Publications by authors named "Annabella Di Giorgio"

47 Publications

Diagnosis of COVID-19 in Patients with Negative Nasopharyngeal Swabs: Reliability of Radiological and Clinical Diagnosis and Accuracy Versus Serology.

Diagnostics (Basel) 2021 Feb 25;11(3). Epub 2021 Feb 25.

Unit of Internal Medicine, Department of Medical Sciences, IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.

Background: The diagnosis of Coronavirus disease 2019 (COVID-19) relies on the positivity of nasopharyngeal swab. However, a significant percentage of symptomatic patients may test negative. We evaluated the reliability of COVID-19 diagnosis made by radiologists and clinicians and its accuracy versus serology in a sample of patients hospitalized for suspected COVID-19 with multiple negative swabs.

Methods: Admission chest CT-scans and clinical records of swab-negative patients, treated according to the COVID-19 protocol or deceased during hospitalization, were retrospectively evaluated by two radiologists and two clinicians, respectively.

Results: Of 254 patients, 169 swab-confirmed cases and one patient without chest CT-scan were excluded. A total of 84 patients were eligible for the reliability study. Of these, 21 patients died during hospitalization; the remaining 63 underwent serological testing and were eligible for the accuracy evaluation. Of the 63, 26 patients showed anti-Sars-Cov-2 antibodies, while 37 did not. The inter-rater agreement was "substantial" (kappa 0.683) between radiologists, "moderate" (kappa 0.454) between clinicians, and only "fair" (kappa 0.341) between radiologists and clinicians. Both radiologic and clinical evaluations showed good accuracy compared to serology.

Conclusions: The radiologic and clinical diagnosis of COVID-19 for swab-negative patients proved to be sufficiently reliable and accurate to allow a diagnosis of COVID-19, which needs to be confirmed by serology and follow-up.
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http://dx.doi.org/10.3390/diagnostics11030386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996330PMC
February 2021

Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years.

Hum Brain Mapp 2021 Feb 17. Epub 2021 Feb 17.

Laboratory of Psychiatric Neuroimaging, Departamento e Instituto de Psiquiatria, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.
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http://dx.doi.org/10.1002/hbm.25364DOI Listing
February 2021

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years.

Hum Brain Mapp 2021 Feb 11. Epub 2021 Feb 11.

Department of Psychology, Center for Brain Science, Harvard University, Cambridge, Massachusetts, USA.

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.
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http://dx.doi.org/10.1002/hbm.25320DOI Listing
February 2021

Greater male than female variability in regional brain structure across the lifespan.

Hum Brain Mapp 2020 Oct 12. Epub 2020 Oct 12.

FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain.

For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.
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http://dx.doi.org/10.1002/hbm.25204DOI Listing
October 2020

Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder.

Hum Brain Mapp 2020 Oct 7. Epub 2020 Oct 7.

Neuroscience Research Australia, Sydney, Australia.

First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
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http://dx.doi.org/10.1002/hbm.25206DOI Listing
October 2020

Mental Health in Patients With Adrenal Incidentalomas: Is There a Relation With Different Degrees of Cortisol Secretion?

J Clin Endocrinol Metab 2021 01;106(1):e130-e139

Unit for Bone Metabolism Diseases and Diabetes, Istituto Auxologico Italiano, IRCCS, Milan, Italy.

Context: Cushing's syndrome frequently causes mental health impairment. Data in patients with adrenal incidentaloma (AI) are lacking.

Objective: We aimed to evaluate psychiatric and neurocognitive functions in AI patients, in relation to the presence of subclinical hypercortisolism (SH), and the effect of adrenalectomy on mental health.

Design: We enrolled 62 AI patients (64.8 ± 8.9 years) referred to our centers. Subclinical hypercortisolism was diagnosed when cortisol after 1mg-dexamethasone suppression test was >50 nmol/L, in the absence of signs of overt hypercortisolism, in 43 patients (SH+).

Interventions: The structured clinical interview for the Diagnostic and Statistical Manual of Mental Disorders-5, and 5 psychiatric scales were performed. The Brief Assessment of Cognition in Schizophrenia (Verbal and Working Memory, Token and Symbol Task, Verbal Fluency, Tower of London) was explored in 26 patients (≤65 years).

