Examining differences in brain metabolism associated with childhood maltreatment and suicidal attempt in euthymic patients with bipolar disorder: A PET and Machine Learning Study.

OBJECTIVE: Childhood maltreatment (CM) is a significant risk factor for the development and severity of bipolar disorder (BD) with increased risk of suicide attempts (SA). This study evaluated whether a machine learning algorithm could be trained to predict if a patient with BD has a history of CM or previous SA based on brain metabolism measured by positron emission tomography. METHODS: Thirty-six euthymic patients diagnosed with BD type I, with and without a history of CM were assessed using the Childhood Trauma Questionnaire. Suicide attempts were assessed through the Mini International Neuropsychiatric Interview (MINI-Plus) and a semi-structured interview. Resting-state positron emission tomography with 18F-fluorodeoxyglucose was conducted, electing only grey matter voxels through the Statistical Parametric Mapping toolbox. Imaging analysis was performed using a supervised machine learning approach following Gaussian Process Classification. RESULTS: Patients were divided into 18 participants with a history of CM and 18 participants without it, along with 18 individuals with previous SA and 18 individuals without such history. The predictions for CM and SA were not significant (accuracy = 41.67%; p = 0.879). CONCLUSION: Further investigation is needed to improve the accuracy of machine learning, as its predictive qualities could potentially be highly useful in determining histories and possible outcomes of high-risk psychiatric patients.

Examining differences in brain metabolism associated with childhood maltreatment and suicidal attempts in euthymic patients with bipolar disorder: a PET and machine learning study

Objective: Childhood maltreatment (CM) is a significant risk factor for the development and severity of bipolar disorder (BD) with increased risk of suicide attempts (SA). This study evaluated whether a machine learning algorithm could be trained to predict if a patient with BD has a history of CM or previous SA based on brain metabolism measured by positron emission tomography. Methods: Thirty-six euthymic patients diagnosed with BD type I, with and without a history of CM were assessed using the Childhood Trauma Questionnaire. Suicide attempts were assessed through the Mini International Neuropsychiatric Interview (MINI-Plus) and a semi-structured interview. Resting-state positron emission tomography with 18F-fluorodeoxyglucose was conducted, electing only grey matter voxels through the Statistical Parametric Mapping toolbox. Imaging analysis was performed using a supervised machine learning approach following Gaussian Process Classification. Results: Patients were divided into 18 participants with a history of CM and 18 participants without it, along with 18 individuals with previous SA and 18 individuals without such history. The predictions for CM and SA were not significant (accuracy = 41.67%; p = 0.879). Conclusion: Further investigation is needed to improve the accuracy of machine learning, as its predictive qualities could potentially be highly useful in determining histories and possible outcomes of high-risk psychiatric patients.

Counterfactual inference with latent variable and its application in mental health care.

This paper deals with the problem of modeling counterfactual reasoning in scenarios where, apart from the observed endogenous variables, we have a latent variable that affects the outcomes and, consequently, the results of counterfactuals queries. This is a common setup in healthcare problems, including mental health. We propose a new framework where the aforementioned problem is modeled as a multivariate regression and the counterfactual model accounts for both observed and a latent variable, where the latter represents what we call the patient individuality factor ( φ ). In mental health, focusing on individuals is paramount, as past experiences can change how people see or deal with situations, but individuality cannot be directly measured. To the best of our knowledge, this is the first counterfactual approach that considers both observational and latent variables to provide deterministic answers to counterfactual queries, such as: what if I change the social support of a patient, to what extent can I change his/her anxiety? The framework combines concepts from deep representation learning and causal inference to infer the value of φ and capture both non-linear and multiplicative effects of causal variables. Experiments are performed with both synthetic and real-world datasets, where we predict how changes in people's actions may lead to different outcomes in terms of symptoms of mental illness and quality of life. Results show the model learns the individually factor with errors lower than 0.05 and answers counterfactual queries that are supported by the medical literature. The model has the potential to recommend small changes in people's lives that may completely change their relationship with mental illness.

Micro-Raman spectroscopy of lipid halo and dense-core amyloid plaques: aging process characterization in the Alzheimer's disease APPswePS1ΔE9 mouse model.

