Submitted by Geandra Rodrigues (geandrar@gmail.com) on 2018-04-19T13:29:11Z No. of bitstreams: 1 andreluciopintocoelhostroppa.pdf: 19317921 bytes, checksum: f8efcd9a0d197ed526f74c9541ac1634 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2018-04-19T13:55:45Z (GMT) No. of bitstreams: 1 andreluciopintocoelhostroppa.pdf: 19317921 bytes, checksum: f8efcd9a0d197ed526f74c9541ac1634 (MD5) / Made available in DSpace on 2018-04-19T13:55:45Z (GMT). No. of bitstreams: 1 andreluciopintocoelhostroppa.pdf: 19317921 bytes, checksum: f8efcd9a0d197ed526f74c9541ac1634 (MD5) Previous issue date: 2018-02-08 / Contexto: Apesar do grande número de estudos encontrados na literatura sobre as relações entre religiosidade/espiritualidade e depressão, outros transtornos mentais e doenças físicas, há uma carência de pesquisas acerca do impacto da religiosidade/espiritualidade em pacientes bipolares, notadamente de estudos longitudinais. Objetivos: Investigar as possíveis relações entre diversas dimensões de religiosidade/espiritualidade sobre sintomas de depressão, mania e qualidade de vida em um estudo longitudinal de 24 meses. Métodos: Estudo observacional longitudinal de dois anos acrescido de aspectos qualitativos, com 168 pacientes bipolares ambulatoriais, avaliando dados sócio demográficos, sintomas de mania (Young Mania Rating Scale), depressão (Montgomery–Asberg Depression Rating Scale), religiosidade (Duke Religious Index), coping religioso (Brief RCOPE) e qualidade de vida (World Health Organization Quality of Life–Brief Version). Análises de regressão linear da associação entre indicadores religiosos e variáveis clínicas foram controladas por variáveis sociodemográficas. Resultados: Entre os 158 pacientes reavaliados após dois anos, Coping Religioso Positivo em T1 predisse melhor qualidade de vida em todos os seus quatro domínios: físico (β 10,2; 95%CI; 4,2–16,1), mental (β 13,4; 95%CI; 7,1–19,7), social (β 10,5; 95%CI, 3,6–17,33) e ambiental (β 11,1; 95%CI; 6,2–16,1) em T2, dois anos depois. Coping Religioso Negativo em T1 predisse pior saúde mental (β -28,1; 95%CI; -52,06– -4,2) e ambiental (β -20,4; 95%CI; -39,3– -1,6) em qualidade de vida. Religiosidade Intrínseca em T1 predisse melhor qualidade de vida ambiental (β 9,56; 95%CI; 2,76–16,36) em T2. Coping Religioso Negativo em T1 predisse sintomas maníacos (β 4.1) em T2. Na investigação qualitativa, 88,2% dos sujeitos relataram que sua fé ajudou a lidar com sua doença e o apoio de sua comunidade religiosa em relação ao tratamento foi apontado por 35,3%. Não houve relato de oposição de líderes religiosos ao tratamento. Limitações: Este é um estudo observacional, inferências causais devem ser feitas com cautela. Conclusão: religiosidade/espiritualidade pode influenciar a qualidade de vida de pacientes com transtorno bipolar, mesmo quando em eutimia. Usar religiosidade/espiritualidade (especialmente coping religioso positivo e negativo) em intervenções psicossociais podem contribuir para melhorar a qualidade de vida de pacientes com transtorno bipolar. / Background: Although several studies have examined the relationship between religiosity/spirituality and depression, there is little research examining the effect of religious involvement on the course of bipolar disorder. This study investigated the effects of religious activity and coping behaviors on the course of depression, mania and quality of life in patients with bipolar disorder. Methods: Two-year longitudinal study of 168 outpatients with bipolar disorder. Linear regression was used to examine associations between religious predictors and outcome variables (manic symptoms, depression, and quality of life), controlling for sociodemographic variables. Results: Among the 158 patients reassessed after two years, positive religious coping at T1 (baseline) predicted better quality of life across all four domains: physical (β 10.2, 95%CI, 4.2 - 16.1), mental (β 13.4; 95%CI; 7.1–19.7), social (β 10.5; 95%CI; 3.6–17.33) and environmental (β 11.1; 95%CI; 6.2–16.1) at T2 (2-years later). Negative religious coping at T1 predicted worse mental (β -28.1; 95%CI; -52.06– -4.2) and environmental (β -20.4; 95%CI; -39.3– -1.6) quality of life. Intrinsic religiosity at T1 predicted better environmental quality of life (β 9.56; 95%CI; 2.76–16.36) at T2. Negative religious coping at T1 predicted manic symptoms (β 4.1) at T2. In the qualitative research, 88.2% of the subjects reported that their faith helped to cope with their illness and the support of their religious community regarding the treatment was pointed out by 35.3%, there was no report of opposition of religious leaders to the treatment. Limitations: This is an observational study, causal inferences must be made cautiously. Conclusions: religiosity/spirituality may influence the quality of life of patients with bipolar disorder over time, even among euthymic patients. Targeting religiosity/spirituality (especially positive and negative religious coping) in psychosocial interventions may enhance the quality of recovery in patients with bipolar disorder.

