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Objectives: Neuroimaging studies have revealed evidence of brain functional abnormalities in bipolar depressive disorder (BDD) and major depressive disorder (MDD). However, few studies to date have compared these two mood disorders directly., Methods: Matched groups of 26 BDD type I patients, 26 MDD patients and 26 healthy controls underwent functional magnetic resonance imaging (fMRI) while performing the n-back working memory task. A whole-brain ANOVA was used to compare the three groups and clusters of significant difference were examined further using region-of-interest (ROI) analysis., Results: The whole-brain ANOVA revealed a single cluster of significant difference in the medial frontal cortex. The BDD and MDD patients both showed failure to deactivate in this area compared to the controls. The BDD patients showed significantly greater failure of deactivation than the MDD patients, which was not accounted for by differences in severity or chronicity of illness between them., Conclusions: Failure of deactivation, considered to reflect default mode network dysfunction, is present to a greater extent in bipolar than unipolar depression. The study of this network may be useful in the search for brain markers that distinguish the two disorders., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A relatively large number of studies have investigated the power of structural magnetic resonance imaging (sMRI) data to discriminate patients with schizophrenia from healthy controls. However, very few of them have also included patients with bipolar disorder, allowing the clinically relevant discrimination between both psychotic diagnostics. To assess the efficacy of sMRI data for diagnostic prediction in psychosis we objectively evaluated the discriminative power of a wide range of commonly used machine learning algorithms (ridge, lasso, elastic net and L0 norm regularized logistic regressions, a support vector classifier, regularized discriminant analysis, random forests and a Gaussian process classifier) on main sMRI features including grey and white matter voxel-based morphometry (VBM), vertex-based cortical thickness and volume, region of interest volumetric measures and wavelet-based morphometry (WBM) maps. All possible combinations of algorithms and data features were considered in pairwise classifications of matched samples of healthy controls (N = 127), patients with schizophrenia (N = 128) and patients with bipolar disorder (N = 128). Results show that the selection of feature type is important, with grey matter VBM (without data reduction) delivering the best diagnostic prediction rates (averaging over classifiers: schizophrenia vs. healthy 75%, bipolar disorder vs. healthy 63% and schizophrenia vs. bipolar disorder 62%) whereas algorithms usually yielded very similar results. Indeed, those grey matter VBM accuracy rates were not even improved by combining all feature types in a single prediction model. Further multi-class classifications considering the three groups simultaneously made evident a lack of predictive power for the bipolar group, probably due to its intermediate anatomical features, located between those observed in healthy controls and those found in patients with schizophrenia. Finally, we provide MRIPredict (https://www.nitrc.org/projects/mripredict/), a free tool for SPM, FSL and R, to easily carry out voxelwise predictions based on VBM images.

Schizophrenia is considered a disorder of abnormal brain connectivity. Although whole brain maps of averaged bivariate voxel correlations have been successfully applied to study connectivity abnormalities in schizophrenia these maps do not adequately explore the multivariate nature of brain connectivity. Here we adapt a novel method for high-dimensional regression (supervised principal component regression) to estimate brain maps of multivariate non redundant connectivity (NRC) from resting functional Magnetic Resonance Imaging (fMRI) data of 116 patients with schizophrenia and 122 matched controls. Disorder related differences in NRC involved caudate hyper-connectivity and hypo-connectivity of several cortical areas such as the dorsal cingulate, the cuneus and the right postcentral cortex. These abnormalities were coupled with abnormalities in the amplitude of signal fluctuations and, to a minor extent, with differences in the dimensionality of connectivity patterns as quantified by the number of supervised principal components. Second level seed correlation analyses linked the observed abnormalities to an additional set of brain regions relevant to schizophrenia such as the thalamus and the temporal cortex. The non redundant connectivity maps proposed here are a new tool that will complement the information provided by other already available voxel based whole brain connectivity measures.

Background: A key finding underlying the continuum of psychosis concept is the presence of psychotic-like experiences (PLEs) in healthy subjects. However, it remains uncertain to what extent these experiences are related to the genetic risk for schizophrenia and how far they actually resemble attenuated forms of psychotic symptoms., Methods: Forty-nine adults with no history of mental illness in first-degree relatives and 59 siblings of patients with schizophrenia were rated on the psychosis section of the Computerized Diagnostic Interview Schedule IV (C DIS-IV) and the Rust Inventory of Schizotypal Cognitions (RISC). Those who rated positive on the CDIS-IV were re-interviewed using the lifetime version of the Present State Examination 9th edition (PSE-9) and the Structured interview for Schizotypy (SIS)., Results: Seventeen (34.69%) of the non-relatives and 22 (37.29%) of the relatives responded positively to one or more of the psychosis questions on the DIS. This difference was not significant. RISC scores were also similar between the groups. At follow-up interview with the PSE-9, 13/40 PLEs (32.50%) in the non-relatives were classified as possible or probable psychotic symptoms compared to 11/46 (23.91%) in the relatives. Using liberal symptom thresholds, 5 of those who attended the follow-up interview (2 non-relatives and 3 relatives) met SIS criteria for schizotypal personality disorder., Conclusions: Rates of PLEs, however considered, do not differ substantially between relatives and non-relatives of patients with schizophrenia. Only a minority of PLEs picked up by screening interviews resemble attenuated forms of psychotic symptoms., (Copyright © 2016. Published by Elsevier B.V.)

Background: Relatively few studies have investigated whether relatives of patients with bipolar disorder show brain functional changes, and these have focused on activation changes. Failure of de-activation during cognitive task performance is also seen in the disorder and may have trait-like characteristics since it has been found in euthymia., Method: A total of 20 euthymic patients with bipolar disorder, 20 of their unaffected siblings and 40 healthy controls underwent functional magnetic resonance imaging during performance of the n-back working memory task. An analysis of variance (ANOVA) was fitted to individual whole-brain maps from each set of patient-relative-matched pair of controls. Clusters of significant difference among the groups were used as regions of interest to compare mean activations/de-activations between them., Results: A single cluster of significant difference among the three groups was found in the whole-brain ANOVA. This was located in the medial prefrontal cortex, a region of task-related de-activation in the healthy controls. Both the patients and their siblings showed significantly reduced de-activation compared with the healthy controls in this region, but the failure was less marked in the relatives., Conclusions: Failure to de-activate the medial prefrontal cortex in both euthymic bipolar patients and their unaffected siblings adds to evidence for default mode network dysfunction in the disorder, and suggests that it may act as a trait marker.

