Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 226
Filtrar
1.
Mol Psychiatry ; 28(8): 3524-3530, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37582857

RESUMO

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.


Assuntos
Transtorno Bipolar , Esquizofrenia , Humanos , Transtorno Bipolar/genética , Esquizofrenia/genética , Fatores de Risco , Encéfalo , Consumo de Bebidas Alcoólicas , Estudo de Associação Genômica Ampla , Herança Multifatorial/genética , Predisposição Genética para Doença/genética
2.
Mol Psychiatry ; 23(5): 1320-1327, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28894300

RESUMO

Chronic methamphetamine use poses potentially devastating consequences for directly affected individuals and for society. Lower dopamine D2-type receptor availability has been observed in striata of methamphetamine users as compared with controls, but an analogous comparison of D1-type receptors has been conducted only on post-mortem material, with no differences in methamphetamine users from controls in the caudate nucleus and putamen and higher D1-receptor density in the nucleus accumbens. Released from neurons when methamphetamine is self-administered, dopamine binds to both D1- and D2-type receptors in the striatum, with downstream effects on cortical activity. Thus, both receptor subtypes may contribute to methamphetamine-induced alterations in cortical morphology and behavior. In this study, 21 methamphetamine-dependent subjects and 23 healthy controls participated in positron emission tomography and structural magnetic resonance imaging for assessment of striatal D1- and D2-type receptor availability and cortical gray-matter thickness, respectively. Although D2-type receptor availability (BPnd) was lower in the methamphetamine group, as shown previously, the groups did not differ in D1-type BPnd. In the methamphetamine group, mean cortical gray-matter thickness was negatively associated with cumulative methamphetamine use and craving for the drug. Striatal D1-type but not D2-type BPnd was negatively associated with global mean cortical gray-matter thickness in the methamphetamine group, but no association was found between gray-matter thickness and BPnd for either dopamine receptor subtype in the control group. These results suggest a role of striatal D1-type receptors in cortical adaptation to chronic methamphetamine use.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Corpo Estriado/metabolismo , Receptores de Dopamina D1/metabolismo , Adulto , Estudos de Casos e Controles , Núcleo Caudado/metabolismo , Dopamina/farmacologia , Feminino , Substância Cinzenta/metabolismo , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Metanfetamina/farmacologia , Núcleo Accumbens/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Receptores de Dopamina D2/metabolismo , Adulto Jovem
3.
Sci Data ; 3: 160110, 2016 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-27922632

RESUMO

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.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno Bipolar/fisiopatologia , Cognição/fisiologia , Inibição Psicológica , Memória/fisiologia , Esquizofrenia/fisiopatologia , Adulto , Feminino , Neuroimagem Funcional , Voluntários Saudáveis , Humanos , Disseminação de Informação , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Análise e Desempenho de Tarefas , Adulto Jovem
4.
Adv Pharmacol ; 76: 67-84, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27288074

RESUMO

The nonmedical use of amphetamine-type stimulants is a worldwide problem, with substantial medical and social consequences. Nonetheless, the identification of a pharmacological treatment for amphetamine use disorder remains elusive. Stimulant users exhibit neurochemical evidence of dopamine-system dysfunction as well as impulsive behaviors that may interfere with the success of treatments for their addiction. This review focuses on the potential role of dopaminergic neurotransmission in impulsivity, both in healthy individuals and chronic stimulant users who meet criteria for methamphetamine dependence. Presented are findings related to the potential contributions of signaling through dopamine D1- and D2-type receptors to self-control impulsivity in methamphetamine- dependent users. The information available points to signaling through striatal D2-type dopamine receptors as a potential therapeutic target for stimulant use disorders, but medications that target D2-type dopamine receptors have not been successful in treating stimulant-use disorders, possibly because D2-type receptors are downregulated. Other means to augment D2-type receptor signaling are therefore under consideration, and one promising approach is the addition of exercise training as an adjunct to behavioral treatment for addiction.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Comportamento Impulsivo/efeitos dos fármacos , Metanfetamina/efeitos adversos , Estimulantes do Sistema Nervoso Central , Corpo Estriado/metabolismo , Dopamina/metabolismo , Humanos , Receptores de Dopamina D2/metabolismo , Transmissão Sináptica
5.
Mol Psychiatry ; 21(11): 1554-1560, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26830141

RESUMO

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.