Le Corps Calleux (CC), principale commissure reliant les deux hémisphères cérébraux, est d'une importance cruciale dans l'intégration des informations interhémisphériques et des fonctions cognitives supérieures. Les modifications du CC pourraient contribuer à des anomalies de connectivité susceptibles d'expliquer les dysfonctionnements des régions cérébrales impliquées dans la physiopathologie de certaines maladies psychiatriques.Toutefois notre connaissance du rôle du CC dans les troubles de l’humeur et les conduites suicidaires est encore très limitée. Nous n'avons que peu d’informations sur l’implication exacte du CC en psychopathologie et sur les facteurs pouvant altérer son intégrité. L’objectif de cette thèse était de mieux préciser les relations existant entre altération du CC, troubles de l’humeur et conduites suicidaires Nous avons montré un lien entre l’atrophie du CC et la survenue de dépression sur une période de 10 ans parmi 467 sujets sains âgés de 65 à 80 ans grâce aux IRM morphologiques de l’étude en population générale Esprit. Dans une étude clinique menée chez 121 femmes plus jeunes (18-50 ans), Nous avons mis en évidence grâce à une technique d’imagerie par tenseur de diffusion (DTI) une altération des parties antérieures du CC chez les femmes bipolaires, tandis que le splénium, la partie postérieure du CC, est atteinte uniquement chez les suicidantes. Nous soulignons également que l’altération du splénium est associée au nombre de tentatives de suicides et au score d’intentionnalité du geste suicidaire. Par ailleurs, Nous avons montré une association de type linéaire entre le niveau d’un marqueur de l’inflammation (CRP) et la réduction de la taille des portions antérieures du CC au sein de la population âgée de l’étude Esprit.Nos travaux suggèrent donc une altération de l’intégrité du CC dans les troubles de l’humeur et les comportements suicidaires à des âges différents de la vie, en population générale et en population clinique. Les études futures devraient permettre de préciser les conséquences des anomalies de communication interhémisphérique mises en évidence dans ces pathologies. / Corpus Callosum (CC), the main commissure connecting the two cerebral hemispheres, is of crucial importance in the integration of interhemispheric information and higher cognitive functions. CC alterations might contribute to abnormal interhemispheric connectivity that may underlie functional abnormalities of brain regions involved in the pathophysiology of psychiatric disorders. However, our understanding of the role of the CC in mood disorders and suicidal behaviour is still very limited. We have little information about the exact involvement of the CC in psychopathology and the factors that could affect its integrity. The objective of this thesis was to further clarify the relationship between alterations of the CC, mood disorders and suicidal behaviour.We have found an association between CC atrophy and incident depression over a 10-year follow-up period among 467 healthy subjects aged 65 to 80 years using the morphological MRI data from the epidemiological study Esprit. In a clinical study of 121 younger women (18-50 years), we have used a diffusion tensor imaging (DTI) technique to show an alteration of the anterior parts of the CC in bipolar women, while the splenium, the posterior part of the CC, is altered only in suicidal women. We have also emphasized that the alteration of splenium is associated with the number of suicide attempts and suicidal intentionality scale score. Furthermore, we showed a linear association between the level of a marker of inflammation (CRP) and a reduced size of the anterior parts of the CC within the population of the Esprit study. Our work therefore suggests impaired integrity of the CC in mood disorders and suicidal behaviours at different stages of life, in general population and in clinical population. Future studies should aim to clarify the consequences of interhemispheric communication anomalies identified in these pathologies.