The deposition of amyloid plaques is considered one of the main microscopic features of Alzheimer's disease (AD). Since plaque formation can precede extensive neurodegeneration and it is the main clinical manifestation of AD, it constitutes a relevant target for new treatment and diagnostic approaches. Micro-Raman spectroscopy, a label-free technique, is an accurate method for amyloid plaque identification and characterization. Here, we present a high spatial resolution micro-Raman hyperspectral study in transgenic APPswePS1ΔE9 mouse brains, showing details of AD tissue biochemical and histological changes without staining. First we used stimulated micro-Raman scattering to identify the lipid-rich halo surrounding the amyloid plaque, and then proceeded with spontaneous (conventional) micro-Raman spectral mapping, which shows a cholesterol and sphingomyelin lipid-rich halo structure around dense-core amyloid plaques. The detailed images of this lipid halo relate morphologically well with dystrophic neurites surrounding plaques. Principal Component Analysis (PCA) of the micro-Raman hyperspectral data indicates the feasibility of the optical biomarkers of AD progression with the potential for discriminating transgenic groups of young adult mice (6-month-old) from older ones (12-month-old). Frequency-specific PCA suggests that plaque-related neurodegeneration is the predominant change captured by Raman spectroscopy, and the main differences are highlighted by vibrational modes associated with cholesterol located majorly in the lipid halo.

Neurochemical abnormalities in the hippocampus of male rats displaying audiogenic seizures, a genetic model of epilepsy.

BACKGROUND: Epilepsy is a disorder characterized by recurrent seizures that affects 1% of the population. However, the neurochemical alterations observed in epilepsy are not fully understood. There are different animal models of epilepsy, such as genetic or drug induced. In the present study, we utilize Wistar Audiogenic Rats (WAR), a murine strain that develops seizures in response to high intensity audio stimulation, in order to investigate abnormalities in glutamatergic and GABAergic systems. METHODS: Synaptosomes and glial plasmalemmal vesicles were prepared from hippocampus and cortex, respectively. Glutamate and GABA release and uptake were assayed by monitoring the fluorescence and using L-[3H]-radiolabeled compounds. Glutamate and calcium concentration in the synaptosomes were also measured. The expression of neuronal calcium sensor 1 (NCS-1) was determined by western blot. RESULTS: Glutamate and GABA release evoked by KCl was decreased in WAR compared to control Wistar rats. Calcium independent release was not considerably different in both groups. The total amount of glutamate of synaptosomes, as well as glutamate uptake by synaptosomes and GPV were also decreased in WAR in comparison with the controls. In addition, [Ca2+]i of hippocampal synaptosomes, as well as NCS-1 expression in the hippocampus, were increased in WAR in comparison with controls. CONCLUSION: In conclusion, our results suggest that WAR have important alterations in the glutamatergic and GABAergic pathways, as well as an increased expression of NCS-1 in the hippocampus and inferior colliculus. These alterations may be linked to the spreading of hyperexcitability and recruitment of various brain regions.

Nonlinear and vibrational microscopy for label-free characterization of amyloid-ß plaques in Alzheimer's disease model.

Given the long subclinical stage of Alzheimer's disease (AD), the study of biomarkers is relevant both for early diagnosis and the fundamental understanding of the pathophysiology of AD. Biomarkers provided by Amyloid-ß (Aß) plaques have led to an increasing interest in characterizing this hallmark of AD due to its promising potential. In this work, we characterize Aß plaques by label-free multimodal imaging: we combine two-photon excitation autofluorescence (TPEA), second harmonic generation (SHG), spontaneous Raman scattering (SpRS), coherent anti-Stokes Raman scattering (CARS), and stimulated Raman scattering (SRS) to describe and compare high-resolution images of Aß plaques in brain tissues of an AD mouse model. Comparing single-laser techniques images, we discuss the origin of the SHG, which can be used to locate the plaque core reliably. We study both the core and the halo with vibrational microscopy and compare SpRS and SRS microscopies for different frequencies. We also combine SpRS spectroscopy with SRS microscopy and present two core biomarkers unexplored with SRS microscopy: phenylalanine and amide B. We provide high-resolution SRS images with the spatial distribution of these biomarkers in the plaque and compared them with images of the amide I distribution. The obtained spatial correlation corroborates the feasibility of these biomarkers in the study of Aß plaques. Furthermore, since amide B enables rapid imaging, we discuss its potential as a novel fingerprint for diagnostic applications.

Transcranial Direct Current Stimulation: No Effect on Aerobic Performance, Heart Rate, or Rating of Perceived Exertion in a Progressive Taekwondo-Specific Test.