Results: The prevalence of psychiatric disorders was 27.4% (SH+ 30.2% vs SH- 21.1%, P = 0.45). SH+ showed a higher prevalence of middle insomnia (by the Hamilton Depression Rating Scale) compared with SH- (51% vs 22%, P = 0.039). Considering the Sheehan Disability Scale, SH+ showed a higher disability score (7 vs 3, P = 0.019), higher perceived stress (4.2 ± 1.9 vs 2.9 ± 1.9, P = 0.015), and lower perceived social support (75 vs 80, P = 0.036) than SH-. High perceived stress was independently associated with SH (odds ratio [OR] = 5.46, confidence interval 95% 1.4-21.8, P = 0.016). Interestingly, SH+ performed better in verbal fluency (49.5 ± 38.9 vs 38.9 ± 9.0, P = 0.012), symbol coding (54.1 ± 6.7 vs 42.3 ± 15.5, P = 0.013), and Tower of London (15.1 vs 10.9, P = 0.009) than SH-. In 8 operated SH+, no significant changes were found.

Conclusions: Subclinical hypercortisolism may influence patients' mental health and cognitive performances, requiring an integrated treatment.
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http://dx.doi.org/10.1210/clinem/dgaa695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765655PMC
January 2021

Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders.

JAMA Psychiatry 2021 Jan;78(1):47-63

Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Maastricht University, the Netherlands.

Importance: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood.

Objective: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia.

Design, Setting, And Participants: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244.

Main Outcomes And Measures: Interregional profiles of group difference in cortical thickness between cases and controls.

Results: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders.

Conclusions And Relevance: In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.2694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450410PMC
January 2021

Increased power by harmonizing structural MRI site differences with the ComBat batch adjustment method in ENIGMA.

Neuroimage 2020 09 26;218:116956. Epub 2020 May 26.

CIBERSAM, Madrid, Spain; FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain.

A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega-analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related heterogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega-analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random-effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning).
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http://dx.doi.org/10.1016/j.neuroimage.2020.116956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524039PMC
September 2020

An overlapping pattern of cerebral cortical thinning is associated with both positive symptoms and aggression in schizophrenia via the ENIGMA consortium.

Psychol Med 2020 09 16;50(12):2034-2045. Epub 2019 Oct 16.

Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.

Background: Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample.

Method: To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls.

Results: The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression.

Conclusion: These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.
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http://dx.doi.org/10.1017/S0033291719002149DOI Listing
September 2020

The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder.

Biol Psychiatry 2019 10 13;86(7):545-556. Epub 2019 Jun 13.

Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, Hartford, Connecticut; Tommy Fuss Center for Neuropsychiatric Disease Research, Boston Children's Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.

Background: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects.

Methods: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects.

Results: FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < -0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects.

Conclusions: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.
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http://dx.doi.org/10.1016/j.biopsych.2019.03.985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068800PMC
October 2019

Assessing Learning Needs and Career Attitudes of Italian Psychiatry Residents: Results from a National Survey Conducted by the Italian Society of Psychopathology Young Psychiatrists Section (SOPSI-GG).

Clin Pract Epidemiol Ment Health 2019 20;15:21-29. Epub 2019 Feb 20.

Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, ASST Fatebenefratelli-Sacco, Milan, Italy.

Objective: No data are available about learning needs and career attitudes of Italian Psychiatry Residents (IPRs). Authors aimed to assess such needs through a survey to generate insight for implementing educational programs close to IPRs' perceived learning needs.

Methods: A 54-item questionnaire was developed in order to investigate career information, educational preference and learning needs of IPRs. A sample of 298 IPRs participated to the survey and was divided into four subgroups according to their location (North, Centre, South and Islands). The subgroups were compared through ANOVA for age and chi-square tests for qualitative variables (including gender and all sub-items of the survey), with Bonferroni post-hoc analysis.