Lithium is a drug used to treat mood disorders and also has many side effects, including central nervous system (CNS) complications (such as cognitive dulling), associated with its use. The mechanism of its action still remains unknown. Over the years, many leads have started emerging. It has been shown to inhibit several enzymes in the cell and has been implicated in altering many neurotransmitter systems and signal transduction pathways (serotonin, dopamine and norepinephrine neurotransmissions). Effect of exposure to therapeutic levels of lithium on mature glutamatergic synapses is being studied and several changes in glutamate receptor subtypes have already been reported. Effects of lithium on developing glutamatergic synapses have not been studied. The thesis tries to document and understand the changes brought about by long term lithium treatment on developing glutamatergic synapses in vitro in hippocampal neuronal cultures. In the present work, patch clamp technique was used to monitor the changes in the postsynapse and fluorescence imaging to study the presynaptic changes. The hippocampal neuronal cultures were treated with 1 mM lithium for 6 days during the synaptogenesis stage (DIV 4-10) and termed as chronic Li treatment (CLi). Following CLi treatment the changes occurring in amplitude and rectification property of the AMPA receptor (AMPAR), a subtype of glutamate ionotropic receptor, mediated miniature excitatory postsynaptic currents (mEPSCs) have been reported (Chapter III). Lithium inhibits protein kinase A (PKA), glycogen synthase kinase–3β (GSK-3β) and glutamate reuptake. Effect of inhibiting PKA, GSK-3β and glutamate reuptake was also studied with a view to understand the molecular basis of lithium action on AMPAR mEPSCs (Chapter IV). It was found that chronic lithium treatment (CLi) caused a reduction in the mean amplitude of mEPSCs mediated by AMPARs and also changed the rectification property of these receptors from being more outwardly rectifying to being more inwardly rectifying, an indication probably of increase in contribution of Ca2+-permeable AMPARs to the synaptic events. AMPAR events in chronic lithium treated cultures were more sensitive to both N-acetyl spermine (NASPM) application and di-fluoro-methyl-ornithine (DFMO) treatment, both specific to Ca2+-permeable AMPARs, indicating that there was an increase in the contribution from Ca2+-permeable AMPARs to the synaptic events. PKA inhibition with H-89 treatment (starting from DIV 4 (for 6 days)) reduced the mean amplitude of AMPAR mEPSCs and increased the mean rectification index (RI). GSK-3β inhibition with SB415286 (starting from DIV 4 (for 6 days)) did not alter the mean mEPSC amplitude but reduced the mean RI. Transient (24 hrs) glutamate reuptake inhibition with threo-β-Hydroxy-Aspartic-Acid (THA) at DIV 4 followed by a period of recovery led to smaller amplitudes but no change in RI. The 24 hr glutamate reuptake block on DIV 4 had long term effects. It led to an increase in AMPAR mEPSC frequency while AMPAR mEPSC amplitudes were reduced. The mean RI decrease seen when glutamate reuptake was blocked for 24 hrs on DIV 10, was absent in DIV 4 THA treated neurons. However, when the neuronal cultures were maintained in the presence of PKA and GSK-3β inhibitors, the DIV 4 THA treated neurons showed AMPAR mEPSC characteristics similar to CLi neurons. Thus, it was seen that individual inhibition of PKA, GSK-3β and glutamate reuptake did not lead to changes in AMPAR mEPSCs similar to that seen in lithium treated neurons. The effect of lithium exposure during synapse development on AMPARs could be reproduced closely by co-inhibiting PKA, GSK-3β and glutamate reuptake. Using the styryl dye FM1-43, the changes induced in presynaptic release by a similar chronic lithium treatment was studied (Chapter V). It was found that lithium exposure (1 mM, DIV 4-10) brought down the extent of dye loading, destaining and also slowed down the rate of dye loss in response to high KCl stimulation (the τfast component of destaining was significantly slower). Minimum loading experiments did not reveal any difference in mode of exocytosis (kiss and run/full-collapse) in control and lithium treated cultures. Chlorpromazine treatment (that inhibits clathrin-mediated endocytosis) affected dye loading to a lesser extent in lithium treated cultures as compared to control. Surprisingly, exposure to hyperosmotic solution 10 minutes after dye wash out boosted the extent of dye loading and destaining in lithium treated cultures (a phenomenon not seen in control). This could happen if the FM1-43 is trapped away from the wash solution during the wash period. This would be possible if endocytosis in CLi takes place, differently from control, through a process involving membrane infoldings similar to bulk endocytosis albeit a slower/compromised one. Taken together, the data presented here indicates that lithium treatment during synaptogenesis affects vesicular recycling mostly at the endocytosis and docking/priming steps (mobilization of vesicles for release). Lithium treated cultures also did not show the high KCl associated presynaptic potentiation observed in control which is a significant finding. In conclusion, chronic lithium treatment affected both the presynaptic and postsynaptic compartments of the glutamatergic synapse. The effect of lithium on AMPAR mEPSC could not be reproduced by individual inhibitions of biochemical effectors but by multiple inhibitions. Thus, the study done here underscores the need to look at the manifold effect of lithium in an integrated way. The study also might have implications in understanding the CNS complications seen in patients taking lithium treatment and in babies perinatally exposed to lithium.

