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Introduction: Cerebellar alterations, including both volumetric changes in the cerebellar vermis and dysfunctions of the corticocerebellar connections, have been documented in psychotic disorders. Starting from the clinical observation of a bipolar patient with cerebellar hypoplasia, the purpose of this review is to summarize the data in the literature about the association between hypoplasia of the cerebellar vermis and psychotic disorders [schizophrenia (SCZ) and bipolar disorder (BD)]., Methods: A bibliographic search on PubMed has been conducted, and 18 articles were finally included in the review: five used patients with BD, 12 patients with SCZ and one subject at psychotic risk., Results: For SCZ patients and subjects at psychotic risk, the results of most of the reviewed studies seem to suggest a gray matter volume reduction coupled with an increase in white matter volumes in the cerebellar vermis, compared to healthy controls. Instead, the results of the studies on BD patients are more heterogeneous with evidence showing a reduction, no difference or even an increase in cerebellar vermis volume compared to healthy controls., Conclusions: From the results of the reviewed studies, a possible correlation emerged between cerebellar vermis hypoplasia and psychotic disorders, especially SCZ, ultimately supporting the hypothesis of psychotic disorders as neurodevelopmental disorders., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Obsessive-compulsive disorder (OCD) is a psychiatric disorder whose etiopathogenesis, according to various neuroimaging studies, seems to be linked to selective dysfunctions in regions within the cortico-striatal-thalamo-cortical circuit. Selective Serotonin Reuptake Inhibitors (SSRIs) are the first-line therapy for OCD but their neurobiological effects on the brain is only partially understood. Therefore, the aim of this review is to highlight structural and functional brain imaging modifications induced by SSRIs treatment., Methods: A literature search on PubMed, Psych-Info and Embase database was performed. Studies including patients with OCD that analyzed the effect of SSRIs through structural and functional Magnetic Resonance Imaging were selected. Seven relevant studies were considered eligible for the present review., Results: Overall, the results of the reviewed studies showed that SSRIs treatment seems to normalize structural, in terms of the white matter and gray matter volumes, and functional activity alterations observed in OCD patients, especially in regions within the prefrontal cortex and striatum., Limitations: The poor design of the studies, the small and heterogeneous samples, differences in age, gender, illness course, comorbidities, treatment protocols and the different magnetic fields used make it difficult to generalize the results., Conclusions: From the available evidence it emerged that SSRIs treatment has proven to be effective in normalizing brain structural and functional alterations observed in OCD patients. However, future neuroimaging investigations should focus on long-term effects of drugs on brain structure and function in OCD patients through longitudinal approaches in order to identify more effective treatments for these patients., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Alterations in insular grey matter (GM) volume has been consistently reported for affective and non-affective psychoses both in chronic and first-episode patients, ultimately suggesting that the insula might represent a good region to study in order to assess the longitudinal course of psychotic disorders. Therefore, in this longitudinal Magnetic Resonance Imaging (MRI) study, we aimed at further investigating the key role of insular volumes in psychosis., Material and Methods: 68 First-Episode Psychosis (FEP) patients, 68 patients with Schizophrenia (SCZ), 47 Bipolar Disorder (BD) patients, and 94 Healthy Controls (HC) were enrolled and underwent a 1.5 T MRI evaluation. A subsample of 99 subjects (10 HC, 23 BD, 29 SCZ, 37 FEP) was rescanned after 2,53 ± 1,68 years. The insular cortex was manually traced and then divided into an anterior and posterior portion. Group and correlation analyses were then performed both at baseline and at follow-up., Results: At baseline, greater anterior and lower posterior insular GM volumes were observed in chronic patients. At follow-up, we found that FEP patients had a significant GM volume increase from baseline to follow-up, especially in the posterior insula whereas chronic patients showed a relative stability. Finally, significant negative correlations between illness severity and pharmacological treatment and insular GM volumes were observed in the whole group of psychotic patients., Conclusions: The longitudinal assessment of both chronic and first-episode patients allowed us to detect a complex pattern of GM abnormalities in selective sub-portions of insular volumes, ultimately suggesting that this structure could represent a key biological marker of psychotic disorders., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Borderline Personality Disorder (BPD) is a severe and disabling psychiatric syndrome, frequently associated with self-injurious behaviours (SIB). In recent years, functional magnetic resonance imaging (fMRI) investigations have tried to identify alterations associated with SIB amongst BPD patients, in order to better delineate possible neurobiological underpinnings of these manifestations. In this mini-review, we aimed at summarizing fMRI studies exploring patterns of neural activation associated with SIB in BPD patients., Methods: Literature searches on PubMed, Psych-Info and Embase databases were performed for all fMRI studies including adult patients with BPD and SIB undergoing different tasks, including painful or thermic stimulation, affective stimulation through the presentation of picturesor the recollection of personal memories as well as tasks that evaluate sustained attention and impulsivity, and reward processing. Thirteen relevant papers were considered eligible for the present review., Results: Patients with BPD and SIB, compared to HC, showed prefrontal, nucleus accumbens overactivation and amygdala deactivation during pain stimulation. During negative affective stimulation, BPD patients showed a hyperactivation of the amygdala and a hypoactivation of the orbitofrontal cortex (OFC), which was also found to be enhanced during a gambling task and during a recalling of aversive memories. In contrast, during cognitive tasks with negative affective interference, BPD patients showed hypoactivation of OFC, anterior cingulated cortex, and basal ganglia., Limitations: The limited number of studies and the heterogeneity regarding the fMRI tasks employed allowed only suggestive conclusions., Conclusions: The reviewed fMRI studies highlighted that BPD patients with a history of SIB showed altered brain activity, compared to HC, in regions involved in inhibitory cognitive processes and affect regulation, which may in turn, explain the overwhelming emotional experiences eliciting SIB in these patients., (Copyright © 2021. Published by Elsevier B.V.)

