Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 14 de 14
Filter
Add more filters










Publication year range
1.
Mol Psychiatry ; 28(8): 3524-3530, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37582857

ABSTRACT

Risky decision-making is a common, heritable endophenotype seen across many psychiatric disorders. Its underlying genetic architecture is incompletely explored. We examined behavior in the Balloon Analogue Risk Task (BART), which tests risky decision-making, in two independent samples of European ancestry. One sample (n = 1138) comprised healthy participants and some psychiatric patients (53 schizophrenia, 42 bipolar disorder, 47 ADHD); the other (n = 911) excluded for recent treatment of various psychiatric disorders but not ADHD. Participants provided DNA and performed the BART, indexed by mean adjusted pumps. We constructed a polygenic risk score (PRS) for discovery in each dataset and tested it in the other as replication. Subsequently, a genome-wide MEGA-analysis, combining both samples, tested genetic correlation with risk-taking self-report in the UK Biobank sample and psychiatric phenotypes characterized by risk-taking (ADHD, Bipolar Disorder, Alcohol Use Disorder, prior cannabis use) in the Psychiatric Genomics Consortium. The PRS for BART performance in one dataset predicted task performance in the replication sample (r = 0.13, p = 0.000012, pFDR = 0.000052), as did the reciprocal analysis (r = 0.09, p = 0.0083, pFDR=0.04). Excluding participants with psychiatric diagnoses produced similar results. The MEGA-GWAS identified a single SNP (rs12023073; p = 3.24 × 10-8) near IGSF21, a protein involved in inhibitory brain synapses; replication samples are needed to validate this result. A PRS for self-reported cannabis use (p = 0.00047, pFDR = 0.0053), but not self-reported risk-taking or psychiatric disorder status, predicted behavior on the BART in our MEGA-GWAS sample. The findings reveal polygenic architecture of risky decision-making as measured by the BART and highlight its overlap with cannabis use.


Subject(s)
Bipolar Disorder , Schizophrenia , Humans , Bipolar Disorder/genetics , Schizophrenia/genetics , Risk Factors , Brain , Alcohol Drinking , Genome-Wide Association Study , Multifactorial Inheritance/genetics , Genetic Predisposition to Disease/genetics
3.
Mol Psychiatry ; 22(3): 336-345, 2017 03.
Article in English | MEDLINE | ID: mdl-28093568

ABSTRACT

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.


Subject(s)
Cognition/physiology , Neurocognitive Disorders/genetics , Adult , Alleles , Female , Gene Frequency/genetics , Genetic Association Studies/methods , Genetic Loci/genetics , Genetic Predisposition to Disease/genetics , Genetic Variation/genetics , Genome-Wide Association Study/methods , Humans , Male , Middle Aged , Multifactorial Inheritance/genetics , Polymorphism, Single Nucleotide/genetics , White People/genetics
4.
Sci Data ; 3: 160110, 2016 12 06.
Article in English | MEDLINE | ID: mdl-27922632

ABSTRACT

This data descriptor outlines a shared neuroimaging dataset from the UCLA Consortium for Neuropsychiatric Phenomics, which focused on understanding the dimensional structure of memory and cognitive control (response inhibition) functions in both healthy individuals (130 subjects) and individuals with neuropsychiatric disorders including schizophrenia (50 subjects), bipolar disorder (49 subjects), and attention deficit/hyperactivity disorder (43 subjects). The dataset includes an extensive set of task-based fMRI assessments, resting fMRI, structural MRI, and high angular resolution diffusion MRI. The dataset is shared through the OpenfMRI project, and is formatted according to the Brain Imaging Data Structure (BIDS) standard.


