Electroconvulsive therapy (ECT) is one of the oldest and most effective treatments for depression; however, its biological underpinnings are poorly understood. Brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis are two chemical messenger systems implicated in the antidepressant action and cognitive side effects of ECT. The Wistar-Kyoto (WKY) strain is a genetic model of depression that shows biological, cognitive, behavioural, and treatment-response abnormalities, making it potentially a useful model in which to investigate the underpinnings of the action of electroconvulsive stimulus (ECS: the amimal model of ECT). In addition, the WKY presents a potentially useful model for translational research on depression. The WKY strain is particularly valuable for the measurement of serum BDNF protein, for which the association with antidepressant treatments is much less clear (mostly stemming from investigations in humans) than that between brain BDNF and antidepressant treatments in rodent studies. The three studies presented add insight into the biological and behavioural effects of ECS. The first study (chapter 2) found no evidence of increased (R)-[11C]rolipram binding (an indirect marker of cyclic-adenosine monophosphate, cAMP) in the brain, despite significant increases of brain BDNF protein expression after repeated ECS. The second study (chapter 3) demonstrated the validity of the WKY strain in the investigation of ECS. Relative to Wistar controls, WKY showed similar antidepressant and cognitive effects (despite some abnormal behavioural responses), immediate but not sustained increases in brain BDNF protein, and a novel finding of increased extra-hypothalamic CRF after 5 daily ECS. The final study (chapter 4) demonstrated baseline strain differences in serum (WKY < Wistar) but not brain BDNF and, in both strains, no change in serum BDNF despite significant changes in brain BDNF after repeated ECS treatment. Preliminary results from a human pilot study investigating similar measures in a small group of people receiving ECT for depression are also presented. The results of this body of work advance our understanding of the activation and role of brain and serum measures of BDNF and the HPA axis in ECS/ECT, and raise important issues in the translation of research from basic science to the human condition of depression.

Electroconvulsive therapy (ECT) is one of the oldest and most effective treatments for depression; however, its biological underpinnings are poorly understood. Brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis are two chemical messenger systems implicated in the antidepressant action and cognitive side effects of ECT. The Wistar-Kyoto (WKY) strain is a genetic model of depression that shows biological, cognitive, behavioural, and treatment-response abnormalities, making it potentially a useful model in which to investigate the underpinnings of the action of electroconvulsive stimulus (ECS: the amimal model of ECT). In addition, the WKY presents a potentially useful model for translational research on depression. The WKY strain is particularly valuable for the measurement of serum BDNF protein, for which the association with antidepressant treatments is much less clear (mostly stemming from investigations in humans) than that between brain BDNF and antidepressant treatments in rodent studies. The three studies presented add insight into the biological and behavioural effects of ECS. The first study (chapter 2) found no evidence of increased (R)-[11C]rolipram binding (an indirect marker of cyclic-adenosine monophosphate, cAMP) in the brain, despite significant increases of brain BDNF protein expression after repeated ECS. The second study (chapter 3) demonstrated the validity of the WKY strain in the investigation of ECS. Relative to Wistar controls, WKY showed similar antidepressant and cognitive effects (despite some abnormal behavioural responses), immediate but not sustained increases in brain BDNF protein, and a novel finding of increased extra-hypothalamic CRF after 5 daily ECS. The final study (chapter 4) demonstrated baseline strain differences in serum (WKY < Wistar) but not brain BDNF and, in both strains, no change in serum BDNF despite significant changes in brain BDNF after repeated ECS treatment. Preliminary results from a human pilot study investigating similar measures in a small group of people receiving ECT for depression are also presented. The results of this body of work advance our understanding of the activation and role of brain and serum measures of BDNF and the HPA axis in ECS/ECT, and raise important issues in the translation of research from basic science to the human condition of depression.