Environ 300 millions de personnes dans le monde souffrent de dépression et environ 30% vont développer une dépression réfractaire. Une dépression est réfractaire quand deux traitements antidépresseurs ou plus échouent à améliorer la condition d’un patient. La stimulation magnétique transcrânienne (TMS) est un traitement sécuritaire et efficace de la dépression réfractaire. Son efficacité et sa tolérabilité ont été largement prouvées grâce à des études randomisées, des méta-analyses et des revues de littérature. Toutefois, jusqu’à présent, le traitement de la dépression réfractaire avec la TMS demeure sous-étudié avec des données en pratique clinique réelle. Pour répondre à cette lacune, nous avons conduit une analyse rétrospective des dossiers médicaux de patients dépressifs réfractaires ayant suivi un traitement de TMS à l’Unité de Neuromodulation Psychiatrique (UNP) du Centre Hospitalier de l’Université de Montréal (CHUM) entre janvier 2012 et mai 2022. Nous avons examiné l’efficacité et la tolérabilité de la TMS pour ces patients. De façon secondaire, nous avons vérifié si des caractéristiques cliniques des patients avant leur traitement de TMS pouvaient être associées avec l’amélioration de leurs symptômes dépressifs à la suite du traitement de TMS. Nous avons également vérifié si nos résultats étaient semblables à ceux retrouvés dans la littérature scientifique. Cette étude offrirait aux cliniciens une perspective réaliste de l’efficacité et de la tolérabilité de la TMS à une clinique de troisième ligne. / Around 300 million people worldwide suffer from depression and around 30% will develop treatment-resistant depression (TRD). Depression is treatment-resistant when two or more antidepressant treatments fail to improve a patient’s condition. Transcranial magnetic stimulation (TMS) is a safe and effective treatment for TRD. Its efficacy and tolerability have been widely demonstrated through randomized studies, meta-analyses, and literature reviews. However, to date, the treatment of TRD with TMS remains under-studied with evidence in real-world clinical practice. To address this gap, we conducted a retrospective chart review of TRD patients who had undergone TMS therapy at the Psychiatric Neuromodulation Unit (UNP) of the University of Montreal Hospital Center (CHUM) between January 2012 and May 2022. We examined the efficacy and tolerability of TMS for these patients. As a secondary measure, we examined whether baseline clinical characteristics of patients could be associated with the improvement of their depressive symptoms following TMS treatment. We also examined whether our results were similar to those found in the scientific literature. This study would provide clinicians with a realistic perspective on the efficacy and tolerability of TMS at a third-line clinic.

No description available.

Abstract Maternal depressed mood during pregnancy is common, but studies on the offspring of antenatally depressed mothers, with a long follow-up, are scarce. The aim was to study whether the adult offspring of antenatally depressed mothers are at an elevated risk of psychoses, depression, bipolar disorder, antisocial and borderline personality disorder, and schizotypal and affective traits. Parental severe mental disorder was considered as both a genetic and environmental risk factor for mental disorders. The data are based on the unselected, prospective, population-based Northern Finland 1966 Birth Cohort of 12,058 live-born children. The data were collected beginning from pregnancy and ending mid-adulthood. The mothers were asked about their mood during pregnancy at the antenatal clinic at 24–28 gestational weeks. Of the mothers, 13.9% rated themselves as depressed (11.8%) or very depressed (2.1%) during pregnancy. Parents’ severe, hospital-treated mental disorders, and the cohort members’ mental disorders were identified mainly by using the Finnish Care Register for Health Care. In this study, the adult offspring of antenatally depressed mothers had an increased risk of depression, and the male offspring for antisocial personality disorder, compared to cohort members without antenatally depressed mothers. The offspring with both maternal antenatal depressed mood and parental severe mental disorder had a markedly elevated risk of schizophrenia and depression, compared to cohort members without one or both of the risk factors. This is the first study where the offspring of antenatally depressed mothers were followed till mid-adulthood, also taking into account parental severe mental disorders. Based on the findings, the prevention of and early intervention in antenatal depression, especially in families with severe mental illness, might present an opportunity to reduce the risk of mental disorders in the offspring. / Tiivistelmä Äitien raskausajan masennus on yleistä, mutta pitkiä seurantatutkimuksia raskausaikana masentuneiden äitien lapsista on vähän. Tutkimuksen tavoitteena oli selvittää, onko raskausaikana masentuneiden äitien aikuisilla jälkeläisillä kohonnut riski sairastua skitsofreniaan, masennukseen, kaksisuuntaiseen mielialahäiriöön, epäsosiaaliseen tai epävakaaseen persoonallisuushäiriöön, ja ilmeneekö heillä enemmän skitsotyyppisiä tai affektiivisia piirteitä. Vanhempien vakavien mielenterveydenhäiriöiden katsottiin olevan sekä mahdollisia geneettisiä että ympäristöön liittyviä riskitekijöitä jälkeläisten mielenterveyshäiriöille. Tutkimus perustuu yleisväestöön pohjautuvaan, prospektiiviseen Pohjois-Suomen vuoden 1966 syntymäkohorttiin, johon kuuluu 12 058 elävänä syntynyttä lasta. Kohortin jäseniä on seurattu sikiöajalta keski-ikään, aina 49 ikävuoteen saakka. Äitien raskaudenaikaista mielialaa tiedusteltiin raskausviikoilla 24–28 neuvolassa. 