Introduction: Cognitive impairment in the euthymic phase is a well-established finding in bipolar disorder. However, its brain structural and/or functional correlates are uncertain., Methods: Thirty-three euthymic bipolar patients with preserved memory and executive function and 28 euthymic bipolar patients with significant memory and/or executive impairment, as defined using two test batteries, the Rivermead Behavioural Memory Test (RBMT) and the Behavioural Assessment of the Dysexecutive Syndrome (BADS), plus 28 healthy controls underwent structural MRI using voxel-based morphometry (VBM). Twenty-seven of the cognitively preserved patients, 23 of the cognitively impaired patients and 28 controls also underwent fMRI during performance of the n-back working memory task., Results: No clusters of grey or white matter volume difference were found between the two patient groups. During n-back performance, the cognitively impaired patients showed hypoactivation compared to the cognitively preserved patients in a circumscribed region in the right dorsolateral prefrontal cortex. Both patient groups showed failure of de-activation in the medial frontal cortex compared to the healthy controls., Conclusions: Cognitive impairment in euthymic bipolar patients appears from this study to be unrelated to structural brain abnormality, but there was some evidence for an association with altered prefrontal function.

Background: Structural pathology in the hippocampus is well-documented in schizophrenia, but brain functional changes have not been consistently found. We used spatial navigation in a virtual reality environment, a task that is known to produce robust hippocampal activation in healthy subjects, to examine task-related activations and de-activations in the disorder., Methods: Twenty-seven DSM IV schizophrenia patients and 32 healthy controls underwent fMRI while they navigated to a goal through a virtual reality town. Activations and de-activations were examined at the whole brain level and also using a region-of-interest (ROI) in the hippocampus., Results: Spatial navigation was associated with activation in the posterior hippocampus and parahippocampal gyrus plus widespread neocortical areas. The patients showed reduced activation compared to the controls in the left dorsolateral prefrontal cortex (DLPFC) and the left occipital/temporal cortex. No differences in hippocampal activation were seen either at the whole-brain level or in the ROI analysis. The patients showed failure of de-activation affecting some but not all subregions of the default mode network., Conclusions: Schizophrenia is associated with task-related hypoactivation in the DLPFC during spatial navigation, but not with functional changes in the hippocampus. The failure of de-activation also found adds to evidence for default mode network dysfunction in the disorder., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Brain volume and thickness abnormalities have been reported in first-episode psychosis (FEP). However, it is unclear if and how they are modulated by brain developmental stage (and, therefore, by age at FEP as a proxy). This is a multicenter cross-sectional case-control brain magnetic resonance imaging (MRI) study. Patients with FEP (n = 196), 65.3% males, with a wide age at FEP span (12-35 y), and healthy controls (HC) (n = 157), matched for age, sex, and handedness, were scanned at 6 sites. Gray matter volume and thickness measurements were generated for several brain regions using FreeSurfer software. The nonlinear relationship between age at scan (a proxy for age at FEP in patients) and volume and thickness measurements was explored in patients with schizophrenia spectrum disorders (SSD), affective psychoses (AFP), and HC. Earlier SSD cases (ie, FEP before 15-20 y) showed significant volume and thickness deficits in frontal lobe, volume deficits in temporal lobe, and volume enlargements in ventricular system and basal ganglia. First-episode AFP patients had smaller cingulate cortex volume and thicker temporal cortex only at early age at FEP (before 18-20 y). The AFP group also had age-constant (12-35-y age span) volume enlargements in the frontal and parietal lobe. Our study suggests that age at first episode modulates the structural brain abnormalities found in FEP patients in a nonlinear and diagnosis-dependent manner. Future MRI studies should take these results into account when interpreting samples with different ages at onset and diagnosis., (© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Delusional disorder has been the subject of very little investigation using brain imaging., Aims: To examine potential structural and/or functional brain abnormalities in this disorder., Method: We used structural imaging (voxel-based morphometry, VBM) and functional imaging (during performance of the n-back task and whole-brain resting connectivity analysis) to examine 22 patients meeting DSM-IV criteria for delusional disorder and 44 matched healthy controls., Results: The patients showed grey matter reductions in the medial frontal/anterior cingulate cortex and bilateral insula on unmodulated (but not on modulated) VBM analysis, failure of de-activation in the medial frontal/anterior cingulate cortex during performance of the n-back task, and decreased resting-state connectivity in the bilateral insula., Conclusions: The findings provide evidence of brain abnormality in the medial frontal/anterior cingulate cortex and insula in delusional disorder. A role for the former region in the pathogenesis of delusions is consistent with several other lines of evidence., (© The Royal College of Psychiatrists 2016.)

Patients with schizophrenia are known to have increased prevalence of abnormalities in midline brain structures, such as a failure of the septum pellucidum to fuse (cavum septum pellucidum) and the absence of the adhesio interthalamica. This is the first study to investigate the prevalence of these abnormalities across a large multidiagnostic sample. Presence of cavum septum pellucidum and absence of the adhesio interthalamica was assessed in 639 patients with chronic schizophrenia, delusional disorder, schizoaffective disorder, bipolar disorder, major depressive disorder, or a first episode of psychosis, mania or unipolar depression. This was compared with 223 healthy controls using logistic-regression-derived odds ratios (OR). Patients with psychotic or mood disorders showed an increased prevalence of both abnormalities (OR of cavum septum pellucidum = 2.1, OR of absence of the adhesio interthalamica = 2.6, OR of both cavum septum pellucidum and absence of the adhesio interthalamica = 3.8, all P < .001). This increased prevalence was separately observed in nearly all disorders as well as after controlling for potential confounding factors. This study supports a general increased prevalence of midline brain abnormalities across mood and psychotic disorders. This nonspecificity may suggest that these disorders share a common neurodevelopmental etiology., (© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Brain structural changes in schizoaffective disorder, and how far they resemble those seen in schizophrenia and bipolar disorder, have only been studied to a limited extent., Method: Forty-five patients meeting DSM-IV and RDC criteria for schizoaffective disorder, groups of patients with 45 matched schizophrenia and bipolar disorder, and 45 matched healthy controls were examined using voxel-based morphometry (VBM)., Results: Analyses comparing each patient group with the healthy control subjects found that the patients with schizoaffective disorder and the patients with schizophrenia showed widespread and overlapping areas of significant volume reduction, but the patients with bipolar disorder did not. A subsequent analysis compared the combined group of patients with the controls followed by extraction of clusters. In regions where the patients differed significantly from the controls, no significant differences in mean volume between patients with schizoaffective disorder and patients with schizophrenia in any of five regions of volume reduction were found, but mean volumes in the patients with bipolar disorder were significantly smaller in three of five., Conclusion: The findings provide evidence that, in terms of structural gray matter brain abnormality, schizoaffective disorder resembles schizophrenia more than bipolar disorder., (© 2015 The Authors. Acta Psychiatrica Scandinavica Published by John Wiley & Sons Ltd.)

