Mauricio H. Serpa

Neuroanatomical Classification in a Population-Based Sample of Psychotic Major Depression and Bipolar I Disorder with 1 Year of Diagnostic Stability

The presence of psychotic features in the course of a depressive disorder is known to increase the risk for bipolarity, but the early identification of such cases remains challenging in clinical practice. In the present study, we evaluated the diagnostic performance of a neuroanatomical pattern classification method in the discrimination between psychotic major depressive disorder (MDD), bipolar I disorder (BD-I), and healthy controls (HC) using a homogenous sample of patients at an early course of their illness. Twenty-three cases of first-episode psychotic mania (BD-I) and 19 individuals with a first episode of psychotic MDD whose diagnosis remained stable during 1 year of followup underwent 1.5 T MRI at baseline. A previously validated multivariate classifier based on support vector machine (SVM) was employed and measures of diagnostic performance were obtained for the discrimination between each diagnostic group and subsamples of age- and gender-matched controls recruited in the same neighborhood of the patients. Based on T1-weighted images only, the SVM-classifier afforded poor discrimination in all 3 pairwise comparisons: BD-I versus HC; MDD versus HC; and BD-I versus MDD. Thus, at the population level and using structural MRI only, we failed to achieve good discrimination between BD-I, psychotic MDD, and HC in this proof of concept study.

Detecting Neuroimaging Biomarkers for Depression: A Meta-analysis of Multivariate Pattern Recognition Studies

BACKGROUND Multiple studies have examined functional and structural brain alteration in patients diagnosed with major depressive disorder (MDD). The introduction of multivariate statistical methods allows investigators to utilize data concerning these brain alterations to generate diagnostic models that accurately differentiate patients with MDD from healthy control subjects (HCs). However, there is substantial heterogeneity in the reported results, the methodological approaches, and the clinical characteristics of participants in these studies. METHODS We conducted a meta-analysis of all studies using neuroimaging (volumetric measures derived from T1-weighted images, task-based functional magnetic resonance imaging [MRI], resting-state MRI, or diffusion tensor imaging) in combination with multivariate statistical methods to differentiate patients diagnosed with MDD from HCs. RESULTS Thirty-three (k = 33) samples including 912 patients with MDD and 894 HCs were included in the meta-analysis. Across all studies, patients with MDD were separated from HCs with 77% sensitivity and 78% specificity. Classification based on resting-state MRI (85% sensitivity, 83% specificity) and on diffusion tensor imaging data (88% sensitivity, 92% specificity) outperformed classifications based on structural MRI (70% sensitivity, 71% specificity) and task-based functional MRI (74% sensitivity, 77% specificity). CONCLUSIONS Our results demonstrate the high representational capacity of multivariate statistical methods to identify neuroimaging-based biomarkers of depression. Future studies are needed to elucidate whether multivariate neuroimaging analysis has the potential to generate clinically useful tools for the differential diagnosis of affective disorders and the prediction of both treatment response and functional outcome.

Multimodal Magnetic Resonance Imaging Study of Treatment-Naïve Adults with Attention-Deficit/Hyperactivity Disorder

Background Attention-Deficit/Hiperactivity Disorder (ADHD) is a prevalent disorder, but its neuroanatomical circuitry is still relatively understudied, especially in the adult population. The few morphometric magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) studies available to date have found heterogeneous results. This may be at least partly attributable to some well-known technical limitations of the conventional voxel-based methods usually employed to analyze such neuroimaging data. Moreover, there is a great paucity of imaging studies of adult ADHD to date that have excluded patients with history of use of stimulant medication. Methods A newly validated method named optimally-discriminative voxel-based analysis (ODVBA) was applied to multimodal (structural and DTI) MRI data acquired from 22 treatment-naïve ADHD adults and 19 age- and gender-matched healthy controls (HC). Results Regarding DTI data, we found higher fractional anisotropy in ADHD relative to HC encompassing the white matter (WM) of the bilateral superior frontal gyrus, right middle frontal left gyrus, left postcentral gyrus, bilateral cingulate gyrus, bilateral middle temporal gyrus and right superior temporal gyrus; reductions in trace (a measure of diffusivity) in ADHD relative to HC were also found in fronto-striatal-parieto-occipital circuits, including the right superior frontal gyrus and bilateral middle frontal gyrus, right precentral gyrus, left middle occipital gyrus and bilateral cingulate gyrus, as well as the left body and right splenium of the corpus callosum, right superior corona radiata, and right superior longitudinal and fronto-occipital fasciculi. Volumetric abnormalities in ADHD subjects were found only at a trend level of significance, including reduced gray matter (GM) in the right angular gyrus, and increased GM in the right supplementary motor area and superior frontal gyrus. Conclusions Our results suggest that adult ADHD is associated with neuroanatomical abnormalities mainly affecting the WM microstructure in fronto-parieto-temporal circuits that have been implicated in cognitive, emotional and visuomotor processes.