13,9 % äideistä raportoi mielialansa masentuneeksi (11,8 %) tai hyvin masentuneeksi (2.1%) raskausaikana. Vanhempien vakavat mielenterveydenhäiriöt ja kohortin jäsenten mielenterveyshäiriöt selvitettiin pääosin hoitoilmoitusrekisteritiedoista. Tutkimuksessa raskaudenaikana masentuneiden äitien lapsilla havaittiin kohonnut depressioriski sekä kohonnut epäsosiaalisen persoonallisuushäiriön riski miehillä, verrattuna kohortin jäseniin, joiden äitien mieliala ei ollut masentunut raskausaikana. Kohortin jäsenillä, joiden äideillä oli raskausajan masennusta ja toisella vanhemmista vakava mielenterveyshäiriö, oli kohonnut riski sairastua skitsofreniaan ja depressioon, verrattuna heihin, joilla oli vain yksi tai ei kumpaakaan näistä riskitekijöistä. Tämä on ensimmäinen tutkimus, jossa raskausaikana masentuneiden äitien lapsia on seurattu keski-ikään saakka, huomioiden myös vanhempien vakavat mielenterveydenhäiriöt. Tutkimuksen tulosten perusteella äidin raskausajan masennusoireiden varhaisen tunnistamisen ja hoidon voitaisiin ajatella vähentävien jälkeläisten mielenterveysongelmien riskiä, etenkin perheissä, joissa on vakavia mielenterveysongelmia.

Made available in DSpace on 2016-03-22T17:26:20Z (GMT). No. of bitstreams: 1 Karen Jansen 2.pdf: 601451 bytes, checksum: e84f12927abaa8f47025474e4930cc3b (MD5) Previous issue date: 2009-10-30 / Objective: To evaluate the prevalence of mania and hypomania episode, as well as associated factors, comorbidities, and quality of life among young from 18 to 24 years old the city of Pelotas, RS. Method: This cross-sectional population-based, which was included to a larger study that evaluated Health Behaviors among young from 18 to 24 years old in the city of Pelotas . The sample selection was through conglomerates, and mania e hypomania episode were assessed using a standardized diagnostic interview short, Mini International Neuropsychiatric Interview (MINI), consistent with the DSM-IV and ICD-10. Results: The sample was 1560 young adults. In this, the prevalence of mania or hypomania episode the lifetime were 7,5% and 5,3%, respectively. The young with mania episode showed more prevalence to anxiety, suicide risk and substance abuse. In addition to minor index to quality of life in all domain of SF- 36 (p<0,001). Conclusion: The high prevalence of mania/hypomania episode in young population, associated to co-morbities disorders indicates that THB can being subdiagnostics. While the decline in the quality of life explain the injury in the person life with such pathology / Objetivo: Avaliar a prevalência de episódio de mania e hipomania, bem como, fatores associados, comorbidades e o impacto na qualidade de vida entre jovens de 18 a 24 anos da cidade de Pelotas, RS. Método: Trata-se de um estudo transversal de base-populacional, no qual a seleção amostral foi realizada por conglomerados e os episódios de mania e hipomania foram avaliados através de uma entrevista diagnóstica padronizada breve, Mini Internacional Neuropsychiatric Interview (MINI), compatível com os critérios do DSM-IV e CID-10. Além disso, foi aplicado um questionário com dados sócio-demográficos, e os instrumentos ASSIST e SF-36. Resultados: A amostra foi composta por 1560 jovens. Destes, a prevalência de episódios de mania ou hipomania ao longo da vida foi de 7,5% e 5,3%, respectivamente. Os jovens com episódio de mania apresentaram maior prevalência de transtornos de ansiedade, risco de suicídio e abuso de substâncias, além de menores níveis de qualidade de vida em todos os domínios do SF-36 (p<0,001). Conclusão: A alta prevalência de episódios de mania/hipomania na população de jovens, associada aos transtornos co-mórbidos indica que os THB podem estar sendo subdiagnosticados. Enquanto, o declínio na qualidade de vida demonstra o prejuízo na vida do individuo com tal patologia

O Transtorno de Oposição e Desafio (TOD) é definido por um padrão recorrente de comportamento desafiante, desobediente e hostil com início na infância e adolescência e caracteriza-se por uma alta taxa de comorbidades. Estudos longitudinais apontam o TOD na infância como um dos principais preditores de psicopatologia na idade adulta. Uma possível explicação para a grande heterogeneidade de comorbidades e trajetórias longitudinais é de que o diagnóstico de TOD abrange distintas dimensões de sintomas, cada qual com seu desfecho. O primeiro objetivo desta tese foi a validação das distintas dimensões do TOD em uma amostra comunitária Brasileira composta de 2512 sujeitos. Através de análise fatorial confirmatória, demonstramos que o modelo que melhor representa a heterogeneidade do TOD é composto por três dimensões: a dimensão \"argumentative/defiant\" que está associada com transtorno de déficit de atenção/hiperatividade (TDAH); a dimensão \"vindictiveness\" que possui associação com transtorno de conduta (TC); e a dimensão \"angry/irritable mood\" onde predominam as associações com transtornos depressivos e de ansiedade. O objetivo seguinte foi investigar o papel da dimensão irritável na classificação nosológica dos transtornos mentais na infância e adolescência. A apresentação da irritabilidade é um aspecto crucial: irritabilidade crônica caracterizada por baixa tolerância à frustração e frequentes explosões de raiva, que é distinta da apresentação episódica, associada ao diagnóstico Transtorno de Humor Bipolar (TB). \"Severe mood dysregulation\", \"disruptive mood dysregulation disorder\", ou dimensão irritável do TOD são formas distintas de classificar o fenótipo de irritabilidade crônica. Entretanto, independente da classificação utilizada, a alta taxa de comorbidades é invariavelmente o denominador comum em estudos sobre irritabilidade. Neste sentido, examinamos o impacto da irritabilidade como uma dimensão subjacente a vários transtornos. Para tanto, avaliamos o impacto da dimensão irritável do TOD através de vários cenários: indivíduos sem diagnóstico, indivíduos com TDAH e sujeitos com transtornos emocionais. Esta 9 investigação foi realizada em duas amostras, uma brasileira constituída por 2.512 sujeitos e uma amostra britânica composta de 7.977 sujeitos. Os resultados demonstram que a irritabilidade está associada ao aumento do prejuízo funcional independente do diagnóstico comórbido concomitante. Seguindo esta linha, investigamos a influência genética na etiologia da irritabilidade. Para tanto, criamos um escore poligênico que incluiu polimorfismos associados à baixa tolerância à frustração, raiva, agressividade reativa e labilidade emocional. O escore poligênico foi altamente preditivo dos níveis de irritabilidade em 350 sujeitos da amostra brasileira. A associação foi específica para irritabilidade e não foi significativa para TDAH, TOD ou medidas contínuas de sintomas. Além disso, a influência genética se manteve mesmo quando fatores ambientais foram incluídos no modelo estatístico. Por fim, quando testada em diferentes ambientes, a influência genética na etiologia da irritabilidade foi mais importante em ambientes de alto risco, sugerindo uma correlação gene-ambiente (rGE). Concluindo, nossos resultados sugerem que a irritabilidade se caracteriza como um traço dimensional subjacente a inúmeros transtornos na infância e adolescência e agregando impacto e prejuízo funcional. Neste sentido, o constructo da irritabilidade se enquadra no conceito do \"Research Domain Criteria\" (RDoC) que propõe o entendimento dos transtornos mentais através de dimensões subjacentes aos diagnósticos clínicos / The Oppositional Defiant Disorder (ODD) is defined as a pattern of disobedient, hostile and defiant behavior beginning in childhood or adolescence and often accompanied by a wide range of comorbidities. Longitudinal studies support ODD as a predictor of psychopathology in adulthood. A potential explanation for such heterogeneity of comorbidities and longitudinal trajectories is that ODD diagnosis encompasses distinct clusters of symptoms, each with its outcome. The first aim of this work was the validation of ODD dimensions in a Brazilian community sample of 2512 subjects. Confirmatory factorial analysis showed that the best model for ODD comprised three dimensions: an \"argumentative/defiant\" dimension, which associates with attention deficit/hyperactivity disorder (ADHD); a \"vindictiveness\" dimension, which associates with conduct disorder (CD); and an \"angry/irritable\" dimension where emotional disorders such as depression and anxiety are the most common associations. The next step was the investigation of the role of the irritable dimension of oppositionality in diagnostic classifications of childhood mental disorders. The pattern of irritability is a crucial point: its chronic presentation as easy annoyance and frequent temper outbursts should be differentiated from the episodic course of irritability associated with the specific diagnosis of Bipolar Disorder (BD). \"Severe mood dysregulation\", \"disruptive mood dysregulation disorder\", and the irritable dimension of oppositionality are different ways to classify the chronic irritability phenotype. However, regardless of the classification, the high rate of comorbidities is invariably the common denominator in studies of irritability. Therefore, we examined the impact of irritability as a dimension cutting across multiple settings: individuals without any diagnosis, subjects with ADHD, and also those with emotional disorders. For that we used two samples, one from Brazil, with 2.512 subjects, and one from the UK, with 7.977 individuals. Results showed that irritability associates with increased functional impairment regardless of concurrent comorbid status. We then investigated the genetic influence on the etiology of irritability. A polygenic score was generated encompassing polymorphisms previously associated with anger, emotional lability and reactive aggression. The polygenic score significantly predicted irritability in 350 subjects in the brazilian sample, yet failed to predict ADHD, ODD, CD and continuous measures of symptoms. Moreover, the association between the polygenic score and irritability remained significant even after taking into account environmental factors. Finally, when stratified across diverse levels of environmental risk, genetic influence upon the etiology of irritability appears to be stronger in high-risk environments. Taken together, our results suggest that irritability is characterized as a dimensional trait that underlies multiple disorders, adding functional impairment. Thus, the construct of irritability fits well within the concept of Research Domain Criteria (RDoC) that suggests that mental disorders should be understood through dimensions underlying diagnostic categories