Background: Psychopathological symptoms during euthymia in Bipolar Disorder (BD) affect quality of life and predispose to the occurrence of new acute episodes, however only few studies investigated potential risk-factors. This study aims to explore the association between childhood trauma (CT), lifetime stressful events (SLEs) and psychopathological symptoms in BD patients during euthymia and controls (HC)., Methods: A total of 261 participants (93 euthymic patients with BD, 168 HC) were enrolled. Generalized linear models and multiple logistic models were used to assess the association among the Symptom Check List-90-R (SCL-90-R), the Infancy Trauma Interview, the Paykel Life Events Scale., Results: The rate of participants reporting CT was higher in BD (n=47; 53%) than HC (n=43; 30%) (p=0.001). The experience of neglect was strongly related to BD (OR 6.5; p=0.003). CT was associated to higher scores on the SCL-90-R subscales (all the subscales except Phobia). No effects of the interaction between CT and diagnosis were found on SCL-90-R. Finally, there was a main effect of CT on lifetime SLEs (p<.001), that was not associated with diagnosis (p=0.833), nor with the interaction between CT and diagnosis (p=0.624)., Limitations: The cross-sectional design does not allow causal inferences; the exclusion of subjects reporting medical or psychiatric comorbidity limits generalizability., Conclusions: CT was associated both to psychopathological symptoms during euthymia and the lifetime SLEs, thus it may represent a vulnerability factor influencing the course of BD. Overall, these data contribute to overcome the limited evidences documenting the influence of environmental factors on euthymic phase in BD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Patterns of coordinated variations of gray matter (GM) morphology across individuals are promising indicators of disease. However, it remains unclear if they can help characterize first-episode psychosis (FEP) and symptoms' severity., Methods: Sixty-seven FEP and 67 matched healthy controls (HC) were assessed with structural MRI to evaluate the existence of distributed GM structural covariance patterns associated to brain areas belonging to salience network. Voxel-based morphometry (VBM) and structural covariance differences, investigated with salience network seed-based Partial Least Square, were applied to explore differences between groups. GM density associations with Raven's intelligent quotient (IQ) and Positive and Negative Syndrome Scale (PANSS) scores were investigated., Results: Univariate VBM results gave trend without significant GM differences across groups. GM and IQ correlated positively in both groups: in FEP, mostly in hippocampus, insula, and fronto-temporal structures, while in HC mostly in amygdala, thalamus and fronto-temporal regions. GM and PANSS scores correlated negatively in FEP, with widespread clusters located in limbic regions. Multivariate analysis showed strong and opposite structural GM covariance with salience network for FEP and HC. Moreover, structural covariance of the salience network in FEP correlated negatively with severity of clinical symptoms., Conclusion: Our study provides evidence supporting the insular dysfunction model of psychosis. Reduced structural GM covariance of the salience network, with its association to symptom's severity, appears a promising morphometry feature for FEP detection., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: Bipolar disorder (BD) is a psychiatric condition causing shifts in mood, energy and activity levels severely altering the quality of life of the patients even in the euthymic phase. Although widely accepted, the neurobiological bases of the disorder in the euthymic phase remain elusive. This study aims at characterizing resting state functional activity of the BD euthymic phase in order to better understand the pathogenesis of the disease and build future neurobiological models., Methods: Fifteen euthymic BD patients (10 females; mean age 40.2; standard deviation 13.5; range 20-61) and 27 healthy controls (HC) (21 females; mean age 37; standard deviation 10.6; range 22-60) underwent a 3T functional MRI scan at rest. Resting state activity was extracted through independent component analysis (ICA) run with automatic dimensionality estimation., Results: ICA identified 22 resting state networks (RSNs). Within-network analysis revealed decreased connectivity in the visual, temporal, motor and cerebellar RSNs of BD patients vs HC. Between-network analysis showed increased connectivity between motor area and the default mode network (DMN) partially overlapping with the fronto-parietal network (FPN) in BD patients., Conclusion: Within-network analysis confirmed existing evidence of altered cerebellar, temporal, motor and visual networks in BD. Increased connectivity between the DMN and the motor area network suggests the presence of alterations of the fronto-parietal regions, precuneus and cingulate cortex in the euthymic condition. These findings indicate that specific connectivity alterations might persist even in the euthymic state suggesting the importance of examining both within and between-network connectivity to achieve a global understanding of the BD euthymic condition., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Neurodevelopment represents a period of increased opportunity and vulnerability, during which a complex confluence of genetic and environmental factors influences brain growth trajectories, cognitive and mental health outcomes. Recently, magnetic resonance imaging (MRI) studies on twins have increased our knowledge of the extent to which genes, the environment and their interactions shape inter-individual brain variability. The present review draws from highly salient MRI studies in young twin samples to provide a robust assessment of the heritability of structural and functional brain changes during development. The available studies suggest that (as with many other traits), global brain morphology and network organization are highly heritable from early childhood to young adulthood. Conversely, genetic correlations among brain regions exhibit heterogeneous trajectories, and this heterogeneity reflects the progressive, experience-related increase in brain network complexity. Studies also support the key role of environment in mediating brain network differentiation via changes of genetic expression and hormonal levels. Thus, rest- and task-related functional brain circuits seem to result from a contextual and dynamic expression of heritability., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Bipolar disorder (BD) is a severe and disabling mental illness, which is characterized by selective gray matter (GM) and white matter (WM) brain alterations, as observed by several imaging studies. However, the clinical course of the disease is uncertain and can vary across BD patients, with some having a benign course and others a severe disability. In this perspective, magnetic resonance imaging (MRI) can help identifying biological markers of worse prognosis., Methods: The present selected review aimed at summarizing structural MRI (sMRI) studies exploring the correlation between brain morphology and features of clinical outcome, which could include treatment response, cognitive impairment and global functioning., Results: Overall, the results from the reviewed sMRI studies reported that WM hyperintensities and GM volume reductions, mainly in fronto-limbic areas, correlate with worse outcome in BD. However, the selected outcome measures vary across studies, thus these observations cannot be conclusive., Limitations: Heterogeneity across studies and inconsistency on the outcome measures adopted limit the conclusion of the present review. Absence of widely shared definitions of outcome should be object of further research on BD in order to indicate more stable features of illness course., Conclusions: In summary, WM hyperintensities and fronto-temporo-limbic GM alterations may be potential indices of worse outcome in BD patients, particularly in terms of illness severity and progression. The identification of stable markers of prognosis can help the clinicians in selecting subgroups of bipolar patients who need specific treatment to preserve cognitive / psychosocial functioning, in the light of personalized approaches. To further characterize outcome in BD, future sMRI studies should a) longitudinally investigate patients with either poor or good course of the disease, and b) correlate neuroimaging measures with clinical, cognitive and genetic markers., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Hippocampal abnormalities have been largely reported in patients with schizophrenia and bipolar disorder, and are considered to be involved in the pathophysiology of the psychosis. The hippocampus consists of several subfields but it remains unclear their involvement in the early stages of psychosis., Aim: The aim of this study was to investigate volumetric alterations in hippocampal subfields in patients at the first-episode psychosis (FEP)., Methods: Magnetic resonance imaging (MRI) data were collected in 134 subjects (58 FEP patients; 76 healthy controls [HC]). A novel automated hippocampal segmentation algorithm was used to segment the hippocampal subfields, based on an atlas constructed from ultra-high resolution imaging on ex vivo hippocampal tissue. The general linear model was used to investigate volume differences between FEP patients and HC, with age, gender and total intracranial volume as covariates., Results: We found significantly lower volumes of bilateral CA1, CA4, and granule cell layer (GCL), and of left CA3, and left molecular layer (ML) in FEP patients compared to HC. Only the volumes of the left hippocampus and its subfields were significantly lower in FEP than HC at the False Discovery Rate (FDR) of 0.1. No correlation was found between hippocampal subfield volume and duration of illness, age of onset, duration of medication, and Positive and Negative Syndrome Scale (PANSS)., Conclusion: We report abnormally low volumes of left hippocampal subfields in patients with FEP, sustaining its role as a putative neural marker of psychosis onset.

