Marcelo Q. Hoexter

Multicenter Voxel-Based Morphometry Mega-Analysis of Structural Brain Scans in Obsessive-Compulsive Disorder

OBJECTIVE Results from structural neuroimaging studies of obsessive-compulsive disorder (OCD) have been only partially consistent. The authors sought to assess regional gray and white matter volume differences between large samples of OCD patients and healthy comparison subjects and their relation with demographic and clinical variables. METHOD A multicenter voxel-based morphometry mega-analysis was performed on 1.5-T structural T1-weighted MRI scans derived from the International OCD Brain Imaging Consortium. Regional gray and white matter brain volumes were compared between 412 adult OCD patients and 368 healthy subjects. RESULTS Relative to healthy comparison subjects, OCD patients had significantly smaller volumes of frontal gray and white matter bilaterally, including the dorsomedial prefrontal cortex, the anterior cingulate cortex, and the inferior frontal gyrus extending to the anterior insula. Patients also showed greater cerebellar gray matter volume bilaterally compared with healthy subjects. Group differences in frontal gray and white matter volume were significant after correction for multiple comparisons. Additionally, group-by-age interactions were observed in the putamen, insula, and orbitofrontal cortex (indicating relative preservation of volume in patients compared with healthy subjects with increasing age) and in the temporal cortex bilaterally (indicating a relative loss of volume in patients compared with healthy subjects with increasing age). CONCLUSIONS These findings partially support the prevailing fronto-striatal models of OCD and offer additional insights into the neuroanatomy of the disorder that were not apparent from previous smaller studies. The group-by-age interaction effects in orbitofrontal-striatal and (para)limbic brain regions may be the result of altered neuroplasticity associated with chronic compulsive behaviors, anxiety, or compensatory processes related to cognitive dysfunction.

Gray matter volumes in obsessive-compulsive disorder before and after fluoxetine or cognitive-behavior therapy: a randomized clinical trial.

Serotonin reuptake inhibitors and cognitive-behavior therapy (CBT) are considered first-line treatments for obsessive-compulsive disorder (OCD). However, little is known about their modulatory effects on regional brain morphology in OCD patients. We sought to document structural brain abnormalities in treatment-naive OCD patients and to determine the effects of pharmacological and cognitive-behavioral treatments on regional brain volumes. Treatment-naive patients with OCD (n=38) underwent structural magnetic resonance imaging scan before and after a 12-week randomized clinical trial with either fluoxetine or group CBT. Matched-healthy controls (n=36) were also scanned at baseline. Voxel-based morphometry was used to compare regional gray matter (GM) volumes of regions of interest (ROIs) placed in the orbitofrontal, anterior cingulate and temporolimbic cortices, striatum, and thalamus. Treatment-naive OCD patients presented smaller GM volume in the left putamen, bilateral medial orbitofrontal, and left anterior cingulate cortices than did controls (p<0.05, corrected for multiple comparisons). After treatment with either fluoxetine or CBT (n=26), GM volume abnormalities in the left putamen were no longer detectable relative to controls. ROI-based within-group comparisons revealed that GM volume in the left putamen significantly increased (p<0.012) in fluoxetine-treated patients (n=13), whereas no significant GM volume changes were observed in CBT-treated patients (n=13). This study supports the involvement of orbitofronto/cingulo-striatal loops in the pathophysiology of OCD and suggests that fluoxetine and CBT may have distinct neurobiological mechanisms of action.

Abnormal Brain Connectivity Patterns in Adults with ADHD: A Coherence Study

Studies based on functional magnetic resonance imaging (fMRI) during the resting state have shown decreased functional connectivity between the dorsal anterior cingulate cortex (dACC) and regions of the Default Mode Network (DMN) in adult patients with Attention-Deficit/Hyperactivity Disorder (ADHD) relative to subjects with typical development (TD). Most studies used Pearson correlation coefficients among the BOLD signals from different brain regions to quantify functional connectivity. Since the Pearson correlation analysis only provides a limited description of functional connectivity, we investigated functional connectivity between the dACC and the posterior cingulate cortex (PCC) in three groups (adult patients with ADHD, n = 21; TD age-matched subjects, n = 21; young TD subjects, n = 21) using a more comprehensive analytical approach – unsupervised machine learning using a one-class support vector machine (OC-SVM) that quantifies an abnormality index for each individual. The median abnormality index for patients with ADHD was greater than for TD age-matched subjects (p = 0.014); the ADHD and young TD indices did not differ significantly (p = 0.480); the median abnormality index of young TD was greater than that of TD age-matched subjects (p = 0.016). Low frequencies below 0.05 Hz and around 0.20 Hz were the most relevant for discriminating between ADHD patients and TD age-matched controls and between the older and younger TD subjects. In addition, we validated our approach using the fMRI data of children publicly released by the ADHD-200 Competition, obtaining similar results. Our findings suggest that the abnormal coherence patterns observed in patients with ADHD in this study resemble the patterns observed in young typically developing subjects, which reinforces the hypothesis that ADHD is associated with brain maturation deficits.

