Resting state networks activity in euthymic bipolar disorder.

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.

Classification of first-episode psychosis in a large cohort of patients using support vector machine and multiple kernel learning techniques.

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.

Case report and systematic review of cerebellar vermis alterations in psychosis.

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.

White matter microstructure alterations in bipolar disorder.

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.

[Searching for psychosocial endophenotypes in schizophrenia: the innovative role of brain imaging]. / Alla ricerca di endofenotipi psicosociali nella schizofrenia: il ruolo innovativo del brain imaging.

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.

Insula volumes in first-episode and chronic psychosis: A longitudinal MRI study.

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.

Correlations between ventricular enlargement and gray and white matter volumes of cortex, thalamus, striatum, and internal capsule in schizophrenia.

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.

The association of childhood trauma, lifetime stressful events and general psychopathological symptoms in euthymic bipolar patients and healthy subjects.

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.

"First-episode psychosis: Structural covariance deficits in salience network correlate with symptoms severity".

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.

Increased left parietal volumes relate to delayed language development in autism: a structural mri study.

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.

Twin MRI studies on genetic and environmental determinants of brain morphology and function in the early lifespan.

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.

Decreased entorhinal cortex volumes in schizophrenia.

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.

Microstructural thalamic changes in schizophrenia: a combined anatomic and diffusion weighted magnetic resonance imaging study.

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.

Hippocampal Subfield Volumes in Patients With First-Episode Psychosis.

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.

Assessment of cerebral blood volume in schizophrenia: A magnetic resonance imaging study.

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.

Normal pituitary volumes in chronic 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.

Longitudinal investigation of the parietal lobe anatomy in bipolar disorder and its association with general functioning.

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.