Background: Midline brain abnormalities might increase susceptibility to both first-episode and chronic mental disorder. Evidence of cavum vergae (CV) abnormality in mental disorders is scarce., Methods: The presence of CV was assessed by a researcher blind to clinical information in a cross-disorder sample of 639 patients with mood and psychotic disorders and in 223 healthy controls. Homogeneous magnetic resonance imaging methods of acquisition and assessment were applied., Results: Seven out of 639 patients with mood or psychotic disorders were detected with CV which corresponds to a prevalence of 1.1%. There were no concurrent cases of CV in the healthy control group. Identified cases which are briefly described were diagnosed from bipolar I disorder (n=2), delusional disorder (n=1), brief psychotic disorder (n=1) and schizoaffective disorder (n=3). Patients with CV had descriptively lower current IQ, executive functioning and memory scores in relation to patients without CV but this was not statistically significant., Limitations: Effects of medication and lack of statistical power of the CV patient group., Conclusions: Midline brain abnormalities, such as CV, might represent an unspecific risk factor for the development of severe mental disorders., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Spherical deconvolution (SD) methods are widely used to estimate the intra-voxel white-matter fiber orientations from diffusion MRI data. However, while some of these methods assume a zero-mean Gaussian distribution for the underlying noise, its real distribution is known to be non-Gaussian and to depend on many factors such as the number of coils and the methodology used to combine multichannel MRI signals. Indeed, the two prevailing methods for multichannel signal combination lead to noise patterns better described by Rician and noncentral Chi distributions. Here we develop a Robust and Unbiased Model-BAsed Spherical Deconvolution (RUMBA-SD) technique, intended to deal with realistic MRI noise, based on a Richardson-Lucy (RL) algorithm adapted to Rician and noncentral Chi likelihood models. To quantify the benefits of using proper noise models, RUMBA-SD was compared with dRL-SD, a well-established method based on the RL algorithm for Gaussian noise. Another aim of the study was to quantify the impact of including a total variation (TV) spatial regularization term in the estimation framework. To do this, we developed TV spatially-regularized versions of both RUMBA-SD and dRL-SD algorithms. The evaluation was performed by comparing various quality metrics on 132 three-dimensional synthetic phantoms involving different inter-fiber angles and volume fractions, which were contaminated with noise mimicking patterns generated by data processing in multichannel scanners. The results demonstrate that the inclusion of proper likelihood models leads to an increased ability to resolve fiber crossings with smaller inter-fiber angles and to better detect non-dominant fibers. The inclusion of TV regularization dramatically improved the resolution power of both techniques. The above findings were also verified in human brain data.

Negative symptoms are a core feature of schizophrenia and their reliable and valid assessment is a prerequisite for developing effective therapeutic interventions. This study examined the psychometric properties and validity of the Spanish version of a new rating instrument, the Clinical Assessment Interview for Negative Symptoms (CAINS). Outpatients and inpatients (N=100) with DSM-IV schizophrenia were administered the translated CAINS, the Positive and Negative Syndrome Scale (PANSS), the Scale for the Assessment of Negative Symptoms (SANS), and the Calgary Depression Scale for Schizophrenia (CDSS). A subsample (N=46) was rated for Parkinsonism using the Extrapyramidal Symptoms Rating Scale (ESRS). The scale showed good inter-rater and intra-rater reliability. Both the CAINS overall and the subscales for motivation/pleasure (CAINS-Map) and expression (CAINS-Exp) scores correlated significantly with the SANS and PANSS negative symptom scale. Significant correlations with positive symptoms and general psychopathology were also found, but these reduced and mostly became insignificant when overall severity of illness was controlled for. Significant correlations with depression also disappeared when severity was controlled for. There was a trend-level correlation between the CAINS total score and Parkinsonism, which reflected an association with the CAINS-Exp subscale only. Factor analysis revealed a two-dimensional structure that explained the 67.44% of the variance. Overall, the Spanish version of the CAINS appears to be a valid tool for measuring negative symptoms in schizophrenia., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Functional imaging studies in relatives of schizophrenic patients have had inconsistent findings, particularly with respect to altered dorsolateral prefrontal cortex activation. Some recent studies have also suggested that failure of deactivation may be seen., Method: A total of 28 patients with schizophrenia, 28 of their siblings and 56 healthy controls underwent functional magnetic resonance imaging during performance of the n-back working memory task. An analysis of variance was fitted to individual whole-brain maps from each set of patient-relative-matched pair of controls. Clusters of significant difference among the groups were then used as regions of interest to compare mean activations and deactivations among the groups., Results: In all, five clusters of significant differences were found. The schizophrenic patients, but not the relatives, showed reduced activation compared with the controls in the lateral frontal cortex bilaterally, the left basal ganglia and the cerebellum. In contrast, both the patients and the relatives showed significant failure of deactivation compared with the healthy controls in the medial frontal cortex, with the relatives also showing less failure than the patients. Failure of deactivation was not associated with schizotypy scores or presence of psychotic-like experiences in the relatives., Conclusions: Both schizophrenic patients and their relatives show altered task-related deactivation in the medial frontal cortex. This in turn suggests that default mode network dysfunction may function as a trait marker for schizophrenia.