What is the Optimal Way to Subdivide Obsessive-Compulsive Disorder?

The clinical presentation of obsessive-compulsive disorder (OCD) varies not only across patients but over the course of the disorder. This diversity indicates that OCD is a heterogeneous disorder, which may have an important impact on psychopathological, longitudinal, genetic, and treatment research. To better understand OCD heterogeneity, more homogeneous phenotypic descriptions are necessary to delimiting clinically meaningful subgroups of patients. Besides phenotypic descriptions, another method of delimiting OCD patient subgroups includes the search for endophenotypes (extended phenotypes) based on neurophysiological, immunological, genetic, neuropsychological, or neuroanatomic (neuroimaging) paradigms. This article will describe some strategies that deal with OCD heterogeneity, including the identification of more homogeneous phenotypical categories, an improved understanding of obsessive-compulsive symptom dimensions and how to use them as quantitative traits, and broadening the diagnostic boundaries of OCD to include other related conditions. The relevance and limitations of each approach are also discussed. Since the etiological mechanisms associated with the expressions of OCD are unknown, there is probably not one but several heuristic strategies to search for more homogeneous OCD subgroup, that combined may provide the most fruitful results.

Higher dopamine transporter density in Parkinson’s disease patients with depression

RationaleDepression is a frequent non-motor symptom in Parkinson’s disease (PD) with increasing rates with the progression of the disease. Molecular imaging studies have shown a reduction of dopamine transporter (DAT) density in depressed PD patients (dPD); however, DAT role in the pathophysiology of PD depression is not clear since clinical matching was inappropriate and DAT reduction could be attributed to PD severity.ObjectivesTo further examine the role of DAT in PD depression, this study compared thoroughly matched depressed vs. non-depressed PD patients (ndPD).Materials and methodsTwenty PD patients (n = 10 ndPD; n = 10 dPD) matched for age and disease severity were submitted to brain SPECT imaging with [99mTc]-TRODAT-1, a DAT radioligand. DAT-binding potential was calculated using regions of interest bilaterally drawn in the striatum, caudate, and putamen. Depression was defined according to Beck Depression Inventory (BDI; cut-off >18).ResultsMean BDI scores were higher in dPD (25.0 ± 5.6) than in ndPD patients (8.0 ± 1.9, p < 0.0001). DAT density was greater on dPD especially in the left caudate (dPD 0.87 ± 0.19 vs. ndDP 0.69 ± 0.18, p = 0.02) and right putamen (dPD 0.37 ± 0.07 vs. ndPD 0.28 ± 0.13, p = 0.03) than in ndPD patients.ConclusionOur results suggest that in vivo DAT density is increased in dPD patients as compared to ndPD, suggesting that DAT is implicated in the pathophysiology of PD depression.

Parkinson's disease and dopamine transporter neuroimaging - a critical review

Parkinsons disease (PD) is a common neurodegenerative disorder that is mainly caused by dopaminergic neuron loss in the substantia nigra. Several nuclear medicine radiotracers have been developed to evaluate PD diagnoses and disease evolution in vivo in PD patients. Positron emission tomography (PET) and single photon computerized emission tomography (SPECT) radiotracers for the dopamine transporter (DAT) provide good markers for the integrity of the presynaptic dopaminergic system affected in PD. Over the last decade, radiotracers suitable for imaging the DAT have been the subject of most efforts. In this review, we provide a critical discussion on the utility of DAT imaging for Parkinsons disease diagnosis (sensitivity and specificity).

Distinct Subcortical Volume Alterations in Pediatric and Adult OCD: A Worldwide Meta- and Mega-Analysis.

OBJECTIVE Structural brain imaging studies in obsessive-compulsive disorder (OCD) have produced inconsistent findings. This may be partially due to limited statistical power from relatively small samples and clinical heterogeneity related to variation in illness profile and developmental stage. To address these limitations, the authors conducted meta- and mega-analyses of data from OCD sites worldwide. METHOD T1 images from 1,830 OCD patients and 1,759 control subjects were analyzed, using coordinated and standardized processing, to identify subcortical brain volumes that differ between OCD patients and healthy subjects. The authors performed a meta-analysis on the mean of the left and right hemisphere measures of each subcortical structure, and they performed a mega-analysis by pooling these volumetric measurements from each site. The authors additionally examined potential modulating effects of clinical characteristics on morphological differences in OCD patients. RESULTS The meta-analysis indicated that adult patients had significantly smaller hippocampal volumes (Cohens d=-0.13; % difference=-2.80) and larger pallidum volumes (d=0.16; % difference=3.16) compared with adult controls. Both effects were stronger in medicated patients compared with controls (d=-0.29, % difference=-4.18, and d=0.29, % difference=4.38, respectively). Unmedicated pediatric patients had significantly larger thalamic volumes (d=0.38, % difference=3.08) compared with pediatric controls. None of these findings were mediated by sample characteristics, such as mean age or scanning field strength. The mega-analysis yielded similar results. CONCLUSIONS The results indicate different patterns of subcortical abnormalities in pediatric and adult OCD patients. The pallidum and hippocampus seem to be of importance in adult OCD, whereas the thalamus seems to be key in pediatric OCD. These findings highlight the potential importance of neurodevelopmental alterations in OCD and suggest that further research on neuroplasticity in OCD may be useful.