The parietal lobe (PL) supports cognitive domains, including attention and memory, which are impaired in bipolar disorder (BD). Although cross-sectional voxel-based morphometry studies found reduced PL grey matter (GM) in BD, none has longitudinally focused on PL anatomy in BD, relating it to patients' functioning. Thirty-eight right-handed BD patients and 42 matched healthy subjects (HS) underwent a Magnetic Resonance Imaging (MRI) scan at baseline. Seventeen BD patients and 16 matched HS underwent a follow-up MRI. PL white matter (WM) and GM volumes were measured. The trajectory of parietal volumes over time and the possible relation with the global functioning were investigated in both BD patients and HS. At baseline, BD patients showed significant reduced PL WM and GM and different WM laterality compared with HS. Furthermore, smaller PL WM volumes predicted lower global functioning in BD, but not in HS. At follow-up, although BD patients reported reduced PL WM compared with HS, no different pattern of volume changes over time was detected between groups. This study suggests the involvement of the PL in the pathophysiology of BD. In particular, PL WM reductions seem to predict an impairment in general functioning in BD and might represent a marker of functional outcome., (Copyright © 2017. Published by Elsevier B.V.)

Several strands of evidence reported a significant overlapping, in terms of clinical symptoms, epidemiology and treatment response, between the two major psychotic disorders-Schizophrenia (SCZ) and Bipolar Disorder (BD). Nevertheless, the shared neurobiological correlates of these two disorders are far from conclusive. This study aims toward a better understanding of possible common microstructural brain alterations in SCZ and BD. Magnetic Resonance Diffusion data of 33 patients with BD, 19 with SCZ and 35 healthy controls were acquired. Diffusion indexes were calculated, then analyzed using Tract-Based Spatial Statistics (TBSS). We tested correlations with clinical and psychological variables. In both patient groups mean diffusion (MD), volume ratio (VR) and radial diffusivity (RD) showed a significant increase, while fractional anisotropy (FA) and mode (MO) decreased compared to the healthy group. Changes in diffusion were located, for both diseases, in the fronto-temporal and callosal networks. Finally, no significant differences were identified between patient groups, and a significant correlations between length of disease and FA and VR within the corpus callosum, corona radiata and thalamic radiation were observed in bipolar disorder. To our knowledge, this is the first study applying TBSS on all the DTI indexes at the same time in both patient groups showing that they share similar impairments in microstructural connectivity, with particular regards to fronto-temporal and callosal communication, which are likely to worsen over time. Such features may represent neural common underpinnings characterizing major psychoses and confirm the central role of white matter pathology in schizophrenia and bipolar disorder.