Falhas na conectividade cerebral e na atividade córtico-límbica podem estar envolvidas no Transtorno Depressivo Maior (TDM). O uso simultâneo da Estimulação Magnética Transcraniana (EMT) e a Tomografia por Emissão de Pósitrons (PET) é um eficiente método não-invasivo para estudar a conectividade funcional interregional do cérebro humano e os mecanismos envolvidos na ação precisa da EMT sobre o córtex préfrontal dorso-lateral (CPFDL), componente do modelo neuroanatômico da depressão. O presente estudo avaliou o padrão de ativação das áreas envolvidas neste modelo, como o CPFDL, tálamo, hipocampo, amígdala, giro do cíngulo e cerebelo, em pacientes com Transtorno Depressivo Maior (TDM), comparados a controles. Dezessete pacientes com TDM e 17 controles foram estudados. A EMT foi aplicada em uma frequência de 3 Hz no CPFDL esquerdo. Um braço robótico para localização precisa do estímulo foi utilizado. Cada indivíduo foi submetido a duas sessões de EMT em três intensidades (90% do Limiar Motor (LM), 100% do LM e 110% do LM) e duas sessões de EMT \"placebo\" (aplicadas como clicks auditivos). Durante a EMT, as imagens foram realizadas em uma câmera GE 4096 e o fluxo sanguíneo cerebral foi medido através da PET utilizando H2 15O. Imagens por Ressonância Magnética (RMI) foram adquiridas para co-registro da PET-RMI, possibilitando a localização precisa do CPFDL. Mudanças significativas no Fluxo Sanguíneo Cerebral (FSC) indicando atividade neural foram detectadas utilizando uma estratégia de subtração sem áreas de interesse prévias. Os pacientes, comparados a controles, apresentaram uma resposta diminuída do FSC na área estimulada (CPFDL esquerdo) na intensidade de 100% do LM. Áreas não diretamente estimuladas que apresentaram uma diminuição do FSC, em pacientes, foram o giro do cíngulo anterior direito (90% do LM) e, dentre as regiões sub-corticais, globo pálido esquerdo (90% e 110% do LM) e tálamo direito (100% do LM). O giro do cíngulo posterior, bilateralmente, e a vermis cerebelar direita apresentaram aumento do FSC em todas as intensidades de estimulação. Este estudo sugere que pacientes com depressão maior podem apresentar um limiar mais alto para a estimulação com EMT do CPFDL esquerdo, e uma resposta córtico-límbica distinta à EMT, quando comparados aos resultados dos indivíduos controles. Estes achados devem ser considerados em estudos que utilizarem EMT para tratamento da depressão. Este estudo sugere que a fisiopatologia do TDM envolve um prejuízo da conectividade córtico-límbica. / Disturbed corticolimbic activity and connectivity may underlie major depressive disorder. The simultaneous use of transcranial magnetic stimulation (TMS) and positron emission tomography (PET) is a powerful noninvasive method to study interregional functional connectivity of the dorsolateral prefrontal cortex (DLPFC), a major component of the neuroanatomic model of depression. Seventeen unmedicated patients with recurrent major depression and 17 healthy volunteers were studied. TMS was delivered at 3 Hz to the left DLPFC by image guided robotic TMS (irTMS) system. Each subject underwent two trials of TMS at each of three intensities (90% MT (motor threshold), 100% MT, 110% MT), and two trials of sham TMS (delivered as auditory clicks). During the TMS, cerebral blood flow (CBF) was measured with H2 15O-Positron Emission Tomography (PET). An anatomical MR scan was acquired for PET-MRI co-registration to facilitate precise location of the DLPFC. Significant changes in cerebral blood flow indicating neural activity were detected using a ROI-free image subtraction strategy. Patients had a decreased response in regional CBF (rCBF) in left DLPFC in the intensity of 100% of MT. Left and right posterior cingulate demonstrated increased CBF across all intensities in depressed patients. Patients also had a decreased response in the right anterior cingulate at 90% of MT and right cerebellar vermis in response to left DLPFC stimulation across all intensities, compared to healthy volunteers. Among subcortical regions, only left globus pallidus and right thalamus showed a significant de-activation across varying TMS intensities. Patients with major depression may have a higher threshold for the TMS stimulation of the left DLPFC and a different corticolimbic response to TMS stimulation than healthy controls, a finding that must be taken into consideration in studies utilizing TMS as a treatment for depression. These findings suggest impaired cortico-limbic connectivity in unipolar depression, which could underlie illness pathophysiology.

