Gianluca Rambaldelli

Altered white matter integrity and development in children with autism: A combined voxel-based morphometry and diffusion imaging study

BACKGROUND A combined protocol of voxel-based morphometry (VBM) and diffusion-weighted imaging (DWI) was applied to investigate the neurodevelopment of gray and white matter in autism. METHODS Twenty children with autism (mean age= 7 ± 2.75 years old; age range: 4-14; 2 girls) and 22 matched normally developing children (mean age = 7.68 ± 2.03 years old; age range: 4-11; 2 girls) underwent magnetic resonance imaging (MRI). VBM was employed by applying the Template-o-Matic toolbox (TOM), a new approach which constructs the age-matched customized template for tissue segmentation. Also, the apparent diffusion coefficients (ADC) of water molecules were obtained from the analysis of DWI. Regions of interests (ROIs), standardized at 5 pixels, were placed in cortical lobes and corpus callosum on the non-diffusion weighted echo-planar images (b = 0) and were then automatically transferred to the corresponding maps to obtain the ADC values. RESULTS Compared to normal children, individuals with autism had significantly: (1) increased white matter volumes in the right inferior frontal gyrus, the right fusiform gyrus, the left precentral and supplementary motor area and the left hippocampus, (2) increased gray matter volumes in the inferior temporal gyri bilaterally, the right inferior parietal cortex, the right superior occipital lobe and the left superior parietal lobule, and (3) decreased gray matter volumes in the right inferior frontal gyrus and the left supplementary motor area. Abnormally increased ADC values in the bilateral frontal cortex and in the left side of the genu of the corpus callosum were also reported in autism. Finally, age correlated negatively with lobar and callosal ADC measurements in individuals with autism, but not in children with normal development. CONCLUSIONS These findings suggest cerebral dysconnectivity in the early phases of autism coupled with an altered white matter maturation trajectory during childhood potentially taking place in the frontal and parietal lobes, which may represent a neurodevelopmental marker of the disorder, possibly accounting for the cognitive and social deficits.

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.

Dorsolateral prefrontal cortex and hippocampus sustain impulsivity and aggressiveness in borderline personality disorder

BACKGROUND Borderline Personality Disorder (BPD) patients are characterized by increased levels of aggressivity and reduction of impulse control, which are behavioural dimensions mainly sustained by hippocampus and dorsolateral prefrontal cortex (DLPFC). In this study we aimed at investigating whether hippocampus and DLPFC anatomy may sustain impulsive and aggressive behaviours in BPD. METHODS Fifteen DSM-IV BPD patients (11 females, 4 males) and fifteen 1:1 matched healthy controls (11 females, 4 males) were studied with a 1.5T magnetic resonance imaging (MRI) and underwent a psychopathological assessment in order to measure the severity of aggressive and impulsive traits. RESULTS Right hippocampal volumes were significantly reduced in BPD patients compared to healthy subjects (p=0.027), particularly in those with a history of childhood abuse (p=0.01). Moreover, in patients but not in controls, right hippocampal volumes significantly inversely correlated with aggressiveness and DLPFC grey matter volumes significantly inversely associated with impulsiveness (p<0.05). CONCLUSIONS Our results provide evidence that hippocampus and DLPFC play a separate and unique role in sustaining the control of impulse and aggressive behaviours in BPD patients.

Brain structural changes associated with chronicity and antipsychotic treatment in schizophrenia

Accumulating evidence suggest a life-long impact of disease related mechanisms on brain structure in schizophrenia which may be modified by antipsychotic treatment. The aim of the present study was to investigate in a large sample of patients with schizophrenia the effect of illness duration and antipsychotic treatment on brain structure. Seventy-one schizophrenic patients and 79 age and gender matched healthy participants underwent brain magnetic resonance imaging (MRI). All images were processed with voxel based morphometry, using SPM5. Compared to healthy participants, patients showed decrements in gray matter volume in the left medial and left inferior frontal gyrus. In addition, duration of illness was negatively associated with gray matter volume in prefrontal regions bilaterally, in the temporal pole on the left and the caudal superior temporal gyrus on the right. Cumulative exposure to antipsychotics correlated positively with gray matter volumes in the cingulate gyrus for typical agents and in the thalamus for atypical drugs. These findings (a) indicate that structural abnormalities in prefrontal and temporal cortices in schizophrenia are progressive and, (b) suggest that antipsychotic medication has a significant impact on brain morphology.