Assuntos
Comportamento Impulsivo/efeitos dos fármacos , Mesencéfalo/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Estimulantes do Sistema Nervoso Central , Dopamina/metabolismo , Feminino , Humanos , Comportamento Impulsivo/fisiologia , Imageamento por Ressonância Magnética , Masculino , Metanfetamina/efeitos adversos , Metanfetamina/metabolismo , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Córtex Pré-Frontal/metabolismo , Receptores de Dopamina D2/fisiologia , Estriado Ventral/efeitos dos fármacos , Estriado Ventral/fisiopatologia
6.
Mol Psychiatry ; 21(2): 229-36, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25600111

RESUMO

Adding supraphysiologic doses of levothyroxine (L-T4) to standard treatment for bipolar depression shows promise, but the mechanisms underlying clinical improvement are unknown. In a previous pilot study, L-T4 treatment reduced depression scores and activity within the anterior limbic network. Here we extended this work in a randomized, double-blind, placebo-controlled study of patients with bipolar depression. Cerebral glucose metabolism was assessed with positron emission tomography and [F-18]fluorodeoxyglucose before and after 6 weeks of treatment with L-T4 (n=15) or placebo (n=10) in 12 volumes of interest (VOIs): the bilateral thalamus, amygdala, hippocampus, dorsal striatum and ventral striatum, and midline cerebellar vermis and subgenual cingulate cortex. Radioactivity in the VOIs, normalized to whole-brain radioactivity was taken as a surrogate index of glucose metabolism, and markers of thyroid function were assayed. Changes in brain activity and their association with clinical response were assessed using statistical parametric mapping. Adjunctive L-T4 treatment produced a significant decline in depression scores during the 6-week treatment. In patients treated with L-T4, we found a significant decrease in regional activity at P<0.05 after Bonferroni correction in the left thalamus, right amygdala, right hippocampus, left ventral striatum and the right dorsal striatum. Decreases in the left thalamus, left dorsal striatum and the subgenual cingulate were correlated with a reduction in depression scores (P<0.05 after Bonferroni correction). Placebo treatment was associated with a significant decrease in activity only in the right amygdala, and no region had a change in activity that was correlated with change in depression scores. The groups differed significantly in the relationship between the changes in depression scores and in activity in the thalamus bilaterally and the left ventral striatum. The findings provide evidence that administration of supraphysiologic thyroid hormone improves depressive symptoms in patients with bipolar disorder by modulating function in components of the anterior limbic network.


Assuntos
Transtorno Bipolar/metabolismo , Tiroxina/efeitos dos fármacos , Tiroxina/metabolismo , Adulto , Tonsila do Cerebelo/metabolismo , Transtorno Bipolar/tratamento farmacológico , Encéfalo/metabolismo , Mapeamento Encefálico , Depressão/complicações , Método Duplo-Cego , Feminino , Glucose/metabolismo , Giro do Cíngulo/metabolismo , Humanos , Sistema Límbico/metabolismo , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Placebos , Tomografia por Emissão de Pósitrons/métodos , Córtex Pré-Frontal/metabolismo , Escalas de Graduação Psiquiátrica , Resultado do Tratamento
8.
Mol Psychiatry ; 20(6): 764-71, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25896164

