suicidal behavior of individuals suffering from a psychiatric disorder.
  •  
32.
  • Schork, Andrew J, et al. (author)
  • All SNPs are not created equal: genome-wide association studies reveal a consistent pattern of enrichment among functionally annotated SNPs.
  • 2013
  • In: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 9:4
  • Journal article (peer-reviewed)abstract
    • Recent results indicate that genome-wide association studies (GWAS) have the potential to explain much of the heritability of common complex phenotypes, but methods are lacking to reliably identify the remaining associated single nucleotide polymorphisms (SNPs). We applied stratified False Discovery Rate (sFDR) methods to leverage genic enrichment in GWAS summary statistics data to uncover new loci likely to replicate in independent samples. Specifically, we use linkage disequilibrium-weighted annotations for each SNP in combination with nominal p-values to estimate the True Discovery Rate (TDR = 1-FDR) for strata determined by different genic categories. We show a consistent pattern of enrichment of polygenic effects in specific annotation categories across diverse phenotypes, with the greatest enrichment for SNPs tagging regulatory and coding genic elements, little enrichment in introns, and negative enrichment for intergenic SNPs. Stratified enrichment directly leads to increased TDR for a given p-value, mirrored by increased replication rates in independent samples. We show this in independent Crohn's disease GWAS, where we find a hundredfold variation in replication rate across genic categories. Applying a well-established sFDR methodology we demonstrate the utility of stratification for improving power of GWAS in complex phenotypes, with increased rejection rates from 20% in height to 300% in schizophrenia with traditional FDR and sFDR both fixed at 0.05. Our analyses demonstrate an inherent stratification among GWAS SNPs with important conceptual implications that can be leveraged by statistical methods to improve the discovery of loci.
  •  
33.
  • Thompson, Paul M., et al. (author)
  • The ENIGMA Consortium : large-scale collaborative analyses of neuroimaging and genetic data
  • 2014
  • In: BRAIN IMAGING BEHAV. - : Springer Science and Business Media LLC. - 1931-7557 .- 1931-7565. ; 8:2, s. 153-182
  • Journal article (peer-reviewed)abstract
    • 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.
  •  
34.
  • Thoresen, Christian, et al. (author)
  • Arousal Modulates Activity in the Medial Temporal Lobe during a Short-Term Relational Memory Task.
  • 2011
  • In: Frontiers in human neuroscience. - 1662-5161. ; 5, s. 177-
  • Journal article (peer-reviewed)abstract
    • This study investigated the effect of arousal on short-term relational memory and its underlying cortical network. Seventeen healthy participants performed a picture by location, short-term relational memory task using emotional pictures. Functional magnetic resonance imaging was used to measure the blood-oxygenation-level dependent signal relative to task. Subjects' own ratings of the pictures were used to obtain subjective arousal ratings. Subjective arousal was found to have a dose-dependent effect on activations in the prefrontal cortex, amygdala, hippocampus, and in higher order visual areas. Serial position analyses showed that high arousal trials produced a stronger primacy and recency effect than low arousal trials. The results indicate that short-term relational memory may be facilitated by arousal and that this may be modulated by a dose-response function in arousal-driven neuronal regions.
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35.
  •  
36.
  • Thoresen, Christian, et al. (author)
  • Frontotemporal hypoactivity during a reality monitoring paradigm is associated with delusions in patients with schizophrenia spectrum disorders
  • 2014
  • In: Cognitive Neuropsychiatry. - 1354-6805 .- 1464-0619. ; 19:2, s. 97-115
  • Journal article (peer-reviewed)abstract
    • Introduction Impaired monitoring of internally generated information has been proposed to be one component in the development and maintenance of delusions. The present study investigated the neural correlates underlying the monitoring processes and whether they were associated with delusions. Methods Twenty healthy controls and 19 patients with schizophrenia spectrum disorders were administrated a reality monitoring paradigm during functional magnetic resonance imaging. During encoding participants were instructed to associate a statement with either a presented (viewed condition) or an imagined picture (imagined condition). During the monitoring session in the scanner, participants were presented with old and new statements and their task was to identify whether a given statement was associated with the viewed condition, imagined condition, or if it was new. Results Patients showed significantly reduced accuracy in the imagined condition with performance negatively associated with degree of delusions. This was accompanied with reduced activity in the left dorsolateral prefrontal cortex and left hippocampus in the patient group. The severity of delusions was negatively correlated with the blood-oxygenation-level dependent response in the left hippocampus. Conclusions The results suggest that weakened monitoring is associated with delusions in patients with schizophrenia spectrum disorder, and that this may be mediated by a frontotemporal dysfunction.