Subject(s)
Attention Deficit Disorder with Hyperactivity/physiopathology , Bipolar Disorder/physiopathology , Cognition/physiology , Inhibition, Psychological , Memory/physiology , Schizophrenia/physiopathology , Adult , Female , Functional Neuroimaging , Healthy Volunteers , Humans , Information Dissemination , Magnetic Resonance Imaging , Male , Middle Aged , Task Performance and Analysis , Young Adult
5.
Mol Psychiatry ; 21(11): 1554-1560, 2016 11.
Article in English | MEDLINE | ID: mdl-26830141

ABSTRACT

Stimulant use disorders are associated with deficits in striatal dopamine receptor availability, abnormalities in mesocorticolimbic resting-state functional connectivity (RSFC) and impulsivity. In methamphetamine-dependent research participants, impulsivity is correlated negatively with striatal D2-type receptor availability, and mesocorticolimbic RSFC is stronger than that in controls. The extent to which these features of methamphetamine dependence are interrelated, however, is unknown. This question was addressed in two studies. In Study 1, 19 methamphetamine-dependent and 26 healthy control subjects underwent [18F]fallypride positron emission tomography to measure ventral striatal dopamine D2-type receptor availability, indexed by binding potential (BPND), and functional magnetic resonance imaging (fMRI) to assess mesocorticolimbic RSFC, using a midbrain seed. In Study 2, an independent sample of 20 methamphetamine-dependent and 18 control subjects completed the Barratt Impulsiveness Scale in addition to fMRI. Study 1 showed a significant group by ventral striatal BPND interaction effect on RSFC, reflecting a negative relationship between ventral striatal BPND and RSFC between the midbrain and striatum, orbitofrontal cortex and insula in methamphetamine-dependent participants, but a positive relationship in the control group. In Study 2, an interaction of the group with RSFC on impulsivity was observed. Methamphetamine-dependent users exhibited a positive relationship of midbrain RSFC to the left ventral striatum with cognitive impulsivity, whereas a negative relationship was observed in healthy controls. The results indicate that ventral striatal D2-type receptor signaling may affect the system-level activity within the mesocorticolimbic system, providing a functional link that may help explain high impulsivity in methamphetamine-dependent individuals.


Subject(s)
Impulsive Behavior/drug effects , Mesencephalon/drug effects , Receptors, Dopamine D2/metabolism , Adult , Amphetamine-Related Disorders/metabolism , Central Nervous System Stimulants , Dopamine/metabolism , Female , Humans , Impulsive Behavior/physiology , Magnetic Resonance Imaging , Male , Methamphetamine/adverse effects , Methamphetamine/metabolism , Middle Aged , Positron-Emission Tomography/methods , Prefrontal Cortex/metabolism , Receptors, Dopamine D2/physiology , Ventral Striatum/drug effects , Ventral Striatum/physiopathology
6.
Neuroscience ; 164(1): 88-107, 2009 Nov 24.
Article in English | MEDLINE | ID: mdl-19450667

ABSTRACT

Refining phenotypes for the study of neuropsychiatric disorders is of paramount importance in neuroscience. Poor phenotype definition provides the greatest obstacle for making progress in disorders like schizophrenia, bipolar disorder, Attention Deficit/Hyperactivity Disorder (ADHD), and autism. Using freely available informatics tools developed by the Consortium for Neuropsychiatric Phenomics (CNP), we provide a framework for defining and refining latent constructs used in neuroscience research and then apply this strategy to review known genetic contributions to memory and intelligence in healthy individuals. This approach can help us begin to build multi-level phenotype models that express the interactions between constructs necessary to understand complex neuropsychiatric diseases. These results are available online through the http://www.phenowiki.org database. Further work needs to be done in order to provide consensus-building applications for the broadly defined constructs used in neuroscience research.