First episode psychosis (FEP) patients are of particular interest for neuroimaging investigations because of the absence of confounding effects due to medications and chronicity. Nonetheless, imaging data are prone to heterogeneity because for example of age, gender or parameter setting differences. With this work, we wanted to take into account possible nuisance effects of age and gender differences across dataset, not correcting the data as a pre-processing step, but including the effect of nuisance covariates in the classification phase. To this aim, we developed a method which, based on multiple kernel learning (MKL), exploits the effect of these confounding variables with a subject-depending kernel weighting procedure. We applied this method to a dataset of cortical thickness obtained from structural magnetic resonance images (MRI) of 127 FEP patients and 127 healthy controls, who underwent either a 3Tesla (T) or a 1.5T MRI acquisition. We obtained good accuracies, notably better than those obtained with standard SVM or MKL methods, up to more than 80% for frontal and temporal areas. To our best knowledge, this is the largest classification study in FEP population, showing that fronto-temporal cortical thickness can be used as a potential marker to classify patients with psychosis., (Copyright © 2016. Published by Elsevier Inc.)

Introduction: Schizophrenia is a severe disabling disorder with heterogeneous illness courses. In this longitudinal study we characterized schizophrenia patients with poor and good outcome (POS, GOS), using functional and imaging metrics. Patients were defined in accordance to Keefe's criteria (i.e. Kraepelinian and non-Kraepelinian patients)., Methods: 35 POS patients, 35 GOS patients and 76 healthy controls (H) underwent clinical, functioning and magnetic resonance imaging (MRI) assessments twice over three years of follow-up. Information on psychopathology, treatment, disability (using the World Health Organization Disability Assessment Scale II, WHO-DAS-2) and prefrontal morphology was collected. Dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC) were manually traced., Results: At baseline, subjects with POS showed significantly decreased right dorsolateral prefrontal cortex (DLPFC) white matter volumes (WM) compared to healthy controls and GOS patients (POS VS HC, p<0.001; POS vs GOS, p=0.03), with shrinkage of left DLPFC WM volumes at follow up (t=2.66, p=0.01). Also, POS patients had higher disability in respect to GOS subjects both at baseline and after 3years at the WHO-DAS-2 (p<0.05)., Discussion: Our study supports the hypothesis that POS is characterized by progressive deficits in brain structure and in "real-life" functioning. These are particularly notable in the DLPFC., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Bipolar disorder (BD) is a major psychiatric illness with a chronic recurrent course, ranked among the worldwide leading disabling diseases. Its pathophysiology is still not completely understood and findings are still inconclusive, though a great interest on the topic has been constantly raised by magnetic resonance imaging, genetic and neuropathological studies. In recent years, diffusion tensor imaging (DTI) investigations have prompted interest in the key role of white matter (WM) abnormalities in BD. In this report, we summarize and comment recent findings from DTI studies in BD, reporting fractional anisotropy as putative measure of WM integrity, as well as recent data from neuropathological studies focusing on oligodendrocyte involvement in WM alterations in BD. DTI research indicates that BD is most commonly associated with a WM disruption within the fronto-limbic network, which may be accompanied by other WM changes spread throughout temporal and parietal regions. Neuropathological studies, mainly focused on the fronto-limbic network, have repeatedly shown a loss in cortical and subcortical oligodendrocyte cell count, although an increased subcortical oligodendrocyte density has been also documented suggesting a putative role in remyelination processes for oligodendrocytes in BD. According to our review, a greater integration between DTI and morphological findings is needed in order to elucidate processes affecting WM, either glial loss or myelin plasticity, on the basis of a more targeted research in BD.

Introduction: The rate of biological change in middle-adulthood is relatively under-studied. Here, we used behavioral testing in conjunction with structural magnetic resonance imaging to examine the effects of chronological age on associative learning proficiency and on brain regions that previous functional MRI studies have closely related to the domain of associative learning., Methods: Participants (n=66) completed a previously established associative learning paradigm, and consented to be scanned using structural magnetic resonance imaging. Age-related effects were investigated both across sub-groups in the sample (younger vs. older) and across the entire sample (using regression approaches)., Results: Chronological age had substantial effects on learning proficiency (independent of IQ and Education Level), with older adults showing a decrement compared to younger adults. In addition, decreases in estimated gray matter volume were observed in multiple brain regions including the hippocampus and the dorsal prefrontal cortex, both of which are strongly implicated in associative learning., Conclusion: The results suggest that middle adulthood may be a more dynamic period of life-span change than previously believed. The conjunctive application of narrowly focused tasks, with conjointly acquired structural MRI data may allow us to enrich the search for, and the interpretation of, age-related changes in cross-sectional samples., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Depressive disorder is a very frequent and heterogeneous syndrome. Structural imaging techniques offer a useful tool in the comprehension of neurobiological alterations that concern depressive disorder. Altered brain structures in depressive disorder have been particularly located in the prefrontal cortex (medial prefrontal cortex and orbitofrontal cortex, OFC) and medial temporal cortex areas (hippocampus). These brain areas belong to a structural and functional network related to cognitive and emotional processes putatively implicated in depressive symptoms. These volumetric alterations may also represent biological predictors of response to pharmacological treatment. In this context, major findings of magnetic resonance (MR) imaging, in relation to treatment response in depressive disorder, will here be presented and discussed.