PURPOSE: To investigate the effects of anodal transcranial direct current stimulation (a-tDCS) on the aerobic performance, heart rate (HR), and rating of perceived exertion (RPE) of highly trained taekwondo athletes. METHODS: Twelve (8 men and 4 women) international/national-level athletes received a-tDCS or sham treatment over the M1 location in a randomized, single-blind crossover design. The stimulation was delivered at 1.5 mA for 15 min using an extracephalic bihemispheric montage. Athletes performed the progressive-specific taekwondo test 10 min after stimulation. HR was monitored continuously during the test, and RPE was registered at the end of each stage and at test cessation. RESULTS: There were no significant differences between sham and a-tDCS in time to exhaustion (14.6 and 14.9, respectively, P = .53, effect size = 0.15) and peak kicking frequency (52 and 53.6, respectively, P = .53, effect size = 0.15) or in HR (P > .05) and RPE responses (P > .05). CONCLUSIONS: Extracephalic bihemispheric a-tDCS over M1 did not influence the aerobic performance of taekwondo athletes or their psychophysiological responses, so athletes and staff should be cautious when using it in a direct-to-consumer manner.

Parent SNAP-IV rating of attention-deficit/hyperactivity disorder: accuracy in a clinical sample of ADHD, validity, and reliability in a Brazilian sample, / Avaliação do instrumento SNAP-IV pelos pais no transtorno de déficit de atenção/hiperatividade: acurácia em uma amostra clínica de TDAH, validade e confiabilidade em uma amostra brasileira,

ABSTRACT Objective: To investigate the psychometric properties of the short or multimodal treatment study version of the Swanson, Nolan, and Pelham, Version IV (SNAP-IV) scale, which measures attention-deficit/hyperactivity disorder and oppositional defiant disorder symptoms. Methods: Participants were 765 parents of children from 4 to 16 years old (641 non-attention-deficit/hyperactivity disorder and 124 attention-deficit/hyperactivity disorder children) from Belo Horizonte, Brazil, who reported sociodemographic characteristics and answered the SNAP-IV. Parents of the clinical sample also underwent the K-SADS-PL interview. Results: Age was significantly associated with SNAP-IV hyperactivity-impulsivity problems (r = −0.14), but not with inattention or oppositional defiant disorder. Sex was a significant influence on attention-deficit/hyperactivity disorder and oppositional defiant disorder severity (all p < 0.001), with boys showing higher scores in the full sample, but not within the attention-deficit/hyperactivity disorder group. Exploratory and confirmatory factor analysis supports a three-factor structure of the SNAP-IV scale. Moderate-to-strong correlations were found between SNAP-IV and K-SADS-PL measures. All SNAP-IV scales showed very high internal consistency coefficients (all above 0.91). SNAP-IV inattention scores were the most predictive of attention-deficit/hyperactivity disorder diagnosis (AUC: 0.877 for the averaging rating method and the raw sum method, and 0.874 for the symptom presence/absence method). Conclusion: The parent SNAP-IV showed good psychometric properties in a Brazilian school and clinical sample.

RESUMO Objetivo: Investigar as propriedades psicométricas da versão curta ou MTA da escala Swanson, Nolan e Pelham, versão IV (SNAP-IV), que mede os sintomas do transtorno de déficit de atenção/hiperatividade e transtorno desafiador de oposição. Métodos: Os participantes incluíram 765 pais de crianças de 4 a 16 anos (641 crianças sem transtorno de déficit de atenção/hiperatividade e 124 com transtorno de déficit de atenção/hiperatividade) de Belo Horizonte, Brasil, que relataram características sociodemográficas e responderam o SNAP-IV. Os pais da amostra clínica também foram submetidos à entrevista com K-SADS-PL. Resultados: A idade foi significativamente associada aos problemas de hiperatividade-impulsividade no SNAP-IV (r = −0,14), mas não à desatenção ou aos transtornos desafiadores de oposição. O sexo foi uma influência significativa na gravidade do transtorno de déficit de atenção/hiperatividade e transtorno desafiador de oposição (todos os p < 0,001), os meninos apresentaram escores mais altos na amostra completa, mas não no grupo de transtorno de déficit de atenção/hiperatividade. A análise fatorial exploratória e confirmatória apoia uma estrutura de três fatores da escala SNAP-IV. Foram encontradas correlações moderadas a fortes entre as medidas dos instrumentos SNAP-IV e K-SADS-PL. Todas as escalas do SNAP-IV mostraram coeficientes de consistência interna muito altos (todos acima de 0,91). Os escores de desatenção do SNAP-IV foram os mais preditivos do diagnóstico de transtorno de déficit de atenção/hiperatividade (AUC - área sob a curva ROC: 0,877 para o método de classificação da média e o método da soma bruta e 0,874 para o método de presença ou ausência de sintomas). Conclusão: A avaliação do SNAP-IV pelos pais apresentou boas propriedades psicométricas em uma escola brasileira e amostra clínica.