  •  
37.
  • Thormodsen, Rune, et al. (author)
  • Prefrontal hyperactivation during a working memory task in early-onset schizophrenia spectrum disorders : an fMRI study.
  • 2011
  • In: Psychiatry Research. - 0165-1781 .- 1872-7123. ; 194:3, s. 257-262
  • Journal article (peer-reviewed)abstract
    • Working memory (WM) dysfunction is increasingly recognized as a core feature of schizophrenia, but few studies have investigated prefrontal activation during WM tasks in early-onset schizophrenia spectrum disorder (EOS). Our aim was to explore prefrontal activation during a WM-task in EOS patients compared to healthy controls using functional magnetic resonance imaging (fMRI). Fifteen patients with EOS and 15 matched healthy controls performed a 0-back and a 2-back task while fMRI data were acquired. Results indicated that even though performance between patients and controls was comparable on both tasks, there was a hyperactivation in patients' ventrolateral prefrontal cortex (VLPFC) during the 2-back task compared to healthy controls. This pattern of activation suggests that, in patients with EOS, the VLPFC compensated in order to match performance of the controls. The activations in the EOS group may reflect the use of a compensatory, cognitive strategy while solving WM-tasks.
  •  
38.
  • Vares, Maria, et al. (author)
  • Association Between Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism and Age of Onset in Schizophrenia
  • 2010
  • In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics. - : Wiley. - 1552-4841. ; 153B:2, s. 610-618
  • Journal article (peer-reviewed)abstract
    • Different lines of evidence indicate that methylenetetrahydrofolate reductase (MTHFR) functional gene polymorphisms, causative in aberrant folate-homocysteine metabolism, are associated with increased vulnerability to several heritable developmental disorders. Opposing views are expressed considering the possible association between MTHFR and susceptibility for schizophrenia. In order to evaluate if age of onset could explain some of this discrepancy we investigated the relationship between two functional MTHFR gene polymorphisms and age at onset in this disorder. Scandinavian patients (n = 820) diagnosed with schizophrenia, schizoaffective disorder, and schizophreniform disorder were investigated. Two functional MTHFR single nucleotide polymorphisms (SNPs; rs1801131 and rs1801133) were genotyped and the effect of MTHFR polymorphisms on the age of onset was examined with survival analysis. In an attempt to replicate the findings from the Scandinavian sample, the association between rs1801133 and age at onset was also analyzed in Chinese high-risk families, with two or more affected siblings (n = 243). Among the Scandinavian patients the functional MTHFR SNP rs1801133 (C677T) significantly affected age at onset of schizophrenia in a dose-dependent manner (P = 0.0015), with lower age of onset with increasing numbers of the mutant T-allele. There was no evidence of rs1801131 (A1298C) affecting age of onset in schizophrenia. Within the Chinese high-risk families carriers of the MTHFR 677T allele showed earlier age at onset than siblings being homozygous for the wild-type allele (P = 0.008). The MTHFR C677T polymorphism may play a role as a modifying factor for age of onset in schizophrenia.
  •  
39.
  • Welander-Vatn, Audun, et al. (author)
  • The neural correlates of cognitive control in bipolar I disorder : an fMRI study of medial frontal cortex activation during a Go/No-go task
  • 2013
  • In: Neuroscience Letters. - : Elsevier Ireland Ltd. - 0304-3940 .- 1872-7972. ; 549, s. 51-56
  • Journal article (peer-reviewed)abstract
    • In addition to dysregulation of mood, bipolar I disorder (BD I) is characterized by abnormalities in the execution of cognitive control. Hypoactivation of a specific sub-region in the cognitive control network, located in the medial frontal cortex, has been described among BD I patients. The aim of this study was to investigate whether patients with BD I showed decreased activation in this brain region as compared to healthy controls when performing a cognitive control task. Twenty-four BD I patients and 24 healthy controls performed a Go/No-go task during a functional magnetic resonance imaging (fMRI) session. Performance and response times were recorded. The BD I subjects had significantly slower response times and more patients made errors of omission compared to the healthy controls during the task. Both BD I subjects and healthy controls demonstrated activations in the brain region of interest during the task, but analyses revealed no statistically significant differences between groups. Although the patients display some deviances in behavioural measures, this study reveals no significant differences between BD I subjects and healthy controls in recruitment of the medial frontal cortex during a Go/No-go task.
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