Results: IPRs were found to pursue, along with traditional and theoretical training, a quite practical approach, characterized by working groups, discussions on clinical cases and practical interactive sessions. The topics of major interest included: clinical psychiatry, psychopharmacology, psychiatric emergencies, communication and relationship skills (97%, 98.0%, 98.3% and 95.7% of the total sample, respectively). Indeed, a strong need for interaction with healthcare professionals emerged (97% of the total sample). North and Centre IPRs were more involved in Day Hospital activities than residents from South Italy and Islands (p<.001). South IPRs appeared to be more prone to invest for their education than residents from other areas (<.01).

Conclusion: Reported findings should be taken into account as a starting point for planning and developing future targeted packages of educational proposals for IPRs and they should stand as a useful pilot study for further investigation in the field.
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http://dx.doi.org/10.2174/1745017901915010021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407657PMC
February 2019

Brain Heterogeneity in Schizophrenia and Its Association With Polygenic Risk.

JAMA Psychiatry 2019 07;76(7):739-748

Norwegian Centre for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Norway.

Importance: Between-individual variability in brain structure is determined by gene-environment interactions, possibly reflecting differential sensitivity to environmental and genetic perturbations. Magnetic resonance imaging (MRI) studies have revealed thinner cortices and smaller subcortical volumes in patients with schizophrenia. However, group-level comparisons may mask considerable within-group heterogeneity, which has largely remained unnoticed in the literature.

Objectives: To compare brain structural variability between individuals with schizophrenia and healthy controls and to test whether respective variability reflects the polygenic risk score (PRS) for schizophrenia in an independent sample of healthy controls.

Design, Setting, And Participants: This case-control and polygenic risk analysis compared MRI-derived cortical thickness and subcortical volumes between healthy controls and patients with schizophrenia across 16 cohorts and tested for associations between PRS and MRI features in a control cohort from the UK Biobank. Data were collected from October 27, 2004, through April 12, 2018, and analyzed from December 3, 2017, through August 1, 2018.

Main Outcomes And Measures: Mean and dispersion parameters were estimated using double generalized linear models. Vertex-wise analysis was used to assess cortical thickness, and regions-of-interest analyses were used to assess total cortical volume, total surface area, and white matter, subcortical, and hippocampal subfield volumes. Follow-up analyses included within-sample analysis, test of robustness of the PRS threshold, population covariates, outlier removal, and control for image quality.

Results: A comparison of 1151 patients with schizophrenia (mean [SD] age, 33.8 [10.6] years; 68.6% male [n = 790] and 31.4% female [n = 361]) with 2010 healthy controls (mean [SD] age, 32.6 [10.4] years; 56.0% male [n = 1126] and 44.0% female [n = 884]) revealed higher heterogeneity in schizophrenia for cortical thickness and area (t = 3.34), cortical (t = 3.24) and ventricle (t range, 3.15-5.78) volumes, and hippocampal subfields (t range, 2.32-3.55). In the UK Biobank sample of 12 490 participants (mean [SD] age, 55.9 [7.5] years; 48.2% male [n = 6025] and 51.8% female [n = 6465]), higher PRS was associated with thinner frontal and temporal cortices and smaller left CA2/3 (t = -3.00) but was not significantly associated with dispersion.

Conclusions And Relevance: This study suggests that schizophrenia is associated with substantial brain structural heterogeneity beyond the mean differences. These findings may reflect higher sensitivity to environmental and genetic perturbations in patients, supporting the heterogeneous nature of schizophrenia. A higher PRS was associated with thinner frontotemporal cortices and smaller hippocampal subfield volume, but not heterogeneity. This finding suggests that brain variability in schizophrenia results from interactions between environmental and genetic factors that are not captured by the PRS. Factors contributing to heterogeneity in frontotemporal cortices and hippocampus are key to furthering our understanding of how genetic and environmental factors shape brain biology in schizophrenia.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.0257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583664PMC
July 2019

Neural signatures of the risk for bipolar disorder: A meta-analysis of structural and functional neuroimaging studies.

Bipolar Disord 2019 05 14;21(3):215-227. Epub 2018 Dec 14.

Department of Medicine (DAME), University of Udine, Udine, Italy.

