Longitudinal evaluation of state-dependent microstructural brain abnormalities in first-episode psychosis patients, associated to the activity of phospholipase a2 enzyme

INTRODUÇÃO: Os transtornos mentais psicóticos são condições frequentes na população geral e estão associados a grande morbidade e disfuncionalidade. Apesar disso, as bases fisiopatológicas destes transtornos ainda estão em investigação. Estudos neuropatológicos post-mortem e de neuroimagem in vivo sugerem haver comprometimento da microestrutura de substância branca (SB) cerebral nestas condições clínicas, associado a alterações da conectividade cerebral. No entanto, nenhuma investigação prévia de neuroimagem avaliou especificamente se tais anormalidades microestruturais podem ser dependentes do estado clínico do paciente, i.e., se tais alterações podem variar de acordo com a fase da doença. Outra linha de investigação biológica em psicoses aponta para alterações na atividade da fosfolipase A2 (PLA2), uma enzima essencial a diversas funções na homeostase cerebral, incluindo manutenção de membrana celular, mielinização e atividade inflamatória. Estudos prévios sugerem haver relação entre alterações na atividade desta enzima e as fases da esquizofrenia. Entretanto, não há estudos translacionais que tenham avaliado como tais alterações se relacionam com anormalidades microestruturais de SB em pacientes psicóticos. OBJETIVOS: Investigar a hipótese de que alterações de microestrutura de SB presentes em pacientes em fase aguda do primeiro episódio psicótico (PEP) sejam potencialmente reversíveis após estabilização clínica; investigar também possíveis alterações estado-dependentes da atividade de PLA2 no PEP; e examinar interações entre manifestações clínicas, microestrutura de SB cerebral e atividade de PLA2 na fisiopatologia do PEP. METODOLOGIA: Pacientes em PEP não afetivo foram avaliados em dois períodos no tempo: durante a fase aguda da doença (T0); após remissão estável de sintomas (T1). Um grupo controle de voluntários saudáveis (CS) também foi avaliado longitudinalmente. Para investigar alterações de microestrutura de SB estado-dependentes, análises voxel-a-voxel de mapas cerebrais de índices de anisotropia (fractional anisotropy, FA) e difusividade (trace, TR) foram conduzidas, assim como o cálculo de correlações entre tais índices de DTI, variáveis clínicas e atividade de PLA2. A atividade dos três principais subgrupos de PLA2 em plaquetas foi estimada através de um método radioenzimático. RESULTADOS: 25 pacientes PEP e 51 CS foram avaliados em T0, com coleta de dados clínico-demográficos, ressonância magnética (RM) e amostra de sangue. Destes, 21 PEP e 36 CS realizaram a segunda aquisição de RM. No baseline (T0), os pacientes PEP apresentaram redução difusa de FA (p < 0,05, FDR), afetando principalmente SB fronto-límbica e fascículos associativos, projetivos e comissurais. As análises longitudinais demonstraram que a remissão clínica se associou a aumentos de FA em tratos de SB acometidos em T0 (p < 0,001, não corrigido), além de robustas correlações inversas entre aumentos de FA e redução sintomas ao longo do tempo (p < 0,05, FDR). As análises de PLA2 não demostraram efeitos estado-dependentes ou correlações consistentes com os índices de DTI. CONCLUSÃO: Alterações da microestrutura de SB afetando tratos cerebrais essenciais para a integração de informação perceptual, cognição e emoções são detectáveis logo após o início do PEP e podem ser parcialmente revertidas em relação direta com a remissão de sintomas psicóticos agudos. Nossos achados reforçam a visão de que anormalidades de SB de tratos cerebrais são um componente neurobiológico central nos transtornos psicóticos agudos, e que a recuperação de tal patologia de SB pode levar à melhora clínica. Por outro lado, a atividade de PLA2 não parece ter associação direta com o estado de doença ou moderar as alterações microestruturais dinâmicas de SB aqui observadas. Estudos com amostras maiores e com um maior número de avaliações ao longo do tempo são necessários para confirmar e ampliar os resultados aqui apresentadosINTRODUCTION: Psychotic disorders are frequent conditions in the general population and are associated to severe morbidity and functional impairment. Notwithstanding, the pathophysiological basis of such disorders is still under investigation. Post-mortem neuropathologic investigations and in vivo neuroimaging studies have pointed to the occurrence of abnormalities in the microstructure of brain white matter (WM) in such clinical conditions, which are associated to changes in brain connectivity. However, no previous neuroimaging investigation has specifically examined whether such microstructural abnormalities would be state-dependent, i.e., whether such changes could relate to the illness phase. Another field of biological investigation in psychosis points to changes in the activity of phospholipase A2 enzyme (PLA2), which is essential to several functions implicated in brain homeostasis, such as the maintenance of cellular membrane, myelination and inflammatory activity. Previous studies suggest the existence of a relationship between changes on PLA2 activity and schizophrenia phase. Nonetheless, no translational study to date has examined the potential interplay between PLA2 activity and WM microstructural abnormalities in psychotic patients. OBJECTIVES: To investigate the hypothesis that WM microstructural changes observed in patients during the acute first-episode psychosis (FEP) are potentially reversible following clinical remission; to investigate possible state-dependent changes in PLA2 activity in FEP; and to examine interactions between clinical manifestations, brain WM microstructure and PLA2 activity in the pathophysiology of FEP. METODOLOGY: Patients with non-affective FEP were evaluated in two time points: during the acute phase (T0) and following sustained remission (T1). A control group of healthy volunteers (HC) was also longitudinally studied. In order to investigate state-dependent WM microstructure changes, voxelwise analyses of brain maps of anisotropy (fractional anisotropy, FA) and diffusivity (trace, TR) indexes were conducted, as well as correlations between such DTI metrics, clinical variables and PLA2 activity. The activity of the three main PLA2 subgroups was assessed in platelets using a radioenzymatic method. RESULTS: 25 FEP and 51 HC were evaluated at T0 (clinical and demographic data, MRI scanning, and blood collection). Out of these, 21 FEP and 36 HC also underwent a second MRI acquisition. At baseline (T0), FEP patients presented widespread reduction of FA (p < 0.05, FDR), affecting mainly fronto-limbic WM and associative, projective and commissural fasciculi. Longitudinal analyses showed that clinical remission was associated with FA increase in WM tracts that were affected at T0 (p < 0.001, uncorrected), besides robust inverse correlations between FA increase and symptoms reduction over time (p < 0.05, FDR). PLA2 analyses failed to show state-dependent effects or consistent correlations to DTI indexes. CONCLUSION: WM changes affecting brain tracts critical to the integration of perceptual information, cognition and emotions are detectable soon after the onset of FEP and may partially reverse in direct relation to the remission of acute psychotic symptoms. Our findings reinforce the view that WM abnormalities are a key neurobiological feature of acute psychotic disorders, and that recovery from such WM pathology can lead to amelioration of symptoms. In the other hand, it seems that PLA2 activity has no direct relationship to the disease state or modulatory effects on the dynamic WM changes observed herein. Studies with larger samples and with more time points evaluations are necessary to confirm and expand the findings reported herei

