RESUMO
Rare apoptosis-promoting functional variants in the apoptosis protease activating factor 1 (APAF1) gene were recently reported to co-segregate with major depression in male members of families from Utah. In order to estimate the impact of these variants on risk for major depressive disorder (MDD) in the general population, we surveyed the frequency of the APAF1 putative MDD risk alleles using re-sequencing in a large sample of northern European and European-American subjects, including a large number of males with MDD. The E777K and N782T APAF1 variants previously described by Harlan et al. [Harlan et al. (2006) Mol Psychiatry 11(1):76-85] were found at low frequencies in affected individuals and population controls. The C450W and Q465R variants were not detected in any of the 632 subjects sequenced. These results show that the APAF1 variants associated with risk for MDD in the Utah pedigrees are very rare in Northern European and European-American populations. In addition, the E777K and N782T variants were found at low frequencies both in patients and population controls, suggesting that these variants have limited impact on risk for MDD.
Assuntos
Alelos , Fator Apoptótico 1 Ativador de Proteases/genética , Transtorno Depressivo Maior/genética , Sequência de Bases , Estudos de Casos e Controles , Primers do DNA , Feminino , Humanos , Masculino , Grupos PopulacionaisRESUMO
Changes in neuroendocrine function may predispose menopausal women to psychological disturbances characterized by depressed mood, anxiety, irritability, fatigue, insomnia, forgetfulness and decline in libido. The acute tryptophan depletion paradigm was employed to examine the serotonergic contribution to mood and cognitive function in menopausal women who were within 4 weeks of recovery from an episode of major depression. Menopausal women whose depression was responsive to treatment with oestradiol, the selective serotonin reuptake inhibitor fluoxetine, or a combination of both treatments underwent assessment of mood and verbal memory on active tryptophan depLetion and sham depletion test days. Although performance on the delayed paragraph recall subtest of the Wechsler Memory Scale was impaired by tryptophan depletion, no subjects experienced a relapse of depression or a significant worsening of mood. Results from this pilot study indicate that menopausal women who have recently recovered from a major depressive episode do not experience a worsening of mood with acute tryptophan depletion, despite the existence in this sample of some known risk factors for depressive relapse as a result of these procedures. While preliminary, the results suggest that serotonin may be less critical to the pathogenesis of depression during the menopause.
Assuntos
Afeto/efeitos dos fármacos , Cognição/efeitos dos fármacos , Transtorno Depressivo Maior/fisiopatologia , Serotonina/fisiologia , Triptofano/deficiência , Adulto , Afeto/fisiologia , Cognição/fisiologia , Transtorno Depressivo Maior/tratamento farmacológico , Quimioterapia Combinada , Estradiol/uso terapêutico , Feminino , Fluoxetina/uso terapêutico , Humanos , Menopausa , Pessoa de Meia-Idade , Projetos Piloto , Recidiva , Fatores de Risco , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Triptofano/sangueRESUMO
Despite an abundance of data in animals, there is little research in humans regarding how estrogen and serotonin (5-HT) may interact to influence cognition. Through the use of estrogen treatment (ET) and tryptophan depletion (TRP-D) in a within-subject design involving healthy menopausal women, we have manipulated both estrogen and 5-HT in order to evaluate their individual and joint effects. Although neither manipulation influenced visuospatial learning, a significant interaction suggested that estrogen exerted a protective effect on verbal memory, such that TRP-D impaired performance to a greater extent before the administration of ET. In consonance with this finding, ET was associated with a small, but positive mood effect on the day following active TRP-D. In addition, ET significantly improved letter-cued verbal fluency with and without TRP-D. Finally, time since last menstrual period was significantly associated with verbal memory scores, such that longer length of hypogonadism resulted in decreased verbal memory performance. These data support the interaction of estrogen and 5-HT in nonreproductive behavior in humans as well as highlight the role of ovarian steroids in cognition.