Objective: Widespread functional and structural alterations in the brain have been extensively reported in unaffected relatives (RELs) of patients with bipolar disorder (BD) who are at genetic risk for BD. A sufficiently powered meta-analysis of structural (sMRI) and functional magnetic resonance imaging (fMRI) alterations in RELs is still lacking.

Methods: Functional and structural magnetic resonance imaging studies investigating RELs and healthy controls (HCs) published by July 2017 were included in the meta-analyses. Study procedures were conducted in accordance with the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. Random-effects coordinate-based meta-analyses were performed across all the studies per imaging modality using Seed-based d Mapping (SDM). For fMRI studies, meta-analyses were calculated for each task type. For sMRI studies, regional volumetric changes-analyses were estimated using R. Finally, multimodal meta-analyses of structural and functional abnormalities were performed.

Results: Sixty-nine imaging studies (2195 RELs and 3169 HCs) were included in the meta-analyses. RELs showed hyperactivation in the fronto-striatal regions as well as parietal hypoactivation during cognition. Also, activation was increased in the amygdala during emotional processing and in the orbitofrontal cortex during reward, respectively. Frontal and superior temporal cortex were hypertrophic in RELs. The right inferior frontal gyrus (rIFG) showed both increased activation during cognitive tasks and greater volume in RELs.

Conclusions: Our findings demonstrate that increased brain volume and activation are present in RELs and may represent intermediate phenotypes for the disorder. Furthermore, some neural changes including increased rIFG volume may be associated with the resilience to BD.
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http://dx.doi.org/10.1111/bdi.12720DOI Listing
May 2019

Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium.

Biol Psychiatry 2018 11 14;84(9):644-654. Epub 2018 May 14.

Division of Mental Health and Addiction, NORMENT, K.G. Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway.

Background: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group.

Methods: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide.

Results: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset.

Conclusions: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.
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http://dx.doi.org/10.1016/j.biopsych.2018.04.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177304PMC
November 2018

Genetic variation is associated with RTN4R expression and working memory processing in healthy humans.

Brain Res Bull 2017 Sep 26;134:162-167. Epub 2017 Jul 26.

Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari "Aldo Moro", Bari, 70124, Italy. Electronic address:

The Nogo receptor (NgR) is implicated in neurodevelopmental processes and it participates in inhibiting axonal growth. Consistent with its high levels of expression in the prefrontal cortex, animal studies indicate that NgR is relevant for prefrontal-related cognitive processing. Given that genetic variation may alter mechanisms of gene expression impacting molecular and systems-level phenotypes, we investigated the association of genetic variation with the expression of the NgR coding gene (RTN4R), as well as with prefrontal correlates at progressively greater biological distance from gene effects. First, we studied the association of single nucleotide polymorphisms (SNPs) with RTN4R mRNA expression in postmortem prefrontal cortex of humans without psychiatric illnesses. Then, we probed in peripheral blood mononuclear cells (PBMCs) the association that we found in prefrontal tissue. Thus, we investigated whether functional genetic variation affecting RTN4R expression is also associated with prefrontal activity during working memory. We found that rs696884 (A/G) predicted these phenotypes. Specifically, the AA genotype was associated with lower RTN4R mRNA expression levels in the prefrontal cortex and PBMCs and inefficient prefrontal activity during working memory compared to the GG genotype. These results suggest that genetic variation associated with RTN4R mRNA expression influences prefrontal physiology in healthy individuals. Furthermore, they highlight the need for further investigations of the role of NgR in the pathophysiology of brain disorders associated with prefrontal dysfunction.
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http://dx.doi.org/10.1016/j.brainresbull.2017.07.015DOI Listing
September 2017

Grey matter volume patterns in thalamic nuclei are associated with familial risk for schizophrenia.

Schizophr Res 2017 02 21;180:13-20. Epub 2016 Jul 21.