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 < 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.

Corpus callosum volumes in recent-onset schizophrenia are correlated to positive symptom severity after 1 year of follow-up

Predicting the prognosis of schizophrenia is of critical importance but there are no valid biomarkers for such purpose. In case–control studies of schizophrenia using magnetic resonance imaging (MRI), the corpus callosum (CC) consistently displays alterations in morphology (Downhill et al., 2000; John et al., 2008), microstructural integrity (Mitelman et al., 2007; Whitford et al., 2010) and functioning (Chaim et al., 2010). In a previous voxel-basedmorphometry (VBM) study comparing recent-onset psychosis (ROP) patients to healthy controls, we reported CC volume reductions in schizophrenia spectrum subjects (Chaim et al, 2010). Herein, we investigated correlations between baseline CC volumes and the clinical prognosis of patients in regard to their symptom severity after 1 year. The patient samplewasdrawn fromapreviously described ROPpool (n=122) (Chaim et al., 2010).We included herein only thosewith confirmed DSM-IV schizophrenia (n=62) or schizoaffective disorder (n=07) (see demographic/clinical data in Table 1). Outcomemeasures were obtained using the Positive andNegative Syndrome Scale (PANSS) 1 year after initial identification of patients. MRI datasets were acquired

Elevated neurotrophin-3 and neurotrophin 4/5 levels in unmedicated bipolar depression and the effects of lithium

BACKGROUND Bipolar disorder (BD) has been associated with diverse abnormalities in neural plasticity and cellular resilience. Neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) support synaptic neuronal survival and differentiation. NT-3 and NT-4/5 levels were found to be altered in BD, potentially representing a physiological response against cellular stress. However, the use of psychopharmacological agents and heterogeneous mood states may constitute important biases in such studies. Thus, we aimed to assess NT-3 and NT-4/5 levels in medication-free BD type I or II individuals in a current depressive episode, before and after 6 weeks of lithium monotherapy and matched with healthy controls. METHODS Twenty-three patients with BD type I or II during a depressive episode and 28 healthy controls were studied. Patients were required to have a 21-item Hamilton Depression Rating Scale score ≥18 and had not undergone any psychopharmacological treatment for at least 6 weeks prior to study entry. Patients were treated with lithium for 6 weeks and plasma NT-3 and NT-4/5 levels were determined at baseline and endpoint using ELISA method. RESULTS Baseline plasma levels of both NT-3 and NT-4/5 were significantly increased in acutely depressed BD subjects in comparison to healthy controls (p=0.040 and 0.039, respectively). The NT-3 and NT-4/5 levels did not significantly change after lithium treatment. NT-3 and NT-4/5 levels were positively correlated to illness duration in BD (p=0.032 and 0.034, respectively). CONCLUSION Our findings suggest that NT-3 and NT-4/5 levels are increased in the depressive phase of BD, which seems directly associated with illness duration. The increased levels of NT-3 and NT-4/5 may underlie a biological response to cellular stress associated with the course of BD.

