Chiara Chiapponi

Age-related brain trajectories in schizophrenia: A systematic review of structural MRI studies

Using the Pubmed database, we performed a detailed literature search for structural magnetic resonance imaging studies on patients with schizophrenia, investigating the relationship between macroscopic and microscopic structural parameters and age, to delineate an age-related trajectory. Twenty-six studies were considered for the review, from January 2000 to June 2012. Research results are heterogeneous because of the multifactorial features of schizophrenia and the multiplicity of the methodological approaches adopted. Some areas, within the amygdala-hippocampus complex, which are affected early in life by schizophrenia, age in a physiological way. Other regions, such as the superior temporal gyrus, appear already impaired at the onset of symptoms, undergo a worsening in the acute phase but later stabilize, progressing physiologically over years. Finally, there are regions, such as the uncinate fasciculus, which are not altered early in life, but are affected around the onset of schizophrenia, with their impairment continuously worsening over time. Further extensive longitudinal studies are needed to understand the timing and the possible degenerative characteristics of structural impairment associated with schizophrenia.

Linking novelty seeking and harm avoidance personality traits to cerebellar volumes

Personality traits are multidimensional traits comprising cognitive, emotional, and behavioral characteristics, and a wide array of cerebral structures mediate individual variability. Differences in personality traits covary with brain morphometry in specific brain regions, and neuroimaging studies showed structural or functional abnormalities of cerebellum in subjects with personality disorders, suggesting a cerebellar role in affective processing and an effect on personality characteristics. To test the hypothesis that cerebellar [white matter (WM) and cortex] volumes are correlated with scores obtained in the four temperamental scales of the Temperament and Character Inventory (TCI) by Cloninger, a total of 125 healthy participants aged 18–67 years of both genders (males = 52) completed the TCI and underwent magnetic resonance imaging. The scores obtained in each temperamental scale were associated with the volumes of cerebellar WM and cortex of right and left hemispheres separately by using linear regression analyses. In line with our hypothesis, novelty seeking (NS) scores were positively associated with WM and cortex cerebellar volumes. Harm avoidance (HA) scores were negatively associated with WM and cortex cerebellar volumes. The range of individual differences in NS and HA scores reflects the range of variances of cerebellar volumes. The present data indicating a cerebellar substrate for some personality traits extend the relationship between personality and brain areas to a structure up to now thought to be involved mainly in motor and cognitive functions, much less in emotional processes and even less in personality individual differences. Hum Brain Mapp 35:285–296, 2014.

White matter hyperintensities segmentation: A new semi-automated method

White matter hyperintensities (WMH) are brain areas of increased signal on T2-weighted or fluid-attenuated inverse recovery magnetic resonance imaging (MRI) scans. In this study we present a new semi-automated method to measure WMH load that is based on the segmentation of the intensity histogram of fluid-attenuated inversion recovery images. Thirty patients with mild cognitive impairment with variable WMH load were enrolled. The semi-automated WMH segmentation included removal of non-brain tissue, spatial normalization, removal of cerebellum and brain stem, spatial filtering, thresholding to segment probable WMH, manual editing for correction of false positives and negatives, generation of WMH map, and volumetric estimation of the WMH load. Accuracy was quantitatively evaluated by comparing semi-automated and manual WMH segmentations performed by two independent raters. Differences between the two procedures were assessed using Student’s t-tests and similarity was evaluated using linear regression model and Dice similarity coefficient (DSC). The volumes of the manual and semi-automated segmentations did not statistically differ (t-value = -1.79, DF = 29, p = 0.839 for rater 1; t-value = 1.113, DF = 29, p = 0.2749 for rater 2), were highly correlated [R2 = 0.921, F(1,29) = 155.54, p < 0.0001 for rater 1; R2 = 0.935, F(1,29) = 402.709, p < 0.0001 for rater 2] and showed a very strong spatial similarity (mean DSC = 0.78, for rater 1 and 0.77 for rater 2). In conclusion, our semi-automated method to measure the load of WMH is highly reliable and could represent a good tool that could be easily implemented in routinely neuroimaging analyses to map clinical consequences of WMH.