Specific linguistic and pragmatic deficits in Italian patients with schizophrenia

OBJECTIVE Verbal communication impairments are prominent features of schizophrenia. The grammatical and pragmatic components of expressive and receptive verbal abilities were systematically examined, for the first time, in Italian patients with schizophrenia. Indeed, most of the language literature is composed of studies on English speaking people. METHOD Elicited narrative production, and syntactic and pragmatic receptive abilities were analyzed in a cohort of 37 patients with schizophrenia and 37 healthy controls. Furthermore, a conversational speech production task was administered to an age- and gender-matched subset of this population. The level of significance was set at p<or=0.01. RESULTS Participants with schizophrenia produced significantly less words on the narrative task and were less fluent on the conversational task than healthy controls. In both narrative and conversational speech they showed significantly poorer syntactic diversity skills. Errors at word level did not distinguish the two groups. At a receptive level, syntactic abilities were selectively impaired in patients with schizophrenia, who were also slower than controls in providing their answers. Metaphor and idiom explanations revealed consistent deficits in patients with respect to controls. CONCLUSIONS Reduced syntactic diversity characterized expressive language skills in schizophrenia. Syntactic abilities were selectively impaired also at the receptive level, suggesting an underlying processing deficit. On the pragmatic test schizophrenia patients were significantly less able to produce appropriate interpretations, indicating the presence of abnormal pragmatic inferential abilities. These findings confirm that language impairment is a key feature of schizophrenia independent of mother language and suggest a possible deficit involving hemispheric lateralization processes.

Thalamic-insular dysconnectivity in schizophrenia: Evidence from structural equation modeling

Structural and functional studies have shown that schizophrenia is often associated with frontolimbic abnormalities in the prefrontal and mediotemporal regions. It is still unclear, however, if such dysfunctional interaction extends as well to relay regions such as the thalamus and the anterior insula. Here, we measured gray matter volumes of five right‐hemisphere regions in 68 patients with schizophrenia and 77 matched healthy subjects. The regions were amygdala, thalamus, and entorhinal cortex (identified as anomalous by prior studies on the same population) and dorsolateral prefrontal cortex and anterior insula (isolated by voxel‐based morphometry analysis). We used structural equation modeling and found altered path coefficients connecting the thalamus to the anterior insula, the amygdala to the DLPFC, and the entorhinal cortex to the DLPFC. In particular, patients exhibited a stronger thalamus‐insular connection than healthy controls. Instead, controls showed positive entorhinal‐DLPFC and negative amygdalar‐DLPFC connections, both of which were absent in the clinical population. Our data provide evidence that schizophrenia is characterized by an impaired right‐hemisphere network, in which intrahemispheric communication involving relay structures may play a major role in sustaining the pathophysiology of the disease. Hum Brain Mapp, 2012.

Schizophrenia severity, social functioning and hippocampal neuroanatomy: three-dimensional mapping study

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.

Increased M1/decreased M2 signature and signs of Th1/Th2 shift in chronic patients with bipolar disorder, but not in those with schizophrenia

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.

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.

Brain morphometry by probabilistic latent semantic analysis

The paper propses a new shape morphometry approach that combines advanced classification techniques with geometric features to identify morphological abnormalities on the brain surface. Our aim is to improve the classification accuracy in distinguishing between normal subjects and schizophrenic patients. The approach is inspired by natural language processing. Local brain surface geometric patterns are quantized to visual words, and their co-occurrences are encoded as visual topic. To do this, a generative model, the probabilistic. Latent Semantic Analysis is learned from quantized shape descriptors (visual words). Finally, we extract from the learned models a generative score, that is used as input of a Support Vector Machine (SVM), defining an hybrid generative/discriminative classification algorithm. An exhaustive experimental section is proposed on a dataset consisting of MRI scans from 64 patients and 60 control subjects. Promising results are reporting by observing accuracies up to 86.13%.