RESUMO

Dysfunction of the mesocorticolimbic system has a critical role in clinical features of addiction. Despite evidence suggesting that midbrain dopamine receptors influence amphetamine-induced dopamine release and that dopamine is involved in methamphetamine-induced neurotoxicity, associations between dopamine receptors and gray-matter volume have been unexplored in methamphetamine users. Here we used magnetic resonance imaging and [(18)F]fallypride positron emission tomography, respectively, to measure gray-matter volume (in 58 methamphetamine users) and dopamine D2/D3 receptor availability (binding potential relative to nondisplaceable uptake of the radiotracer, BPnd) (in 31 methamphetamine users and 37 control participants). Relationships between these measures and self-reported drug craving were examined. Although no difference in midbrain D2/D3 BPnd was detected between methamphetamine and control groups, midbrain D2/D3 BPnd was positively correlated with gray-matter volume in the striatum, prefrontal cortex, insula, hippocampus and temporal cortex in methamphetamine users, but not in control participants (group-by-midbrain D2/D3 BPnd interaction, P<0.05 corrected for multiple comparisons). Craving for methamphetamine was negatively associated with gray-matter volume in the insula, prefrontal cortex, amygdala, temporal cortex, occipital cortex, cerebellum and thalamus (P<0.05 corrected for multiple comparisons). A relationship between midbrain D2/D3 BPnd and methamphetamine craving was not detected. Lower midbrain D2/D3 BPnd may increase vulnerability to deficits in gray-matter volume in mesocorticolimbic circuitry in methamphetamine users, possibly reflecting greater dopamine-induced toxicity. Identifying factors that influence prefrontal and limbic volume, such as midbrain BPnd, may be important for understanding the basis of drug craving, a key factor in the maintenance of substance-use disorders.


Assuntos
Comportamento de Procura de Droga/fisiologia , Substância Cinzenta/patologia , Mesencéfalo/patologia , Metanfetamina , Receptores de Dopamina D2/metabolismo , Transtornos Relacionados ao Uso de Substâncias , Benzamidas/farmacocinética , Antagonistas de Dopamina/farmacocinética , Feminino , Fluordesoxiglucose F18/farmacocinética , Substância Cinzenta/efeitos dos fármacos , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Mesencéfalo/diagnóstico por imagem , Mesencéfalo/efeitos dos fármacos , Metanfetamina/farmacologia , Tomografia por Emissão de Pósitrons , Ligação Proteica/efeitos dos fármacos , Análise de Regressão , Transtornos Relacionados ao Uso de Substâncias/patologia , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Fatores de Tempo
9.
Brain Behav Immun ; 37: 73-7, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24365060

RESUMO

BACKGROUND: Hypothyroidism induced by an autoimmune process is associated with neuropsychiatric symptoms and metabolic abnormalities in the brain. The aim of this study was to examine the relationship between autoimmune thyroiditis and regional brain function in hypothyroid patients. METHODS: Cerebral glucose metabolism, as an index of brain function, was assessed in regional whole-brain analyses using positron emission tomography (PET) and [18F]fluorodeoxyglucose in thirteen hypothyroid patients with autoimmune thyroiditis suffering from neuropsychiatric symptoms. The primary biological measures were radioactivity in pre-selected brain regions, relative to whole-brain radioactivity, as a surrogate index of glucose metabolism, and serum levels of thyroglobulin (TG) and thyroid peroxidase (TPO) antibodies as endocrine markers of autoimmune thyroiditis. RESULTS: Serum levels of anti-TG antibodies in hypothyroid patients were significantly correlated with glucose metabolism in the perigenual anterior cingulate cortex, a brain region previously shown to regulate affect and emotional homeostasis. CONCLUSION: Thyroid autoimmune processes may play an important role in the still poorly defined pathogenic correlates of disturbed function in brain regions critically involved in emotional processing in hypothyroid conditions.


Assuntos
Anticorpos/sangue , Encéfalo/metabolismo , Giro do Cíngulo/imunologia , Giro do Cíngulo/metabolismo , Tireoidite Autoimune/imunologia , Tireoidite Autoimune/metabolismo , Adulto , Encéfalo/diagnóstico por imagem , Feminino , Fluordesoxiglucose F18 , Giro do Cíngulo/diagnóstico por imagem , Humanos , Hipotireoidismo/complicações , Hipotireoidismo/diagnóstico por imagem , Hipotireoidismo/metabolismo , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Tireoidite Autoimune/complicações , Tireoidite Autoimune/diagnóstico por imagem
10.
Transl Psychiatry ; 2: e80, 2012 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-22832817