We here present data on immune gene expression of chemokines, chemokine receptors, cytokines and regulatory T-cell (T-reg) markers in chronic patients suffering from either schizophrenia (SCZ, N=20) or bipolar disorder (BD=20) compared with healthy controls (HCs, N=20). We extracted RNA from peripheral blood mononuclear cells and performed real-time (RT)-PCR to measure mRNA levels of chemokines, chemokine receptors, cytokines and T-reg markers. All the analyses were Bonferroni-corrected. The classical monocyte activation (M1) markers il6, ccl3 were significantly increased in BD as compared with both HC and SCZ patients (P=0.03 and P=0.002; P=0.024 and P=0.021, respectively), whereas markers of alternative (M2) monocyte activation ccl1, ccl22 and il10 were coherently decreased (controls: P=0.01, P=0.001 and P=0.09; SCZ subjects: P=0.02, P=0.05 and P=0.011, respectively). Concerning T-cell markers, BD patients had compared with HC downregulated ccr5 (P=0.02) and upregulated il4 (P=0.04) and compared with both healthy and SCZ individuals downregulated ccl2 (P=0.006 and P=0.003) and tgfβ (P=0.004 and P=0.007, respectively). No significant associations were found between any immune gene expression and clinical variables (prior hospitalizations, Brief Psychiatric Rating Scale, medications' dosages and lifetime administration). Although some markers are expressed by different immune cell types, these findings suggest a coherent increased M1/decrease M2 signature in the peripheral blood of BD patients with potential Th1/Th2 shift. In contrast, all the explored immune marker levels were preserved in SCZ. Further larger studies are needed to investigate the relevance of inflammatory response in BD, trying to correlate it to psychopathology, treatment and outcome measures and, possibly, to brain connectivity.

Introduction: In recent years the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology has often been used by international or national health authorities, or scientific societies, for developing evidence-based treatment recommendations. However, the GRADE approach has never been used by practicing physicians who aim at harmonizing their prescribing behaviours paying due attention to the best available evidence. This paper describes the experience of a working group of psychiatrists who adopted the GRADE approach to develop clinical recommendations on the use of psychotropic drugs in specialist mental healthcare., Case Description: The project was conducted in the Department of Mental Health of Verona, Italy, a city located in the north of Italy. At the beginning of 2012, psychiatrists with a specific interest in the rational use of psychotropic drugs were identified and appointed as members of a Guideline Development Group (GDG). The first task of the GDG was the identification of controversial areas in the use of psychotropic drugs, the definition of scoping questions, and the identification of outcomes of interest. The GDG was supported by a scientific secretariat, who searched the evidence, identified one or more systematic reviews matching the scoping questions, and drafted GRADE tables., Discussion and Evaluation: On the basis of efficacy, acceptability, tolerability and safety data, considering the risk of bias and confidence in estimates, and taking also into consideration preferences, values and practical aspects in favour and against the intervention under scrutiny, a draft recommendation with its strength was formulated and agreed by GDG members. Recommendations were submitted for consideration to all specialists of the Department, discussed in two plenary sessions open to the whole staff, and finally approved at the end of 2012., Conclusion: The present project of guideline development raised several challenging and innovating aspects, including a "bottom-up" approach, as it was motivated by reasons that found agreement among specialists, those who developed the recommendations were those who were supposed to follow them, and values, preferences and feasibility issues were considered paying due attention to local context variables.

Background: Hippocampal shrinkage is commonly reported in schizophrenia, but its role in the illness is still poorly understood. In particular, it is unclear how clinical and psychosocial variables relate to hippocampal volumes., Aims: To investigate neuroanatomic differences in the hippocampus using three-dimensional (3D) computational image analysis., Method: We used high-resolution magnetic resonance imaging and surface-based modelling to map the 3D profile of hippocampal differences in adults with schizophrenia (n = 67) and a healthy control group (n = 72). Manual tracings were used to create 3D parametric mesh models of the hippocampus. Regression models were used to relate diagnostic measures to maps of radial distance, and colour-coded maps were generated to show the profile of associations., Results: There was no detectable difference between the schizophrenia and control groups in hippocampal radial distance. In the schizophrenia group, however, bilateral shape deflation was associated with greater illness severity (length of illness, positive and negative symptoms) and with poorer social functioning (educational level, quality of life and health status), which survived Bonferroni correction., Conclusions: Illness severity and poor social functioning may be associated with hippocampal deflation in schizophrenia. As a structural sign of poor outcome, imaging measures might help to identify a subgroup of patients who may need specific treatment to resist hippocampal shrinkage, such as cognitive rehabilitation or physical exercise.

