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1.
Transl Psychiatry ; 9(1): 12, 2019 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-30664633

RESUMO

Schizophrenia is a severe mental disorder characterized by numerous subtle changes in brain structure and function. Machine learning allows exploring the utility of combining structural and functional brain magnetic resonance imaging (MRI) measures for diagnostic application, but this approach has been hampered by sample size limitations and lack of differential diagnostic data. Here, we performed a multi-site machine learning analysis to explore brain structural patterns of T1 MRI data in 2668 individuals with schizophrenia, bipolar disorder or attention-deficit/ hyperactivity disorder, and healthy controls. We found reproducible changes of structural parameters in schizophrenia that yielded a classification accuracy of up to 76% and provided discrimination from ADHD, through it lacked specificity against bipolar disorder. The observed changes largely indexed distributed grey matter alterations that could be represented through a combination of several global brain-structural parameters. This multi-site machine learning study identified a brain-structural signature that could reproducibly differentiate schizophrenia patients from controls, but lacked specificity against bipolar disorder. While this currently limits the clinical utility of the identified signature, the present study highlights that the underlying alterations index substantial global grey matter changes in psychotic disorders, reflecting the biological similarity of these conditions, and provide a roadmap for future exploration of brain structural alterations in psychiatric patients.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno Bipolar/fisiopatologia , Substância Cinzenta/fisiopatologia , Esquizofrenia/fisiopatologia , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Transtorno Bipolar/diagnóstico por imagem , Estudos de Casos e Controles , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Aprendizado de Máquina , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esquizofrenia/diagnóstico por imagem , Adulto Jovem
2.
Neuroimage ; 189: 459-467, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30641241

RESUMO

Encoding and retrieval of emotionally arousing stimuli depend on the activation of multiple interconnected brain regions, with people showing differences in their individual strength of emotional perception and recollection. Understanding the association between these brain regions and the behavioral outcome might therefore have important clinical implications as dysfunctional emotional memory processes are characteristic of many psychiatric disorders. Based on behavioral and fMRI data collected from healthy young adults (N = 1'385), we investigated brain activation patterns, arousal ratings and memory performance during encoding and retrieval of negative and neutral pictures. We performed multi-voxel pattern analysis (MVPA) and voxel-wise association analyses. Subjects' individual strength of perceived arousal at encoding and subjects' memory performance at recognition could be predicted from the fMRI data of the respective tasks by using a topographically identical network of brain regions. This network was mainly left lateralized including dense clusters of voxels in the occipital and parietal lobe and including the amygdala. Voxel-wise association analyses confirmed the close link between the brain activation of both tasks and their relation to the respective behavioral outcome. These results point to the importance of the here identified brain network for emotional memory processes in health and, possibly, disease.

3.
Mol Psychiatry ; 2018 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-30279459

RESUMO

The hippocampus is a heterogeneous structure, comprising histologically distinguishable subfields. These subfields are differentially involved in memory consolidation, spatial navigation and pattern separation, complex functions often impaired in individuals with brain disorders characterized by reduced hippocampal volume, including Alzheimer's disease (AD) and schizophrenia. Given the structural and functional heterogeneity of the hippocampal formation, we sought to characterize the subfields' genetic architecture. T1-weighted brain scans (n = 21,297, 16 cohorts) were processed with the hippocampal subfields algorithm in FreeSurfer v6.0. We ran a genome-wide association analysis on each subfield, co-varying for whole hippocampal volume. We further calculated the single-nucleotide polymorphism (SNP)-based heritability of 12 subfields, as well as their genetic correlation with each other, with other structural brain features and with AD and schizophrenia. All outcome measures were corrected for age, sex and intracranial volume. We found 15 unique genome-wide significant loci across six subfields, of which eight had not been previously linked to the hippocampus. Top SNPs were mapped to genes associated with neuronal differentiation, locomotor behaviour, schizophrenia and AD. The volumes of all the subfields were estimated to be heritable (h2 from 0.14 to 0.27, all p < 1 × 10-16) and clustered together based on their genetic correlations compared with other structural brain features. There was also evidence of genetic overlap of subicular subfield volumes with schizophrenia. We conclude that hippocampal subfields have partly distinct genetic determinants associated with specific biological processes and traits. Taking into account this specificity may increase our understanding of hippocampal neurobiology and associated pathologies.