Background: The Bipolar Depression Rating Scale (BDRS) arguably better captures symptoms in bipolar depression especially depressive mixed states than traditional unipolar depression rating scales. The psychometric properties of the Spanish adapted version, BDRS-S, are reported., Methods: The BDRS was translated into Spanish by two independent psychiatrists fluent in English and Spanish. After its back-translation into English, the BDRS-S was administered to 69 DSMI-IV bipolar I and II patients who were recruited from two Spanish psychiatric hospitals. The Hamilton Depression Rating Scale (HDRS), the Montgomery-Asberg Depression Rating Scale (MADRS) and the Young Mania Rating Scale (YMRS) were concurrently administered. 42 patients were reviewed via video by four psychiatrists blind to the psychopathological status of those patients. In order to assess the BDRS-S intra-rater or test-retest validity, 22 subjects were assessed by the same investigator performing two evaluations within five days., Results: The BDRS-S had a good internal consistency (Cronbach׳s α=0.870). We observed strong correlations between the BDRS-S and the HDRS (r=0.874) and MADRS (r=0.854) and also between the mixed symptom cluster score of the BDRS-S and the YMRS (r=0.803). Exploratory factor analysis revealed a three factor solution: psychological depressive symptoms cluster, somatic depressive symptoms cluster and mixed symptoms cluster., Limitations: A relatively small sample size for a 20-item scale., Conclusions: The BDRS-S provides solid psychometric performance and in particular captures depressive or mixed symptoms in Spanish bipolar patients., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Little is known about how functional imaging changes in bipolar disorder relate to different phases of the illness., Aims: To compare cognitive task activation in participants with bipolar disorder examined in different phases of illness., Method: Participants with bipolar disorder in mania (n = 38), depression (n = 38) and euthymia (n = 38), as well as healthy controls (n = 38), underwent functional magnetic resonance imaging during performance of the n-back working memory task. Activations and de-activations were compared between the bipolar subgroups and the controls, and among the bipolar subgroups. All participants were also entered into a linear mixed-effects model., Results: Compared with the controls, the mania and depression subgroups, but not the euthymia subgroup, showed reduced activation in the dorsolateral prefrontal cortex, the parietal cortex and other areas. Compared with the euthymia subgroup, the mania and depression subgroups showed hypoactivation in the parietal cortex. All three bipolar subgroups showed failure of de-activation in the ventromedial frontal cortex. Linear mixed-effects modelling revealed a further cluster of reduced activation in the left dorsolateral prefrontal cortex in the patients; this was significantly more marked in the mania than in the euthymia subgroup., Conclusions: Bipolar disorder is characterised by mood state-dependent hypoactivation in the parietal cortex. Reduced dorsolateral prefrontal activation is a further feature of mania and depression, which may improve partially in euthymia. Failure of de-activation in the medial frontal cortex shows trait-like characteristics., (Royal College of Psychiatrists.)

Background and Objectives: The DASH-II scale is a specific instrument for measuring psychopathological symptoms in people with severe and profound intellectual disability (ID). The aim of the study is the validation of the Spanish version, evaluating its reliability and validity. At the same time we examine the prevalence of mental disorders in our sample., Material and Methods: Two reviewers independently passed the Spanish version of the DASH-II (DASH-II-S) to 83 users to establish inter-rater reliability. To assess inter-rater reliability or test-retest reliability, fifty participants were reassessed by the same rater within 7 days., Results: DASH-II-S showed good internal consistency (Cronbach's α=0.879) and good reliability, both intra and inter-rater reliability. The prevalence of psychopathology in the sample is 94%, and the use of psychotropic drugs is also high, with 61.4% receiving one or more antipsychotics., Conclusions: DASH-II-S is a valid and reliable instrument that can be used for the assessment of psychopathology in people with ID. The translated version retains the psychometric properties of the original English version. Moreover, the high prevalence of mental disorders in this population may explain the widespread use of psychotropic drugs, but it forces us to continuous reassessment and justification., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: The subgenual anterior cingulate cortex (sgACC) is considered to be an important site of abnormality in major depressive disorder. However, structural alterations in this region have not been a consistent finding and functional imaging studies have also implicated additional areas., Method: A total of 32 patients with major depressive disorder, currently depressed, and 64 controls underwent structural imaging with MRI. Also, 26 patients and 52 controls were examined using functional magnetic resonance imaging (fMRI) during performance of the n-back working memory task. Structural and functional changes were evaluated using whole-brain, voxel-based methods., Results: The depressed patients showed volume reductions in the sgACC and orbitofrontal cortex bilaterally, plus in both temporal poles and the hippocampus/parahippocampal gyrus on the left. Functional imaging revealed task-related hypo-activation in the left lateral prefrontal cortex and other regions, as well as failure of deactivation in a subcallosal medial frontal cortical area which included the sgACC., Conclusions: Whole-brain, voxel-based analysis finds evidence of both structural and functional abnormality in the sgACC in major depressive disorder. The fact that the functional changes in this area took the form of failure of deactivation adds to previous findings of default mode network dysfunction in the disorder.

Background: Evidence from decades of magnetic resonance imaging (MRI) research in bipolar disorder has been summarized in meta-analyses of various MRI modalities. Notably, although structural MRI studies suggest gray matter reductions are restricted to specific cortical regions, functional MRI has also shown involvement of subcortical dysfunction. Such disparity in results is open to discussion and requires further exploration with additional MRI modalities., Methods: We applied whole-brain high angular resolution molecular diffusion imaging to compare different properties of the water diffusion process in brain tissues, using different contrasts. Specifically, we looked at fractional anisotropy, mean diffusivity, probability of return to the origin, and generalized fractional anisotropy in a sample of 40 euthymic patients with bipolar disorder and 40 well-matched healthy control subjects., Results: Convergent abnormalities were detected by contrasts in various tissue types. Apart from alterations in white matter (in corpus callosum, cingulum bundle, corona radiata, and superior fronto-occipital fasciculus) and cortical gray matter (in medial frontal cortex, left insula, Heschl's gyrus, and cerebellum), three of the contrasts (fractional anisotropy, mean diffusivity, and generalized fractional anisotropy) revealed abnormalities in subcortical structures, including the hippocampus, the thalamus and the caudate nucleus., Conclusions: Our findings point to a wider pattern of axonal pathology in bipolar disorder than previously thought. Although findings related to cortical gray matter are consistent with structural meta-analyses, subcortical abnormalities suggest a cytoarchitectonic basis for previously reported subcortical dysfunction. Diffusion results could be interpreted in terms of loss of tissue volume and/or altered membrane permeability, agreeing with both hypotheses of mitochondrial malfunction and neuroinflammation., (© 2013 Society of Biological Psychiatry Published by Society of Biological Psychiatry All rights reserved.)