State-dependent microstructural white matter changes in drug-naive patients with first-episode psychosis

BACKGROUND Diffusion tensor imaging (DTI) studies have consistently shown white matter (WM) microstructural abnormalities in schizophrenia. Whether or not such alterations could vary depending on clinical status (i.e. acute psychosis v. remission) remains to be investigated. METHODS Twenty-five treatment-naïve first-episode psychosis (FEP) patients and 51 healthy-controls (HC) underwent MRI scanning at baseline. Twenty-one patients were re-scanned as soon as they achieved sustained remission of symptoms; 36 HC were also scanned twice. Rate-of-change maps of longitudinal DTI changes were calculated for in order to examine WM alterations associated with changes in clinical status. We conducted voxelwise analyses of fractional anisotropy (FA) and trace (TR) maps. RESULTS At baseline, FEP presented reductions of FA in comparison with HC [p < 0.05, false-discovery rate (FDR)-corrected] affecting fronto-limbic WM and associative, projective and commissural fasciculi. After symptom remission, patients showed FA increase over time (p < 0.001, uncorrected) in some of the above WM tracts, namely the right anterior thalamic radiation, right uncinate fasciculus/inferior fronto-occipital fasciculus, and left inferior fronto-occipital fasciculus/inferior longitudinal fasciculus. We also found significant correlations between reductions in PANSS scores and FA increases over time (p < 0.05, FDR-corrected). CONCLUSIONS 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 in brain tracts are a key neurobiological feature of acute psychotic disorders, and recovery from such WM pathology can lead to amelioration of symptoms.

Poverty, low education, and the expression of psychotic-like experiences in the general population of São Paulo, Brazil

The aim of our study was to assess psychotic-like experiences in the general population aged 18-30 years old of the city of São Paulo, Brazil. A household survey was conducted with 1950 young-adults randomly drawn from the citys general population. The validated 92-item Portuguese version of the Prodromal Questionnaire (PQ) was used for face-to-face interviews. Latent class analysis was conducted. Mean age was of 24 years; 51.1% of the sample was of women. Mean total score on the PQ was 22.06 (SD=17.16). Considering a suggested cut-off of 14 in the positive subscale, 30.8% of individuals were above the threshold for ultra-high risk for psychosis detection. Latent class analysis resulted in a three classes clusterization. Class 1 (20%; n=390) had the highest overall PQ scores (mean=49.31,SD=10.783), class 2 (43%; n=835) had intermediate scores (mean=23.37,SD=6.56), and class 3 (37%; n=721) had the lowest scores (mean=5.81,SD=3.74). Class 1 had significantly more individuals with less education and significantly more individuals with lower socioeconomic class. Poverty and low education might be associated with the psychotic expression in the general population, amplifying their actions on the psychosis gradient in developing countries. The psychosis continuum might be constituted by three distinct quantitatively different classes.

Distinct cognitive performance and patterns of drug use among early and late onset cocaine users

INTRODUCTION Adolescence is a crucial period for neurodevelopment, but few studies have investigated the impact of early cocaine use on cognitive performance and patterns of substance use. METHODS We evaluated 103 cocaine dependent inpatients divided in two groups: early-onset users (EOG; n=52), late-onset users (LOG; n=51), and 63 healthy controls. Neuropsychological functioning was evaluated using Digits Forward (DF) and Backward (DB), Trail Making Test (TMT), Stroop Color Word Test (SCWT), Controlled Oral Word Association Test (COWAT), Wisconsin Card Sorting Test (WCST), Rey Osterrieth Complex Figure Test (ROCFT), Frontal Assessment Battery (FAB), and Iowa Gambling Test (IGT). Use of alcohol and other drugs was assessed with the Addiction Severity Index (ASI-6). RESULTS Analyses of covariance controlling for age, IQ and years of education showed that EOG presented worse performance in attention span (DF, p=0.020), working memory (DB, p=0.001), sustained attention (WCST, p=0.030), declarative memory (ROCFT, p=0.031) and general executive functioning (FAB, p=0.003) when compared with the control group. LOG presented impairments on divided attention (TMT, p=0.003) and general executive functioning (FAB, p=0.001) in relation to the control group. EOG presented higher use of cannabis and alcohol than LOG (p≤0.001). CONCLUSION Early-onset cocaine users display more pronounced neuropsychological alterations than controls, as well as a greater frequency of polydrug consumption than LOG. The prominent cognitive deficits in EOG probably reflect the deleterious interference of cocaine use with early stages of neurodevelopment. This may be related to more severe clinical characteristics of substance disorder in this subgroup, including polysubstance abuse.

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

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.