Subject(s)
Genome , Intelligence/genetics , Memory , Models, Genetic , Phenotype , Humans , Multivariate Analysis
7.
Neuroscience ; 164(1): 30-42, 2009 Nov 24.
Article in English | MEDLINE | ID: mdl-19344640

ABSTRACT

Phenomics is an emerging transdiscipline dedicated to the systematic study of phenotypes on a genome-wide scale. New methods for high-throughput genotyping have changed the priority for biomedical research to phenotyping, but the human phenome is vast and its dimensionality remains unknown. Phenomics research strategies capable of linking genetic variation to public health concerns need to prioritize development of mechanistic frameworks that relate neural systems functioning to human behavior. New approaches to phenotype definition will benefit from crossing neuropsychiatric syndromal boundaries, and defining phenotypic features across multiple levels of expression from proteome to syndrome. The demand for high throughput phenotyping may stimulate a migration from conventional laboratory to web-based assessment of behavior, and this offers the promise of dynamic phenotyping-the iterative refinement of phenotype assays based on prior genotype-phenotype associations. Phenotypes that can be studied across species may provide greatest traction, particularly given rapid development in transgenic modeling. Phenomics research demands vertically integrated research teams, novel analytic strategies and informatics infrastructure to help manage complexity. The Consortium for Neuropsychiatric Phenomics at UCLA has been supported by the National Institutes of Health Roadmap Initiative to illustrate these principles, and is developing applications that may help investigators assemble, visualize, and ultimately test multi-level phenomics hypotheses. As the transdiscipline of phenomics matures, and work is extended to large-scale international collaborations, there is promise that systematic new knowledge bases will help fulfill the promise of personalized medicine and the rational diagnosis and treatment of neuropsychiatric syndromes.


Subject(s)
Genetic Techniques , Genome , Phenotype , Animals , Biomedical Research/methods , Humans , Mental Disorders/genetics , Models, Genetic
8.
Summit Transl Bioinform ; 2009: 90-4, 2009 Mar 01.
Article in English | MEDLINE | ID: mdl-21347177

ABSTRACT

PubAtlas (www.pubatlas.org) is a web service and standalone program providing literature maps for the biomedical research literature. It accepts user-defined sets of terms (PubMed queries) as input, and permits 'BLASTing' of one set against another: for all terms x and y in these sets, deriving the results of the pairwise intersections x AND y. This all vs. all capability extends PubMed with a literature analysis interface. Correspondingly, the basic form of literature map that PubAtlas provides for exploring associations among sets of terms is an interactive tabular display, in heatmap/microarray format.PubAtlas supports development of specialized lexica -- hierarchies of controlled terminology that can represent sets of related concepts or a 'user-defined query language'. PubAtlas also provides historical perspectives on the literature, with temporal query features that highlight historical patterns. Generally, it is a framework for extending the PubMed interface, and an extensible platform for producing interactive literature maps.

9.
Mol Psychiatry ; 13(4): 350-60, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18180765

ABSTRACT

The human genome project has stimulated development of impressive repositories of biological knowledge at the genomic level and new knowledge bases are rapidly being developed in a 'bottom-up' fashion. In contrast, higher-level phenomics knowledge bases are underdeveloped, particularly with respect to the complex neuropsychiatric syndrome, symptom, cognitive, and neural systems phenotypes widely acknowledged as critical to advance molecular psychiatry research. This gap limits informatics strategies that could improve both the mining and representation of relevant knowledge, and help prioritize phenotypes for new research. Most existing structured knowledge bases also engage a limited set of contributors, and thus fail to leverage recent developments in social collaborative knowledge-building. We developed a collaborative annotation database to enable representation and sharing of empirical information about phenotypes important to neuropsychiatric research (www.Phenowiki.org). As a proof of concept, we focused on findings relevant to 'cognitive control', a neurocognitive construct considered important to multiple neuropsychiatric syndromes. Currently this knowledge base tabulates empirical findings about heritabilities and measurement properties of specific cognitive task and rating scale indicators (n=449 observations). It is hoped that this new open resource can serve as a starting point that enables broadly collaborative knowledge-building, and help investigators select and prioritize endophenotypes for translational research.