Processing of emotions has been an enduring topic of interest in neuroimaging research, but studies have mostly used facial emotional stimuli. The aim of this study was to determine neural networks involved in emotion processing using scenic emotional visual stimuli. One hundred and twenty photographs from the International Affective Picture System (IAPS), including ecological scenes of disgust, fear, happiness, and sadness, were presented to 40 healthy participants while they underwent functional magnetic imaging resonance (fMRI). Afterwards they evaluated the emotional content of the pictures in an offline task. The occipito-temporal cortex and the amygdala-hippocampal complex showed a non-specific emotion-related activation, which was more marked in response to negative emotions than to happiness. The temporo-parietal cortex and the ventral anterior cingulate gyrus showed deactivation, with the former being marked for all emotions except fear and the latter being most marked for disgust. The fusiform gyrus showed activation in response to disgust and deactivation in response to happiness or sadness. Brain regions involved in processing of scenic emotion therefore resemble those reported for facial expressions of emotion in that they respond to a range of different emotions, although there appears to be specificity in the intensity and direction of the response.

Background: The pathological basis of tardive dyskinesia is unknown. Although its clinical features implicate the basal ganglia, imaging studies have not found clear evidence that it is associated with volume changes in these or other brain structures., Aims: To determine, using voxel-based structural imaging, whether there are regions of grey matter volume change in people with schizophrenia who also have tardive dyskinesia compared with those without tardive dyskinesia., Method: A total of 81 people with chronic schizophrenia, 32 with tardive dyskinesia and 49 without, were examined using magnetic resonance imaging (MRI) and whole-brain, optimised voxel-based morphometry. A comparison group of 61 healthy controls was also examined., Results: Compared with those without tardive dyskinesia, patients with tardive dyskinesia showed a pattern of volume reductions in predominantly subcortical regions, including the basal ganglia and the thalamus. Within the basal ganglia, volume reductions were seen in the caudate nucleus, to a lesser extent in the putamen, and only marginally in the globus pallidus. The patients with tardive dyskinesia, but not those without, showed significant volume reductions in the basal ganglia compared with the healthy controls but both groups had smaller volumes than controls in other affected areas., Conclusions: The pathological process or processes that underlie the development of tardive dyskinesia are not just neurochemical in nature, but affect brain structure.

Wavelet-based methods have been developed for statistical analysis of functional MRI and PET data, where the wavelet transformation is employed as a tool for efficient signal representation. A number of studies using these approaches have reported better estimation capabilities, in terms of increased sensitivity and specificity, than the standard statistical analyses in the spatial domain. In line with these previous studies, the present report proposes a statistical analysis in the wavelet domain for the estimation of inter-group differences from structural MRI data. The procedure, called wavelet-based morphometry (WBM), was implemented under a voxel-based morphometry (VBM) style analysis. It was evaluated by comparing the gray-matter images of a group of 32 healthy subjects whose images were artificially altered to induce thinning of the cortex, with a different group of 32 healthy subjects whose images were unaltered. In order to quantify the performance of the reconstruction from a practical perspective, the same comparison was also conducted with standard VBM using SPM's Gaussian random fields and FSL's cluster-based statistics, family-wise error corrected, for datasets spatially-normalized via two different registration methods (i.e., SyN and FNIRT). The effect of using different amounts of smoothing, Battle-Lemarié filters and resolution levels in the wavelet transform was also investigated. Results support the proposed approach as a different and promising methodology to assess the structural morphometric differences between different populations of subjects., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Formal thought disorder (FTD) in schizophrenia has been found to be associated with volume reductions in the left superior temporal cortex. However, there have been negative findings and some studies have also found associations in other cortical regions., Method: Fifty-one schizophrenic patients were evaluated for presence of FTD with the Thought, Language and Communication (TLC) scale and underwent whole-brain structural MRI using optimized voxel-based morphometry (VBM). Fifty-nine matched healthy controls were also scanned., Results: Compared to 31 patients without FTD (global TLC rating 0 or 1), 20 patients with FTD (global TLC rating 2-5) showed clusters of volume reduction in the medial frontal and orbitofrontal cortex bilaterally, and in two left-sided areas approximating to Broca's and Wernicke's areas. The pattern of FTD-associated volume reductions was largely different from that found in a comparison between the healthy controls and the patients without FTD. Analysis of correlations within regions-of-interest based on the above clusters indicated that the 'fluent disorganization' component of FTD was correlated with volume reductions in both Broca's and Wernicke's areas, whereas poverty of content of speech was correlated with reductions in the medial frontal/orbitofrontal cortex., Conclusions: The findings point to a relationship between FTD in schizophrenia and structural brain pathology in brain areas involved in language and executive function., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Schizo-affective disorder has not been studied to any significant extent using functional imaging. The aim of this study was to examine patterns of brain activation and deactivation in patients meeting strict diagnostic criteria for the disorder., Method: Thirty-two patients meeting research diagnostic criteria (RDC) for schizo-affective disorder (16 schizomanic and 16 schizodepressive) and 32 matched healthy controls underwent functional magnetic resonance imaging (fMRI) during performance of the n-back task. Linear models were used to obtain maps of activations and deactivations in the groups., Results: Controls showed activation in a network of frontal and other areas and also deactivation in the medial frontal cortex, the precuneus and the parietal cortex. Schizo-affective patients activated significantly less in prefrontal, parietal and temporal regions than the controls, and also showed failure of deactivation in the medial frontal cortex. When task performance was controlled for, the reduced activation in the dorsolateral prefrontal cortex (DLPFC) and the failure of deactivation of the medial frontal cortex remained significant., Conclusions: Schizo-affective disorder shows a similar pattern of reduced frontal activation to schizophrenia. The disorder is also characterized by failure of deactivation suggestive of default mode network dysfunction.

Objectives: Manic patients have been found to show reduced activation in the prefrontal cortex and other regions during performance of cognitive tasks. However, little is known about de-activations associated with the disorder. This study aimed to examine, at the whole-brain level, abnormal patterns of task-related activation and de-activation during performance of a working memory task., Methods: Twenty-nine DSM-IV bipolar patients and 46 healthy controls underwent fMRI during performance of the n-back task. The patients were scanned while they were in a manic episode. Linear models were used to obtain maps of within-group activations and areas of differential activation between the groups., Results: The manic patients showed reduced activation compared to the controls in the bilateral dorsolateral prefrontal cortex and the right parietal cortex. They also showed failure of de-activation in the medial frontal cortex, extending to the temporal poles and parts of the limbic system bilaterally. The failure of activation in the dorsolateral prefrontal cortex disappeared when differences in task performance were controlled for in the analysis. However, the medial frontal failure of de-activation survived controlling for this., Conclusions: This study suggests that, in addition to reduced prefrontal activation, failure of de-activation is an important functional imaging abnormality in mania. This, together with its location in the medial prefrontal cortex, implies default mode network dysfunction in the disorder.