4.
Transl Psychiatry ; 8(1): 31, 2018 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-29382824

RESUMO

The large biological distance between genetic risk loci and their mechanistic consequences in the tissue of interest limits the ability to establish functionality of susceptibility variants for genetically complex traits. Such a biological gap may be reduced through the systematic study of molecular mediators of genomic action, such as epigenetic modification. Here, we report the identification of robust genetic estimators of whole-blood CpG methylation, which can serve as intermediate molecular traits amenable to association testing with other genetically complex traits. We describe the relationship between these estimators and gene expression, demonstrate their genome-wide applicability to association testing even in the absence of individual genotypic data, and show that these estimators powerfully identify methylation-related genomic loci associated with polygenic traits and common diseases, such as schizophrenia. The use of genetic estimators for blood DNA methylation, which are made publically available, can serve as a valuable tool for the identification of epigenetic underpinnings of complex traits.

5.
eNeuro ; 5(1)2018 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29464194

RESUMO

Working memory (WM) is an important cognitive domain for everyday life functioning and is often disturbed in neuropsychiatric disorders. Functional magnetic resonance imaging (fMRI) studies in humans show that distributed brain areas typically described as fronto-parietal regions are implicated in WM tasks. Based on data from a large sample of healthy young adults (N = 1369), we applied independent component analysis (ICA) to the WM-fMRI signal and identified two distinct networks that were relevant for differences in individual WM task performance. A parietally-centered network was particularly relevant for individual differences in task measures related to WM performance ("WM dependent") and a frontally-centered network was relevant for differences in attention-dependent task performance. Importantly, frontal areas that are typically considered as key regions for WM were either involved in both WM-dependent and attention-dependent performance, or in attention-dependent performance only. The networks identified here are provided as publicly available datasets. These networks can be applied in future studies to derive a low-dimensional representation of the overall WM brain activation.

6.
Neuroimage ; 167: 354-365, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29175611

RESUMO

While much is known about immediate brain activity changes induced by the confrontation with emotional stimuli, the subsequent temporal unfolding of emotions has yet to be explored. To investigate whether exposure to emotionally aversive pictures affects subsequent resting-state networks differently from exposure to neutral pictures, a resting-state fMRI study implementing a two-group repeated-measures design in healthy young adults (N = 34) was conducted. We focused on investigating (i) patterns of amygdala whole-brain and hippocampus connectivity in both a seed-to-voxel and seed-to-seed approach, (ii) whole-brain resting-state networks with an independent component analysis coupled with dual regression, and (iii) the amygdala's fractional amplitude of low frequency fluctuations, all while EEG recording potential fluctuations in vigilance. In spite of the successful emotion induction, as demonstrated by stimuli rating and a memory-facilitating effect of negative emotionality, none of the resting-state measures was differentially affected by picture valence. In conclusion, resting-state networks connectivity as well as the amygdala's low frequency oscillations appear to be unaffected by preceding exposure to widely used emotionally aversive visual stimuli in healthy young adults.