Assuntos
Cognição/efeitos dos fármacos , Estradiol/farmacologia , Menopausa/efeitos dos fármacos , Triptofano/deficiência , Afeto/efeitos dos fármacos , Estradiol/sangue , Feminino , Hormônios/sangue , Humanos , Memória/efeitos dos fármacos , Pessoa de Meia-Idade , Testes Neuropsicológicos/estatística & dados numéricos , Fatores de Tempo , Triptofano/sangue , Aprendizagem Verbal/efeitos dos fármacos , Percepção Visual/efeitos dos fármacosRESUMO
A growing literature suggests that hormonal fluctuations occurring across the menstrual cycle, during and after pregnancy, and during the menopausal transition are associated with onset of affective disorders or exacerbation of existing disorders. This influence of the neuroendocrine system on psychiatric disorders is thought to be mediated by an abnormality in central nervous system response to neuroactive steroids such as estradiol, progesterone, and the progesterone derivative allopregnanolone (ALLO). This interplay is considerably complex as neuroactive steroids modulate the function of multiple neurotransmitter systems throughout various stages of development. While one could choose to study any number of steroid-neurotransmitter interactions, our group in addition to others has focused our investigative efforts on unraveling the contribution of neuroactive steroids to psychiatric syndromes and disorders via their modulation of gamma aminobutyric acid (GABA), the brain's major inhibitory neurotransmitter. The goal of this article is two-fold: to synthesize the clinical and preclinical research focusing on the interplay between neuroactive steroids and GABA as they relate to neuropsychiatric and substance use disorders in women and to integrate data from our laboratory using proton magnetic resonance spectroscopy into this context.
Assuntos
Transtornos Mentais/fisiopatologia , Neurotransmissores/fisiologia , Esteroides/fisiologia , Ácido gama-Aminobutírico/fisiologia , Afeto/fisiologia , Depressão Pós-Parto/fisiopatologia , Feminino , Humanos , Menstruação/psicologia , Gravidez , Complicações na Gravidez/fisiopatologia , Complicações na Gravidez/psicologia , Síndrome Pré-Menstrual/fisiopatologia , Abandono do Hábito de Fumar , Transtornos Relacionados ao Uso de Substâncias/fisiopatologiaRESUMO
Both the neurotransmitter serotonin and the ovarian steroid estrogen have been implicated in the modulation of mood and cognition. Although significant functional interactions between estrogen and serotonin are acknowledged, the nature of their relationship has not been fully elucidated. Research using ovariectomized animals has identified estrogen-induced changes in serotonin transmission, binding, and metabolism in brain regions implicated in the regulation of affect and cognition. Studies in humans, particularly of menopausal women undergoing estrogen treatment, have provided some support for these findings and identified instances in which change in mood or cognition is accompanied by alterations in serotonin function and hormonal status. However, it is apparent that further research is required to understand the neural processes involved in the interplay between estrogen and serotonin. By reviewing animal and human data regarding estrogen and serotonin's effects on mood and cognition, the authors aim to better define their relationship and highlight areas for further research.
Assuntos
Afeto/fisiologia , Encéfalo/fisiologia , Cognição/fisiologia , Estrogênios/fisiologia , Serotonina/fisiologia , Animais , Feminino , Humanos , MasculinoRESUMO
Neuroticism and extraversion are personality traits associated with negative and positive mood states, respectively, confounding trait and state factors that may affect brain responses to emotional stimuli. The authors dissociated these factors using fMRI and the emotional Stroop attention task: Anterior cingulate (AC) response to positive stimuli varied as a function of personality trait, but not mood state, whereas AC response to negative stimuli varied as a function of mood state, but not personality trait. Negative mood, but not personality trait, also increased the functional connectivity between AC and other regions. Variance in AC activation can thus be ascribed to an intersubject variable (extraversion) when responding to positive stimuli and an intrasubject variable (mood) when responding to negative stimuli. The former may explain stable differences between extraverts and introverts. The latter may provide an adaptive mechanism to expand an individual's dynamic range in response to potentially dangerous or threatening stimuli.