Background: Genetic studies have found that the interleukin-1β gene (IL1B, 2q13) influences the risk for schizophrenia, but the underlying biological mechanisms of the association are still unclear. Investigation of the effects of genetic variability in this gene on brain function could provide more information about its role in the disorder., Methods: The present study examined the effects of a functional polymorphism at IL1B gene promoter (-511C/T; rs16944) on brain correlates of working memory performance in schizophrenia. Forty-eight schizophrenia patients and 46 control subjects underwent functional magnetic resonance imaging while performing the n-back task., Results: In the pooled sample, genetic variability at this locus was associated with differential brain activation in a bilateral frontal region including the dorsolateral prefrontal cortex. There was also a significant diagnosis × genotype interaction effect in an overlapping frontal region: the IL1B polymorphism did not affect activation in the control subjects in this area, but the schizophrenia patients who were T carriers showed significantly higher activation than the CC homozygotes., Conclusions: The findings support a role for IL1B variability in the dorsolateral prefrontal cortex dysfunction classically associated with schizophrenia., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Deficits in memory and executive performance are well-established features of bipolar disorder and schizophrenia. By contrast, data on cognitive impairment in schizoaffective disorder are scarce and the findings are conflicting., Method: We used the Wechsler Memory Scale (WMS-III) and the Behavioural Assessment of the Dysexecutive Syndrome (BADS) to test memory and executive function in 45 schizophrenic patients, 26 schizomanic patients and 51 manic bipolar patients in comparison to 65 healthy controls. The patients were tested when acutely ill., Results: All three patient groups performed significantly more poorly than the controls on global measures of memory and executive functioning, but there were no differences among the patient groups. There were few differences in memory and executive function subtest scores within the patient groups. There were no differences in any test scores between manic patients with and without psychotic symptoms., Conclusions: Schizophrenic, schizomanic and manic patients show a broadly similar degree of executive and memory deficits in the acute phase of illness. Our results do not support a categorical differentiation across different psychotic categories with regard to neuropsychological deficits.

Background: It is not known whether first-episode psychosis is characterized by the same prefrontal cortex functional imaging abnormalities as chronic schizophrenia., Method: Thirty patients with a first episode of non-affective functional psychosis and 28 healthy controls underwent functional magnetic resonance imaging (fMRI) during performance of the n-back working memory task. Voxel-based analyses of brain activations and deactivations were carried out and compared between groups. The connectivity of regions of significant difference between the patients and controls was also examined., Results: The first-episode patients did not show significant prefrontal hypo- or hyperactivation compared to controls. However, they showed failure of deactivation in the medial frontal cortex. This area showed high levels of connectivity with the posterior cingulate gyrus/precuneus and parts of the parietal cortex bilaterally. Failure of deactivation was significantly greater in first-episode patients who had or went on to acquire a DSM-IV diagnosis of schizophrenia than in those who did not, and in those who met RDC criteria for schizophrenia compared to those who did not., Conclusions: First-episode psychosis is not characterized by hypo- or hyperfrontality but instead by a failure of deactivation in the medial frontal cortex. The location and connectivity of this area suggest that it is part of the default mode network. The failure of deactivation seems to be particularly marked in first-episode patients who have, or progress to, schizophrenia.

Background: Although it is accepted that patients with delusional disorder can show co-existing depression, comorbidity with bipolar disorder is not a recognised feature., Method: Case report of patients who showed both delusional disorder and mania or hypomania. The patients were examined using lifetime structured psychiatric interview where possible., Results: Four patients are described who met criteria for delusional disorder, with durations ranging from 2 to 15 years, and also experienced one or more episodes of mania or hypomania., Limitations: Case reports cannot quantify a clinical association., Conclusions: These cases suggest that there is an association between delusional disorder and affective disorder which goes beyond the occurrence of depressive symptoms in the disorder., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Cognitive impairment is an established feature of schizophrenia. However, little is known about its relationship to the structural and functional brain abnormalities that characterise the disorder. Aims To identify structural and/or functional brain abnormalities associated with schizophrenic cognitive impairment., Method: We carried out structural magnetic resonance imaging (MRI) and voxel-based morphometry in 26 participants who were cognitively impaired and 23 who were cognitively preserved, all with schizophrenia, plus 39 matched controls. Nineteen of those who were cognitively impaired and 18 of those who were cognitively preserved plus 34 controls also underwent functional MRI during performance of a working memory task., Results: No differences were found between the participants who were cognitively intact and those who were cognitively impaired in lateral ventricular volume or whole brain volume. Voxel-based morphometry also failed to reveal clusters of significant difference in grey and white matter volume between these two groups. However, during performance of the n-back task, the participants who were cognitively impaired showed hypoactivation compared with those who were cognitively intact in the dorsolateral prefrontal cortex among other brain regions., Conclusions: Cognitive impairment in schizophrenia is not a function of the structural brain abnormality that accompanies the disorder but has correlates in altered brain function.