This thesis presents the first randomised controlled trial (RCT) to investigate whether supplemented probiotic bacteria-"live microorganisms that, when administered in adequate amounts, confer a health benefit on the host" (Sanders, 2008)-affect mood and other psychological outcomes in people presenting with low mood. Seventy-nine participants with at least moderate symptoms of depression were randomised in a double-blind manner to receive either a probiotic preparation containing Lactobacillus helveticus and Bifidobacterium longum or a matched placebo for eight weeks. The RCT phase was followed by an open label extension in which all participants were offered the active study product for a further 8 weeks. Participants were followed up at 6 months post-study. Based on the existing evidence from gut-brain axis research, and on models linking depression with inflammation, immune activation, low vitamin D levels, and the gut microbiota (outlined in Chapters 1 and 2), it was hypothesised that: the overall sample would have elevated levels of inflammatory biomarkers and low levels of vitamin D at baseline, and that this would be associated with scores on psychological and irritable bowel syndrome (IBS) outcome measures; that group differences (active treatment versus placebo) would be observed in scores on psychological outcome measures after eight weeks of probiotic intervention; that group differences would also be observed in blood levels of proinflammatory cytokines, hsCRP, vitamin D and BDNF, and scores on a measure of gut function/IBS, and that levels of these variables may predict or impact on treatment response; and that group differences would be observed on outcome measures at the point of the 6-month follow-up between those who continued to take the probiotic and those who discontinued probiotic use. In total, 58 of the 77 participants who provided baseline blood samples (75%) had at least one marker of inflammation elevated outside the normal reference range at baseline. Baseline vitamin D was approaching the deficient level, displayed a seasonal pattern, and was associated with severity on one measure of cognition. No significant differences were found between the active treatment and placebo groups on any psychological outcome measure, the measure of gut function or in the level of any blood-based biomarker in the randomised phase. Baseline vitamin D level was found to moderate treatment effect on several outcome measures. The results of the open label extension supported the lack of efficacy observed in the randomised phase, and also allowed for the comparison of efficacy over intervention periods of varying durations. The results of the follow-up at 6 months post-trial indicated that, while mean scores on psychological outcome measures remained lower than baseline, there was regression on some outcome measures after the study. When the participants who replied to the 6 month follow-up questionnaire were divided into groups based on their self-reported dominant treatment since the trial (probiotics/nutrition, standard treatment or no treatment) there was no difference in mood or other psychological outcomes among the groups at 6 months. The current trial found no evidence that this probiotic formulation is effective in treating the symptoms of depression or IBS, or in moderating the levels of inflammatory and other biomarkers in a sample recruited with moderate depression. This finding does not support the theory proposed in several narrative reviews which suggests probiotics as a possible intervention for depression and other mental health outcomes, but is supported by the systematic review of human probiotics studies presented in Chapter 3 which found overall limited evidence of probiotic efficacy for psychological outcomes. Future studies in the area should attempt to further broaden this field, in particular by recruiting samples with mild and/or non-chronic depression for interventional studies, or by approaching probiotics as a preventative or adjuvant treatment strategy for depression.

