Fabrizio Piras

Magnetic resonance imaging markers of Parkinson's disease nigrostriatal signature

One objective of modern neuroimaging is to identify markers that can aid in diagnosis, disease progression monitoring and long-term drug impact analysis. In this study, Parkinson-associated physiopathological modifications were characterized in six subcortical structures by simultaneously measuring quantitative magnetic resonance parameters sensitive to complementary tissue characteristics (i.e. volume atrophy, iron deposition and microstructural damage). Thirty patients with Parkinsons disease and 22 control subjects underwent 3-T magnetic resonance imaging with T₂*-weighted, whole-brain T₁-weighted and diffusion tensor imaging scans. The mean R₂* value, mean diffusivity and fractional anisotropy in the pallidum, putamen, caudate nucleus, thalamus, substantia nigra and red nucleus were compared between patients with Parkinsons disease and control subjects. Comparisons were also performed using voxel-based analysis of R₂*, mean diffusivity and fractional anisotropy maps to determine which subregion of the basal ganglia showed the greater difference for each parameter. Averages of each subregion were then used in a logistic regression analysis. Compared with control subjects, patients with Parkinsons disease displayed significantly higher R₂* values in the substantia nigra, lower fractional anisotropy values in the substantia nigra and thalamus, and higher mean diffusivity values in the thalamus. Voxel-based analyses confirmed these results and, in addition, showed a significant difference in the mean diffusivity in the striatum. The combination of three markers was sufficient to obtain a 95% global accuracy (area under the receiver operating characteristic curve) for discriminating patients with Parkinsons disease from controls. The markers comprising discriminating combinations were R₂* in the substantia nigra, fractional anisotropy in the substantia nigra and mean diffusivity in the putamen or caudate nucleus. Remarkably, the predictive markers involved the nigrostriatal structures that characterize Parkinsons physiopathology. Furthermore, highly discriminating combinations included markers from three different magnetic resonance parameters (R₂*, mean diffusivity and fractional anisotropy). These findings demonstrate that multimodal magnetic resonance imaging of subcortical grey matter structures is useful for the evaluation of Parkinsons disease and, possibly, of other subcortical pathologies.

Education mediates microstructural changes in bilateral hippocampus

Education has been extensively considered an influential factor in the modulation of interindividual differences in cognitive performance and cerebral structure. Consequently, education has been linked to the concept of reserve, which refers to an unspecified aspect of brain structure or function that enables people with more education to cope better with brain pathology or age‐related changes. Nevertheless, the education‐related neural mechanisms involved in reserve are still not completely understood. In this study, 150 healthy subjects were submitted to a comprehensive sociodemographic, clinical and cognitive assessment, and a high‐resolution structural MRI and diffusion tensor imaging scan protocol. Data of micro‐ (mean diffusivity, MD) and macro‐ (volume) structural changes of six bilateral deep gray matter structures (thalamus, caudate nucleus, putamen, hippocampus, amygdala, and globus pallidus) were analyzed with reference to years of formal education. Results show that decreased MD in both left and right hippocampi was the only structural parameter that, along with decreasing age, significantly correlated with higher education. The present findings suggest that the hippocampal formation might be one site where education‐mediated microstructural changes occur, possibly compensating for cognitive decline. Hum Brain Mapp, 2011.

Brain circuitries of obsessive compulsive disorder: a systematic review and meta-analysis of diffusion tensor imaging studies.

The potential role of white matter (WM) abnormalities in the pathophysiology of obsessive compulsive disorder (OCD) is substantially unexplored. Apart from alterations in the WM tracts within cortico-striato-thalamo-cortical circuitry, recent theorizations predict the existence of more widespread WM abnormalities. In this paper we systematically reviewed the current diffusion tensor imaging literature in OCD and purposely evaluated the prevalence and functional significance of specific WM tissue changes in the disorder. The relationship between clinical variables (medication status, symptom severity) and WM microstructural changes was also assessed. The reviewed studies are consistent with the existence of microstructural alterations in the fronto-basal pathways targeting the orbitofrontal cortex and the anterior cingulate cortex. Moreover, altered anatomical connectivity between lateral frontal and parietal regions and microstructural abnormalities in intra-hemispheric bundles linking distinctive areas of the prefrontal cortex to posterior parietal and occipital association cortices, are consistently reported. Finally, microstructural abnormalities in the corpus callosum, characterized by decreased connectivity in the rostrum and hyperconnectivity in the genu, are substantiated by a large body of evidence.

Functional anatomy of derivational morphology

Lexical morphology involves two types of suffixes: inflectional suffixes, which have a grammatical function, and derivational suffixes with a word formation function. In this study, functional magnetic resonance imaging (fMRI) was used during processing of Italian derived and inflected words. In the derivational task, subjects were asked to produce nouns derived from verbs and from adjectives (e.g., to observe--observation; kind--kindness). After the presentation of the derived noun, they had to generate the corresponding verb (e.g., failure--to fail: generation task). In the inflectional task, subjects had to produce the past participle of the verb or the plural form of the adjective or the derived noun. Behavioural data were collected in separate sessions in two different conditions. In the first experiment, as in the fMRI study, vocal reaction times (RTs) were measured from the offset of the auditory stimulus to the onset of the participants response. In the second experiment, run with a different group of participants, RTs were recorded starting from the onset of the auditory stimulus to the onset of the response. The fMRI results showed that, relative to the inflectional task and to a repetition task, the derivational task, but not the verb generation task, brought about an activation of left fronto-parietal regions, documenting a specific involvement of these areas in the processing of derived words. Although less extended, similar activation was found for verb inflection but was absent for noun and adjective plural forms. Analysis of behavioral data indicated that an explanation in terms of task difficulty was unlikely related to the imaging results.