Background: Studies of procedural learning in schizophrenia have been inconsistent, sometimes finding it to be preserved and sometimes impaired. This study examined three factors that could account for the variability among findings: type of task, presence of general intellectual impairment, and the extrapyramidal side effects of neuroleptic treatment., Methods: Forty-three patients with schizophrenia and 22 normal control subjects were examined with three different paradigms: the pursuit rotor, mirror reading, and probabilistic learning ("weather prediction"). A subgroup of intellectually preserved patients was also examined. Patients with and without tardive dyskinesia and with and without Parkinsonism were also compared., Results: The schizophrenic patients showed learning comparable to the control subjects on the pursuit rotor and mirror reading but were impaired on the probabilistic learning task. However, this last difference disappeared when the subgroup of intellectually preserved patients was compared with a subgroup of matched control subjects. Patients with and without tardive dyskinesia or Parkinsonism showed similar learning on all three tasks, but patients with tardive dyskinesia showed poorer overall performance than those without., Conclusions: Procedural learning tends to be preserved in schizophrenia, and when impairment is found, differences in the overall level of intellectual function might be the determining factor., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Abnormal interactions between areas of the brain have been pointed as possible causes for schizophrenia. However, the nature of these disturbances and the anatomical location of the regions involved are still unclear. Here, we describe a method to estimate maps of net levels of connectivity in the resting brain, and we apply it to look for differential patterns of connectivity in schizophrenia. This method uses partial coherences as a basic measure of covariability, and it minimises the effect of major physiological noise. When overall (net) connectivity maps of a sample of 40 patients with schizophrenia were compared with the maps from a matched sample of 40 controls, a single area of abnormality was found. It is an area of patient hyper-connectivity and is located frontally, in medial and orbital structures, clearly overlapping the anterior node of the default mode network (DMN). When this area is used as a region of interest in a second-level analysis, it shows functional hyper-connections with several cortical and subcortical structures. Interestingly, the most significant abnormality is found with the caudate, which has a bilateral pattern of abnormality, pointing to a possible DMN-striatum deviant relation in schizophrenia. However, hyper-connectivity observed with other regions (right hippocampus and amygdala, and other cortical structures) suggests a more pervasive alteration of brain connectivity in this disease., (Copyright © 2010 Wiley-Liss, Inc.)

The Val158Met polymorphism in the COMT gene has been found to be associated with differences in brain activation in both healthy subjects and patients with schizophrenia. The predominant finding has been increased prefrontal activation associated with the Val allele; however, genotype-related de-activations have not been studied. In this study 42 schizophrenia patients and 31 controls underwent fMRI while performing the n-back task. Brain differences related to presence/absence of disease and presence/absence of the Val/Val genotype were examined. Both disease and Val/Val genotype were associated with failure of de-activation in a cluster centred in the medial prefrontal cortex. There was no interaction between disease and genotype at this location, but clusters where there were significant interactions emerged in the right prefrontal cortex and left temporal/parietal cortex. These findings suggest that Val158Met polymorphism influences task-related de-activations in the default mode network in both healthy subjects and schizophrenia patients to an equivalent extent. However the Val158Met polymorphism also has disease-specific effects on DLPFC activation in schizophrenia., (Copyright © 2010. Published by Elsevier Inc.)

Neuroimaging studies have found evidence of altered brain structure and function in schizophrenia, but have had complex findings regarding the localization of abnormality. We applied multimodal imaging (voxel-based morphometry (VBM), functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) combined with tractography) to 32 chronic schizophrenic patients and matched healthy controls. At a conservative threshold of P=0.01 corrected, structural and functional imaging revealed overlapping regions of abnormality in the medial frontal cortex. DTI found that white matter abnormality predominated in the anterior corpus callosum, and analysis of the anatomical connectivity of representative seed regions again implicated fibres projecting to the medial frontal cortex. There was also evidence of convergent abnormality in the dorsolateral prefrontal cortex, although here the laterality was less consistent across techniques. The medial frontal region identified by these three imaging techniques corresponds to the anterior midline node of the default mode network, a brain system which is believed to support internally directed thought, a state of watchfulness, and/or the maintenance of one's sense of self, and which is of considerable current interest in neuropsychiatric disorders.

Psychotic symptoms are a key feature in eating disorders. Restrictive-type anorectics are more prone to suffer them, coherent with recent neurocognitive findings reporting attentional and processing deficits in restrictive anorexia partially common to schizophrenia. Psychotic crises urge psychiatrists to make an accurate differential diagnosis with endogenous psychoses and carefully judge treatment options. If attentively attended, such crises can give us clues to understand the patient s functioning and consider new strategies. We report two transient psychotic episodes in restrictive-type anorectic female patients, one with a previous experience. Onset of psychotic symptoms was related to severe malnutrition only in one of them (body mass index <15). We discuss risk factors, clinical presentation and treatment, focusing on the emotional disturbances maintained after recovery. Causes for psychotic features in these patients are reviewed and treatment individually tailored. An integrative understanding of eating disorders as a unique meeting point between psychosis and neurosis is encouraged.

Background: Functional imaging studies using working memory tasks have documented both prefrontal cortex (PFC) hypo- and hyperactivation in schizophrenia. However, these studies have often failed to consider the potential role of task-related deactivation., Method: Thirty-two patients with chronic schizophrenia and 32 age- and sex-matched normal controls underwent functional magnetic resonance imaging (fMRI) scanning while performing baseline, 1-back and 2-back versions of the n-back task. Linear models were used to obtain maps of activations and deactivations in the groups., Results: The controls showed activation in the expected frontal regions. There were also clusters of deactivation, particularly in the anterior cingulate/ventromedial PFC and the posterior cingulate cortex/precuneus. Compared to the controls, the schizophrenic patients showed reduced activation in the right dorsolateral prefrontal cortex (DLPFC) and other frontal areas. There was also an area in the anterior cingulate/ventromedial PFC where the patients showed apparently greater activation than the controls. This represented a failure of deactivation in the schizophrenic patients. Failure to activate was a function of the patients' impaired performance on the n-back task, whereas the failure to deactivate was less performance dependent., Conclusions: Patients with schizophrenia show both failure to activate and failure to deactivate during performance of a working memory task. The area of failure of deactivation is in the anterior prefrontal/anterior cingulate cortex and corresponds to one of the two midline components of the 'default mode network' implicated in functions related to maintaining one's sense of self.

Here we develop a measure of functional connectivity describing the degree of covariability between a brain region and the rest of the brain. This measure is based on previous formulas for the mutual information (MI) between clusters of regions in the frequency domain. Under the current scenario, the MI can be given as a simple monotonous function of the multiple coherence and it leads to an easy visual representation of connectivity patterns. Computationally efficient formulas, adequate for short time series, are presented and applied to functional magnetic resonance imaging (fMRI) data measured in subjects (N=34) performing a working memory task or being at rest. While resting state coherence in high (0.17-0.25 Hz) and middle (0.08-0.17 Hz) frequency intervals is bilaterally salient in several limbic and temporal areas including the insula, the amygdala, and the primary auditory cortex, low frequencies (<0.08 Hz) have greatest connectivity in frontal structures. Results from the comparison between resting and N-back conditions show enhanced low frequency coherence in many of the areas previously reported in standard fMRI activation studies of working memory, but task related reductions in high frequency connectivity are also found in regions of the default mode network. Finally, potentially confounding effects of head movement and regional volume on MI are identified and addressed.