RESUMO

Individuals who abuse methamphetamine (MA) exhibit heightened aggression, but the neurobiological underpinnings are poorly understood. As variability in the serotonin transporter (SERT) gene can influence aggression, this study assessed possible contributions of this gene to MA-related aggression. In all, 53 MA-dependent and 47 control participants provided self-reports of aggression, and underwent functional magnetic resonance imaging while viewing pictures of faces. Participants were genotyped at two functional polymorphic loci in the SERT gene: the SERT-linked polymorphic region (SERT-LPR) and the intron 2 variable number tandem repeat polymorphism (STin2 VNTR); participants were then classified as having high or low risk for aggression according to individual SERT risk allele combinations. Comparison of SERT risk allele loads between groups showed no difference between MA-dependent and control participants. Comparison of self-report scores showed greater aggression in MA-dependent than control participants, and in high genetic risk than low-risk participants. Signal change in the amygdala was lower in high genetic risk than low-risk participants, but showed no main effect of MA abuse; however, signal change correlated negatively with MA use measures. Whole-brain differences in activation were observed between MA-dependent and control groups in the occipital and prefrontal cortex, and between genetic high- and low-risk groups in the occipital, fusiform, supramarginal and prefrontal cortex, with effects overlapping in a small region in the right ventrolateral prefrontal cortex. The findings suggest that the investigated SERT risk allele loads are comparable between MA-dependent and healthy individuals, and that MA and genetic risk influence aggression independently, with minimal overlap in associated neural substrates.


Assuntos
Agressão/fisiologia , Alelos , Transtornos Relacionados ao Uso de Anfetaminas/genética , Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Encéfalo/fisiopatologia , Estimulantes do Sistema Nervoso Central , Emoções/fisiologia , Predisposição Genética para Doença/genética , Variação Genética/genética , Genótipo , Metanfetamina , Rede Nervosa/fisiopatologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/psicologia , Tonsila do Cerebelo/fisiopatologia , Mapeamento Encefálico , Estimulantes do Sistema Nervoso Central/efeitos adversos , Expressão Facial , Feminino , Lobo Frontal/fisiopatologia , Humanos , Íntrons/genética , Imageamento por Ressonância Magnética , Masculino , Metanfetamina/efeitos adversos , Pessoa de Meia-Idade , Repetições Minissatélites/genética , Lobo Occipital/fisiopatologia , Reconhecimento Visual de Modelos/fisiologia , Córtex Pré-Frontal/fisiopatologia , Síndrome de Abstinência a Substâncias/genética , Síndrome de Abstinência a Substâncias/fisiopatologia , Inquéritos e Questionários
14.
J Clin Endocrinol Metab ; 94(8): 2922-9, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19435829

RESUMO

CONTEXT: Hypothyroidism is frequently associated with subtle behavioral and psychiatric symptoms. The consequences of inadequate thyroid hormone availability to brain metabolism are poorly understood. OBJECTIVE: This study assessed the relationships between neuropsychiatric symptoms and changes in relative regional cerebral glucose metabolism in hypothyroid patients undergoing thyroid hormone replacement therapy. DESIGN, SETTING, AND OUTCOME MEASURE: Relative regional cerebral glucose metabolism was compared in 13 previously untreated hypothyroid patients and 10 healthy control participants. Effects of thyroid hormone replacement therapy (levothyroxine, 3 months) were assessed using neuropsychiatric measures and positron emission tomography with [(18)F]fluorodeoxyglucose. RESULTS: Before treatment, hypothyroid patients exhibited lower regional activity than control subjects in the bilateral amygdala, hippocampus, and perigenual anterior cingulate cortex (ACC), left subgenual ACC, and right posterior cingulate cortex. Severity of depressive symptoms covaried negatively with pretreatment activity in the bilateral middle frontal gyrus and right subgenual and dorsal ACC. Thyroid hormone replacement therapy abolished pretreatment group differences in regional activity, robustly increased activity in the ventral ACC, and significantly reduced both clinician-rated and self-rated behavioral and psychiatric symptoms. Increased activity within the ventral ACC was associated with reduced somatic complaints, whereas increased activity within the dorsal ACC was associated with reduced depressive symptoms. CONCLUSIONS: Reduction of the behavioral complaints during thyroid hormone therapy is associated with a restoration of metabolic activity in brain areas that are integral to the regulation of affect and cognition. The findings suggest that thyroid hormone modulates regional glucose metabolism and psychiatric symptoms in the mature brain.