Psychiatry Unit, Bari University Hospital, Piazza Giulio Cesare 11, 70124, Bari, Italy; IRCCS "Casa Sollievo della Sofferenza", Viale Cappuccini, 1, I-71013 San Giovanni Rotondo, Italy. Electronic address:

Previous evidence suggests reduced thalamic grey matter volume (GMV) in patients with schizophrenia (SCZ). However, it is not considered an intermediate phenotype for schizophrenia, possibly because previous studies did not assess the contribution of individual thalamic nuclei and employed univariate statistics. Here, we hypothesized that multivariate statistics would reveal an association of GMV in different thalamic nuclei with familial risk for schizophrenia. We also hypothesized that accounting for the heterogeneity of thalamic GMV in healthy controls would improve the detection of subjects at familial risk for the disorder. We acquired MRI scans for 96 clinically stable SCZ, 55 non-affected siblings of patients with schizophrenia (SIB), and 249 HC. The thalamus was parceled into seven regions of interest (ROIs). After a canonical univariate analysis, we used GMV estimates of thalamic ROIs, together with total thalamic GMV and premorbid intelligence, as features in Random Forests to classify HC, SIB, and SCZ. Then, we computed a Misclassification Index for each individual and tested the improvement in SIB detection after excluding a subsample of HC misclassified as patients. Random Forests discriminated SCZ from HC (accuracy=81%) and SIB from HC (accuracy=75%). Left anteromedial thalamic volumes were significantly associated with both multivariate classifications (p<0.05). Excluding HC misclassified as SCZ improved greatly HC vs. SIB classification (Cohen's d=1.39). These findings suggest that multivariate statistics identify a familial background associated with thalamic GMV reduction in SCZ. They also suggest the relevance of inter-individual variability of GMV patterns for the discrimination of individuals at familial risk for the disorder.
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http://dx.doi.org/10.1016/j.schres.2016.07.005DOI Listing
February 2017

Prefrontal activity during working memory is modulated by the interaction of variation in CB1 and COX2 coding genes and correlates with frequency of cannabis use.

Cortex 2016 08 21;81:231-8. Epub 2016 May 21.

Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy. Electronic address:

The CB1 cannabinoid receptor is targeted in the brain by endocannabinoids under physiological conditions as well as by delta9-tetrahydrocannabinol under cannabis use. Furthermore, its signaling appears to affect brain cognitive processing. Recent findings highlight a crucial role of cyclooxygenase-2 (COX-2) in the mechanism of intraneuronal CB1 signaling transduction, while others indicate that two single nucleotide polymorphisms (SNPs) (rs1406977 and rs20417) modulate expression of CB1 (CNR1) and COX-2 (PTGS2) coding genes, respectively. Here, our aim was to use fMRI to investigate in healthy humans whether these SNPs interact in modulating prefrontal activity during working memory processing and if this modulation is linked with cannabis use. We recruited 242 healthy subjects genotyped for CNR1 rs1406977 and PTGS2 rs20417 that performed the N-back working memory task during fMRI and were interviewed using the Cannabis Experience Questionnaire (CEQ). We found that the interaction between CNR1 rs1406977 and PTGS2 rs20417 is associated with dorsolateral prefrontal cortex (DLPFC) activity such that specific genotype configurations (CNR1 C carriers/PTGS2 C carriers and CNR1 TT/PTGS2 GG) predict lower cortical response versus others in spite of similar behavioral accuracy. Furthermore, DLPFC activity in the cluster associated with the CNR1 by PTGS2 interaction was negatively correlated with behavioral efficiency and positively correlated with frequency of cannabis use in cannabis users. These results suggest that a genetically modulated balancing of signaling within the CB1-COX-2 pathway may reflect on more or less efficient patterns of prefrontal activity during working memory. Frequency of cannabis use may be a factor for further modulation of CNR1/PTGS2-mediated cortical processing associated with this cognitive process.
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http://dx.doi.org/10.1016/j.cortex.2016.05.010DOI Listing
August 2016

Association of familial risk for schizophrenia with thalamic and medial prefrontal functional connectivity during attentional control.

Schizophr Res 2016 May 21;173(1-2):23-9. Epub 2016 Mar 21.