Subject(s)
Cognition/physiology , Cooperative Behavior , Databases as Topic , Knowledge Bases , Phenotype , Computational Biology , Database Management Systems , Humans
10.
Neuroreport ; 12(18): 3953-7, 2001 Dec 21.
Article in English | MEDLINE | ID: mdl-11742218

ABSTRACT

While undergoing fMRI, six patients with DSM IV diagnosis of panic disorder and six normal controls performed directed imagery of neutral, moderate and high anxiety situations based on an individually determined behavioral hierarchy. Brain activity was compared during high vs neutral anxiety blocks for each group of subjects using SPM99b. Panic patients showed increased activity in inferior frontal cortex, hippocampus and throughout the cingulate both anterior and posterior, extending into the orbitofrontal cortex and encompassing both hemispheres. These areas may constitute the important circuit in the psychopathology of panic disorder. We propose that this pattern of activity may enhance the encoding and retrieval of strong emotional events, facilitating the recapitulation of traumatic experiences and leading to panic disorder in vulnerable individuals.


Subject(s)
Brain/physiology , Magnetic Resonance Imaging , Panic Disorder/physiopathology , Adult , Anxiety/physiopathology , Female , Frontal Lobe/physiology , Gyrus Cinguli/physiology , Hippocampus/physiology , Humans , Male
11.
Arch Gen Psychiatry ; 58(3): 280-8, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11231835

ABSTRACT

BACKGROUND: Previously we proposed that dorsolateral prefrontal cortex (PFC) supports a specific working memory (WM) subcomponent: the ability to represent and maintain context information necessary to guide appropriate task behavior. By context, we mean prior task-relevant information represented in such a form that it supports selection of the appropriate behavioral response. Furthermore, we hypothesized that WM deficits in schizophrenia reflect impaired context processing due to a disturbance in dorsolateral PFC. We use functional magnetic resonance imaging to examine PFC activation in medication-naive, first-episode patients with schizophrenia during a WM, task-isolating context processing. METHODS: Fourteen first-episode, medication-naive patients with schizophrenia and 12 controls similar in age, sex, and parental education underwent functional magnetic resonance imaging during performance of an A-X version of the Continuous Performance Test. RESULTS: Patients with schizophrenia demonstrated deficits in dorsolateral PFC activation in task conditions requiring context processing but showed intact activation of posterior and inferior PFC. In addition, patients demonstrated intact activation of the primary motor and somatosensory cortex in response to stimulus processing demands. CONCLUSIONS: These results demonstrate selectivity in dorsolateral PFC dysfunction among medication-naive first-episode patients with schizophrenia, suggesting that a specific deficit in PFC function is present at illness onset, prior to the administration of medication or the most confounding effects of illness duration. Furthermore, these results are consistent with the hypothesis that WM deficits in patients with schizophrenia reflect an impairment in context processing due to a disturbance in dorsolateral PFC function.


Subject(s)
Cognition Disorders/physiopathology , Magnetic Resonance Imaging/statistics & numerical data , Neuropsychological Tests/statistics & numerical data , Prefrontal Cortex/physiopathology , Schizophrenia/physiopathology , Schizophrenic Psychology , Adult , Antipsychotic Agents/administration & dosage , Cerebral Cortex/anatomy & histology , Cerebral Cortex/physiopathology , Cognition Disorders/diagnosis , Female , Humans , Male , Motor Cortex/physiology , Prefrontal Cortex/anatomy & histology , Psychiatric Status Rating Scales/statistics & numerical data , Schizophrenia/diagnosis , Somatosensory Cortex/physiology , Task Performance and Analysis
12.
Neuroimage ; 11(5 Pt 1): 424-46, 2000 May.
Article in English | MEDLINE | ID: mdl-10806029