Assuntos
Tonsila do Cerebelo/fisiologia , Nível de Alerta/fisiologia , Conectoma/métodos , Eletroencefalografia/métodos , Emoções/fisiologia , Rede Nervosa/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Adolescente , Adulto , Tonsila do Cerebelo/diagnóstico por imagem , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Rede Nervosa/diagnóstico por imagem , Adulto Jovem
7.
Sci Rep ; 7(1): 13669, 2017 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-29057891

RESUMO

Studies assessing the existence and magnitude of epistatic effects on complex human traits provide inconclusive results. The study of such effects is complicated by considerable increase in computational burden, model complexity, and model uncertainty, which in concert decrease model stability. An additional source introducing significant uncertainty with regard to the detection of robust epistasis is the biological distance between the genetic variation and the trait under study. Here we studied CpG methylation, a genetically complex molecular trait that is particularly close to genomic variation, and performed an exhaustive search for two-locus epistatic effects on the CpG-methylation signal in two cohorts of healthy young subjects. We detected robust epistatic effects for a small number of CpGs (N = 404). Our results indicate that epistatic effects explain only a minor part of variation in DNA-CpG methylation. Interestingly, these CpGs were more likely to be associated with gene-expression of nearby genes, as also shown by their overrepresentation in DNase I hypersensitivity sites and underrepresentation in CpG islands. Finally, gene ontology analysis showed a significant enrichment of these CpGs in pathways related to HPV-infection and cancer.

8.
Proc Natl Acad Sci U S A ; 114(34): 9176-9181, 2017 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-28790188

RESUMO

Emotional enhancement of memory by noradrenergic mechanisms is well-described, but the long-term consequences of such enhancement are poorly understood. Over time, memory traces are thought to undergo a neural reorganization, that is, a systems consolidation, during which they are, at least partly, transferred from the hippocampus to neocortical networks. This transfer is accompanied by a decrease in episodic detailedness. Here we investigated whether norepinephrine (NE) administration into the basolateral amygdala after training on an inhibitory avoidance discrimination task, comprising two distinct training contexts, alters systems consolidation dynamics to maintain episodic-like accuracy and hippocampus dependency of remote memory. At a 2-d retention test, both saline- and NE-treated rats accurately discriminated the training context in which they had received footshock. Hippocampal inactivation with muscimol before retention testing disrupted discrimination of the shock context in both treatment groups. At 28 d, saline-treated rats showed hippocampus-independent retrieval and lack of discrimination. In contrast, NE-treated rats continued to display accurate memory of the shock-context association. Hippocampal inactivation at this remote retention test blocked episodic-like accuracy and induced a general memory impairment. These findings suggest that the NE treatment altered systems consolidation dynamics by maintaining hippocampal involvement in the memory. This shift in systems consolidation was paralleled by time-regulated DNA methylation and transcriptional changes of memory-related genes, namely Reln and Pkmζ, in the hippocampus and neocortex. The findings provide evidence suggesting that consolidation of emotional memories by noradrenergic mechanisms alters systems consolidation dynamics and, as a consequence, influences the maintenance of long-term episodic-like accuracy of memory.


Assuntos
Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Memória de Longo Prazo/efeitos dos fármacos , Norepinefrina/farmacologia , Agonistas alfa-Adrenérgicos/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Moléculas de Adesão Celular Neuronais/genética , Metilação de DNA/efeitos dos fármacos , Discriminação (Psicologia)/efeitos dos fármacos , Discriminação (Psicologia)/fisiologia , Proteínas da Matriz Extracelular/genética , Agonistas de Receptores de GABA-A/farmacologia , Hipocampo/metabolismo , Hipocampo/fisiologia , Masculino , Memória de Longo Prazo/fisiologia , Muscimol/farmacologia , Proteínas do Tecido Nervoso/genética , Norepinefrina/administração & dosagem , Ratos Sprague-Dawley , Serina Endopeptidases/genética , Transcriptoma/efeitos dos fármacos
9.
Brain Behav ; 7(7): e00721, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28729929

RESUMO

INTRODUCTION: Memory functions are highly variable between healthy humans. The neural correlates of this variability remain largely unknown. METHODS: Here, we investigated how differences in free recall performance are associated with DTI-based properties of the brain's structural connectome and with grey matter volumes in 664 healthy young individuals tested in the same MR scanner. RESULTS: Global structural connectivity, but not overall or regional grey matter volumes, positively correlated with recall performance. Moreover, a set of 22 inter-regional connections, including some with no previously reported relation to human memory, such as the connection between the temporal pole and the nucleus accumbens, explained 7.8% of phenotypic variance. CONCLUSIONS: In conclusion, this large-scale study indicates that individual memory performance is associated with the level of structural brain connectivity.