Older adults who stay physically and mentally active appear to have better cognitive function compared to their less active counterparts. In fact, those who perform either regular exercise or cognitive training (CT) can maintain and improve their cognitive functioning, even in their later years. Resistance training (RT) causes an increase in specific hormones that are responsible for improved brain functioning; however, many questions about how these hormones respond to RT are unanswered. Understanding how these hormones respond to RT can help researchers and clinicians create optimal training programs for older adults. Research shows that combining exercise and CT may be better for the brain compared to either activity performed alone; however, nobody has looked at RT combined with CT. We believe that combining RT and CT where CT is performed when an individual’s hormones are highest (right after RT) could have a big effect on brain function in a short period of time. This work represents a two-part study looked at: 1) how these hormones respond to a session of RT, and 2) the effect of combined RT and CT on cognitive function in older adults. Our participants performed CT immediately after RT, 3 times per week for 8 weeks. Specific hormones which are important for brain function were measured immediately before and for 2 hours after an acute bout of RT before and after 8-weeks of RT. Cognitive function was measured before and after the RT training period. Our primary findings were: 1) significant increases in brain derived neurotrophic factor immediately after RT and 2) participants cognitive function improved after 8 weeks of training. This is important because short-term combined RT and CT can lead to significant improvements in cognitive functioning. Also, this work will allow researchers to begin designing exercise programs that can maximize the brain’s ability to change, even at an old age. / Thesis (Master, Kinesiology & Health Studies) -- Queen's University, 2012-09-21 15:29:35.509

Electroconvulsive therapy (ECT) is one of the oldest and most effective treatments for depression; however, its biological underpinnings are poorly understood. Brain-derived neurotrophic factor (BDNF) and the hypothalamic-pituitary-adrenal (HPA) axis are two chemical messenger systems implicated in the antidepressant action and cognitive side effects of ECT. The Wistar-Kyoto (WKY) strain is a genetic model of depression that shows biological, cognitive, behavioural, and treatment-response abnormalities, making it potentially a useful model in which to investigate the underpinnings of the action of electroconvulsive stimulus (ECS: the amimal model of ECT). In addition, the WKY presents a potentially useful model for translational research on depression. The WKY strain is particularly valuable for the measurement of serum BDNF protein, for which the association with antidepressant treatments is much less clear (mostly stemming from investigations in humans) than that between brain BDNF and antidepressant treatments in rodent studies. The three studies presented add insight into the biological and behavioural effects of ECS. The first study (chapter 2) found no evidence of increased (R)-[11C]rolipram binding (an indirect marker of cyclic-adenosine monophosphate, cAMP) in the brain, despite significant increases of brain BDNF protein expression after repeated ECS. The second study (chapter 3) demonstrated the validity of the WKY strain in the investigation of ECS. Relative to Wistar controls, WKY showed similar antidepressant and cognitive effects (despite some abnormal behavioural responses), immediate but not sustained increases in brain BDNF protein, and a novel finding of increased extra-hypothalamic CRF after 5 daily ECS. The final study (chapter 4) demonstrated baseline strain differences in serum (WKY < Wistar) but not brain BDNF and, in both strains, no change in serum BDNF despite significant changes in brain BDNF after repeated ECS treatment. Preliminary results from a human pilot study investigating similar measures in a small group of people receiving ECT for depression are also presented. The results of this body of work advance our understanding of the activation and role of brain and serum measures of BDNF and the HPA axis in ECS/ECT, and raise important issues in the translation of research from basic science to the human condition of depression.

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 95-113).

Thesis (Ph. D.)--University of Alabama at Birmingham, 2008. / Title from first page of PDF file (viewed Sept. 16, 2008). Includes bibliographical references.

A prevalência de Doença Mental Grave (do inglês Severe Mental Illness, SMI) atinge 5,4% em um ano segundo os estudos Baltimore Epidemiologic Catchment Area e National Comorbidity Survey. O conceito de SMI surgiu na década de 1970 para o planejamento dos serviços de saúde e apresentou importância crescente a partir do movimento de desinstitucionalização psiquiátrica. Uma das definições para SMI deriva do NIMH (National Institute of Mental Health) em 1987, e utiliza como critérios a presença de prejuízo funcional, decorrente de déficits em aspectos básicos do dia-a-dia, bem como a duração da doença. Casos agudos de SMI podem necessitar tratamento em Unidade de Internação Psiquiátrica em Hospital Geral (UIPHG). No entanto, há poucos estudos disponíveis no Brasil avaliando esta modalidade de tratamento e os desfechos destes pacientes. Evidências também apontam que os pacientes com transtornos psiquiátricos apresentam níveis reduzidos de Fator Neurotrófico Derivado do Cérebro (Brain-Derived Neurotrophic Factor, BDNF). O BDNF age no sistema nervoso central (SNC) promovendo crescimento e diferenciação de neurônios. Dentro deste contexto, a presente tese apresenta como objetivo principal a avaliação naturalística de desfechos clínicos e funcionais, associados à avaliação dos níveis séricos de BDNF, em pacientes com SMI. Os pacientes que foram encaminhados para tratamento na Unidade de Internação Psiquiátrica do Hospital de Clínicas de Porto Alegre foram incluídos se apresentassem os critérios de SMI: Avaliação Global de Funcionamento (Global Assessment of Functioning, GAF) menor ou igual a 50 e tempo de tratamento maior ou igual a dois anos. As avaliações ocorreram em dois momentos (admissão e alta). Compreenderam avaliação sociodemográfica, clínica e coleta de sangue (com dosagem de BDNF sérico). Foram realizadas avaliação diagnóstica pelo Mini-International Neuropsychiatric Interview (MINI) e aplicação das escalas Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression scale (CGI-S), GAF e World Health Organization Quality of Life Instrument—Short Version (WHOQOL-Bref). Ainda, foram aplicadas escalas específicas nos diagnósticos principais (i.e., depressão maior, depressão bipolar, episódio maníaco, esquizofrenia): Hamilton Depression Rating Scale (HAM-D); Young Mania Rating Scale (YMRS). O primeiro artigo desta tese descreve os desfechos clínicos, funcionais e também de qualidade de vida durante a internação psiquiátrica. Observou-se melhora significativa nos parâmetros avaliados nos pacientes com SMI como um todo. Os pacientes com episódio maníaco apresentaram maior chance (em relação aos com episódio depressivo) de atingir remissão pela CGI (OR: 4.03; 95% CI: 1.14-14.30; p=0.03). A duração média da hospitalização (LOS) foi 28,95 (± 19,86) dias. No segundo artigo, observou-se redução dos níveis séricos de BDNF nos pacientes com SMI em relação aos controles saudáveis, independentemente do diagnóstico. Houve aumento significativo no BDNF entre a admissão e a alta. Os resultados apresentados replicam dados previamente publicados a partir de amostra única de pacientes com SMI, sua característica diferencial. Estes resultados reforçam que a internação em UIPHG, uma intervenção relativamente breve, demonstra desfechos positivos e é alternativa bem estabelecida no tratamento da SMI. Além disso, a redução inespecífica do BDNF sérico seguida de um pequeno aumento associado ao tratamento reforçam a possibilidade do BDNF como marcador transdiagnóstico de transtorno mental. / The estimated prevalence of Severe Mental Illness (SMI) according to Baltimore Epidemiologic Catchment Area and National Comorbidity Survey studies is 5.4% in one year. One suggested definition of Severe Mental Illness (SMI) derives from the 1987 National Institute of Mental Health (NIMH) definition and is based on two criteria: 1. duration, characterized as involving “prolonged illness”, and 2. disability, which includes dangerous or disturbing social behavior, and mild impairment in achieving basic needs. These acute psychiatric conditions may require psychiatric inpatient treatment located in acute wards in General Hospitals. However, little data is currently available evaluating the characteristics and the outcomes during an acute inpatient stay in Brazil. Evidence also suggests that Brain-derived neurotrophic factor (BDNF) levels are significantly decreased in neuropsychiatric disorders. BDNF is found throughout the brain and is involved in neurogenesis and neuroplasticity. So, the main objectives of this work are to evaluate SMI patients’ outcomes during treatment in a psychiatric unit in a general hospital by symptomatology, functionality, quality of life and by the evaluation of BDNF serum levels. After the admission to a psychiatric unit in a general hospital in Brazil, patients were included and if they had two of the SMI criteria: Global Assessment of Functioning (GAF) ≤ 50 and duration of services contact ≥ 2 years. Patients were assessed in admission and upon discharge with Mini-International Neuropsychiatric Interview (MINI), Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression Scale (CGI), GAF, World Health Organization’s QOL Instrument—Short Version (WHOQOL-Bref) and diagnostic specific scales (Hamilton Depression Rating Scale, HAM-D; Young Mania Rating Scale, YMRS; and Hamilton Anxiety Rating Scale, HAM-A). Blood samples were also obtained. The first manuscript showed that SMI patients had marked and significant improvements in symptomatic and functional measures during psychiatric hospitalization. Patients with manic episode had higher chance of CGI remission (OR: 4.03; 95% CI: 1.14-14.30; p=0.03) when compared with patients with depressive episode. Mean LOS was 28.95 (± 19.86) days. The second manuscript showed that BDNF serum levels were equally reduced among different SMI diagnoses. Also, the observed improvements in SMI patients were associated with a significant, but small increase in mean serum BDNF levels. Therefore, the results replicate evidence from previous findings in single samples, suggesting that SMI patients can have marked acute improvements during a a relatively short intervention (approximately 1 month) represented by the psychiatric hospitalization in a general tertiary hospital. Also, the similar reduction observed in BDNF levels among SMI patients with different diagnoses and the significant increase but non-restoration indicate that BDNF serum levels could be considered a marker for the presence of an unspecific psychiatric disorder and possibly a transdiagnostic and unspecific marker of disease activity.