Assuntos
Encéfalo/metabolismo , Glucose/metabolismo , Terapia de Reposição Hormonal , Hipotireoidismo/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Hormônios Tireóideos/uso terapêutico , Adulto , Idoso , Feminino , Giro do Cíngulo/fisiologia , Humanos , Hipotireoidismo/diagnóstico por imagem , Hipotireoidismo/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Tireotropina/sangue , Tiroxina/sangue , Tomografia Computadorizada de Emissão de Fóton Único
15.
Neuroscience ; 164(1): 30-42, 2009 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-19344640

RESUMO

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.


Assuntos
Técnicas Genéticas , Genoma , Fenótipo , Animais , Pesquisa Biomédica/métodos , Humanos , Transtornos Mentais/genética , Modelos Genéticos
16.
Mol Psychiatry ; 14(2): 197-205, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18180761

RESUMO

Brief intensive cognitive-behavioral therapy (CBT) using exposure and response prevention significantly improves obsessive-compulsive disorder (OCD) symptoms in as little as 4 weeks. However, it has been thought that much longer treatment was needed to produce the changes in brain function seen in neuroimaging studies of OCD. We sought to elucidate the brain mediation of response to brief intensive CBT for OCD and determine whether this treatment could induce functional brain changes previously seen after longer trials of pharmacotherapy or standard CBT. [(18)F]-fluorodeoxyglucose positron emission tomography brain scans were obtained on 10 OCD patients before and after 4 weeks of intensive individual CBT. Twelve normal controls were scanned twice, several weeks apart, without treatment. Regional glucose metabolic changes were compared between groups. OCD symptoms, depression, anxiety and overall functioning improved robustly with treatment. Significant changes in normalized regional glucose metabolism were seen after brief intensive CBT (P=0.04). Compared to controls, OCD patients showed significant bilateral decreases in normalized thalamic metabolism with intensive CBT but had a significant increase in right dorsal anterior cingulate cortex activity that correlated strongly with the degree of improvement in OCD symptoms (P=0.02). The rapid response of OCD to intensive CBT is mediated by a distinct pattern of changes in regional brain function. Reduction of thalamic activity may be a final common pathway for improvement in OCD, but response to intensive CBT may require activation of dorsal anterior cingulate cortex, a region involved in reappraisal and suppression of negative emotions.


Assuntos
Encéfalo/metabolismo , Terapia Cognitivo-Comportamental/métodos , Glucose/metabolismo , Transtorno Obsessivo-Compulsivo/patologia , Transtorno Obsessivo-Compulsivo/terapia , Adulto , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Feminino , Fluordesoxiglucose F18/metabolismo , Lateralidade Funcional , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Adulto Jovem
17.
Mol Psychiatry ; 14(2): 123-42, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18698321

