Precision non-implantable neuromodulation therapies: a perspective for the depressed brain

Current first-line treatments for major depressive disorder (MDD) include pharmacotherapy and cognitive-behavioral therapy. However, one-third of depressed patients do not achieve remission after multiple medication trials, and psychotherapy can be costly and time-consuming. Although non-implantable neuromodulation (NIN) techniques such as transcranial magnetic stimulation, transcranial direct current stimulation, electroconvulsive therapy, and magnetic seizure therapy are gaining momentum for treating MDD, the efficacy of non-convulsive techniques is still modest, whereas use of convulsive modalities is limited by their cognitive side effects. In this context, we propose that NIN techniques could benefit from a precision-oriented approach. In this review, we discuss the challenges and opportunities in implementing such a framework, focusing on enhancing NIN effects via a combination of individualized cognitive interventions, using closed-loop approaches, identifying multimodal biomarkers, using computer electric field modeling to guide targeting and quantify dosage, and using machine learning algorithms to integrate data collected at multiple biological levels and identify clinical responders. Though promising, this framework is currently limited, as previous studies have employed small samples and did not sufficiently explore pathophysiological mechanisms associated with NIN response and side effects. Moreover, cost-effectiveness analyses have not been performed. Nevertheless, further advancements in clinical trials of NIN could shift the field toward a more "precision-oriented" practice.

Neuroimaging adolescents with depression in a middle-income country: feasibility of an fMRI protocol and preliminary results

Objective: To test the feasibility and to present preliminary results of a neuroimaging protocol to evaluate adolescent depression in a middle-income setting. Methods: We assessed psychotropic medication-free adolescents (age range 14-16 years) with a diagnosis of major depressive disorder (MDD). Participants underwent a comprehensive clinical evaluation and both structural and functional magnetic resonance imaging (fMRI). In this pilot study, a preliminary single-group analysis of resting-state fMRI (rs-fMRI) data was performed, with a focus on the default mode network (DMN), cognitive control network (CCN), and salience network (SN). Results: The sample included 29 adolescents with MDD (mean age 16.01, SD 0.78) who completed the protocol. Only two participants were excluded due to MRI quality issues (head movement), and were not included in the analyses. The scans showed significant connectivity between the medial prefrontal cortex and posterior cingulate cortex (DMN), the ACC and anterior insula (SN), and the lateral prefrontal cortex and dorsal parietal cortex (CCN). Conclusion: We demonstrated the feasibility of implementing a complex neuroimaging protocol in a middle-income country. Further, our preliminary rs-fMRI data revealed patterns of resting-state connectivity consistent with prior research performed in adolescents from high-income countries.

Electroencephalographic findings in patients with major depressive disorder during cognitive or emotional tasks: a systematic review

Objective: Major depressive disorder (MDD) is a prevalent psychiatric condition characterized by multiple symptoms that cause great distress. Uncovering the brain areas involved in MDD is essential for improving therapeutic strategies and predicting response to interventions. This systematic review discusses recent findings regarding cortical alterations in depressed patients during emotional or cognitive tasks, as measured by electroencephalography (EEG). Methods: A search of the MEDLINE/PubMed and Cochrane databases was carried out using the keywords EEG and depression, confined to article title. Results: The studies identified reveal the frontal cortex as an important brain structure involved in the complex neural processes associated with MDD. Findings point to disorganization of right-hemisphere activity and deficient cognitive processing in MDD. Depressed individuals tend to ruminate on negative information and respond with a pattern of relatively higher right frontal activity to emotional stimuli associated with withdrawal and isolation. Conclusion: Patients with MDD may have altered dynamic patterns of activity in several neuroanatomical structures, especially in prefrontal and limbic areas involved in affective regulation. Identification of these alterations might help predict the response of patients to different interventions more effectively and thus maximize the effects both of pharmacotherapeutic and of psychotherapeutic strategies.