Introdução O fator neurotrófico derivado do cérebro (BDNF) tem um papel crítico no desenvolvimento e plasticidade neuronal. Acredita-se que a alteração na sinalização do BDNF contribua para a patogênese da esquizofrenia (SZ), especialmente em relação ao déficit cognitivo. Alguns estudos com pacientes esquizofrênicos têm mostrado um efeito benéfico, e outros um efeito prejudicial, da clozapina (CLZ) na cognição. Objetivos O presente estudo tem por objetivo avaliar a associação entre a dose diária de CLZ e os níveis séricos de BDNF em pacientes com SZ. Material e Métodos Foram selecionados dois grupos de pacientes com SZ (n=44) de acordo critério do DSM-IV-TR, cronicamente medicados com CLZ (n=31) e antipsicóticos típicos (n=13). Foram coletados 5ml de amostras de sangue por venopunção. Resultados Os níveis séricos de BDNF foram correlacionados significativamente com a dose diária de CLZ (r=0.394, p=0.028), mas não com a dose diária de antipsicóticos típicos (r=0.208, p=0.496). Conclusão Este estudo sugere que os níveis de BDNF sérico estão correlacionados com a dose diária de CLZ, e que isto deve levar à melhora na cognição observada nos pacientes com SZ tratados com CLZ. Apesar da forte evidência de que a administração crônica de CLZ é efetiva para pacientes com SZ, ainda não se sabe como os antipsicóticos atípicos regulam a expressão do BDNF. A concentração sérica de BDNF na SZ merece futuras investigações, visando o papel das neurotrofinas na resposta cognitiva ao tratamento com CLZ e outros antipsicóticos atípicos. / Introduction Brain-derived neurotrophic factor (BDNF) plays a critical role in neurodevelopment and neuroplasticity. Altered BDNF signaling is thought to contribute to the pathogenesis of schizophrenia (SZ) especially in relation to cognitive deficits. Clozapine (CLZ) has shown a beneficial effect on cognition in SZ in some studies and a detrimental effect in others. Objectives The aim of the present study was to evaluate the association between CLZ daily dose and serum BDNF levels. Methods Two groups of chronically medicated DSM-IV-TR SZ patients (n=44), on treatment with CLZ (n=31) and typical antipsychotics (n=13) had 5ml blood samples collected by venipuncture. Results Serum BDNF levels were significantly correlated with CLZ daily dose (r=0.394, p=0.028), but not with typical antipsychotic daily dose (r=0.208, p=0.496). Conclusion This study suggests that serum BDNF levels are correlated with CLZ daily dose, and this may lead to the cognitive enhancement as seen in patients with SZ under CLZ. Despite the strong evidence that chronic administration of CLZ is effective for patients with SZ, it is still unknown whether atypical antipsychotic drugs regulate BDNF expression. Serum BDNF concentration in SZ merits further investigations with regard to the role of neurotrophins in the cognitive response to treatment with CLZ and other atypical antipsychotics.