Department of Basic Medical Sciences, Neuroscience and Sense Organs, Università degli Studi di Bari "Aldo Moro", 70124 Bari, Italy; Psychiatry Unit, Bari University Hospital, 70124 Bari, Italy. Electronic address:

Anomalies in behavioral correlates of attentional processing and related brain activity are crucial correlates of schizophrenia and associated with familial risk for this brain disorder. However, it is not clear how brain functional connectivity during attentional processes is key for schizophrenia and linked with trait vs. state related variables. To address this issue, we investigated patterns of functional connections during attentional control in healthy siblings of patients with schizophrenia, who share with probands genetic features but not variables related to the state of the disorder. 356 controls, 55 patients with schizophrenia on stable treatment with antipsychotics and 40 healthy siblings of patients with this brain disorder underwent the Variable Attentional Control (VAC) task during fMRI. Independent Component Analysis (ICA) is allowed to identify independent components (IC) of BOLD signal recorded during task performance. Results indicated reduced connectivity strength in patients with schizophrenia as well as in their healthy siblings in left thalamus within an attentional control component and greater connectivity in right medial prefrontal cortex (PFC) within the so-called Default Mode Network (DMN) compared to healthy individuals. These results suggest a relationship between familial risk for schizophrenia and brain functional networks during attentional control, such that this biological phenotype may be considered a useful intermediate phenotype in order to link genes effects to aspects of the pathophysiology of this brain disorder.
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http://dx.doi.org/10.1016/j.schres.2016.03.014DOI Listing
May 2016

BDNF rs6265 methylation and genotype interact on risk for schizophrenia.

Epigenetics 2016 18;11(1):11-23. Epub 2016 Feb 18.

a Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro' , Bari , Italy.

Epigenetic mechanisms can mediate gene-environment interactions relevant for complex disorders. The BDNF gene is crucial for development and brain plasticity, is sensitive to environmental stressors, such as hypoxia, and harbors the functional SNP rs6265 (Val(66)Met), which creates or abolishes a CpG dinucleotide for DNA methylation. We found that methylation at the BDNF rs6265 Val allele in peripheral blood of healthy subjects is associated with hypoxia-related early life events (hOCs) and intermediate phenotypes for schizophrenia in a distinctive manner, depending on rs6265 genotype: in ValVal individuals increased methylation is associated with exposure to hOCs and impaired working memory (WM) accuracy, while the opposite is true for ValMet subjects. Also, rs6265 methylation and hOCs interact in modulating WM-related prefrontal activity, another intermediate phenotype for schizophrenia, with an analogous opposite direction in the 2 genotypes. Consistently, rs6265 methylation has a different association with schizophrenia risk in ValVals and ValMets. The relationships of methylation with BDNF levels and of genotype with BHLHB2 binding likely contribute to these opposite effects of methylation. We conclude that BDNF rs6265 methylation interacts with genotype to bridge early environmental exposures to adult phenotypes, relevant for schizophrenia. The study of epigenetic changes in regions containing genetic variation relevant for human diseases may have beneficial implications for the understanding of how genes are actually translated into phenotypes.
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http://dx.doi.org/10.1080/15592294.2015.1117736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846123PMC
December 2016

Rasd2 Modulates Prefronto-Striatal Phenotypes in Humans and 'Schizophrenia-Like Behaviors' in Mice.

Neuropsychopharmacology 2016 Feb 31;41(3):916-27. Epub 2015 Jul 31.

Ceinge Biotecnologie Avanzate, Naples, Italy.