ABSTRACT

Investigations of working memory (WM) systems in the frontal cortex have revealed two stimulus dimensions along which frontal cortical representations may be functionally organized. One hypothesized dimension dissociates verbal from nonverbal WM processes, dividing left from right frontal regions. The second hypothesized dimension dissociates spatial from nonspatial WM, dividing dorsal from ventral frontal regions. Here we used functional magnetic resonance imaging to probe WM processes associated with three different types of stimuli: letters (verbal and nonspatial), abstract shapes (nonverbal and nonspatial), and locations (nonverbal and spatial). In a series of three experiments using the "n-back" WM paradigm, direct statistical comparisons were made between activation patterns in each pairwise combination of the three stimulus types. Across the experiments, no regions that demonstrated responses to WM manipulations were discovered to be unique to any of the three stimulus types. Therefore, no evidence was found to support either a left/right verbal/nonverbal dissociation or a dorsal/ventral spatial/nonspatial dissociation. While this could reflect a limitation of the present behavioral and imaging techniques, other factors that could account for the data are considered, including subjects' strategy selection, encoding of information into WM, and the nature of representational schemes in prefrontal cortex.


Subject(s)
Memory/physiology , Pattern Recognition, Visual/physiology , Prefrontal Cortex/physiology , Space Perception/physiology , Adolescent , Adult , Female , Humans , Magnetic Resonance Imaging , Male , Photic Stimulation
13.
J Cogn Neurosci ; 12(2): 298-309, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10771413

ABSTRACT

Studies of a range of higher cognitive functions consistently activate a region of anterior cingulate cortex (ACC), typically posterior to the genu and superior to the corpus collosum. In particular, this ACC region appears to be active in task situations where there is a need to override a prepotent response tendency, when responding is underdetermined, and when errors are made. We have hypothesized that the function of this ACC region is to monitor for the presence of "crosstalk" or competition between incompatible responses. In prior work, we provided initial support for this hypothesis, demonstrating ACC activity in the same region both during error trials and during correct trials in task conditions designed to elicit greater response competition. In the present study, we extend our testing of this hypothesis to task situations involving underdetermined responding. Specifically, 14 healthy control subjects performed a verb-generation task during event-related functional magnetic resonance imaging (fMRI), with the on-line acquisition of overt verbal responses. The results demonstrated that the ACC, and only the ACC, was more active in a series of task conditions that elicited competition among alternative responses. These conditions included a greater ACC response to: (1) Nouns categorized as low vs. high constraint (i.e., during a norming study, multiple verbs were produced with equal frequency vs. a single verb that produced much more frequently than any other); (2) the production of verbs that were weak associates, rather than, strong associates of particular nouns; and (3) the production of verbs that were weak associates for nouns categorized as high constraint. We discuss the implication of these results for understanding the role that the ACC plays in human cognition.


Subject(s)
Brain Mapping , Cognition/physiology , Conflict, Psychological , Gyrus Cinguli/physiology , Linguistics , Adolescent , Adult , Female , Frontal Lobe/physiology , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged
14.
Neuroimage ; 10(6): 642-57, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10600410

ABSTRACT

This paper presents a pair of studies designed to empirically explore the severity of potential artifacts associated with overt verbal responding during fMRI scanning and to examine several different solutions to these artifacts. In Study One, we compared susceptibility artifacts, signal-to-noise ratios, and activation patterns when overt versus covert verbal responses were elicited during fMRI scanning, using both individual and group analyses. The results indicated that different patterns of brain activation were elicited during covert as compared to overt verbal responses. This suggests that covert responses cannot be used as a simple substitute for overt verbal responses. Further, the results suggested that the use of overt verbal responses during fMRI scanning can produce interpretable results if: (1) the primary comparison is between two conditions that both use overt verbal responses, and (2) analyses are conducted on pooled group data rather than individual participant data. In Study Two, we evaluated the feasibility and validity of a method for acquiring participants' overt responses during fMRI scanning. The results indicated that our method was very accurate in acquiring the content of participant's responses. Further, inspection of the responses demonstrated that participants do not always comply with task instructions and highlighted the importance of obtaining behavioral performance measures during fMRI scanning.


Subject(s)
Brain/physiology , Magnetic Resonance Imaging , Verbal Behavior/physiology , Adult , Artifacts , Feasibility Studies , Female , Humans , Male , Middle Aged , Movement/physiology
SELECTION OF CITATIONS
SEARCH DETAIL
...