Childhood maltreatment in individuals at risk of psychosis: Results from the Brazilian SSAPP cohort

BACKGROUND Childhood maltreatment is a known risk factor for the development of mental disorders, such as psychotic symptoms. An extensive body of literature about childhood maltreatment and mental health has been developed in wealthy countries, but information about this connection is lacking in developing countries. AIMS To explore a possible relationship between childhood maltreatment and ultra-high risk of psychosis in a non-help-seeking population in a low- and middle-income country. METHODS A household survey was conducted in Sao Paulo, Brazil, involving over 2,500 individuals aged 18-30 years who were randomly selected from the general population. The participants underwent screening with the Prodromal Questionnaire. Ultra-high risk status was assessed using the Structured Interview for Prodromal Syndromes, and childhood maltreatment was assessed using the Childhood Trauma Questionnaire. The final sample comprised 87 ultra-high risk individuals and 115 controls. RESULTS Childhood maltreatment was significantly more present among ultra-high risk individuals. In ultra-high risk individuals, physical and emotional neglect were inversely related to grandiosity symptoms, physical abuse was related to perceptual abnormalities and physical neglect was related to disorganized speech and thought. CONCLUSION This is the first study to investigate the relationship between childhood maltreatment and ultra-high risk status and psychopathological features in a large Latin American sample. Further studies in this field are necessary to better understand the specific influence of various early life adversities on psychosis risk