Rasd2 is a thyroid hormone target gene, which encodes for a GTP-binding protein enriched in the striatum where, among other functions, it modulates dopaminergic neurotransmission. Here we report that human RASD2 mRNA is abundant in putamen, but it also occurs in the cerebral cortex, with a distinctive expression pattern that differs from that present in rodents. Consistent with its localization, we found that a genetic variation in RASD2 (rs6518956) affects postmortem prefrontal mRNA expression in healthy humans and is associated with phenotypes of relevance to schizophrenia, including prefrontal and striatal grey matter volume and physiology during working memory, as measured with magnetic resonance imaging. Interestingly, quantitative real-time PCR analysis indicated that RASD2 mRNA is slightly reduced in postmortem prefrontal cortex of patients with schizophrenia. In the attempt to uncover the neurobiological substrates associated with Rasd2 activity, we used knockout mice to analyze the in vivo influence of this G-protein on the prepulse inhibition of the startle response and psychotomimetic drug-related behavioral response. Data showed that Rasd2 mutants display deficits in basal prepulse inhibition that, in turn, exacerbate gating disruption under psychotomimetic drug challenge. Furthermore, we documented that lack of Rasd2 strikingly enhances the behavioral sensitivity to motor stimulation elicited by amphetamine and phencyclidine. Based on animal model data, along with the finding that RASD2 influences prefronto-striatal phenotypes in healthy humans, we suggest that genetic mutation or reduced levels of this G-protein might have a role in cerebral circuitry dysfunction underpinning exaggerated psychotomimetic drugs responses and development of specific biological phenotypes linked to schizophrenia.
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http://dx.doi.org/10.1038/npp.2015.228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707838PMC
February 2016

Altered prefrontal cortex activity during working memory task in Bipolar Disorder: A functional Magnetic Resonance Imaging study in euthymic bipolar I and II patients.

J Affect Disord 2015 Sep 21;184:116-22. Epub 2015 May 21.

Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Dipartimento di Salute Mentale, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milano, Italy.

Background: Working memory (WM) deficits are among the most frequently impaired cognitive domains in patients with Bipolar Disorder (BD), being considered promising cognitive endophenotype of the disorder. However, the related neurobiological correlates still deserve further investigation. The present study was aimed to explore whether dorsolateral prefrontal cortex (DLPFC) activity during WM processing was abnormal in euthymic bipolar patients and may represent a potential trait-related phenotype associated with the disorder.

Methods: Using 3 Tesla functional Magnetic Resonance Imaging (3T fMRI), we studied 28 euthymic bipolar patients (15 BDI and 13 BDII), and 27 healthy controls (HCs), matched for a series of socio-demographic variables, while performing the N-back task for WM assessment.

Results: We found that euthymic bipolar patients showed increased right middle frontal gyrus engagement compared with HCs (FWE-corrected p = 1 × 10(-3)), regardless of WM load, and in spite of similar WM behavioral performance between groups. In particular, BDI patients had greater BOLD signal change compared to HCs (post-hoc Tukey HSD, p = 1 × 10(-3)), while BDII patients expressed an intermediate pattern of activation between BDI patients and HCs. No other significant effects were detected in the corrected whole-brain analysis.

Limitations: Sample size, cross-sectional assessment and potential influence of some clinical variables.

Conclusions: Results provide direct evidence of a primary physiological abnormality in DLPFC function in BDI and II, even in the absence of behavioral differences with HCs. Such exaggerated fMRI response suggests inefficient WM processing in prefrontal circuitry, and further studies are warranted to investigate whether the dysfunction is related to the genetic risk for the disorder.
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http://dx.doi.org/10.1016/j.jad.2015.05.026DOI Listing
September 2015

Aversive emotional interference impacts behavior and prefronto-striatal activity during increasing attentional control.

Front Behav Neurosci 2015 21;9:97. Epub 2015 Apr 21.

Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari "Aldo Moro" Bari, Italy ; pRED, NORD DTA Neuroscience, Hoffman-La Roche Ltd Basel, Switzerland.

Earlier studies have demonstrated that emotional stimulation modulates attentional processing during goal-directed behavior and related activity of a brain network including the inferior frontal gyrus (IFG) and the caudate nucleus. However, it is not clear how emotional interference modulates behavior and brain physiology during variation in attentional control, a relevant question for everyday life situations in which both emotional stimuli and cognitive load vary. The aim of this study was to investigate the impact of negative emotions on behavior and activity in IFG and caudate nucleus during increasing levels of attentional control. Twenty two healthy subjects underwent event-related functional magnetic resonance imaging while performing a task in which neutral or fearful facial expressions were displayed before stimuli eliciting increasing levels of attentional control processing. Results indicated slower reaction time (RT) and greater right IFG activity when fearful compared with neutral facial expressions preceded the low level of attentional control. On the other hand, fearful facial expressions preceding the intermediate level of attentional control elicited faster behavioral responses and greater activity in the right and left sides of the caudate. Finally, correlation analysis indicated a relationship between behavioral correlates of attentional control after emotional interference and right IFG activity. All together, these results suggest that the impact of negative emotions on attentional processing is differentially elicited at the behavioral and physiological levels as a function of cognitive load.
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http://dx.doi.org/10.3389/fnbeh.2015.00097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404908PMC
May 2015

Prefronto-striatal physiology is associated with schizotypy and is modulated by a functional variant of DRD2.