A fingerprint of amyloid plaques in a bitransgenic animal model of Alzheimer's disease obtained by statistical unmixing analysis of hyperspectral Raman data.

The global prevalence of Alzheimer's disease (AD) points to endemic levels, especially considering the increase of average life expectancy worldwide. AD diagnosis based on early biomarkers and better knowledge of related pathophysiology are both crucial in the search for medical interventions that are able to modify AD progression. In this study we used unsupervised spectral unmixing statistical techniques to identify the vibrational spectral signature of amyloid ß aggregation in neural tissues, as early biomarkers of AD in an animal model. We analyzed spectral images composed of a total of 55 051 Raman spectra obtained from the frontal cortex and hippocampus of five bitransgenic APPswePS1ΔE9 mice, and colocalized amyloid ß plaques by other fluorescence techniques. The Raman signatures provided a multifrequency fingerprint consistent with the results of synthesized amyloid ß fibrils. The fingerprint obtained from unmixed analysis in neural tissues is shown to provide a detailed image of amyloid plaques in the brain, with the potential to be used as biomarkers for non-invasive early diagnosis and pathophysiology studies in AD on the retina.

Pericytes Act as Key Players in Spinal Cord Injury.

Spinal cord injury results in locomotor impairment attributable to the formation of an inhibitory fibrous scar, which prevents axonal regeneration after trauma. The scarcity of knowledge about the molecular and cellular mechanisms involved in scar formation after spinal cord lesion impede the design of effective therapies. Recent studies, by using state-of-the-art technologies, including genetic tracking and blockage of pericytes in combination with optogenetics, reveal that pericyte blockage facilitates axonal regeneration and neuronal integration into the local neural circuitry. Strikingly, a pericyte subset is essential during scarring after spinal cord injury, and its arrest results in motor performance improvement. The arising knowledge from current research will contribute to novel approaches to develop therapies for spinal cord injury. We review novel advances in our understanding of pericyte biology in the spinal cord.

Neural stem cell niche heterogeneity.

In mammals, new neurons can be generated from neural stem cells in specific regions of the adult brain. Neural stem cells are characterized by their abilities to differentiate into all neural lineages and to self-renew. The specific microenvironments regulating neural stem cells, commonly referred to as neurogenic niches, comprise multiple cell populations whose precise contributions are under active current exploration. Understanding the cross-talk between neural stem cells and their niche components is essential for the development of therapies against neurological disorders in which neural stem cells function is altered. In this review, we describe and discuss recent studies that identified novel components in the neural stem cell niche. These discoveries bring new concepts to the field. Here, we evaluate these recent advances that change our understanding of the neural stem cell niche heterogeneity and its influence on neural stem cell function.

Parent SNAP-IV rating of attention-deficit/hyperactivity disorder: accuracy in a clinical sample of ADHD, validity, and reliability in a Brazilian sample.

OBJECTIVE: To investigate the psychometric properties of the short or multimodal treatment study version of the Swanson, Nolan, and Pelham, Version IV (SNAP-IV) scale, which measures attention-deficit/hyperactivity disorder and oppositional defiant disorder symptoms. METHODS: Participants were 765 parents of children from 4 to 16 years old (641 non-attention-deficit/hyperactivity disorder and 124 attention-deficit/hyperactivity disorder children) from Belo Horizonte, Brazil, who reported sociodemographic characteristics and answered the SNAP-IV. Parents of the clinical sample also underwent the K-SADS-PL interview. RESULTS: Age was significantly associated with SNAP-IV hyperactivity-impulsivity problems (r=-0.14), but not with inattention or oppositional defiant disorder. Sex was a significant influence on attention-deficit/hyperactivity disorder and oppositional defiant disorder severity (all p<0.001), with boys showing higher scores in the full sample, but not within the attention-deficit/hyperactivity disorder group. Exploratory and confirmatory factor analysis supports a three-factor structure of the SNAP-IV scale. Moderate-to-strong correlations were found between SNAP-IV and K-SADS-PL measures. All SNAP-IV scales showed very high internal consistency coefficients (all above 0.91). SNAP-IV inattention scores were the most predictive of attention-deficit/hyperactivity disorder diagnosis (AUC: 0.877 for the averaging rating method and the raw sum method, and 0.874 for the symptom presence/absence method). CONCLUSION: The parent SNAP-IV showed good psychometric properties in a Brazilian school and clinical sample.

Pericyte Plasticity in the Brain.