The neuroanatomical correlates of cognitive insight in schizophrenia

Insight has been mostly studied from a clinical perspective. Recently, attention moved to cognitive insight or the ability to monitor and correct ones erroneous convictions. Here, we investigated the neuroanatomical correlates of cognitive insight. We administered the Beck cognitive insight scale to 45 outpatients with a schizophrenia diagnosis and 45 age- and gender-matched healthy control subjects who underwent a MRI investigation, including high-resolution volumetric and diffusion tensor imaging sequences. Gray and white matter volume, mean diffusivity and fractional anisotropy were used as dependent variables and were analyzed on a voxel-by-voxel basis with reference to the cognitive insight indexes. Self-reflectiveness was positively related to gray matter volume of the right ventro-lateral prefrontal cortex (VLPFC). No statistically significant results emerged from the DTI analyses, and no significant relationships were found for self-certainty and global cognitive insight. Reduced self-reflectiveness is related to a reduced volume of the VLPFC, an area involved in generating and maintaining in working memory different hypotheses about the self. This line of research focusing on the metacognitive features of insight in schizophrenia can provide relevant information to identify patients who are most vulnerable to lack of insight and develop effective cognitive therapeutic strategies.

Suicidal attempts and increased right amygdala volume in schizophrenia

Suicide is a major cause of death in schizophrenia. Neurobiological studies suggest that suicidality is associated with abnormal brain structure and connectivity in fronto-temporo-limbic regions. However, it is still unclear whether suicidality in schizophrenia is related to volumetric abnormalities in subcortical structures that play a key role in emotion regulation, aggression and impulse control. Therefore, we aimed to examine whether the volume of selected subcortical regions is associated with previous suicidal attempts and self-aggression in schizophrenia. For this cross-sectional study, we recruited 50 outpatients with schizophrenia and 50 healthy controls (HC) matched for age and gender. Fourteen patients had a history of one or more suicide attempts. Different forms of aggression were assessed using the Modified Overt Aggression Scale. All participants underwent structural MR imaging at 3 Tesla. Physical volumetric measures were calculated for the lateral ventricles, thalamus, hippocampus, amygdala, caudate, putamen, pallidum and accumbens using an automatic segmentation method on T1-weighted high-resolution (voxel size 1×1×1mm(3)) images. Multivariate and follow-up univariate ANOVAs revealed a selective increase in volume in the right amygdala of patients with a history of suicidality compared both to patients without such a history and HC. Moreover, in the entire patient group increased right amygdala volume was related to increased self-aggression. Our findings suggest that right amygdala hypertrophy may be a risk factor for suicide attempts in patients with schizophrenia and this could be relevant for suicide prevention.

COMT Genetic Reduction Produces Sexually Divergent Effects on Cortical Anatomy and Working Memory in Mice and Humans

Genetic variations in catechol-O-methyltransferase (COMT) that modulate cortical dopamine have been associated with pleiotropic behavioral effects in humans and mice. Recent data suggest that some of these effects may vary among sexes. However, the specific brain substrates underlying COMT sexual dimorphisms remain unknown. Here, we report that genetically driven reduction in COMT enzyme activity increased cortical thickness in the prefrontal cortex (PFC) and postero-parieto-temporal cortex of male, but not female adult mice and humans. Dichotomous changes in PFC cytoarchitecture were also observed: reduced COMT increased a measure of neuronal density in males, while reducing it in female mice. Consistent with the neuroanatomical findings, COMT-dependent sex-specific morphological brain changes were paralleled by divergent effects on PFC-dependent working memory in both mice and humans. These findings emphasize a specific sex-gene interaction that can modulate brain morphological substrates with influence on behavioral outcomes in healthy subjects and, potentially, in neuropsychiatric populations.

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.

Parallel recovery in a bilingual aphasic: a neurolinguistic and fMRI study.

In bilingual aphasics, the neural correlates of rehabilitation benefits and their generalization across languages are still scarcely understood. The authors present the case of a highly proficient bilingual woman (Flemish, L1/Italian, L2) with chronic aphasia who, in the presence of the same pattern of impairment in both languages, showed parallel recovery in both languages after long-term rehabilitation therapy in L2. The authors postulated that this recovery was due to the engagement of the same neural substrates. To confirm this the authors used an event-related functional magnetic resonance imaging (fMRI) paradigm to explore cortical activation during an overt picture naming task, performed in both Flemish and Italian once before and once after 2 weeks of training in L2. Behaviorally, the patient showed complete recovery of both languages. The fMRI results indicated that the same cerebral regions were recruited for both languages before and after training. Increasing activations were observed perilesionally and in homologous contralesional areas. Our data, in agreement with previous results of fMRI studies in healthy bilinguals, indicate a promising direction for future research on the neural mechanisms associated with recovery in bilingual aphasics.