Use of a Bayesian Network Model to predict psychiatric illness in individuals with 'at risk mental states' from a general population cohort

The 'at risk mental state' (ARMS) paradigm has been introduced in psychiatry to study prodromal phases of schizophrenia. With time it was seen that the ARMS state can also precede mental disorders other than schizophrenia, such as depression and anxiety. However, several problems hamper the paradigm's use in preventative medicine, such as varying transition rates across studies, the use of non-naturalistic samples, and the multifactorial nature of psychiatric disorders. To strengthen ARMS predictive power, there is a need for a holistic model incorporating-in an unbiased fashion-the small-effect factors that cause mental disorders. Bayesian networks, a probabilistic graphical model, was used in a populational cohort of 83 ARMS individuals to predict conversion to psychiatric illness. Nine predictors-including state, trait, biological and environmental factors-were inputted. Dopamine receptor 2 polymorphism, high private religiosity, and childhood trauma remained in the final model, which reached an 85.51% (SD = 0.1190) accuracy level in predicting conversion. This is the first time a robust model was produced with Bayesian networks to predict psychiatric illness among at risk individuals from the general population. This could be an important tool to strengthen predictive measures in psychiatry which should be replicated in larger samples to provide the model further learning

Grey and white matter volumes either in treatment-naïve or hormone-treated transgender women: a voxel-based morphometry study

Abstract Many previous magnetic resonance imaging (MRI) studies have documented sex differences in brain morphology, but the patterns of sexual brain differences in transgender women – male sex assigned at birth – with a diagnosis of gender dysphoria (TW) have been rarely investigated to date. We acquired T1-weighted MRI data for the following four (n = 80) groups: treatment-naïve TW (TNTW), TW treated with cross-sex hormones for at least one year (TTW), cisgender men, and cisgender women (cisgender individuals as controls). Differences in whole-brain and regional white matter volume and grey matter volume (GMV) were assessed using voxel-based morphometry. We found lower global brain volumes and regional GMVs in a large portion of the posterior-superior frontal cortex in the cisgender women group than in the TTW and cisgender men groups. Additionally, both transgender groups exhibited lower bilateral insular GMVs than the cisgender women group. Our results highlight differences in the insula in both transgender groups; such differences may be characteristic of TW. Furthermore, these alterations in the insula could be related to the neural network of body perception and reflect the distress that accompanies gender dysphoria

High IQ May "Mask" the Diagnosis of ADHD by Compensating for Deficits in Executive Functions in Treatment-Naïve Adults With ADHD

Objective: To evaluate and compare the performance of adults with ADHD with high and standard IQ in executive functions (EF) tasks. Method: We investigated the neuropsychological performance of 51 adults with ADHD, compared with 33 healthy controls (HC) while performing a wide battery of neuropsychological tests that measure executive functioning. Adults with clinical diagnosis of ADHD were divided into two groups according to their IQ level (IQ ≥ 110—ADHD group with more elevated IQ, and IQ &lt; 110—ADHD group with standard IQ). Results: The ADHD group with standard IQ presented a worse executive functioning compared with the HC group in the following measures: Stroop 2 ( p = .000) and 3 ( p = .000), Trail Making Test (TMT) B ( p = .005), Wisconsin Card-Sorting Test (WCST)—perseverative errors ( p = .022) and failures to maintain set ( p = .020), Continuous Performance Test (CPT)—omission errors ( p = .005) and commission errors ( p = .000), and Frontal Assessment Battery (FAB)—conceptualization ( p = .016). The ADHD group with more elevated IQ presented only impairments in the CPT—commission errors ( p = .019) when compared with the control group. Conclusion: Adults with ADHD and more elevated IQ show less evidence of executive functioning deficits compared with those with ADHD and standard IQ, suggesting that a higher degree of intellectual efficiency may compensate deficits in executive functions, leading to problems in establishing a precise clinical diagnosis. </jats:p