Assuntos
Encéfalo/diagnóstico por imagem , Conectoma , Substância Cinzenta/diagnóstico por imagem , Rememoração Mental/fisiologia , Adulto , Imagem de Tensor de Difusão , Feminino , Humanos , Masculino , Adulto Jovem
10.
J Neurosci ; 37(28): 6661-6672, 2017 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-28592692

RESUMO

The identification of genes related to encoding, storage, and retrieval of memories is a major interest in neuroscience. In the current study, we analyzed the temporal gene expression changes in a neuronal mRNA pool during an olfactory long-term associative memory (LTAM) in Caenorhabditis elegans hermaphrodites. Here, we identified a core set of 712 (538 upregulated and 174 downregulated) genes that follows three distinct temporal peaks demonstrating multiple gene regulation waves in LTAM. Compared with the previously published positive LTAM gene set (Lakhina et al., 2015), 50% of the identified upregulated genes here overlap with the previous dataset, possibly representing stimulus-independent memory-related genes. On the other hand, the remaining genes were not previously identified in positive associative memory and may specifically regulate aversive LTAM. Our results suggest a multistep gene activation process during the formation and retrieval of long-term memory and define general memory-implicated genes as well as conditioning-type-dependent gene sets.SIGNIFICANCE STATEMENT The identification of genes regulating different steps of memory is of major interest in neuroscience. Identification of common memory genes across different learning paradigms and the temporal activation of the genes are poorly studied. Here, we investigated the temporal aspects of Caenorhabditis elegans gene expression changes using aversive olfactory associative long-term memory (LTAM) and identified three major gene activation waves. Like in previous studies, aversive LTAM is also CREB dependent, and CREB activity is necessary immediately after training. Finally, we define a list of memory paradigm-independent core gene sets as well as conditioning-dependent genes.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Regulação da Expressão Gênica/fisiologia , Memória de Longo Prazo/fisiologia , Proteínas do Tecido Nervoso/genética , Proteoma/metabolismo , Animais , Aprendizagem por Associação/fisiologia , Proteínas de Caenorhabditis elegans/genética , Mapeamento Cromossômico , Perfilação da Expressão Gênica , Genoma/genética , Proteoma/genética
11.
Nat Commun ; 8: 15193, 2017 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-28443631

RESUMO

Increasing age is tightly linked to decreased thickness of the human neocortex. The biological mechanisms that mediate this effect are hitherto unknown. The DNA methylome, as part of the epigenome, contributes significantly to age-related phenotypic changes. Here, we identify an epigenetic signature that is associated with cortical thickness (P=3.86 × 10-8) and memory performance in 533 healthy young adults. The epigenetic effect on cortical thickness was replicated in a sample comprising 596 participants with major depressive disorder and healthy controls. The epigenetic signature mediates partially the effect of age on cortical thickness (P<0.001). A multilocus genetic score reflecting genetic variability of this signature is associated with memory performance (P=0.0003) in 3,346 young and elderly healthy adults. The genomic location of the contributing methylation sites points to the involvement of specific immune system genes. The decomposition of blood methylome-wide patterns bears considerable potential for the study of brain-related traits.