Objective: To explore linguistic abilities in schizophrenia and bipolar disorder. Specifically, the aims of this study were to: i) investigate microlinguistic (lexicon, morphology, syntax) and macrolinguistic (discourse coherence, pragmatics) dimensions of speech production and ii) evaluate syntactic comprehension skills in both schizophrenia and bipolar disorder., Method: Linguistic performance of 30 Italian-speaking patients with schizophrenia, 30 participants with bipolar disorder and 30 healthy controls comparable for age and educational level has been assessed using a story-telling task and a computer-based test of syntactic comprehension., Results: In narrative production, compared with healthy participants, those with schizophrenia had slight problems in speech rate and deficits at both local and global discourse coherence, whereas patients with bipolar disorder showed reduced mean length of utterance. As regards syntactic comprehension, both groups of patients collected more grammatical errors than controls, but they differed with regard to the number and kind of grammatical construction they missed., Conclusion: Linguistic deficits have been detected in both groups of patients, being, however, more severe and generalized in schizophrenia than in bipolar disorder. Such results help us in improving our understanding of the potential psychopathological overlapping between these disorders., (© 2012 John Wiley & Sons A/S.)

Schizophrenia is a disease with heterogeneous features and often a disabling longitudinal outcome. In order to achieve a better understanding of the disease, a detailed characterization and definition of symptomatology, social functioning and cognitive performance of patients is required. Imaging techniques may allow to identify measurable markers of different subgroups of patients, who share common clinical course and, probably, a similar hereditary pathway. The review offers a description of cross-sectional, predictive and longitudinal studies on the relationship between biological, clinical and psychosocial features of patients with schizophrenia. Patients with a more severe and disabling course of illness present larger ventricles, smaller prefrontal, temporal and occipital cortices and smaller subcortical regions such as basal ganglia, the thalamus and limbic areas. These alterations are predictive of a worse prognosis, as observed in predictive and longitudinal studies, both on chronic and first episode patients. The detection of more homogenous groups of patients with schizophrenia will help neurobiological research progress in this field. Furthermore, patients with similar clinical and biological features could undergo more tailored therapeutic and rehabilitative strategies.

Genetic, neuropathological and magnetic resonance imaging findings support the presence of diffuse white matter cytoarchitectural disruption in bipolar disorder. In this study, diffusion-weighted imaging (DWI) was applied to study cortical white matter microstructure organisation in 24 patients with DSM-IV bipolar disorder and 35 matched normal controls. DWI images were obtained using a 1.5 Tesla scanner and apparent diffusion coefficient (ADC) values were determined over regions of interest placed, bilaterally, in the frontal, temporal, parietal, and occipital white matter. Significantly increased ADC values were found in bipolar patients with respect to normal controls in the right temporal lobe, left parietal lobe and bilateral occipital lobes. ADC values did not associate significantly with age or with clinical variables (p>0.05). Diffuse cortical white matter alterations on DWI in bipolar disorder denote widespread disruption of white matter integrity and may be due to altered myelination and/or axonal integrity.

Ventricular enlargement is one of the most consistent abnormal structural brain findings in schizophrenia and has been used to infer brain shrinkage. However, whether ventricular enlargement is related to local overlying cortex and/or adjacent subcortical structures or whether it is related to brain volume change globally has not been assessed. We systematically assessed interrelations of ventricular volumes with gray and white matter volumes of 40 Brodmann areas (BAs), the thalamus and its medial dorsal nucleus and pulvinar, the internal capsule, caudate and putamen. We acquired structural MRI ( patients with schizophrenia (n = 64) and healthy controls (n = 56)) and diffusion tensor fractional anisotropy (FA) (untreated schizophrenia n = 19, controls n = 32). Volumes were assessed by manual tracing of central structures and a semi-automated parcellation of BAs. Patients with schizophrenia had increased ventricular size associated with decreased cortical gray matter volumes widely across the brain; a similar but less pronounced pattern was seen in normal controls; local correlations (e.g. temporal horn with temporal lobe volume) were not appreciably higher than non-local correlations (e.g. temporal horn with prefrontal volume). White matter regions adjacent to the ventricles similarly did not reveal strong regional relationships. FA and center of mass of the anterior limb of the internal capsule also appeared differentially influenced by ventricular volume but findings were similarly not regional. Taken together, these findings indicate that ventricular enlargement is globally interrelated with gray matter volume diminution but not directly correlated with volume loss in the immediately adjacent caudate, putamen, or internal capsule.

Recent brain imaging studies have shed light on understanding the pathogenesis of mood disorders. Evidence of structural, chemical, and functional brain changes, particularly in prefrontal cortex, cingulate, and amygdala, has been revealed in major depressive disorder (MDD). Furthermore, imaging techniques have been applied to monitor the effects of antidepressants (ADs) both in the brains of healthy volunteers and MDD patients. Although with some discrepancies due to the differences in study designs and patient samples, imaging findings have shown that ADs, particularly those having effects on the serotonergic system, modulate the volumes, functions and biochemistry of brain structures, i.e. dorsolateral prefrontal cortex, anterior cingulate and amygdala, which have been demonstrated abnormal in MDD by earlier imaging studies. This paper reviews imaging studies conducted in MDD patients and healthy controls treated with different ADs., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The neural basis of language and motor deficits in autism is still not completely clear. The aim of this study was to explore the involvement of the parietal lobe in language and motor development in autism, in view of the recognized role of this region in language and imitation functions. Twenty-eight autistic children underwent an extensive clinical assessment and an MRI examination. A significant direct correlation between age at first word and left parietal gray matter volumes was found (r=0.50, p=0.007). Conversely, age at reaching milestones of motor development, such as the ability to sit and to walk unaided, was not significantly associated with parietal size, after correcting for chronological age and for gender. To the best of our knowledge, this is the first structural MRI report demonstrating a role of left parietal gray matter volumes in delayed language development in autistic children representative of the 'real world' autistic population.