Falhas na conectividade cerebral e na atividade córtico-límbica podem estar envolvidas no Transtorno Depressivo Maior (TDM). O uso simultâneo da Estimulação Magnética Transcraniana (EMT) e a Tomografia por Emissão de Pósitrons (PET) é um eficiente método não-invasivo para estudar a conectividade funcional interregional do cérebro humano e os mecanismos envolvidos na ação precisa da EMT sobre o córtex préfrontal dorso-lateral (CPFDL), componente do modelo neuroanatômico da depressão. O presente estudo avaliou o padrão de ativação das áreas envolvidas neste modelo, como o CPFDL, tálamo, hipocampo, amígdala, giro do cíngulo e cerebelo, em pacientes com Transtorno Depressivo Maior (TDM), comparados a controles. Dezessete pacientes com TDM e 17 controles foram estudados. A EMT foi aplicada em uma frequência de 3 Hz no CPFDL esquerdo. Um braço robótico para localização precisa do estímulo foi utilizado. Cada indivíduo foi submetido a duas sessões de EMT em três intensidades (90% do Limiar Motor (LM), 100% do LM e 110% do LM) e duas sessões de EMT \"placebo\" (aplicadas como clicks auditivos). Durante a EMT, as imagens foram realizadas em uma câmera GE 4096 e o fluxo sanguíneo cerebral foi medido através da PET utilizando H2 15O. Imagens por Ressonância Magnética (RMI) foram adquiridas para co-registro da PET-RMI, possibilitando a localização precisa do CPFDL. Mudanças significativas no Fluxo Sanguíneo Cerebral (FSC) indicando atividade neural foram detectadas utilizando uma estratégia de subtração sem áreas de interesse prévias. Os pacientes, comparados a controles, apresentaram uma resposta diminuída do FSC na área estimulada (CPFDL esquerdo) na intensidade de 100% do LM. Áreas não diretamente estimuladas que apresentaram uma diminuição do FSC, em pacientes, foram o giro do cíngulo anterior direito (90% do LM) e, dentre as regiões sub-corticais, globo pálido esquerdo (90% e 110% do LM) e tálamo direito (100% do LM). O giro do cíngulo posterior, bilateralmente, e a vermis cerebelar direita apresentaram aumento do FSC em todas as intensidades de estimulação. Este estudo sugere que pacientes com depressão maior podem apresentar um limiar mais alto para a estimulação com EMT do CPFDL esquerdo, e uma resposta córtico-límbica distinta à EMT, quando comparados aos resultados dos indivíduos controles. Estes achados devem ser considerados em estudos que utilizarem EMT para tratamento da depressão. Este estudo sugere que a fisiopatologia do TDM envolve um prejuízo da conectividade córtico-límbica. / Disturbed corticolimbic activity and connectivity may underlie major depressive disorder. The simultaneous use of transcranial magnetic stimulation (TMS) and positron emission tomography (PET) is a powerful noninvasive method to study interregional functional connectivity of the dorsolateral prefrontal cortex (DLPFC), a major component of the neuroanatomic model of depression. Seventeen unmedicated patients with recurrent major depression and 17 healthy volunteers were studied. TMS was delivered at 3 Hz to the left DLPFC by image guided robotic TMS (irTMS) system. Each subject underwent two trials of TMS at each of three intensities (90% MT (motor threshold), 100% MT, 110% MT), and two trials of sham TMS (delivered as auditory clicks). During the TMS, cerebral blood flow (CBF) was measured with H2 15O-Positron Emission Tomography (PET). An anatomical MR scan was acquired for PET-MRI co-registration to facilitate precise location of the DLPFC. Significant changes in cerebral blood flow indicating neural activity were detected using a ROI-free image subtraction strategy. Patients had a decreased response in regional CBF (rCBF) in left DLPFC in the intensity of 100% of MT. Left and right posterior cingulate demonstrated increased CBF across all intensities in depressed patients. Patients also had a decreased response in the right anterior cingulate at 90% of MT and right cerebellar vermis in response to left DLPFC stimulation across all intensities, compared to healthy volunteers. Among subcortical regions, only left globus pallidus and right thalamus showed a significant de-activation across varying TMS intensities. Patients with major depression may have a higher threshold for the TMS stimulation of the left DLPFC and a different corticolimbic response to TMS stimulation than healthy controls, a finding that must be taken into consideration in studies utilizing TMS as a treatment for depression. These findings suggest impaired cortico-limbic connectivity in unipolar depression, which could underlie illness pathophysiology.