Assuntos
Envelhecimento/genética , Metilação de DNA/genética , Epigênese Genética/genética , Sistema Imunitário/imunologia , Memória/fisiologia , Neocórtex/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Ilhas de CpG/genética , Transtorno Depressivo Maior/genética , Feminino , Variação Genética/genética , Humanos , Sistema Imunitário/citologia , Masculino , Pessoa de Meia-Idade , Suíça , Adulto Jovem
12.
J Psychiatr Res ; 91: 116-123, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28334615

RESUMO

Depressive symptoms exist on a continuum, the far end of which is found in depressive disorders. Utilizing the continuous spectrum of depressive symptoms may therefore contribute to the understanding of the biological underpinnings of depression. Gene set enrichment analysis (GSEA) is an important tool for the identification of gene groups linked to complex traits, and was applied in the present study on genome-wide association study (GWAS) data of depression scores and their brain-level structural correlates in healthy young individuals. On symptom level (i.e. depression scores), robust enrichment was identified for two gene sets: NCAM1 Interactions and Collagen Formation. Depression scores were also associated with decreased fractional anisotropy (FA) - a brain white matter property - within the forceps minor and the left superior temporal longitudinal fasciculus. Within each of these tracts, mean FA value of depression score-associated voxels was used as a phenotype in a subsequent GSEA. The NCAM1 Interactions gene set was significantly enriched in these tracts. By linking the NCAM1 Interactions gene set to depression scores and their structural brain correlates in healthy participants, the current study contributes to the understanding of the molecular underpinnings of depressive symptomatology.


Assuntos
Encéfalo/patologia , Antígeno CD56/genética , Colágeno/genética , Depressão/genética , Depressão/patologia , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Anisotropia , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Colágeno/metabolismo , Imagem de Tensor de Difusão , Feminino , Estudos de Associação Genética , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Adulto Jovem
13.
Neuropsychopharmacology ; 42(2): 485-494, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27644128

RESUMO

Glucocorticoids reduce phobic fear in patients with anxiety disorders. Previous studies have shown that fear-related activation of the amygdala can be mediated through the visual cortical pathway, which includes the fusiform gyrus, or through other pathways. However, it is not clear which of the pathways that activate the amygdala is responsible for the pathophysiology of a specific phobia and how glucocorticoid treatment alleviates fear processing in these neural networks. We recorded the brain activity with functional magnetic resonance imaging in patients with spider phobia, who received either 20 mg of cortisol or a placebo while viewing pictures of spiders. We also tested healthy participants who did not receive any medication during the same task. We performed dynamic causal modelling (DCM), a connectivity analysis, to examine the effects of cortisol on the networks involved in processing fear and to examine if there was an association between these networks and the symptoms of the phobia. Cortisol administration suppressed the phobic stimuli-related amygdala activity to levels comparable to the healthy participants and reduced subjective phobic fear. The DCM analysis revealed that cortisol administration suppressed the aberrant inputs into the amygdala that did not originate from the visual cortical pathway, but rather from a fast subcortical pathway mediated by the pulvinar nucleus, and suppressed the interactions between the amygdala and fusiform gyrus. This network changes were distinguishable from healthy participants and considered the residual changes under cortisol administration. We also found that the strengths of the aberrant inputs into the amygdala were positively correlated with the severity of spider phobia. This study demonstrates that patients with spider phobia show an aberrant functional connectivity of the amygdala when they are exposed to phobia-related stimuli and that cortisol administration can alleviate this fear-specific neural connectivity.


Assuntos
Tonsila do Cerebelo/fisiopatologia , Medo/fisiologia , Glucocorticoides/administração & dosagem , Hidrocortisona/administração & dosagem , Transtornos Fóbicos/fisiopatologia , Adulto , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Mapeamento Encefálico , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiopatologia , Aranhas , Córtex Visual/efeitos dos fármacos , Córtex Visual/fisiopatologia , Adulto Jovem
14.
J Psychiatr Res ; 83: 260-268, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27710795

RESUMO

DNA methylation represents an important link between structural genetic variation and complex phenotypes. The study of genome-wide CpG methylation and its relation to traits relevant to psychiatry has become increasingly important. Here, we analyzed quality metrics of 394,043 CpG sites in two samples of 568 and 319 mentally healthy young adults. For 25% of all CpGs we observed medium to large common epigenetic variation. These CpGs were overrepresented in open sea and shore regions, as well as in intergenic regions. They also showed a strong enrichment of significant hits in association analyses. Furthermore, a significant proportion of common DNA methylation is at least partially genetically driven and thus may be observed similarly across tissues. These findings could be of particular relevance for studies of complex neuropsychiatric traits, which often rely on proxy tissues.