Mutual information tools have been recently applied to quantify the connectivity between brain regions in functional magnetic resonance imaging (fMRI). Here we develop measures of mutual information between clusters of brain regions in the frequency domain. The properties and limitations of the method are exemplified through a single resting state fMRI dataset, and with a comparison involving frontostriatal connections in schizophrenic patients and healthy controls.

Background: The Calgary Depression Scale for Schizophrenia (CDSS) is a valid tool to assess depression in schizophrenics and has been translated, adapted, and validated to be used in different non-English languages. Therefore, it may be predicted that a Spanish version of this scale will be also a valid instrument to assess symptoms of depression in patients with schizophrenia., Objective: We determined the validity of the Spanish version of the Calgary scale (CDSS-S)., Methods: Outpatients and inpatients (n=93) diagnosed as having schizophrenia by DSM-IV criteria confirmed by SCID-IV interview were included. The Positive and Negative Syndrome Scale (PANSS), Hamilton Depression Rating Scale (HDRS-17 and HDRS-21 items), Montgomery-Asberg Depression Rating Scale (MADRS), Extrapyramidal Symptoms Rating Scale (ESRS), and Barnes Acathisia Rating Scale were administered by a first rater, whereas the CDSS-S was assessed by a second independent rater., Results: The internal consistency (Cronbach's alpha 0.83) and the interrater reliability (>0.73 intraclass correlation coefficient [ICC] for single items and 0.92 for total score) were good. The test-retest reliability was high (ICC of 0.89). The scale showed a good construct validity with statistically significant correlations with HDRS-17, HDRS-21, MADRS, and G6 item (depression) of PANSS. The CDSS showed no correlation with the positive subscale of PANSS and a weak correlation with the negative subscale, general psychopathology subscale, and total score of PANSS. A cut point of five showed 94.7% sensitivity, 86.5% specificity, and 70% and 98% positive and negative predictive values, respectively., Conclusions: The Spanish version of CDSS is a valid instrument to assess depressive episodes for stabilized and acute patients with schizophrenia.

The 5-HT2A receptor binding parameters using [3H]ketanserine and its intracellular signal inositol 1,4,5 trisphosphate (IP3) concentrations were determined in platelets from schizophrenic patients so as to assess differences with respect to a control group and to a standardized antipsychotic drug treatment. Seventy-five antipsychotic-free patients with a DSM-IV diagnosis of paranoid schizophrenia were included in the study. Blood samples were collected before the onset of antipsychotic treatment (baseline values) and after 3 weeks of treatment. Antipsychotic-free schizophrenic patients showed significantly increased basal 5-HT2A densities in comparison to the control group, together with a significantly increase (23%) in the 5-HT2A binding density in those patients treated with risperidone. These changes could be attributed to an up-regulation of 5-HT2A receptors caused by previous treatment with antipsychotic drugs, which is consistent with the chronic effect of 5-HT2A antagonists to up-regulate the number of binding sites. With regard to second messenger IP3 concentrations, basal concentrations in schizophrenic patients were not significantly different from control values, nor was there any significant difference between basal vs. posttreatment values. These results are possibly related to failure of second messenger systems of 'translating' extracellular messages generated presynaptically into effective neurotransmitter signals in schizophrenic patients.

Rheumatic fibromyalgia, also known as fibrositis or myofascial pain, is a common syndrome whose diagnoses, founded mainly on physical examination, usually delays due to symptom unspecificity, amount of complementary tests requested and intercourse with psychiatric disorders. Psychyatrists and psychologists get often involved in fibromyalgia treatment. Its proper knowledge prevents not only physicians and patients' psychological discourage but also development of depression and mental health expenses, as well as allows designing a treatment plan according to the main symptoms which may offer improvement chances to fibromyalgia patients. This article intends to offer an up-to-date and complete information about this entity, focused on psychiatric aspects, to better identify and manage such a puzzling disease.

The serotonin (5-hydroxytryptamine, 5-HT) uptake sites assessed with both [3H]imipramine and [3H]paroxetine, and the 5-HT2A receptors were simultaneously measured in platelets from 24 male subjects meeting the American Psychiatric Association's DSM-IV criteria for alcohol dependence and admitted for inpatient detoxification. Blood samples from alcoholic patients were collected during acute alcohol intoxication (day 0), during withdrawal (day 1), and after 2 weeks of abstinence (day 14). All patients met the criteria for type II alcoholism. Alcohol misuse was found to be associated with an increased number and a lower affinity of [3H]paroxetine binding in comparison to the control values. Abstinence from alcohol for 2 weeks (day 14) resulted in a decrease in the number of 5-HT uptake sites labelled with [3H]paroxetine compared to normal values, together with a significant decrease in the number of 5-HT2A binding sites. The present data indicate that altered serotonergic function existing in alcoholic patients is a reversible phenomenon that normalizes after detoxification and withdrawal.

In this study, drug inhibition and saturation experiments on the binding of the highly selective 5-HT4 antagonist [3H]GR 113808 were performed in human brain membranes so as to better characterize this binding site. Drug competition studies were carried out by incubating 0.2 nM [3H]GR 113808 in the presence of increasing concentrations of six different drugs, i.e. 5-HT, 5-CT, ondansetron, tropisetron, BIMU 1 and BIMU 8 (mixed 5-HT3 and 5-HT4 agonists). The binding displaced by 5-HT showed a drug inhibition constant (Ki) value of 197nM. The use of 5-CT or ondansetron also showed the existence of single-site models albeit with Ki values in the micromolar range (11,5 microM). Tropisetron, BIMU 1 and BIMU 8 displaced bound [3H]GR 113808 according to a two-site binding model, with the high affinity component in the nanomolar range and the low affinity site in the micro or milimolar range. Saturation experiments revealed high binding densities in basal ganglia (187 fmol/mg in putamen, and 149 fmol/mg in caudate nucleus), while lower densities were observed in cortical regions (49 fmol/mg in temporal cortex, 45 fmol/mg in parietal cortex and 71 fmol/mg in cingulate cortex). The apparent affinity (Kd) was similar in the brain regions studied, ranging from 0.13 to 0.34 nmol/l. Despite the enrichment of 5-HT receptors in human brain, their functional correlate in brain diseases remains to be clarified.