As leucemias correspondem a 30% dos tumores pediátricos, e constituem as neoplasias mais frequentes em indivíduos com menos de 15 anos. Apesar da elevada taxa de cura, frequentemente a ela está associada resistência à quimioterapia e efeitos colaterais tardios. Por isso, novas estratégias de tratamento, diagnóstico e prognóstico são necessárias. O fator neurotrófico derivado do cérebro (BDNF) e seus receptores de quinase relacionados à tropomiosina (tropomyosin related kinase, ou Trk) estão envolvidos com muitos processos na medula óssea (MO). Entretanto, o papel do BDNF em leucemias agudas (LA) pediátricas ainda não é bem conhecido. O objetivo desse estudo foi analisar os níveis de BDNF em amostras de MO ou sangue periférico (SP) de crianças com LA, e iniciar a caracterização dos efeitos de agonistas e antagonistas de neurotrofinas sobre culturas primárias de leucemias linfóides agudas em diferentes momentos terapêuticos Foram coletadas amostras de MO ou SP de crianças e adolescentes com leucemia linfóide aguda (LLA), crianças e adolescentes com leucemia mielóide aguda (LMA), e indivíduos saudáveis (IS) da mesma faixa etária. Para análise dos níveis séricos de BDNF utilizou-se kit de imuno-ensaio enzimático tipo sanduíche. Quando comparados aos IS os níveis de BDNF de pacientes com LA, ao diagnóstico, foram significativamente menores. Resultados similares foram observados nos pacientes durante indução, consolidação, diagnóstico e tratamento de recidiva. Da mesma forma, os níveis de BDNF foram inferiores em pacientes que receberam transfusão de plaquetas e, ao diagnóstico naqueles pacientes que foram a óbito. Para a caracterização dos efeitos de agonistas e antagonistas de neurotrofinas em cultura de células, amostras de pacientes ao momento do diagnóstico e no momento de indução do tratamento foram utilizadas. Os linfócitos foram extraídos e, após plaqueamento, as células foram tratadas com BDNF (Sigma, B3795), NGF (Sigma, SRP3015) e K252a (Sigma, 05288) por 72 horas. A viabilidade foi avaliada pelo método de exclusão por azul de Tripan. Devido às dificuldades no cultivo das células, esses dados ainda estão em análise. / Leukemias account for 30% of pediatric tumors and are the most frequent cancers in people under 15 years. Despite the high cure rate, often it is associated with resistance to chemotherapy and late side effects. Therefore, new strategies for treatment, diagnosis and prognosis are necessary. The brain-derived neurotrophic factor (BDNF) and their kinase receptor related tropomyosin (tropomyosin related kinase, and Trk) are involved in many processes in bone marrow (BM), however, the role of BDNF in acute leukemias (AL) pediatric it is not well known. The aim of this study was to analyze the BDNF levels in BM samples or peripheral blood (PB) of children with AL, and start the characterization of the effects of agonists and antagonists on neurotrophin primary cultures of acute lymphoblastic leukemias in different therapeutic moments. BM or PB samples were collected from children and adolescents with acute lymphoblastic leukemia (ALL), children and adolescents with acute myeloid leukemia (AML), and healthy individuals (HI) of the same age. For analysis of serum levels of BDNF was used sandwich enzyme immunoassay kit. When compared to HI, BDNF levels in patients with AL at diagnosis were significantly lower. Similar results were observed in patients during induction, consolidation, diagnosis and treatment of relapse. Similarly, BDNF levels were lower in patients receiving platelet transfusion and at diagnosis in patients that died. To characterize the effects of agonists and antagonists for neurotrophin in cell culture, samples of patients at diagnosis and at the time of induction treatment were used. Lymphocytes were extracted and, after plating, cells were treated with BDNF (Sigma B3795), NGF (Sigma, SRP3015) and K252a (Sigma, 05288) for 72 hours. Viability was assessed by exclusion of trypan blue method. Due to difficulties in cell culture, these data are still under analysis.