New evidence for the cerebellar involvement in personality traits

Following the recognition of its role in sensory-motor coordination and learning, the cerebellum has been involved in cognitive, emotional, and even personality domains. This study investigated the relationships between cerebellar macro- and micro-structural variations and temperamental traits measured by Temperament and Character Inventory (TCI). High resolution T1-weighted, and Diffusion Tensor Images of 100 healthy subjects aged 18–59 years were acquired by 3 Tesla Magnetic Resonance scanner. In multiple regression analyses, cerebellar Gray Matter (GM) or White Matter (WM) volumes, GM Mean Diffusivity (MD), and WM Fractional Anisotropy (FA) were used as dependent variables, TCI scores as regressors, gender, age, and education years as covariates. Novelty Seeking scores were associated positively with the cerebellar GM volumes and FA, and negatively with MD. No significant association between Harm Avoidance, Reward Dependence or Persistence scores and cerebellar structural measures was found. The present data put toward a cerebellar involvement in the management of novelty.

GABA system in schizophrenia and mood disorders: A mini review on third-generation imaging studies

Third-generation neuroimaging research has been enriched by advances in magnetic resonance spectroscopy (MRS) measuring the concentration of important neurotrasmitters, such as the inhibitory amino acid GABA. Here, we performed a systematic mini-review on brain MRS studies measuring GABA concentration in patients affected by schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). We wondered whether multimodal investigations could overcome intrinsic technical limits of MRS giving a broader view of mental disorders pathogenesis. In SZ, unimodal studies gave mixed results, as increased, decreased, or unaltered GABA levels were reported depending on region, disease phase, and treatment. Conversely, multimodal results showed reduced level of glutamate, but not of GABA, in patients mirrored by in vitro biochemical findings revealing hippocampal reduction in glutamate signaling in SZ, and no deficits in GABA synthesis. Moreover, a mouse model confirmed the unique pathological characteristic of glutamate function in SZ. Unimodal studies in BD revealed again, inconsistent results, while no multimodal investigations including MRS on GABA exist. In MDD, unimodal studies could not differentiate patients from controls nor characterize high-risk subjects and remitted patients. However, a multimodal study combining functional magnetic resonance imaging and MRS revealed that cingulate cortex activity is related to glutamate, N-acetylaspartate levels and anhedonia in patients, and to GABA concentration in healthy subjects, improving the distinction between MDD and physiology. Overall, our results show that unimodal studies do not indicate GABA as a biomarker for the psychiatric disorders considered. Conversely, multimodal studies can widen the understanding of the link between psychopathology, genetics, neuroanatomy, and functional–biochemical brain activity in mental disorders. Although scarce, multimodal approaches seem promising for moving from GABA MRS unimodal-descriptive to causal level, and for integrating GABA results into a more comprehensive interpretation of mental disorder pathophysiology.

Brain structure, cognition and negative symptoms in schizophrenia are associated with serum levels of polysialic acid-modified NCAM.

The neural cell adhesion molecule (NCAM) is a glycoprotein implicated in cell–cell adhesion, neurite outgrowth and synaptic plasticity. Polysialic acid (polySia) is mainly attached to NCAM (polySia-NCAM) and has an essential role in regulating NCAM-dependent developmental processes that require plasticity, that is, cell migration, axon guidance and synapse formation. Post-mortem and genetic evidence suggests that dysregulation of polySia-NCAM is involved in schizophrenia (SZ). We enrolled 45 patients diagnosed with SZ and 45 healthy individuals who were submitted to polySia-NCAM peripheral quantification, cognitive and psychopathological assessment and structural neuroimaging (brain volumes and diffusion tensor imaging). PolySia-NCAM serum levels were increased in SZ patients, independently of antipsychotic treatment, and were associated with negative symptoms, blunted affect and declarative memory impairment. The increased polySia-NCAM levels were associated with decreased volume in the left prefrontal cortex, namely Brodmann area 46, in patients and increased volume in the same brain area of healthy individuals. As this brain region is involved in the pathophysiology of SZ and its associated phenomenology, the data indicate that polySia-NCAM deserves further scrutiny because of its possible role in early neurodevelopmental mechanisms of the disorder.

Effects of a novel schizophrenia risk variant rs7914558 at CNNM2 on brain structure and attributional style

BACKGROUNDnA single nucleotide polymorphism (rs7914558) within the cyclin M2 (CNNM2) gene was recently identified as a common risk variant for schizophrenia. The mechanism by which CNNM2 confers risk is unknown.nnnAIMSnTo determine the impact of the rs7914558 risk G allele [corrected] on measures of neurocognition, social cognition and brain structure.nnnMETHODnPatients with schizophrenia (n = 400) and healthy controls (n = 160) completed measures of neuropsychological function and social cognition. Structural magnetic resonance imaging data were also acquired from an overlapping sample of Irish healthy controls (n = 159) and an independent sample of Italian patients (n = 82) and healthy controls (n = 39).nnnRESULTSnNo effects of genotype on neuropsychological test performance were observed. However, a dosage effect of the risk allele was found for an index of social cognition (i.e. attributional style), such that risk status was associated with reduced self-serving bias across groups (GG>AG>AA, P<0.05). Using voxel-based morphometry to investigate neuroanatomical regions putatively supporting social cognition, risk carriers had relatively increased grey matter volume in the right temporal pole and right anterior cingulate cortex (Pcorrected<0.05) in the Irish healthy controls sample; neuroanatomical associations between CNNM2 and grey matter volume in anterior cingulate cortex were also observed in the Italian schizophrenia and healthy controls samples.nnnCONCLUSIONSnAlthough the biological role of CNNM2 in schizophrenia remains unknown, these data suggest that this CNNM2 risk variant rs7914558 may have an impact on neural systems relevant to social cognition. How such effects may mediate the relationship between genotype and disease risk remains to be established.

Gray and white matter trajectories in patients with bipolar disorder

Findings on brain structural abnormalities in patients with bipolar disorder (BP) are inconsistent and little is known about age‐related evolution of these changes. We employed a cross‐sectional, case–control study to compare structural age‐related brain trajectories in patients with BP and healthy control subjects (HC) over a period of approximately 50 years. The primary aim was to understand whether white (WM) and gray matter (GM) abnormalities are present from the beginning of the illness and how they change over time.

Hippocampal volume and depressive symptoms are linked to serum IL-18 in schizophrenia

Objective: Since schizophrenia (SCZ) is often accompanied by hippocampal abnormalities and dysregulation of cytokine production, this study aimed to investigate the impact of the cytokine interleukin (IL)-18, whose biological system appears to be perturbed in SCZ, on brain structure and clinical severity in patients with chronic SCZ. Methods: The serum levels of IL-18, including its free bioactive form (i.e., the cytokine fraction not bound to its specific endogenous inhibitor IL-18 binding protein), were evaluated in a case-control study involving 71 individuals with SCZ diagnosis and 29 healthy controls. All participants underwent brain MRI automatic evaluation for hippocampal volume estimation. The Positive and Negative Syndrome Scale (PANSS) was administered to measure severity of symptoms in patients with SCZ. Results: Lower amounts of free IL-18 were related to smaller hippocampal volume measures in patients with SCZ. Furthermore, in line with a possible neuroprotective effect of the cytokine, higher levels of free IL-18 corresponded to lower subscores of PANSS depression in patients with SCZ. Conclusions: These findings demonstrate that the levels of circulating bioactive IL-18 are related to both hippocampal volume and severity of psychopathologic symptoms in patients with SCZ, confirming the involvement of the cytokine in SCZ pathophysiology and suggesting hippocampal-dependent and neuroprotective functions of IL-18 in this clinical context.

Hippocampus age-related microstructural changes in schizophrenia: A case-control mean diffusivity study

Macrostructural-volumetric abnormalities of the hippocampus have been described in schizophrenia. Here, we characterized age-related changes of hippocampal mean diffusivity as an index of microstructural damage by carrying out a neuroimaging study in 85 patients with a DSM-IV-TR diagnosis of schizophrenia and 85 age- and gender-matched healthy controls. We performed analyses of covariance, with diagnosis as fixed factor, mean diffusivity as dependent variable and age as covariate. Patients showed an early increase in mean diffusivity in the right and left hippocampus that increased with age. Thus, microstructural hippocampal changes associated with schizophrenia cannot be confined to a specific time window.