Assuntos
Afeto/fisiologia , Extroversão Psicológica , Giro do Cíngulo/fisiologia , Introversão Psicológica , Personalidade/fisiologia , Adolescente , Adulto , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Estimulação Luminosa/métodosRESUMO
While cognitive changes and mood instability are frequent symptoms reported by menopausal women, the degree to which the decline in estrogen production is responsible is not yet clear. Several lines of evidence suggest that estrogen may produce its effects on cognition and mood through modulation of serotonergic function. To test this hypothesis, we used the tryptophan depletion (TD) paradigm to lower central serotonin levels and pharmacologically manipulated estrogen levels in healthy menopausal women. We examined the individual and combined effects of estradiol and serotonin on working memory, emotion processing and task-related brain activation. Eight healthy predominantly early postmenopausal women underwent TD or sham depletion followed by functional magnetic resonance imaging (fMRI) both before and after short-term transdermal estradiol 75-150 µg/d administration. There was an estradiol treatment by TD interaction for brain activation during performance on both the N-back Task (working memory) and Emotion Identification Task (affective processing). During the 2-back condition, TD attenuated activation prior to, but not after, estradiol treatment in the right and left dorsal lateral prefrontal and middle frontal/cingulate gyrus. During emotion identification, TD heightened activation in the orbital frontal cortex and bilateral amygdala, and this effect was attenuated by estradiol treatment. These results provide preliminary evidence that serotonergic effects directly mediate the impact of estrogen on brain activation during working memory and affective processing.
Assuntos
Afeto/fisiologia , Encéfalo/fisiologia , Estrogênios/fisiologia , Memória de Curto Prazo/fisiologia , Menopausa/fisiologia , Menopausa/psicologia , Serotonina/fisiologia , Administração Cutânea , Administração Oral , Aminoácidos/administração & dosagem , Aminoácidos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Estudos Cross-Over , Método Duplo-Cego , Estradiol/administração & dosagem , Estradiol/sangue , Estradiol/farmacologia , Feminino , Neuroimagem Funcional/métodos , Neuroimagem Funcional/psicologia , Humanos , Imageamento por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/psicologia , Pessoa de Meia-Idade , Desempenho Psicomotor/fisiologia , Serotonina/metabolismo , Triptofano/administração & dosagem , Triptofano/sangue , Triptofano/farmacologiaRESUMO
In a series of exploratory analyses, we examined the roles of gender, reproductive status and negative affect on smoking abstinence in subjects participating in a large (n=385) 6-week randomized clinical trial (RCT) of nicotine patch therapy, with varying doses of oral naltrexone (0mg, 25mg, 50mg, 100mg) treatment. Negative affect was assessed daily during the first post-quit week via telephone interactive voice response (IVR). Weight and adverse events were recorded weekly. In the intent to treat sample, the effects of dose on continuous abstinence were non-significant in the overall model for men and women. In the 295 study completers, there was a significant effect of dose on continuous abstinence in women only (F=8.53, p=0.04). In the 100mg group, 71% of women were continuously abstinent compared to 41% in the placebo group (p<0.05). Women in the active naltrexone groups gained less weight (F=2.91, df=3, p=0.04). Women in the 100mg vs. placebo group were less adherent with medication (F=3.19, p<0.05). These effects were not significant in men. Naltrexone treatment condition (100mg vs. placebo, p=0.02, odds ratio (OR)=0.28), gender (OR=0.55 p=0.09), and IVR ratings of negative affect (OR 1.02, p=0.04) predicted abstinence at Week 1 in study completers. Menstrual cycle status on quit day had a modest affect on abstinence. These data suggest that naltrexone dose, gender, and negative affect play a role in smoking abstinence, particularly in the early stages of treatment. When used in conjunction with nicotine replacement therapy, naltrexone dose may be important in women.