Cerebral pericytes are perivascular cells that stabilize blood vessels. Little is known about the plasticity of pericytes in the adult brain in vivo. Recently, using state-of-the-art technologies, including two-photon microscopy in combination with sophisticated Cre/loxP in vivo tracing techniques, a novel role of pericytes was revealed in vascular remodeling in the adult brain. Strikingly, after pericyte ablation, neighboring pericytes expand their processes and prevent vascular dilatation. This new knowledge provides insights into pericyte plasticity in the adult brain.

Brazilian version of the Cognitive Failures Questionnaire (CFQ): cross-cultural adaptation and evidence of validity and reliability

Objective: Cognitive failures are simple mistakes in routine activities, such as forgetting commitments and experiencing difficulty concentrating. The Cognitive Failures Questionnaire (CFQ) was designed to assess the frequency of these errors in everyday life. Although widely used in psychiatry and psychology, both in clinical and research settings, it has not been adapted for use in Brazil. Our objective was to perform cross-cultural adaptation of the CFQ for the Brazilian reality and assess its validity and reliability. Methods: The original version of the CFQ was translated into Brazilian Portuguese by two independent researchers, analyzed by a multidisciplinary board of experts, and back-translated into English. The final version was administered to 225 adults. Validity was assessed by correlation with the Self Reporting Questionnaire-20 (SRQ-20) and the Adult Attention Deficit/Hyperactivity Disorder Self-Report Scale (ASRS-18). Reliability was analyzed by calculating internal consistency and test-retest stability. Results: The adapted version of the CFQ showed significant correlations with SRQ-20 (r = -0.311), ASRS-18 inattention (r = 0.696), and hyperactivity/impulsivity (r = 0.405) scores. Reliability analysis suggests high internal consistency (0.906) and temporal stability (0.813). Conclusion: The Brazilian Portuguese version of the CFQ showed moderate correlations with other measures of mental health, as well as adequate reliability.

Spinal cord hypometabolism associated with infection by human T-cell lymphotropic virus type 1(HTLV-1).

BACKGROUND: HTLV-1 infection is endemic in Brazil. About 1 to 2% of the Brazilian population is estimated to be infected, but most infected HTLV-1 individuals do not know about their own infection, which favors the continuity of sexual and vertical virus transmission. In addition, HTLV-1 associated central nervous system diseases and their pathophysiologic mechanisms are not fully understood. This study aimed to evaluate the correlation of spinal cord metabolism, viral and inflammatory profiles with features of neurological presentation in HTLV-1 infected individuals. METHODOLOGY: This is a cross-sectional study of a cohort including 48 HTLV-1 infected individuals clinically classified as asymptomatic-AG (N = 21), symptomatic-SG (N = 11) and HAM/TSP-HG (N = 16) and a nested case-control study with HTLV-1 infected individuals-HIG (N = 48) and HTLV-1 non infected controls-CG (N = 30) that had their spinal cord analysed by Positron Emission Tomography with 18F-Fluordeoxyglucose (18F-FDG PET/CT). HTLV-1 infected individuals had 18F-FDG PET/CT results analyzed with clinical and demographic data, proviral load, cytokines and chemokines in the blood and cerebrospinal fluid (CSF). PRINCIPAL FINDINGS: 18F-FDG PET/CT showed hypometabolism in the thoracic spinal cord in HTLV-1 infected individuals. The method had an accuracy of 94.4% to identify HAM/TSP. A greater involvement of the thoracic spinal cord was observed, although hypometabolism was also observed in the cervical spinal cord segment in HTLV-1 infected individuals. Individuals with HAM/TSP showed a pro-inflammatory profile in comparison to asymptomatic and symptomatic groups, with a higher level of Interferon-inducible T-cell alpha chemoattractant (ITAC/CXCL11), IL-6, IL-12p70 in the plasma; and ITAC, IL-4, IL-5, IL-8 (CXCL8) and TNF-alpha in the CSF. Using regression, thoracic spinal cord SUV (standardized uptake value) and CSF ITAC level were identified as the HAM/TSP predictors in the multivariate model. CONCLUSIONS: 18F-FDG PET/CT imaging showed spinal cord hypometabolism in most HTLV-1 infected individuals, even in the asymptomatic HTLV-1 group. Thoracic spinal cord hypometabolism and CSF-ITAC levels were identified predictors of HAM/TSP. SIGNIFICANCE: Our findings suggested that in most HTLV-1 infected individuals there was compromise of central nervous system (CNS) structures despite of the lack of clinical symptoms. To explain the found hypometabolism, the role of microcirculatory and metabolic factors in the pathogenesis of neurological diseases associated with HTLV-1 infection must be further investigated. It is paramount to evaluate the central nervous function and to compare the performance among HTLV-1 infected individuals considered asymptomatic to the uninfected controls.