Imaging studies have tried to identify morphological outcome measures of schizophrenia in the last two decades. In particular, longitudinal studies have reported a correlation between larger ventricles, decreased prefrontal volumes and worse outcome. This would potentially allow to isolate subtypes of schizophrenia patients with a worse prognosis and more evident biological impairments, ultimately helping in designing specific rehabilitation interventions.

Sertindole, a 2nd generation antipsychotic with low movement disorder side effects, was compared with haloperidol in a 6-week crossover study. Fifteen patients with schizophrenia (mean age=42.6, range=22-59, 11 men and 4 women) received sertindole (12-24 mg) or haloperidol (4-16 mg) for 6 weeks and then received a FDG-PET scan and an anatomical MRI. Patients were then crossed to the other treatment and received a second set of scans at week 12. Dose was adjusted by a physician blind to the medication type. Brodmann areas were identified stereotaxically using individual MRI templates applied to the coregistered FDG-PET image. Sertindole administration was associated with higher dorsolateral prefrontal cortex metabolic rates than haloperidol and lower orbitofrontal metabolic rates than haloperidol. This effect was greatest for gray matter of the dorsolateral Brodmann areas 8, 9, 10, 44, 45, and 46. Patients were further contrasted with an approximately age and sex-matched group of 33 unmedicated patients with schizophrenia and with a group of 55 normal volunteers. Sertindole administration was associated with greater change toward normal values and away from the values found in the unmedicated comparison group for dorsolateral prefrontal cortex gray matter and white matter underlying medial prefrontal and cingulate cortex. These results are consistent with the low motor side-effect profile of sertindole, greater improvement on prefrontal cognitive tasks with sertindole than haloperidol, and with the tendency of 2nd generation antipsychotic drugs to have greater frontal activation than haloperidol.

Objective: Several magnetic resonance imaging (MRI) and postmortem studies have supported the role of the thalamus in the pathophysiology of schizophrenia. Interestingly, a recent small diffusion weighted imaging (DWI) study showed abnormal thalamic microstructure in patients with schizophrenia. The objective of our study was to use structural MRI and DWI to explore for the first time both thalamic volumes and integrity in schizophrenia., Methods: We measured thalamic volumes and apparent diffusion coefficient (ADC) measures bilaterally in 71 patients with schizophrenia, representative of those living in the geographically defined catchment area of South Verona (i.e., 100 000 inhabitants), and 75 individuals without schizophrenia. The presence of the adhesio interthalamica was also detected., Results: We found no significant differences in thalamus size between patients with schizophrenia and participants in the control group, with only a trend for decreased left volumes. No abnormal frequency of the adhesio interthalamica was found. In contrast, significantly increased thalamic ADC values were shown in schizophrenia patients. Age significantly inversely correlated with thalamic volumes in both groups and correlated positively with posterior ADCs in patients with schizophrenia. No significant associations between clinical variables and either volumes or ADC values were reported., Conclusion: Widespread altered microstructure integrity and partially preserved thalamus size were found in schizophrenia patients. Therefore, subtle thalamic structural abnormalities are present in schizophrenia, even with maintained volumes. This may result from disruption at the cytoarchitecture level, ultimately supporting corticothalamic misconnection. Future imaging studies should further explore thalamic tissue coherence and its role for cognitive disturbances in patients at high risk for schizophrenia and in first-degree relatives.

Background: The entorhinal cortex is located in the medial temporal lobe and is involved in memory and learning. Previous MRI studies reported conflicting findings in schizophrenia, showing normal or reduced entorhinal size., Objectives: To explore entorhinal cortex volumes in a large sample of patients with schizophrenia recruited from the geographically defined catchment area of South Verona (i.e. 100,000 inhabitants). We also investigated the size of hippocampus as part of the medial temporal lobe., Methods: 70 patients with schizophrenia and 77 normal controls underwent a session of MRI (TR=2060 ms, TE=3.9 ms, slice thickness=1.25 mm). Entorhinal and hippocampal volumes were explored using the Brains2 software., Results: A significant group effect was found for total entorhinal cortex but not for hippocampus, with patients suffering from schizophrenia having smaller entorhinal volumes compared to normal subjects (F=6.24, p=0.01), particularly on the right side (F=9.76, p=0.002). Also, the laterality index for entorhinal cortex was higher in normal individuals than in patients with schizophrenia (F=5.45, p=0.02)., Conclusions: Consistent with some of the previous reports, our study confirmed the presence of abnormally decreased entorhinal volumes, particularly on the right side, in a large number of patients with schizophrenia and also found altered asymmetry. This may play a major role in the psychopathology and cognitive disturbances of the disease. Future longitudinal MRI studies including high-risk subjects and drug-free, first-episode patients are crucial to further understand whether entorhinal cortex shrinkage is already present at the onset of the illness or appears as a consequence of the illness.