RESUMO

Amphetamine stimulants have been used medically since early in the twentieth century, but they have a high abuse potential and can be neurotoxic. Although they have long been used effectively to treat attention deficit hyperactivity disorder (ADHD) in children and adolescents, amphetamines are now being prescribed increasingly as maintenance therapy for ADHD and narcolepsy in adults, considerably extending the period of potential exposure. Effects of prolonged stimulant treatment have not been fully explored, and understanding such effects is a research priority. Because the pharmacokinetics of amphetamines differ between children and adults, reevaluation of the potential for adverse effects of chronic treatment of adults is essential. Despite information on the effects of stimulants in laboratory animals, profound species differences in susceptibility to stimulant-induced neurotoxicity underscore the need for systematic studies of prolonged human exposure. Early amphetamine treatment has been linked to slowing in height and weight growth in some children. Because the number of prescriptions for amphetamines has increased several fold over the past decade, an amphetamine-containing formulation is the most commonly prescribed stimulant in North America, and it is noteworthy that amphetamines are also the most abused prescription medications. Although early treatment does not increase risk for substance abuse, few studies have tracked the compliance and usage profiles of individuals who began amphetamine treatment as adults. Overall, there is concern about risk for slowed growth in young patients who are dosed continuously, and for substance abuse in patients first medicated in late adolescence or adulthood. Although most adult patients also use amphetamines effectively and safely, occasional case reports indicate that prescription use can produce marked psychological adverse events, including stimulant-induced psychosis. Assessments of central toxicity and adverse psychological effects during late adulthood and senescence of adults who receive prolonged courses of amphetamine treatment are warranted. Finally, identification of the biological factors that confer risk and those that offer protection is also needed to better specify the parameters of safe, long-term, therapeutic administration of amphetamines to adults.


Assuntos
Anfetamina/efeitos adversos , Comportamento/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/efeitos adversos , Síndromes Neurotóxicas/etiologia , Transtornos Relacionados ao Uso de Substâncias/etiologia , Anfetamina/história , Animais , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/história , Prescrições de Medicamentos/estatística & dados numéricos , História do Século XX , História do Século XXI , Humanos , Narcolepsia/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/classificação
18.
Mol Psychiatry ; 13(9): 897-908, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17938635

RESUMO

Changes in brain function during the initial weeks of abstinence from chronic methamphetamine abuse may substantially affect clinical outcome, but are not well understood. We used positron emission tomography with [F-18]fluorodeoxyglucose (FDG) to quantify regional cerebral glucose metabolism, an index of brain function, during performance of a vigilance task. A total of 10 methamphetamine-dependent subjects were tested after 5-9 days of abstinence, and after 4 additional weeks of supervised abstinence. A total of 12 healthy control subjects were tested at corresponding times. Global glucose metabolism increased between tests (P=0.01), more in methamphetamine-dependent (10.9%, P=0.02) than control subjects (1.9%, NS). Glucose metabolism did not change in subcortical regions of methamphetamine-dependent subjects, but increased in neocortex, with maximal increase (>20%) in parietal regions. Changes in reaction time and self-reports of negative affect varied more in methamphetamine-dependent than in control subjects, and correlated both with the increase in parietal glucose metabolism, and decrease in relative activity (after scaling to the global mean) in some regions. A robust relationship between change in self-reports of depressive symptoms and relative activity in the ventral striatum may have great relevance to treatment success because of the role of this region in drug abuse-related behaviors. Shifts in cortical-subcortical metabolic balance either reflect new processes that occur during early abstinence, or the unmasking of effects of chronic methamphetamine abuse that are obscured by suppression of cortical glucose metabolism that continues for at least 5-9 days after cessation of methamphetamine self-administration.


Assuntos
Córtex Cerebral/metabolismo , Glucose/metabolismo , Metanfetamina/efeitos adversos , Síndrome de Abstinência a Substâncias/metabolismo , Estimulação Acústica/métodos , Adulto , Atenção/fisiologia , Mapeamento Encefálico , Estudos de Casos e Controles , Córtex Cerebral/diagnóstico por imagem , Depressão/etiologia , Feminino , Fluordesoxiglucose F18/metabolismo , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética/métodos , Masculino , Tomografia por Emissão de Pósitrons/métodos , Tempo de Reação/fisiologia , Síndrome de Abstinência a Substâncias/complicações , Síndrome de Abstinência a Substâncias/diagnóstico por imagem , Síndrome de Abstinência a Substâncias/patologia , Análise e Desempenho de Tarefas
19.
Acta Psychiatr Scand ; 112(2): 149-58, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15992397