Assuntos
Ilhas de CpG/genética , Epigênese Genética/genética , Saúde Mental , Adulto , Metilação de DNA/genética , Epigenômica/métodos , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Voluntários Saudáveis , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
16.
NPJ Microgravity ; 2: 16040, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28725745

RESUMO

Dysregulation of the immune system occurs during spaceflight and may represent a crew health risk during exploration missions because astronauts are challenged by many stressors. Therefore, it is crucial to understand the biology of immune modulation under spaceflight conditions in order to be able to maintain immune homeostasis under such challenges. In the framework of the THESEUS project whose aim was to develop an integrated life sciences research roadmap regarding human space exploration, experts working in the field of space immunology, and related disciplines, established a questionnaire sent to scientists around the world. From the review of collected answers, they deduced a list of key issues and provided several recommendations such as a maximal exploitation of currently available resources on Earth and in space, and to increase increments duration for some ISS crew members to 12 months or longer. These recommendations should contribute to improve our knowledge about spaceflight effects on the immune system and the development of countermeasures that, beyond astronauts, could have a societal impact.

17.
JAMA Psychiatry ; 72(10): 1029-36, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26332608

RESUMO

IMPORTANCE: Human episodic memory performance is linked to the function of specific brain regions, including the hippocampus; declines as a result of increasing age; and is markedly disturbed in Alzheimer disease (AD), an age-associated neurodegenerative disorder that primarily affects the hippocampus. Exploring the molecular underpinnings of human episodic memory is key to the understanding of hippocampus-dependent cognitive physiology and pathophysiology. OBJECTIVE: To determine whether biologically defined groups of genes are enriched in episodic memory performance across age, memory encoding-related brain activity, and AD. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter collaborative study, which began in August 2008 and is ongoing, gene set enrichment analysis was done by using primary and meta-analysis data from 57 968 participants. The Swiss cohorts consisted of 3043 healthy young adults assessed for episodic memory performance. In a subgroup (n = 1119) of one of these cohorts, functional magnetic resonance imaging was used to identify gene set-dependent differences in brain activity related to episodic memory. The German Study on Aging, Cognition, and Dementia in Primary Care Patients cohort consisted of 763 elderly participants without dementia who were assessed for episodic memory performance. The International Genomics of Alzheimer's Project case-control sample consisted of 54 162 participants (17 008 patients with sporadic AD and 37 154 control participants). Analyses were conducted between January 2014 and June 2015. Gene set enrichment analysis in all samples was done using genome-wide single-nucleotide polymorphism data. MAIN OUTCOMES AND MEASURES: Episodic memory performance in the Swiss cohort and German Study on Aging, Cognition, and Dementia in Primary Care Patients cohort was quantified by picture and verbal delayed free recall tasks. In the functional magnetic resonance imaging experiment, activation of the hippocampus during encoding of pictures served as the phenotype of interest. In the International Genomics of Alzheimer's Project sample, diagnosis of sporadic AD served as the phenotype of interest. RESULTS: In the discovery sample, we detected significant enrichment for genes constituting the calcium signaling pathway, especially those related to the elevation of cytosolic calcium (P = 2 × 10-4). This enrichment was replicated in 2 additional samples of healthy young individuals (P = .02 and .04, respectively) and a sample of healthy elderly participants (P = .004). Hippocampal activation (P = 4 × 10-4) and the risk for sporadic AD (P = .01) were also significantly enriched for genes related to the elevation of cytosolic calcium. CONCLUSIONS AND RELEVANCE: By detecting consistent significant enrichment in independent cohorts of young and elderly participants, this study identified that calcium signaling plays a central role in hippocampus-dependent human memory processes in cognitive health and disease, contributing to the understanding and potential treatment of hippocampus-dependent cognitive pathology.


Assuntos
Doença de Alzheimer/genética , Sinalização do Cálcio/genética , Hipocampo/fisiopatologia , Memória Episódica , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/fisiopatologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Neuroimagem Funcional , Humanos , Imagem por Ressonância Magnética , Masculino , Memória/fisiologia , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
18.
Proc Natl Acad Sci U S A ; 112(35): E4939-48, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26261317

RESUMO

Episodic memory performance is the result of distinct mental processes, such as learning, memory maintenance, and emotional modulation of memory strength. Such processes can be effectively dissociated using computational models. Here we performed gene set enrichment analyses of model parameters estimated from the episodic memory performance of 1,765 healthy young adults. We report robust and replicated associations of the amine compound SLC (solute-carrier) transporters gene set with the learning rate, of the collagen formation and transmembrane receptor protein tyrosine kinase activity gene sets with the modulation of memory strength by negative emotional arousal, and of the L1 cell adhesion molecule (L1CAM) interactions gene set with the repetition-based memory improvement. Furthermore, in a large functional MRI sample of 795 subjects we found that the association between L1CAM interactions and memory maintenance revealed large clusters of differences in brain activity in frontal cortical areas. Our findings provide converging evidence that distinct genetic profiles underlie specific mental processes of human episodic memory. They also provide empirical support to previous theoretical and neurobiological studies linking specific neuromodulators to the learning rate and linking neural cell adhesion molecules to memory maintenance. Furthermore, our study suggests additional memory-related genetic pathways, which may contribute to a better understanding of the neurobiology of human memory.


Assuntos
Biologia Computacional , Memória , Processos Mentais , Adulto , Feminino , Voluntários Saudáveis , Humanos , Imagem por Ressonância Magnética , Masculino , Adulto Jovem
19.
PLoS One ; 10(3): e0120640, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25781012

RESUMO

The dorsolateral prefrontal cortex (DLPFC) plays a key role in working memory. Evidence indicates that transcranial magnetic stimulation (TMS) over the DLPFC can interfere with working memory performance. Here we investigated for how long continuous theta-burst stimulation (cTBS) over the DLPFC decreases working memory performance and whether the effect of cTBS on performance depends on working memory load. Forty healthy young subjects received either cTBS over the left DLPFC or sham stimulation before performing a 2-, and 3-back working memory letter task. An additional 0-back condition served as a non-memory-related control, measuring general attention. cTBS over the left DLPFC significantly impaired 2-back working memory performance for about 15 min, whereas 3-back and 0-back performances were not significantly affected. Our results indicate that the effect of left DLPFC cTBS on working memory performance lasts for roughly 15 min and depends on working memory load.


Assuntos
Memória de Curto Prazo , Córtex Pré-Frontal/fisiologia , Ritmo Teta , Adolescente , Adulto , Feminino , Humanos , Masculino , Estimulação Magnética Transcraniana
20.
Trends Cogn Sci ; 19(4): 183-7, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25727774

RESUMO

Our knowledge about the molecular and neural mechanisms of emotional and cognitive processes has increased exponentially in the past decades. Unfortunately, there has been no translation of this knowledge into the development of novel and improved pharmacological treatments for psychiatric disorders. We comment on some of the reasons for failed drug discovery in psychiatry, particularly on the use of ill-suited disease models and on the use of diagnostic constructs unrelated to the underlying biological mechanisms. Furthermore, we argue that the use of human genetic findings together with biologically informed phenotypes and advanced data-mining methodology will catalyze the identification of promising drug targets and, finally, will lead to improved therapeutic outcomes.


Assuntos
Descoberta de Drogas/métodos , Genoma Humano , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/genética , Animais , Mineração de Dados/métodos , Humanos , Modelos Biológicos , Farmacogenética/métodos , Fenótipo , Psicotrópicos/farmacologia
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