Differential prefrontal gray matter correlates of treatment response to fluoxetine or cognitive-behavioral therapy in obsessive-compulsive disorder

Nearly one-third of patients with obsessive-compulsive disorder (OCD) fail to respond to adequate therapeutic approaches such as serotonin reuptake inhibitors and/or cognitive-behavioral therapy (CBT). This study investigated structural magnetic resonance imaging (MRI) correlates as potential pre-treatment brain markers to predict treatment response in treatment-naïve OCD patients randomized between trials of fluoxetine or CBT. Treatment-naïve OCD patients underwent structural MRI scans before randomization to a 12-week clinical trial of either fluoxetine or group-based CBT. Voxel-based morphometry was used to identify correlations between pretreatment regional gray matter volume and changes in symptom severity on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Brain regional correlations of treatment response differed between treatment groups. Notably, symptom improvement in the fluoxetine treatment group (n=14) was significantly correlated with smaller pretreatment gray matter volume within the right middle lateral orbitofrontal cortex (OFC), whereas symptom improvement in the CBT treatment group (n=15) was significantly correlated with larger pretreatment gray matter volume within the right medial prefrontal cortex (mPFC). No significant a priori regional correlations of treatment response were identified as common between the two treatment groups when considering the entire sample (n=29). These findings suggest that pretreatment gray matter volumes of distinct brain regions within the lateral OFC and mPFC were differentially correlated to treatment response to fluoxetine versus CBT in OCD patients. This study further implicates the mPFC in the fear/anxiety extinction process and stresses the importance of lateral portions of the OFC in mediating fluoxetines effectiveness in OCD. Clinical registration information: http://clinicaltrials.gov-NCT00680602.

Neuropsychological predictors of response to randomized treatment in obsessive-compulsive disorder

OBJECTIVE To identify neuropsychological predictors of treatment response to cognitive-behavioral therapy (CBT) and fluoxetine in treatment-naïve adults with obsessive-compulsive disorder (OCD). METHOD Thirty-eight adult outpatients with OCD underwent neuropsychological assessment, including tasks of intellectual function, executive functioning and visual and verbal memory, before randomization to a 12-week clinical trial of either CBT or fluoxetine. Neuropsychological measures were used to identify predictors of treatment response in OCD. RESULTS Neuropsychological measures that predicted a better treatment response to either CBT or fluoxetine were higher verbal IQ (Wechsler Abbreviated Scale of Intelligence) (p=0.008); higher verbal memory on the California Verbal Learning Test (p=0.710); shorter time to complete part D (Dots) (p<0.001), longer time to complete part W (Words) (p=0.025) and less errors on part C (Colors) (p<0.001) in the Victoria Stroop Test (VST). Fewer perseverations on the California Verbal Learning Test, a measure of mental flexibility, predicted better response to CBT, but worse response to fluoxetine (p=0.002). CONCLUSION In general, OCD patients with better cognitive and executive abilities at baseline were more prone to respond to either CBT or fluoxetine. Our finding that neuropsychological measures of mental flexibility predicted response to treatment in opposite directions for CBT and fluoxetine suggests that OCD patients with different neuropsychological profiles may respond preferentially to one type of treatment versus the other. Further studies with larger samples of OCD patients are necessary to investigate the heuristic value of such findings in a clinical context.

Evaluation of pattern recognition and feature extraction methods in ADHD prediction

Attention Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder, being one of the most prevalent psychiatric disorders in childhood. The neural substrates associated with this condition, both from structural and functional perspectives, are not yet well established. Recent studies have highlighted the relevance of neuroimaging not only to provide a more solid understanding about the disorder but also for possible clinical support. The ADHD-200 Consortium organized the ADHD-200 global competition making publicly available, hundreds of structural magnetic resonance imaging (MRI) and functional MRI (fMRI) datasets of both ADHD patients and typically developing (TD) controls for research use. In the current study, we evaluate the predictive power of a set of three different feature extraction methods and 10 different pattern recognition methods. The features tested were regional homogeneity (ReHo), amplitude of low frequency fluctuations (ALFF), and independent components analysis maps (resting state networks; RSN). Our findings suggest that the combination ALFF+ReHo maps contain relevant information to discriminate ADHD patients from TD controls, but with limited accuracy. All classifiers provided almost the same performance in this case. In addition, the combination ALFF+ReHo+RSN was relevant in combined vs. inattentive ADHD classification, achieving a score accuracy of 67%. In this latter case, the performances of the classifiers were not equivalent and L2-regularized logistic regression (both in primal and dual space) provided the most accurate predictions. The analysis of brain regions containing most discriminative information suggested that in both classifications (ADHD vs. TD controls and combined vs. inattentive), the relevant information is not confined only to a small set of regions but it is spatially distributed across the whole brain.