Brain atrophy has consistently been observed in schizophrenia, representing a 'gross' evidence of anatomical abnormalities. Reduced cerebral blood volume (CBV) may accompany brain size decrement in schizophrenia, as suggested by prior small SPECT studies. In this study, we non-invasively investigated the hemisphere CBV in a large sample of patients suffering from schizophrenia with perfusion-weighted imaging (PWI). PWI images were obtained, following intravenous injection of paramagnetic contrast agent (Gadolinium-DTPA), for 54 DSM-IV patients with schizophrenia (mean age+/-SD=39.19+/-12.20 years; 34 males, 20 females) and 24 normal controls (mean age+/-SD=44.63+/-10.43 years; 9 males, 15 females) with a 1.5T Siemens magnet using an echo-planar sequence (TR=2160 ms, TE=47 ms, slice thickness=5mm). The contrast of enhancement (CE), a semi-quantitative parameter inversely estimating the CBV, were calculated pixel by pixel as the ratio of the maximum signal intensity drop during the passage of contrast agent (Sm) by the baseline pre-bolus signal intensity (So) (CE=Sm/Sox100) for right and left hemisphere on two axial images. Specifically, higher CE values correspond to lower CBV and viceversa Compared to normal controls, patients with schizophrenia had significantly higher bilateral hemisphere CE values (p=0.02) and inverse CE laterality index (p=0.02). This study showed abnormally reduced and inverse hemisphere CBV in a large population of patients with schizophrenia. Hypothetically, chronic low CBV may sustain neural hypoactivation and concomitant increase of free radicals, ultimately resulting in neuronal loss and cognitive impairments. Thus, altered intracranial hemodynamics may accompany brain atrophy and cognitive deficits, being a crucial factor in the pathophysiology of schizophrenia.

Background: Several, although not all, of the previous small diffusion-weighted imaging (DWI) studies have shown cortical white-matter disruption in schizophrenia., Aims: To investigate cortical white-matter microstructure with DWI in a large community-based sample of people with schizophrenia., Method: Sixty-eight people with schizophrenia and 64 healthy controls underwent a session of DWI to obtain the apparent diffusion coefficient (ADC) of white-matter water molecules. Regions of interest were placed in cortical lobes., Results: Compared with controls, the schizophrenia group had significantly greater ADCs in frontal, temporal and occipital white matter (analysis of covariance, P < 0.05)., Conclusions: Our findings confirm the presence of cortical white-matter microstructure disruption in frontal and temporo-occipital lobes in the largest sample of people with schizophrenia thus for studied with this technique. Future brain imaging studies, together with genetic investigations, should further explore white-matter integrity and genes encoding myelin-related protein expression in people with first-episode schizophrenia and those at high risk of developing the disorder.

Several magnetic resonance imaging (MRI) studies have shown cerebral atrophy in established schizophrenia, although not in all reports. Discrepancies may mostly be due to population and postprocessing differences. Recently, disruption of cortical white matter integrity has also been reported in chronic patients with schizophrenia. In this study we explored tridimensional (3D) cerebral volumes and white matter microstructure in schizophrenia with structural and diffusion magnetic resonance. Twenty-five patients with established schizophrenia and 25 1:1 matched normal controls underwent a session of MRI using a Siemens 1.5T-scanner. 3D brain volume reconstruction was performed with the semi-automatic software Amira (TGS, San Diego, CA), whereas the apparent diffusion coefficients (ADCs) of cortical white matter water molecules were obtained with in-house developed softwares written in MatLab (The Mathworks-Inc., Natick, MA). Compared to controls, patients with schizophrenia had significantly smaller gray matter intracranium and total brain volumes, increased 4th ventricle volumes, and greater temporal and occipital ADCs. Patients treated with typical antipsychotic medication (N = 9) had significantly larger right lateral and 4th ventricles compared to those on atypical antipsychotic drugs. Intracranial volumes significantly inversely correlated with left temporal ADC in patients with schizophrenia. Also, age correlated directly with right, left, and 3rd ventricle volumes and inversely with gray matter intracranium volumes in individuals with schizophrenia. This study confirmed the presence of cortical atrophy in patients with schizophrenia, especially in those on typical antipsychotic drugs, and the existence of white matter disruption. It also suggested that physiological aging effects on brain anatomy may be abnormally pronounced in schizophrenia.

Pituitary volumes were shown to be abnormally large in pre- or first-psychotic episode patients and abnormally reduced in established schizophrenia by magnetic resonance imaging (MRI) studies. We present here the results of the second ever published MRI study exploring pituitary size in a large population of patients with chronic schizophrenia recruited from the geographically defined catchment area of South Verona, Italy. No significant differences for pituitary volumes were reported between 65 subjects with chronic schizophrenia and 65 normal individuals (mean age+/-S.D.=42.31+/-11.44 and 40.54+/-11.12 years). In contrast to Pariante et al. (2004), normal pituitary size was found in our population of chronic schizophrenia. Discrepancies between these two studies may partially be accounted by sample age and gender. Considering increased pituitary volumes in pre- or first-psychotic episode patients, we put forward the hypothesis that pituitary size may normalize or reduce with the progression of the illness as a result of reduced numbers of acute episodes and consequent diminished hypothalamus-pituitary-adrenal axis activity. To better test this hypothesis, future large MRI studies should investigate pituitary volumes in chronic schizophrenia longitudinally, also collecting pituitary hormones and cortisol, and comparing the effects of typical and atypical antipsychotics on pituitary size in a randomized trial.