Assuntos
Ciclo Menstrual , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Nicotina/administração & dosagem , Caracteres Sexuais , Abandono do Hábito de Fumar , Administração Cutânea , Adulto , Idoso , Idoso de 80 Anos ou mais , Peso Corporal/efeitos dos fármacos , Feminino , Humanos , Entrevistas como Assunto , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Naltrexona/efeitos adversos , Antagonistas de Entorpecentes/efeitos adversos , Nicotina/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
Despite behavioral evidence that variation in ovarian hormones is associated with changes in affect, the neural basis of these processes is poorly understood. We combined functional magnetic resonance imaging (fMRI) with quantitative analysis of ovarian hormones in a within-subject design to investigate brain activation patterns during affective response inhibition, comparing activation between the early follicular (low estrogen and progesterone) and mid-luteal (high estrogen and progesterone) phases of the menstrual cycle in healthy women. There was significantly increased activation in the anterior cingulate and dorsolateral prefrontal cortex (DLPFC) while inhibiting response to positive words during the luteal, compared to the follicular phase. Furthermore, luteal phase estradiol level positively correlated with DLPFC activation while inhibiting response to positive words and negatively correlated with activation in several structures while inhibiting response to negative words, supporting estrogen's modulation of affective processing.
Assuntos
Encéfalo/fisiologia , Emoções/fisiologia , Estrogênios/sangue , Inibição Psicológica , Neurônios/fisiologia , Adulto , Comportamento/fisiologia , Encéfalo/anatomia & histologia , Mapeamento Encefálico , Feminino , Humanos , Fase Luteal , Imageamento por Ressonância Magnética , Ciclo Menstrual , Pré-Menopausa/fisiologia , Valores de ReferênciaRESUMO
Previous research has investigated the association of personality traits with brain activation in response to emotional stimuli. Our current research efforts are directed at understanding the temporal dynamics of networks of structures associated with particular personality traits, and gain insights into the functional contributions of more narrowly defined trait-facets that comprise these personality traits. To begin this process, we conducted a functional magnetic resonance imaging (fMRI) study using an emotional attention task (emotional Stroop paradigm) and addressed the question whether individual differences in extraversion and its lower-level facets were associated with differences in activation, and in functional connectivity, of the anterior cingulate (AC) cortex. We replicated our earlier finding that extraversion was associated with increased AC activation to positive, relative to neutral, word stimuli, but now show that distinct facets of extraversion can account for this association. When analyzing for functional connectivity, we found that greater extraversion across individuals was associated with greater functional connectivity between the AC and the inferior parietal lobule, and that this association could also be accounted for by distinct facets of extraversion. Our data suggest that extraversion and some of its lower-level facets are associated with individual differences across a network of structures believed to be critical in cognitive and affective processing.
Assuntos
Emoções/fisiologia , Extroversão Psicológica , Giro do Cíngulo/fisiologia , Adolescente , Adulto , Mapeamento Encefálico/métodos , Feminino , Humanos , Masculino , Estimulação Luminosa/métodos , Desempenho Psicomotor/fisiologia , Tempo de Reação/fisiologiaRESUMO
The effect of life stress on depression is moderated by a repeat length variation in the transcriptional control region of the serotonin transporter gene, which renders carriers of the short variant vulnerable for depression. We investigated the underlying neural mechanisms of these epigenetic processes in individuals with no history of psychopathology by using multimodal magnetic resonance-based imaging (functional, perfusion, and structural), genotyping, and self-reported life stress and rumination. Based on functional MRI and perfusion data, we found support for a model by which life stress interacts with the effect of serotonin transporter genotype on amygdala and hippocampal resting activation, two regions involved in depression and stress. Life stress also differentially affected, as a function of serotonin transporter genotype, functional connectivity of the amygdala and hippocampus with a wide network of other regions, as well as gray matter structural features, and affected individuals' level of rumination. These interactions may constitute a neural mechanism for epigenetic vulnerability toward, or protection against, depression.
Assuntos
Encéfalo/fisiologia , Epigênese Genética/genética , Neurônios/fisiologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Estresse Psicológico/fisiopatologia , Adulto , Encéfalo/irrigação sanguínea , Circulação Cerebrovascular , Depressão/genética , Humanos , Masculino , Modelos Neurológicos , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismoRESUMO
Affective neuroscience has seen an explosion of research efforts using modern neuroimaging approaches to uncover the neural basis of emotion and personality. The first section of this paper reviews studies from the domains of affective and forensic neuroimaging. These studies illustrate some of the topics likely to be the subject of future ethical debates. The second section relates limitations of the neuroimaging approach to ethical considerations in predicting future psychopathology on the basis of brain state analysis.