Activity/rest rhythm of depressed adolescents undergoing therapy: case studies / Ritmo de atividade e repouso em adolescentes deprimidos durante terapia: estudos de caso

Abstract Introduction: Disorders of circadian rhythms have been reported in studies of both depressed children and of depressed adolescents. The aim of this study was to evaluate whether there is a relationship between the 24-hour spectral power (24h SP) of the activity/rest rhythm and the clinical course of depression in adolescents. Methods: Six 14 to 17-year-old adolescents were recruited for the study. They were all suffering from major depressive disorder, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria, as identified by the Schedule for Affective Disorders and Schizophrenia for School Aged Children: Present and Lifetime Version (K-SADS-PL). Depressive symptoms were assessed using the Children's Depression Rating Scale - Revised (CDRS-R) and clinical evaluations. Locomotor activity was monitored over a period of 13 consecutive weeks. Activity was measured for 10-minute periods using wrist-worn activity monitors. All patients were prescribed sertraline from after the first week up until the end of the study. Results: We found a relationship between high CDRS values and low 24-hour spectral power. Conclusions: The 24h SP of the activity/rest rhythm correlated significantly (negatively) with the clinical ratings of depression.

Resumo Introdução: Distúrbios do ritmo circadiano têm sido relatados em estudos com crianças e adolescentes deprimidos. O objetivo deste estudo foi avaliar se existe relação entre a potência espectral de 24 horas do ritmo de atividade e repouso e sintomas clínicos de depressão em adolescentes. Métodos: Seis adolescentes com idade entre 14 e 17 anos foram recrutados para o estudo. Eles foram diagnosticados com depressão maior de acordo com os critérios do Manual Diagnóstico e Estatístico de Transtornos Mentais, 4ª edição (DSM-IV), identificados utilizando-se o instrumento Schedule for Affective Disorders and Schizophrenia for School Aged Children: Present and Lifetime Version (K-SADS-PL). Os sintomas depressivos foram avaliados pelo questionário Children's Depression Rating Scale - Revised (CDRS-R) e por avaliações clínicas. A atividade motora foi monitorada por um período de 13 semanas consecutivas e registrada a cada 10 minutos utilizando-se monitores de atividades usados no pulso. Todos os pacientes utilizaram o antidepressivo sertralina começando após a primeira semana até o final do estudo. Resultados: Foi observada uma relação entre escores altos no CDRS-R e valores baixos de potência espectral de 24 horas no ritmo de atividade e repouso. Conclusão: A potência espectral de 24 horas do ritmo de atividade e repouso apresentou uma correlação significativa (negativa) com os sintomas clínicos de depressão.

Awareness of memory deficits is useful to distinguish between depression and mild cognitive impairment in the elderly

Objective: To investigate whether the level of awareness of memory deficits is useful for discriminating between major depressive disorder (MDD) and mild cognitive impairment (MCI) in the elderly. Methods: Sixty-three consecutively referred patients (38 women and 25 men) with memory concerns comprising three groups (clinical control, MDD and MCI) underwent a memory test (Rey Auditory Verbal Learning Test [RAVLT]) and completed the Memory Assessment Complaints-Questionnaire (MAC-Q). Level of awareness was estimated by the difference between the MAC-Q score and the score on the fifth presentation of the RAVLT. Memory performance, Mini-Mental State Examination (MMSE) and depressive symptoms (Geriatric Depression Scale [GDS]) were also assessed. Results: The control (n=25), MDD (n=16), and MCI (n=22) groups were similar in age, educational level, and MMSE (p > 0.05). Among the groups, the MDD group had the most memory complaints, whereas the MCI group had the worst objective memory performance. Level of awareness was capable of discriminating between MDD and MCI (p < 0.05), but not between MDD and clinical controls (p > 0.05). MDD subjects tended to underestimate their memory functioning as compared to controls (p < 0.05). Conclusion: Level of awareness of memory deficits was significantly useful to discriminate between MCI and MDD, which is a common difficulty faced by clinicians. Future studies with larger samples are needed to confirm these findings.

Sensory processing patterns, coping strategies, and quality of life among patients with unipolar and bipolar disorders

Objective: To compare sensory processing, coping strategies, and quality of life (QoL) in unipolar and bipolar patients; to examine correlations between sensory processing and QoL; and to investigate the relative contribution of sociodemographic characteristics, sensory processing, and coping strategies to the prediction of QoL. Methods: Two hundred sixty-seven participants, aged 16-85 years (53.6±15.7), of whom 157 had a diagnosis of unipolar major depressive disorder and 110 had bipolar disorder type I and type II, completed the Adolescent/Adult Sensory Profile, Coping Orientations to Problems Experienced, and 12-item Short-Form Health Survey version 2. The two groups were compared with multivariate analyses. Results: The unipolar and bipolar groups did not differ concerning sensory processing, coping strategies, or QoL. Sensory processing patterns correlated with QoL independently of mediation by coping strategies. Correlations between low registration, sensory sensitivity, sensation avoidance, and reduced QoL were found more frequently in unipolar patients than bipolar patients. Higher physical QoL was mainly predicted by lower age and lower sensory sensitivity, whereas higher mental QoL was mainly predicted by coping strategies. Conclusion: While age may predict physical QoL, coping strategies predict mental QoL. Future studies should further investigate the impact of sensory processing and coping strategies on patients’ QoL in order to enhance adaptive and functional behaviors related to affective disturbances.

Anesthesiologist: the patient's perception / O anestesiologista: a visão do doente

BACKGROUND AND OBJECTIVES: Anesthesia is still a major concern for patients, although the anesthetic complications have decreased significantly. Additionally, the role assigned to the anesthesiologist remains inaccurate. The aim of this study was to evaluate the concerns with anesthesia and assess the patient's knowledge about the anesthesiologist's duties. METHODS: Prospective study conducted over three months with patients in the preoperative anesthetic visit in a university hospital. Demographic information about the level of education and prior anesthesia was obtained. The knowledge of patients regarding the anesthesiologists' education was evaluated. Patients' concerns and anesthesiologist and surgeon responsibilities were classified with a 5-point scale. The analysis was performed with SPSS 21, and p < 0.05 was considered statistically significant. RESULTS: We included 204 patients, and 135 (66.2%) recognized the anesthesiologist as a specialist physician. Not waking up after surgery and postoperative infection were the main concerns compared to all others (p < 0.05). Women expressed more concern than men about not waking up after surgery, nausea and postoperative vomiting, medical problems, and waking up during surgery (p < 0.05). Ensure that patients do not wake up during surgery was the anesthesiologist task most recognized, compared to all other (p < 0.05). The surgeon was more recognized (p < 0.05) than the anesthesiologist in post-operative, antibiotics administration, and blood transfusions pain management. CONCLUSIONS: Patients need to be informed about the current safety of anesthesia and the anesthesiologist's functions. The patient involvement will demystify some fears and reassure the confidence in the health system.

JUSTIFICATIVA/OBJETIVOS: A anestesia ainda é uma preocupação importante para os doentes, embora as complicações anestésicas tenham diminuído significativamente. Adicionalmente, o papel atribuído ao anestesiologista permanece impreciso. Avaliar as preocupações com a anestesia e verificar o conhecimento dos doentes acerca das funções do anestesiologista foram os objetivos deste estudo. MÉTODOS: Estudo prospetivo decorrido durante 3 meses em doentes com consulta de anestesia pré-operatória num Hospital Universitário. Foi questionada informação demográfica, nível de educação e anestesia prévia. Foi avaliado o conhecimento dos doentes relativamente à educação do anestesiologista. As preocupações dos doentes, responsabilidades dos anestesiologistas e cirurgiões foram classificadas usando uma escala de 5 pontos. A análise foi realizada com SPSS 21, p < 0,05 foi considerado estatisticamente significativo. RESULTADOS: Foram incluídos 204 doentes. 135 (66,2%) reconheceram o anestesiologista como médico especialista. Não acordar após a cirurgia e infeção pós-operatória foram as principais preocupações, comparativamente a todas as outras (p < 0,05). As mulheres manifestaram maior preocupação do que os homens com (p < 0,05): não acordar após a cirurgia, náuseas e vómitos pós-operatórios, problemas médicos e acordar durante a cirurgia. Assegurar que os doentes não acordem durante a cirurgia foi a tarefa mais reconhecida no anestesiologista, comparativamente a todas as outras (p < 0,05). O cirurgião foi mais reconhecido (p < 0,05) do que o anestesiologista na gestão da dor pós-operatória, administração de antibióticos e transfusões sanguíneas. CONCLUSÕES: Os doentes necessitam de ser informados acerca da atual segurança da anestesia e sobre as funções do anestesiologista. Envolver o doente irá desmistificar alguns receios e reassegurar a confiança no sistema de saúde.

The joint structure of major depression, anxiety disorders, and trait negative affect

Background: Dimensional models of psychopathology demonstrate that two correlated factors of fear and distress account for the covariation among depressive and anxiety disorders. Nevertheless, these models tend to exclude variables relevant to psychopathology, such as temperament traits. This study examined the joint structure of DSM-IV-based major depression and anxiety disorders along with trait negative affect in a representative sample of adult individuals residing in the cities of São Paulo and Rio de Janeiro, Brazil. Methods: The sample consisted of 3,728 individuals who were administered sections D (phobic, anxiety and panic disorders) and E (depressive disorders) of the Composite International Diagnostic Interview (CIDI) 2.1 and a validated version of the Positive and Negative Affect Schedule. Data were analyzed using correlational and structural equation modeling. Results: Lifetime prevalence ranged from 2.4% for panic disorder to 23.2% for major depression. Most target variables were moderately correlated. A two-factor model specifying correlated fear and distress factors was retained and confirmed for models including only diagnostic variables and diagnostic variables along with trait negative affect. Conclusions: This study provides support for characterization of internalizing psychopathology and trait negative affect in terms of correlated dimensions of distress and fear. These results have potential implications for psychiatric taxonomy and for understanding the relationship between temperament and psychopathology. .

Impaired cognition in depression and Alzheimer (AD): a gradient from depression to depression in AD / Alterações cognitivas na depressão e na doença de Alzheimer: um gradiente da depressão até a doença de Alzheimer

Objective To assess cognition in major depressed (MD), Alzheimer's disease (AD), and depression in AD elderly. Method Subjects were evaluated by Mini Mental, Rey Auditory Verbal Learning Test, Rey Complex Figure, Digit Span, Similarities, Trail Making A/B, Verbal Fluency and Stroop. One-way ANOVA and multivariate models were used to compare the performance of each group on neuropsychological tests. Results We evaluated 212 subjects. Compared to MD, attention, working memory, processing speed and recall showed significantly better in controls. Controls showed significantly higher performance in all cognitive measures, except in attention compared to AD. Verbal fluency, memory, processing speed and abstract reasoning in MD was significantly higher compared to AD. AD was significantly better in general cognitive state than depression in AD. All other cognitive domains were similar. Conclusion A decreasing gradient in cognition appeared from the control to depression in AD, with MD and AD in an intermediate position. .

Objetivo Avaliar a cognição em idosos com depressão Maior (DM), doença de Alzheimer (DA) e Depressão na DA. Método Utilizou-se o Mini Mental, Rey Auditory Verbal Learning Test, Figura de Rey, Dígitos, Semelhanças, Trail Making A/B, Fluência Verbal e Stroop. ANOVA one-way e modelos multivariados foram utilizados para comparar o desempenho dos grupos. Resultados Foram avaliados 212 sujeitos. Comparado com DM, controles apresentaram desempenho significativamente melhor na atenção, memória de trabalho, velocidade de processamento e evocação. Os controles apresentaram desempenho significativamente superior em todas as avaliações, exceto na atenção comparado com DA. Fluência verbal, memória, velocidade de processamento e raciocínio abstrato na DM foi significativamente maior comparado com DA. DA foi significativamente melhor no estado cognitivo geral comparado a depressão na DA, os outros domínios foram semelhantes. Conclusão Observou-se um gradiente decrescente na cognição dos controles até a Depressão na DA, com os grupos DM e DA com desempenhos intermediários. .

Avances en el estudio de la neurobiología de la depresión: rol de la hormona concentradora de melanina / Progress made in studies in the neurobiology of depression: a role for the melanin-concentrating hormone

Introducción: la depresión mayor (DM) es una enfermedad psiquiátrica frecuente, con importante morbilidad y una relación estrecha con el suicidio. Objetivo: hacer una puesta a punto de los avances en el estudio de la neurobiología de la DM, enfocándonos en el posible rol de la hormona concentradora de melanina (MCH) en esta patología. Metodología: revisión de la bibliografía con énfasis en nuestros propios trabajos originales. Resultados: la MCH es un neuromodulador peptídico sintetizado por neuronas del hipotálamo. Las neuronas MCHérgicas envían proyecciones hacia diversas regiones del sistema nervioso central, incluyendo las áreas vinculadas con la regulación de la vigilia y del sueño, así como a diversas estructuras del sistema límbico que participan en la regulación del humor. Aunque numerosos estudios han relacionado el sistema MCHérgico con el control de la homeostasis energética, hallazgos recientes han permitido señalar un rol de este sistema en los mecanismos de generación del sueño. A su vez, una convergencia de datos provenientes de diversos estudios sugiere que la MCH estaría involucrada en la fisiopatología de la DM. Nuestros propios estudios preclínicos tienden a indicar que la MCH promueve la generación del sueño REM y un estado tipo depresivo. Ambos efectos estarían siendo mediados a través de la modulación de la actividad de las neuronas serotoninérgicas del núcleo dorsal del rafe. Conclusiones: estudios preclínicos sugieren un rol protagónico del sistema MCHérgico en la fisiopatología de la depresión. Resta confirmar si esta afirmación es cierta en pacientes con DM...

Pathophysiology of mood disorders in temporal lobe epilepsy / Fisiopatologia dos transtornos de humor na epilepsia do lobo temporal

OBJECTIVE: There is accumulating evidence that the limbic system is pathologically involved in cases of psychiatric comorbidities in temporal lobe epilepsy (TLE) patients. Our objective was to develop a conceptual framework describing how neuropathological, neurochemical and electrophysiological aspects might contribute to the development of psychiatric symptoms in TLE and the putative neurobiological mechanisms that cause mood disorders in this patient subgroup. METHODS: In this review, clinical, experimental and neuropathological findings, as well as neurochemical features of the limbic system were examined together to enhance our understanding of the association between TLE and psychiatric comorbidities. Finally, the value of animal models in epilepsy and mood disorders was discussed. CONCLUSIONS:TLE and psychiatric symptoms coexist more frequently than chance would predict. Alterations and neurotransmission disturbance among critical anatomical networks, and impaired or aberrant plastic changes might predispose patients with TLE to mood disorders. Clinical and experimental studies of the effects of seizures on behavior and electrophysiological patterns may offer a model of how limbic seizures increase the vulnerability of TLE patients to precipitants of psychiatric symptoms.

OBJETIVO: Há evidências crescentes do envolvimento do sistema límbico nas comorbidades psiquiátricas associadas à epilepsia do lobo temporal (ELT). Nosso objetivo foi descrever o panorama atual das alterações neuropatológicas, neuroquímicas e eletrofisiológicas que podem contribuir para o desenvolvimento de sintomas psiquiátricos na ELT e explorar possíveis mecanismos neurobiológicos que podem levar ao aparecimento das desordens de humor nesse subgrupo de pacientes. MÉTODOS: Achados clínicos, de modelos experimentais e neuropatológicos foram revistos, assim como características neuroquímicas do sistema límbico foram examinadas em conjunto para auxiliar nossa compreensão sobre a associação entre ELT e transtornos de humor. CONCLUSÕES: A ELT e os sintomas psiquiátricos coexistem numa frequência muito maior do que o acaso poderia sugerir. Alterações e desregulação de redes anatômicas essenciais, além de mudanças plásticas aberrantes ou deficientes, podem predispor o cérebro de pacientes com ELT a transtornos de humor. Estudos experimentais e clínicos sobre o efeito das crises no comportamento e nos padrões eletrofisiológicos podem oferecer um modelo de como as crises límbicas aumentam a vulnerabilidade a sintomas psiquiátricos em pacientes com ELT.

Morning and nocturnal serum melatonin rhythm levels in patients with major depressive disorder: an analytical cross-sectional study / Medir los niveles del ritmo de melatonina día-noche entre los pacientes con trastorno depresivo mayor: un estudio analítico transversal

CONTEXT AND OBJECTIVE: The pineal gland is an adaptive organ that precisely regulates the biological rhythms of melatonin brain hemostasis. Variation in the regulation of melatonin rhythms is a likely cause of depressive disorder. The purpose of this study was to measure serum melatonin levels in patients with major depressive disorder (MDD) and normal control subjects. DESIGN AND SETTING: Analytical cross-sectional study at the industrial medical unit of the Iron Smelting Company of Isfahan, Iran. METHODS: The morning and nocturnal serum melatonin levels of patients and controls were measured using the enzyme-linked immunosorbent assay (ELISA) method. All data were assessed using variance analysis. RESULTS: The morning and nocturnal serum melatonin levels of depressed and healthy subjects differed (P < 0.05). The nocturnal serum melatonin levels of depressed women were lower than those of depressed men (P < 0.05). CONCLUSIONS: The findings of this study showed that the nocturnal serum melatonin levels in the depressed patients were lower than in the controls. Thus, the peak melatonin phase in the depressed patients was reached with delay. CLINICAL TRIAL REGISTRATION NUMBER: NCT01357083.

CONTEXTO Y OBJETIVO: La glándula pineal actúa precisamente regulando los ritmos biológicos de melatonina de hemostasia cerebral, como un órgano adaptativo. La modificación del ritmo de melatonina puede ser el motivo probable del trastorno depresivo. Este estudio se realizó con el objetivo de medir los niveles de melatonina entre los pacientes con trastorno depresivo mayor y los sanos. DISEÑO Y ESPACIO: Estudio analítico transversal-la unidad medicina laboral de empresa de Zob Ahan de Isfahán-Irán. MÉTODO: Los niveles de melatonina en suero día-noche se midó entre dos grupos (pacientes y sanos) utilizando el método de ELISA (Ensayo por inmunoabsorción ligado a enzimas). Todos los datos se hizo utilizando el análisis de la varianza. RESULTADOS: El nivel de melatonina en suero día-noche era distinto entre los deprimidos y los saludables (P < 0.05). El nivel de melatonina en suero en las mujeres deprimidas fue menos que los varones deprimidos (P < 0.05). CONCLUSIONES: Esta investigación muestra que el nivel de melatonina nocturna en los deprimidos ha sido menos que los controlados, pues el pico de fase de melatonina en los pacientes deprimidos alcanza con retraso. NÚMERO DE REGISTRO DE ENSAYO CLÍNICO: NCT01357083.

Acute exercise improves cognition in the depressed elderly: the effect of dual-tasks

OBJECTIVE: The goal of this study was to assess the acute effect of physical exercise on the cognitive function of depressed elderly patients in a dual-task experiment. INTRODUCTION: Physical exercise has a positive effect on the brain and may even act as a treatment for major depressive disorder. However, the effects of acute cardiovascular exercise on cognitive function during and after one session of aerobic training in elderly depressive patients are not known. METHODS: Ten elderly subjects diagnosed with major depressive disorder performed neuropsychological tests during and after a moderate physical exercise session (65-75 percentHRmax). A Digit Span Test (Forward and Backward) and a Stroop Color-Word Test were used to assess cognitive function. The elderly participants walked on an electric treadmill for 30 minutes and underwent the same cognitive testing before, during, immediately after, and 15 minutes after the exercise session. In the control session, the same cognitive testing was conducted, but without exercise training. RESULTS: The results of the Digit Span Test did not change between the control and the exercise sessions. The results of the Stroop Color-Word Test improved after physical exercise, indicating a positive effect of exercise on cognition. CONCLUSIONS: These data suggest that the cognitive functions of depressed elderly persons, especially attention and inhibitory control, are not impaired during and after an acute session of physical exercise. In contrast, the effect of dual-tasks showed beneficial results for these subjects, mainly after exercise. The dual-task may be a safe and useful tool for assessing cognitive function.

Verbal fluency in Alzheimer's disease, Parkinson's disease, and major depression

OBJECTIVE: To compare verbal fluency among Alzheimer's disease, Parkinson's disease, and major depression and to assess the sociodemographic and clinical factors associated with the disease severity. METHODS: Patients from an outpatient university center with a clinical diagnosis of Alzheimer's disease, Parkinson's disease or major depression were studied. Severity was staged using the Hoehn & Yahr scale, the Hamilton Depression scale and the Clinical Dementia Rating for Parkinson's disease, major depression, and Alzheimer's disease, respectively. All subjects were tested with the Mini-Mental State Examination, the digit span test, and the verbal fluency test (animals). We fit four types of regression models for the count variable: Poisson model, negative binomial model, zero-inflated Poisson model, and zero-inflated negative binomial model. RESULTS: The mean digit span and verbal fluency scores were lower in patients with Alzheimer's disease (n = 34) than in patients with major depression (n = 52) or Parkinson's disease (n = 17) (p<0.001). The average number of words listed was much lower for Alzheimer's disease patients (7.2 words) compared to the patients presenting with major depression (14.6 words) or Parkinson's disease (15.7 words) (KW test = 32.4; p<0.01). Major depression and Parkinson's disease groups listed 44 percent (ROM = 1.44) and 48 percent (ROM = 1.48) more words, respectively, compared to those patients with Alzheimer's disease; these results were independent of age, education, disease severity and attention. Independently of diagnosis, age, and education, severe disease showed a 26 percent (ROM = 0.74) reduction in the number of words listed when compared to mild cases. CONCLUSIONS: Verbal fluency provides a better characterization of Alzheimer's disease, major depression, and Parkinson's disease, even at later stages.

Neuromodulation approaches for the treatment of major depression: challenges and recommendations from a working group meeting / Estratégias de neuromodulação para o tratamento da depressão maior: desafios e recomendações de uma força-tarefa

The use of neuromodulation as a treatment for major depressive disorder (MDD) has recently attracted renewed interest due to development of other non-pharmacological therapies besides electroconvulsive therapy (ECT) such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), deep brain stimulation (DBS), and vagus nerve stimulation (VNS). METHOD: We convened a working group of researchers to discuss the updates and key challenges of neuromodulation use for the treatment of MDD. RESULTS: The state-of-art of neuromodulation techniques was reviewed and discussed in four sections: [1] epidemiology and pathophysiology of MDD; [2] a comprehensive overview of the neuromodulation techniques; [3] using neuromodulation techniques in MDD associated with non-psychiatric conditions; [4] the main challenges of neuromodulation research and alternatives to overcome them. DISCUSSION: ECT is the first-line treatment for severe depression. TMS and tDCS are strategies with a relative benign profile of side effects; however, while TMS effects are comparable to antidepressant drugs for treating MDD; further research is needed to establish the role of tDCS. DBS and VNS are invasive strategies with a possible role in treatment-resistant depression. In summary, MDD is a chronic and incapacitating condition with a high prevalence; therefore clinicians should consider all the treatment options including invasive and non-invasive neuromodulation approaches.

O uso de técnicas de neuromodulação para o tratamento do transtorno depressivo maior (TDM) tem despertado um renovado interesse nos últimos anos com o desenvolvimento de outras intervenções não-farmacólogicas além da eletroconvulsoterapia (ECT), como a estimulação magnética transcraniana (EMT), a estimulação transcraniana por corrente continua (ETCC), a estimulação cerebral profunda (DBS) e a estimulação de nervo vago (VNS). MÉTODO: Nós organizamos um grupo de trabalho com vários pesquisadores para discutir os avanços recentes e os principais desafios para o uso da neuromodulação no tratamento do TDM. RESULTADOS: O estado-da-arte da neuromodulação foi revisado e discutido em quatro seções: [1] epidemiologia e fisiopatologia do TDM; [2] uma revisão das técnicas de neuromodulação; [3] o uso das técnicas de neuromodulação na depressão que ocorre associada ou em virtude de condições não-psiquiátricas; [4] os principais desafios da pesquisa na neuromodulação e alternativas para superá-los. DISCUSSÃO: ECT é o tratamento de primeira linha para depressão grave. EMT e ETCC são estratégias com um perfil benigno de efeitos adversos; contudo, enquanto os efeitos da EMT são comparáveis ao das drogas antidepressivas para o tratamento da TDM, a eficácia da ETCC ainda precisa ser estabelecida por mais pesquisas clínicas. DBS e VNS são intervenções invasivas com um papel possível para a depressão refratária. Em resumo, TDM é uma condição crônica, incapacitante e de alta prevalência; portanto na prática clínica todas as opções de tratamento possíveis, incluindo as farmacológicas e não-farmacológicas, devem ser consideradas.

A via L-arginina-óxido nítrico no transtorno depressivo e sua associação com a função plaquetária e o estresse oxidativo / L-arginine-nitric oxide pathway in depressive disorder associate with platelet function and oxidative stress

O transtorno depressivo (TD) é um fator de risco cardiovascular independente que apresenta elevada morbi-mortalidade. Recentes evidências sugerem a participação do óxido nítrico (NO), potente vasodilatador e anti-agregante plaquetário, na patogênese de doenças cardiovasculares e psiquiátricas. A síntese do NO ocorre através da conversão do aminoácido L-arginina em L-citrulina e NO, pela ação da enzima NO sintase (NOS). Esta tese aborda o papel da via L-arginina-NO em plaquetas de pacientes com TD e sua associação com a função plaquetária e estresse oxidativo. Para análise comportamental da depressão em modelo animal, foi utilizado o modelo de estresse pós-natal de separação única (SMU). Os animais foram divididos em quatro grupos para a realização do estudo: Grupo Controle Sedentário (GCS), Grupo Controle Exercício (GCE), Grupo SMU Sedentário (SMUS) e Grupo SMU Exercício (SMUE). O treinamento físico (TF) dos animais englobou 8 semanas, com duração de 30 minutos e uma velocidade de treinamento estabelecida pelo teste máximo (TE). Para o estudo em humanos, 10 pacientes com TD com score Hamilton: 20+-1, (média de idade: 38+-4anos), foram pareados com 10 indivíduos saudáveis (média de idade: 38+-3anos). Os estudos em humanos e animais foram aprovados pelos Comitês de Ética: 1436 - CEP/HUPE e CEUA/047/2010, respectivamente. Foi mensurado em humanos e em animais: transporte de L-arginina, concentração GMPc, atividade das enzimas NOS e superóxido dismutase (SOD) em plaquetas e cortisol sistêmico. Experimentos realizados somente em humanos: expressão das enzimas NOS, arginase e guanilato ciclase através de Western Blotting. A agregação plaquetária foi induzida por colágeno e foi realizada análise sistêmica de proteína C-reativa, fibrinogênio e L-arginina. Para o tratamento estatístico utilizou-se três testes estatísticos para avaliar as diferenças das curvas de sobrevida: Kaplan-Meier, e os testes de Tarone-Ware e Peto-Prentice. Em humanos, houve uma redução...

Major depressive disorder (MDD) is an independent cardiovascular risk factor that presents high morbimortality. Recent evidence suggests the involvement of nitric oxide (NO), a potent vasodilator and anti-aggregating effect, in the pathogenesis of cardiovascular and psychiatric diseases. Nitric oxide (NO) is synthesized through conversion of the amino acid L-arginine into L-citrulline and NO by the enzyme NO synthase (NOS). This thesis addresses the role of the L-arginine-NO pathway in platelets from patients with MDD and its association with platelet function and oxidative stress. For a behavioural analysis of depression in an animal model, we used the single maternal separation (SMS) model, where the offspring was separated from its mother for eight minutes. The animals were divided into four groups for the study: Sedentary Control Group (SCG), Exercise Control Group (ECG), SMS Sedentary Group (SSMS) and SMS Exercise Group (ESMS). Physical training (PT) of the animals took 8 weeks, with a duration of 30 minutes and a training speed established by the maximum test (ET) of 14m/min. For the human study, there were ten MDD patients with Hamilton score: 20+-1 (mean age: 38+-4 years) and 10 healthy subjects (mean age: 38+-3 years). The human and animal studies were approved by the Ethics Committee: 1436 - CEP/HUPE and CEUA/047/2010 respectively. The following were measured in human and animal models: L-arginine transport, NOS and superoxide dismutase (SOD) activities, cGMP concentration and analysis of systemic cortisol. Experiments performed only in humans: NOS, arginase and guanylate cyclae expression evaluated by Western Blotting. Platelet aggregation was induced by collagen, and C-reactive protein, fibrinogen, and L-arginine were systemically analyzed. For statistical treatment, three statistical tests were used to evaluate the differences in survival curves: Kaplan-Meier, and the Tarone-Ware and Peto-Prentice tests. In humans, there was a reduction...

Expression of neuronal nitric oxide synthase in the hippocampal formation in affective disorders

Hippocampal output is increased in affective disorders and is mediated by increased glutamatergic input via N-methyl-D-aspartate (NMDA) receptor and moderated by antidepressant treatment. Activation of NMDA receptors by glutamate evokes the release of nitric oxide (NO) by the activation of neuronal nitric oxide synthase (nNOS). The human hippocampus contains a high density of NMDA receptors and nNOS-expressing neurons suggesting the existence of an NMDA-NO transduction pathway which can be involved in the pathogenesis of affective disorders. We tested the hypothesis that nNOS expression is increased in the human hippocampus from affectively ill patients. Immunocytochemistry was used to demonstrate nNOS-expressing neurons in sections obtained from the Stanley Consortium postmortem brain collection from patients with major depression (MD, N = 15), bipolar disorder (BD, N = 15), and schizophrenia (N = 15) and from controls (N = 15). nNOS-immunoreactive (nNOS-IR) and Nissl-stained neurons were counted in entorhinal cortex, hippocampal CA1, CA2, CA3, and CA4 subfields, and subiculum. The numbers of Nissl-stained neurons were very similar in different diagnostic groups and correlated significantly with the number of nNOS-IR neurons. Both the MD and the BD groups had greater number of nNOS-IR neurons/400 µm² in CA1 (mean ± SEM: MD = 9.2 ± 0.6 and BD = 8.4 ± 0.6) and subiculum (BD = 6.7 ± 0.4) when compared to control group (6.6 ± 0.5) and this was significantly more marked in samples from the right hemisphere. These changes were specific to affective disorders since no changes were seen in the schizophrenic group (6.7 ± 0.8). The results support the current view of the NMDA-NO pathway as a target for the pathophysiology of affective disorders and antidepressant drug development.

Estimulação magnética transcraniana: um estudo controlado do padrão da ativação cerebral na depressão maior utilizando a tomografia por emissão de pósitrons / A TMS/PET study on brain activity and connectivity in recurrent major depression

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)...

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...