RESUMO

OBJECTIVE: Methadone Maintenance Therapy (MMT) and detoxification to abstinence are among the most common treatment options for opiate-dependent patients. This paper compares personality traits in detoxified former heroin users and those on MMT in order to assess their relevance to treatment selection. METHOD: Twenty-six formerly heroin-dependent subjects receiving MMT (MM), 33 formerly heroin-dependent subjects withdrawn from MMT (MW), and 43 healthy controls were compared on the Millon Clinical Multiaxial Inventory-II (MCMI-II) and the Temperament and Character Inventory (TCI). RESULTS: On the TCI, MM patients had higher novelty seeking and lower self-directedness scores than controls. Both MM and MW subjects scored higher than controls on multiple MCMI-II scales. MW but not MM subjects scored higher than controls on two Cluster A Scales and the delusional disorder scale. CONCLUSION: Schizophrenia-spectrum pathology in former opiate users may be greater than previously recognized and could potentially be relevant to treatment selection.


Assuntos
Analgésicos Opioides/uso terapêutico , Dependência de Heroína/psicologia , Dependência de Heroína/reabilitação , Metadona/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/reabilitação , Inventário de Personalidade/estatística & dados numéricos , Suspensão de Tratamento/estatística & dados numéricos , Adulto , Análise de Variância , Comportamento/fisiologia , Feminino , Humanos , Masculino , Transtornos Relacionados ao Uso de Opioides/psicologia , Transtornos da Personalidade/diagnóstico , Valores de Referência , Fatores de Tempo
20.
Mol Psychiatry ; 10(5): 456-69, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15724143

RESUMO

Supplementation of standard treatment with high-dose levothyroxine (L-T(4)) is a novel approach for treatment-refractory bipolar disorders. This study tested for effects on brain function associated with mood alterations in bipolar depressed patients receiving high-dose L-T(4) treatment adjunctive to ongoing medication (antidepressants and mood stabilizers). Regional activity and whole-brain analyses were assessed with positron emission tomography and [(18)F]fluorodeoxyglucose in 10 euthyroid depressed women with bipolar disorder, before and after 7 weeks of open-label adjunctive treatment with supraphysiological doses of L-T(4) (mean dose 320 microg/day). Corresponding measurements were acquired in an age-matched comparison group of 10 healthy women without L-T(4) treatment. The primary biological measures were relative regional activity (with relative brain radioactivity taken as a surrogate index of glucose metabolism) in preselected brain regions and neuroendocrine markers of thyroid function. Treatment-associated changes in regional activity (relative to global activity) were tested against clinical response. Before L-T(4) treatment, the patients exhibited significantly higher activity in the right subgenual cingulate cortex, left thalamus, medial temporal lobe (right amygdala, right hippocampus), right ventral striatum, and cerebellar vermis; and had lower relative activity in the middle frontal gyri bilaterally. Significant behavioral and cerebral metabolic effects accompanied changes in thyroid hormone status. L-T(4) improved mood (remission in seven patients; partial response in three); and decreased relative activity in the right subgenual cingulate cortex, left thalamus, right amygdala, right hippocampus, right dorsal and ventral striatum, and cerebellar vermis. The decrease in relative activity of the left thalamus, left amygdala, left hippocampus, and left ventral striatum was significantly correlated with reduction in depression scores. Results of the whole-brain analyses were generally consistent with the volume of interest results. We conclude that bipolar depressed patients have abnormal function in prefrontal and limbic brain areas. L-T(4) may improve mood by affecting circuits involving these areas, which have been previously implicated in affective disorders.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/metabolismo , Lobo Frontal/metabolismo , Sistema Límbico/metabolismo , Tiroxina/administração & dosagem , Tiroxina/metabolismo , Adulto , Afeto/efeitos dos fármacos , Antidepressivos/metabolismo , Antidepressivos/uso terapêutico , Transtorno Bipolar/diagnóstico por imagem , Mapeamento Encefálico , Esquema de Medicação , Quimioterapia Combinada , Feminino , Fluordesoxiglucose F18/metabolismo , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/efeitos dos fármacos , Humanos , Sistema Límbico/diagnóstico por imagem , Sistema Límbico/efeitos dos fármacos , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Psicotrópicos/administração & dosagem , Valores de Referência , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA