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Background: Early-life stress is associated with alterations in telomere length, a marker of accumulated stress and aging, and a risk factor for psychiatric disorders. Nonhuman primate maternal variable foraging demand (VFD) is a validated early-life stress model, resulting in anxiety- and depressive-like symptoms in offspring. Previous studies reported increased plasma glucagon-like peptide 1 (pGLP-1) along with insulin resistance in this model. We investigated whether VFD rearing related to adult telomere length and to these neuroendocrine markers. Methods: Adult leukocyte telomere length was measured in VFD-reared (12 males, 13 females) and non-VFD–reared (9 males, 26 females) bonnet macaques. Associations between adult telomere length and adolescent fasting pGLP-1 or insulin resistance in VFD-reared versus non-VFD–reared groups were examined using regression modeling, controlling for sex, weight, and age. Results: VFD subjects had relatively longer telomeres than non-VFD subjects (p = .017), and females relatively longer than males (p = .0004). Telomere length was positively associated with pGLP-1 (p = .0009) and with reduced insulin sensitivity (p < .0001) in both sexes, but not as a function of rearing group. Conclusions: Unexpectedly, VFD was associated with longer adult telomere length. Insulin resistance may lead to higher pGLP-1 levels in adolescence, which could protect telomere length in VFD offspring as adults. Associations between adult telomere length and adolescent insulin resistance and high pGLP-1 may reflect an adaptive, compensatory response after early-life stress exposure.

Introduction Using proton magnetic resonance spectroscopy imaging, the effects of early life stress on nonhuman primate striatal neuronal integrity were examined as reflected by N -acetyl aspartate (NAA) concentrations. NAA measures were interrogated through examining their relationship to previously documented early life stress markers—cerebrospinal fluid corticotropin-releasing factor concentrations, hippocampal volume, body mass, and behavioral timidity. Rodent models of depression exhibit increases in neurotrophic effects in the nucleus accumbens. We hypothesized that rearing under conditions of early life stress (variable foraging demand, VFD) would produce persistent elevations of NAA concentrations (in absolute or ratio form) in ventral striatum/caudate nucleus (VS/CN) with altered correlation to early life stress markers. Methods Eleven bonnet macaque males reared under VFD conditions and seven age-matched control subjects underwent proton magnetic resonance spectroscopy imaging during young adulthood. Voxels were placed over VS/CN to capture nucleus accumbens. Cisternal cerebrospinal fluid corticotropin-releasing factor concentrations, hippocampal volume, body mass, and response to a human intruder had been previously determined. Results VFD-reared monkeys exhibited significantly increased NAA/creatine concentrations in right VS/CN in comparison to normally reared controls, controlling for multiple comparisons. In comparison to controls, VFD cerebrospinal fluid corticotropin-releasing factor concentrations were directly associated with right VS/CN absolute NAA. Left hippocampal volume was inversely associated with left VS/CN NAA/creatine in VFD reared but not in controls. Disruption of a normative inverse correlation between left VS/CN NAA and body mass was noted in VFD. Only non-VFD subjects exhibited a direct relationship between timidity response to an intruder and right VS/CN NAA. Conclusion Early life stress produced persistent increases in VS/CN NAA, which demonstrated specific patterns of association (or lack thereof) to early life stress markers in comparison to non-VFD subjects. The data are broadly consistent with a stable nonhuman primate phenotype of anxiety and mood disorder vulnerability whereby in vivo indicators of neuronal integrity, although reduced in hippocampus, are increased in striatum. The findings may provide a catalyst for further studies in humans and other species regarding a reciprocal hippocampal/nucleus accumbens relationship in affective disorders.

Objective: Borderline personality disorder (BPD) is a devastating condition that causes intense disruption of patients' lives and relationships. Proper understanding of BPD neurobiology could help provide the basis for earlier and effective interventions. As neuroimaging studies of patients with BPD are still scarce, volumetric and geometric features of the cortical structure were assessed to ascertain whether structural cortical alterations are present in BPD patients. Methods: Twenty-five female outpatients with BPD underwent psychiatric evaluation (SCID-I and II) and a 1.5 T magnetic resonance imaging (MRI) brain scan. The control group comprised 25 healthy age-matched females. Images were processed with the FreeSurfer package, which allows analysis of cortical morphology with more detailed descriptions of volumetric and geometric features of cortical structure. Results: Compared with controls, BPD patients exhibited significant cortical abnormalities in the fronto-limbic and paralimbic regions of both hemispheres. Conclusion: Significant morphologic abnormalities were observed in patients with BPD on comparison with a healthy control group through a multimodal approach. This study highlights the involvement of regions associated with mood regulation, impulsivity, and social behavior in BPD patients and presents a new approach for further investigation through a method of structural analysis based on distinct and simultaneous volumetric and geometric parameters.

Background: Thalamic volume measures have been linked to obsessive-compulsive disorder (OCD) in children and adolescents. However, it is unclear if alterations in thalamic volumes occur before or after symptom onset and if there is a relation to the presence of sub-clinical obsessive-compulsive symptoms (OCS). Here, we explore the relationship between OCS and the rate of thalamic volume change in a cohort of children and youth at high risk to develop a mental disorder. A secondary aim was to determine if there is a relationship between OCS and the individual's OCD polygenic risk score (OCD-PRS) and between the rate of thalamic volume change and the OCD-PRS.Methods: The sample included 378 children enrolled in the longitudinal Brazilian High-Risk Cohort for Mental Conditions. Participants were assessed for OCS and the symmetrized percent change (SPC) of thalamic volume across two time-points separated by 3 years, along with the OCD-PRS. Zero-altered negative binomial models were used to analyze the relationship between OCS and thalamic SPC. Multiple linear regressions were used to examine the relationship between thalamic SPC and OCD-PRS.Results: A significant relationship between OCS and the right thalamus SPC (p = 0.042) was found. There was no significant relationship between changes in thalamic volume SPC and OCD-PRS.Conclusions: The findings suggest that changes in the right thalamic volume over the course of 3 years in children may be associated to OCS. Future studies are needed to confirm these results and further characterize the specific nature of OCS symptoms associated with thalamic volumes.

Abstract Background Adaptive behavior can be impaired in different neurodevelopmental disorders and may be influenced by confounding factors, such as intelligence quotient (IQ) and socioeconomic classification. Our main objective was to verify whether adaptive behavior profiles differ in three conditions—Williams Beuren syndrome (WBS), Down syndrome (DS), and autism spectrum disorder (ASD), as compared with healthy controls (HC) and with each other. Although the literature points towards each disorder having a characteristic profile, no study has compared profiles to establish the specificity of each one. A secondary objective was to explore potential interactions between the conditions and socioeconomic status, and whether this had any effect on adaptive behavior profiles. Methods One hundred and five adolescents were included in the study. All adolescents underwent the following evaluations: the Vineland Adaptive Behavior Scale (VABS), the Wechsler Intelligence Scale for Children (WISC), and the Brazilian Economic Classification Criteria. Results Our results demonstrated that the WBS group performed better than the DS group in the communication domain, β = −15.08, t(3.45), p = .005, and better than the ASD group in the socialization domain, β = 8.92, t(−2.08), p = .013. The DS group also performed better than the ASD group in socialization, β = 16.98, t(−2.32), p = .024. IQ was an important confounding factor, and socioeconomic status had an important effect on the adaptive behavior of all groups. Conclusions There is a heterogeneity regarding adaptive behavior profiles in WBS, DS, and ASD. These data are important to better design specific strategies related to the health and social care of each particular group.

Background The anterior cingulate gyrus is involved in the extinction of conditioned fear responses and is implicated in the pathophysiology of posttraumatic stress disorder. The expression of N-acetylaspartate and choline may be altered in the anterior cingulate gyri of children and adolescents with posttraumatic stress disorder. Methods We conducted a proton magnetic resonance spectroscopy study, longitudinally investigating N-acetylaspartate/creatine and choline/creatine ratios in the anterior cingulate gyri of children and adolescents, aged from 8 to 12 years, who had been exposed to various forms of violence or were non-trauma control. Based on baseline posttraumatic stress symptoms (“sub-clinical”), participants were divided into two groups: posttraumatic stress (n = 19) and control (n = 19). Proton magnetic resonance spectroscopy scans were repeated a year later in trauma exposed participants. Trauma assessments included the Childhood Trauma Questionnaire. Results Exploratory analyses revealed a significant negative correlation between follow-up anterior cingulate gyrus N-acetylaspartate/creatine and Childhood Trauma Questionnaire scores in posttraumatic stress (r = −0.62, p = 0.01) but not control group (r = 0.16, p = 0.66). However, we found no significant differences in anterior cingulate gyrus N-acetylaspartate/creatine or choline/creatine between posttraumatic stress and control. In addition, there were no significant effects of time, group, or time-by-group interactions. Conclusions In this pediatric population, anterior cingulate gyrus N-acetylaspartate/creatine and choline/creatine were not affected by posttraumatic stress and on average these metabolites remained stable over time. However, the study provided intriguing preliminary evidence revealing that participants suffering from posttraumatic stress at baseline have shown, a year later, reduced anterior cingulate gyrus N-acetylaspartate/creatine among those with high trauma severity. This pilot evidence warrants replication in future studies to confirm these findings and to determine the longitudinal effects and interactions between childhood posttraumatic stress and trauma.

Objective: Functional neuroimaging techniques represent fundamental tools in the context of translational research integrating neurobiology, psychopathology, neuropsychology, and therapeutics. In addition, cognitive-behavioral therapy (CBT) has proven its efficacy in the treatment of anxiety disorders and may be useful in phobias. The literature has shown that feelings and behaviors are mediated by specific brain circuits, and changes in patterns of interaction should be associated with cerebral alterations. Based on these concepts, a systematic review was conducted aiming to evaluate the impact of CBT on phobic disorders measured by functional neuroimaging techniques. Methods: A systematic review of the literature was conducted including studies published between January 1980 and April 2012. Studies written in English, Spanish or Portuguese evaluating changes in the pattern of functional neuroimaging before and after CBT in patients with phobic disorders were included. Results: The initial search strategy retrieved 45 studies. Six of these studies met all inclusion criteria. Significant deactivations in the amygdala, insula, thalamus and hippocampus, as well as activation of the medial orbitofrontal cortex, were observed after CBT in phobic patients when compared with controls. Conclusion: In spite of their technical limitations, neuroimaging techniques provide neurobiological support for the efficacy of CBT in the treatment of phobic disorders. Further studies are needed to confirm this conclusion.

OBJECTIVE: To report structural and functional neuroimaging studies exploring the potential role of the orbitofrontal cortex (OFC) in the pathophysiology of the most prevalent psychiatric disorders (PD). METHOD: A non-systematic literature review was conducted by means of MEDLINE using the following terms as parameters: "orbitofrontal cortex", "schizophrenia", "bipolar disorder", "major depression", "anxiety disorders", "personality disorders" and "drug addiction". The electronic search was done up to July 2011. DISCUSSION: Structural and functional OFC abnormalities have been reported in many PD, namely schizophrenia, mood disorders, anxiety disorders, personality disorders and drug addiction. Structural magnetic resonance imaging studies have reported reduced OFC volume in patients with schizophrenia, mood disorders, PTSD, panic disorder, cluster B personality disorders and drug addiction. Furthermore, functional magnetic resonance imaging studies using cognitive paradigms have shown impaired OFC activity in all PD listed above. CONCLUSION: Neuroimaging studies have observed an important OFC involvement in a number of PD. However, future studies are clearly needed to characterize the specific role of OFC on each PD as well as understanding its role in both normal and pathological behavior, mood regulation and cognitive functioning.OBJETIVO: Relatar estudos de neuroimagens estruturais e funcionais explorando o papel potencial do córtex orbitofrontal (COF) na fisiopatologia dos transtornos psiquiátricos (TP) mais prevalentes. MÉTODO: Foi realizada uma revisão não sistemática da literatura no MEDLINE, usando como parâmetros os seguintes termos: "córtex orbitofrontal", "esquizofrenia", "transtorno bipolar", "depressão maior", "transtornos ansiosos", "transtornos de personalidade" e "dependência a drogas". A pesquisa eletrônica foi feita até julho de 2011. DISCUSSÃO: Foram relatadas anormalidades estruturais e funcionais do COF em muitos TP, particularmente esquizofrenia, transtornos afetivos, transtornos ansiosos, transtornos de personalidade e dependência a drogas. Estudos de aquisição de imagens estruturais por ressonância magnética relataram a redução do volume do COF em pacientes portadores de esquizofrenia, transtornos afetivos, TEPT, transtorno do pânico, transtornos de personalidade do grupo B e dependência a drogas. Além disso, estudos de aquisição de imagens funcionais por ressonância magnética empregando paradigmas cognitivos demonstraram alterações na atividade do COF em todos os TP anteriormente relacionados. CONCLUSÃO: Estudos de neuroimagens observaram um envolvimento importante do COF em vários TP. Entretanto, estudos futuros são claramente necessários para caracterizar o papel específico do COF em cada TP, assim como para a compreensão de seu papel tanto no comportamento normal como no patológico, na regulação do humor e no funcionamento cognitivo.

OBJECTIVE: The aim of this study was to examine the cerebellar volume of subjects at different stages of Alzheimer's disease and to investigate whether volume reductions in this structure are related to cognitive decline. METHOD: Ninety-six subjects from an epidemiological study were submitted to a magnetic resonance imaging scan and evaluated using the Mini-Mental State Examination and the Functional Activities Questionnaire. Subjects were divided into five groups according to the Clinical Dementia Rating scale. Twenty-six subjects from the original group who had no dementia diagnosis at baseline were re-evaluated for the onset of dementia after two years. RESULTS: The volumes of the cerebellar hemispheres, posterior cerebellar lobe, vermis and temporal lobe were found to be reduced as a function of the severity of the disease. There were significant positive correlations between the volume of the temporal lobe and cerebellum and the language, attention, and total scores in the Mini-Mental State Examination and the Functional Activities Questionnaire. A logistic regression analysis demonstrated that reduced temporal lobe, posterior cerebellar lobe and vermal volume at baseline is a risk factor for the onset of dementia. CONCLUSION: This is the first study demonstrating that reduced cerebellar volume is already apparent at the predementia stage. The results of this study support the involvement of the cerebellum in the progression of dementia. Whereas the cerebellum might not be directly associated with the origin of Alzheimer's disease, it may provide useful information related to its prognosis.OBJETIVO: O objetivo deste estudo foi examinar o volume cerebelar em indivíduos em diferentes fases da doença de Alzheimer e investigar se sua redução estaria relacionada com o declínio cognitivo. MÉTODO: Noventa e seis indivíduos de um estudo epidemiológico foram submetidos à ressonância magnética e avaliados por meio do Mini Exame do Estado Mental e do Questionário de Atividades Funcionais. Os sujeitos foram divididos em cinco grupos de acordo com a Escala de Gravidade da Demência. Vinte e seis indivíduos do grupo original que não tinham o diagnóstico de demência no início do estudo foram reavaliados após dois anos para detectar o desenvolvimento da doença. RESULTADOS: Os volumes dos hemisférios cerebelares, lobo cerebelar posterior, vermis e lobo temporal estavam diminuídos proporcionalmente à gravidade da doença. Houve correlações positivas e significativas entre o Questionário de Atividades Funcionais, Mini Exame do Estado Mental e seus respectivos subtestes para linguagem e atenção com os volumes dos lobos temporal e cerebelar. A análise de regressão logística demonstrou que o volume reduzido do lobo temporal, lobo cerebelar posterior e vermis pode ser um fator de risco para o futuro desenvolvimento de demência. CONCLUSÃO: Este é o primeiro estudo que demonstrou que o volume do cerebelo pode estar reduzido na fase pré-demência e reforça o papel dessa estrutura na progressão da doença de Alzheimer. Considerando que o cerebelo pode não estar diretamente associado com a origem da doença de Alzheimer, este achado tem valor para o prognóstico.

OBJECTIVE: To compare the effectiveness of intramuscular olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone as the first medication(s) used to treat patients with agitation and aggressive behavior. METHOD: One hundred fifty patients with agitation caused by psychotic or bipolar disorder were randomly assigned under double-blind conditions to receive olanzapine, ziprasidone, haloperidol plus midazolam, haloperidol plus promethazine or haloperidol alone. The Overt Agitation Severity Scale, Overt Aggression Scale and Ramsay Sedation Scale were applied within 12 hours after the first dosage. RESULTS: All medications produced a calming effect within one hour of administration, but only olanzapine and haloperidol reduced agitation by less than 10 points, and only olanzapine reduced aggression by less than four points in the first hour. After twelve hours, only patients treated with haloperidol plus midazolam had high levels of agitation and aggression and also more side effects. Ziprasidone, olanzapine and haloperidol alone had more stable results for agitation control, while ziprasidone, haloperidol plus promethazine and olanzapine had stable results for aggression control. CONCLUSION: Olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol were effective in controlling agitation and aggression caused by mental illness over 12 hours. Although all the drugs had advantages and disadvantages, haloperidol plus midazolam was associated with the worst results in all the observed parameters.OBJETIVO: Comparar a eficácia da olanzapina, ziprasidona, haloperidol associado ao midazolam, haloperidol associado à prometazina e haloperidol isoladamente por via intramuscular como primeira escolha no tratamento de pacientes em agitação e agressividade. MÉTODO: Cento e cinquenta pacientes com agitação psicomotora por transtorno psicótico ou transtorno bipolar foram recrutados para estudo duplo-cego e receberam olanzapina, ziprasidona, haloperidol associado a midazolam, haloperidol associado a prometazina ou haloperidol isoladamente. Foram aplicadas as escalas Overt Agitation Severity Scale, Overt Aggression Scale e Ramsay Sedation Scale no período de 12 horas após a primeira aplicação. RESULTADOS: Todas as medicações foram capazes de acalmar os pacientes após uma hora da administração. Apenas a olanzapina e o haloperidol reduziram a agitação para menos de 10 pontos e apenas a olanzapina reduziu a agressividade para menos de quatro pontos nesse período. Doze horas depois, apenas o haloperidol com midazolam apresentou valores altos para a agitação e agressividade, e também esteve relacionado com maior proporção de efeitos colaterais. A ziprasidona, a olanzapina e o haloperidol apresentaram resultados mais estáveis para o controle da agitação e a ziprasidona, haloperidol associado a prometazina e olanzapina para o controle da agressividade. CONCLUSÃO: A olanzapina, a ziprasidona, o haloperidol associado a prometazina, o haloperidol associado ao midazolam e o haloperidol isoladamente foram efetivos no controle da agitação e da agressividade secundária a transtornos mentais dentro de 12 horas. Todas as drogas apresentaram vantagens e desvantagens, exceto pela associação haloperidol e midazolam que demonstrou os piores resultados em todos os parâmetros.

OBJECTIVE: The objective of this update article is to report structural and functional neuroimaging studies exploring the potential role of cerebellum in the pathophysiology of psychiatric disorders. METHOD: A non-systematic literature review was conducted by means of Medline using the following terms as a parameter: "cerebellum", "cerebellar vermis", "schizophrenia", "bipolar disorder", "depression", "anxiety disorders", "dementia" and "attention deficit hyperactivity disorder". The electronic search was done up to April 2008. DISCUSSION: Structural and functional cerebellar abnormalities have been reported in many psychiatric disorders, namely schizophrenia, bipolar disorder, major depressive disorder, anxiety disorders, dementia and attention deficit hyperactivity disorder. Structural magnetic resonance imaging studies have reported smaller total cerebellar and vermal volumes in schizophrenia, mood disorders and attention deficit hyperactivity disorder. Functional magnetic resonance imaging studies using cognitive paradigms have shown alterations in cerebellar activity in schizophrenia, anxiety disorders and attention deficit hyperactivity disorder. In dementia, the cerebellum is affected in later stages of the disease. CONCLUSION: Contrasting with early theories, cerebellum appears to play a major role in different brain functions other than balance and motor control, including emotional regulation and cognition. Future studies are clearly needed to further elucidate the role of cerebellum in both normal and pathological behavior, mood regulation, and cognitive functioning.OBJETIVO: Este artigo de atualização tem como objetivo avaliar estudos em neuroimagem estrutural e funcional a fim de explorar o papel do cerebelo na patofisiologia dos transtornos psiquiátricos. MÉTODO: Uma revisão não sistemática foi realizada através do Medline utilizando-se como parâmetro os seguintes termos: "cerebellum", "cerebellar vermis", "schizophrenia", "bipolar disorder", "depression", "anxiety disorders", "dementia" e "attention deficit hyperactivity disorder". A busca eletrônica foi feita até abril de 2008. DISCUSSÃO: Anormalidades cerebelares estruturais e funcionais têm sido relatadas em muitos transtornos psiquiátricos, entre eles a esquizofrenia, transtorno bipolar, transtorno depressivo, transtornos ansiosos, demências e transtorno de déficit de atenção e hiperatividade. Estudos utilizando imagem por ressonância magnética estrutural relataram a diminuição do volume total do cerebelo e do vermis cerebelar na esquizofrenia, transtornos do humor e transtorno de falta de atenção com hiperatividade. Estudos utilizando ressonância magnética funcional e paradigmas cognitivos têm demonstrado alterações na atividade cerebelar na esquizofrenia, transtornos ansiosos e transtorno de falta de atenção com hiperatividade. Nas demências, o cerebelo é afetado nos estágios mais avançados dessas doenças. CONCLUSÃO: Contrastando com as primeiras teorias, o cerebelo parece apresentar um papel mais importante em diferentes funções cerebrais além do controle motor e do equilíbrio, incluindo a regulação emocional e cognição. Futuros estudos são necessários para melhor elucidar o papel do cerebelo em ambos os comportamentos, normal e patológico, na regulação do humor e nas funções cognitivas.

OBJECTIVE: The aim of this study was to examine the cerebellar volume of subjects at different stages of Alzheimer's disease and to investigate whether volume reductions in this structure are related to cognitive decline. METHOD: Ninety-six subjects from an epidemiological study were submitted to a magnetic resonance imaging scan and evaluated using the Mini-Mental State Examination and the Functional Activities Questionnaire. Subjects were divided into five groups according to the Clinical Dementia Rating scale. Twenty-six subjects from the original group who had no dementia diagnosis at baseline were re-evaluated for the onset of dementia after two years. RESULTS: The volumes of the cerebellar hemispheres, posterior cerebellar lobe, vermis and temporal lobe were found to be reduced as a function of the severity of the disease. There were significant positive correlations between the volume of the temporal lobe and cerebellum and the language, attention, and total scores in the Mini-Mental State Examination and the Functional Activities Questionnaire. A logistic regression analysis demonstrated that reduced temporal lobe, posterior cerebellar lobe and vermal volume at baseline is a risk factor for the onset of dementia. CONCLUSION: This is the first study demonstrating that reduced cerebellar volume is already apparent at the predementia stage. The results of this study support the involvement of the cerebellum in the progression of dementia. Whereas the cerebellum might not be directly associated with the origin of Alzheimer's disease, it may provide useful information related to its prognosis.OBJETIVO: O objetivo deste estudo foi examinar o volume cerebelar em indivíduos em diferentes fases da doença de Alzheimer e investigar se sua redução estaria relacionada com o declínio cognitivo. MÉTODO: Noventa e seis indivíduos de um estudo epidemiológico foram submetidos à ressonância magnética e avaliados por meio do Mini Exame do Estado Mental e do Questionário de Atividades Funcionais. Os sujeitos foram divididos em cinco grupos de acordo com a Escala de Gravidade da Demência. Vinte e seis indivíduos do grupo original que não tinham o diagnóstico de demência no início do estudo foram reavaliados após dois anos para detectar o desenvolvimento da doença. RESULTADOS: Os volumes dos hemisférios cerebelares, lobo cerebelar posterior, vermis e lobo temporal estavam diminuídos proporcionalmente à gravidade da doença. Houve correlações positivas e significativas entre o Questionário de Atividades Funcionais, Mini Exame do Estado Mental e seus respectivos subtestes para linguagem e atenção com os volumes do lobo temporal e cerebelar. A análise de regressão logística demonstrou que o volume reduzido do lobo temporal, lobo cerebelar posterior e vermis pode ser um fator de risco para o futuro desenvolvimento de demência. CONCLUSÃO: Este é o primeiro estudo que demonstrou que o volume do cerebelo pode estar reduzido na fase pré-demência e reforça o papel dessa estrutura na progressão da doença de Alzheimer. Considerando que o cerebelo pode não estar diretamente associado com a origem da doença de Alzheimer, este achado tem valor para o prognóstico.