Front Behav Neurosci 2014 9;8:235. Epub 2014 Jul 9.

Department of Basic Medical Science, Psychiatric Neuroscience Group, Neuroscience and Sense Organs, University of Bari Aldo Moro Bari, Italy ; IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo Foggia, Italy ; pRED, NORD DTA, Hoffmann-La Roche, Ltd. Basel, Switzerland.

"Schizotypy" is a latent organization of personality related to the genetic risk for schizophrenia. Some evidence suggests that schizophrenia and schizotypy share some biological features, including a link to dopaminergic D2 receptor signaling. A polymorphism in the D2 gene (DRD2 rs1076560, guanine > thymine (G > T)) has been associated with the D2 short/long isoform expression ratio, as well as striatal dopamine signaling and prefrontal cortical activity during different cognitive operations, which are measures that are altered in patients with schizophrenia. Our aim is to determine the association of schizotypy scores with the DRD2 rs1076560 genotype in healthy individuals and their interaction with prefrontal activity during attention and D2 striatal signaling. A total of 83 healthy subjects were genotyped for DRD2 rs1076560 and completed the Schizotypal Personality Questionnaire (SPQ). Twenty-six participants underwent SPECT with [(123)I]IBZM D2 receptor radiotracer, while 68 performed an attentional control task during fMRI. We found that rs1076560 GT subjects had greater SPQ scores than GG individuals. Moreover, the interaction between schizotypy and the GT genotype predicted prefrontal activity and related attentional behavior, as well as striatal binding of IBZM. No interaction was found in GG individuals. These results suggest that rs1076560 GT healthy individuals are prone to higher levels of schizotypy, and that the interaction between rs1076560 and schizotypy scores modulates phenotypes related to the pathophysiology of schizophrenia, such as prefrontal activity and striatal dopamine signaling. These results provide systems-level qualitative evidence for mapping the construct of schizotypy in healthy individuals onto the schizophrenia continuum.
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http://dx.doi.org/10.3389/fnbeh.2014.00235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089730PMC
July 2014

Expression of DISC1-interactome members correlates with cognitive phenotypes related to schizophrenia.

PLoS One 2014 18;9(6):e99892. Epub 2014 Jun 18.

Medical Genetics Section, Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, United Kingdom; Centre for Cognitive Ageing and Cognitive Epidemiology, Medical Genetics Section, Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.

Cognitive dysfunction is central to the schizophrenia phenotype. Genetic and functional studies have implicated Disrupted-in-Schizophrenia 1 (DISC1), a leading candidate gene for schizophrenia and related psychiatric conditions, in cognitive function. Altered expression of DISC1 and DISC1-interactors has been identified in schizophrenia. Dysregulated expression of DISC1-interactome genes might, therefore, contribute to schizophrenia susceptibility via disruption of molecular systems required for normal cognitive function. Here, the blood RNA expression levels of DISC1 and DISC1-interacting proteins were measured in 63 control subjects. Cognitive function was assessed using neuropsychiatric tests and functional magnetic resonance imaging was used to assess the activity of prefrontal cortical regions during the N-back working memory task, which is abnormal in schizophrenia. Pairwise correlations between gene expression levels and the relationship between gene expression levels and cognitive function and N-back-elicited brain activity were assessed. Finally, the expression levels of DISC1, AKAP9, FEZ1, NDEL1 and PCM1 were compared between 63 controls and 69 schizophrenic subjects. We found that DISC1-interactome genes showed correlated expression in the blood of healthy individuals. The expression levels of several interactome members were correlated with cognitive performance and N-back-elicited activity in the prefrontal cortex. In addition, DISC1 and NDEL1 showed decreased expression in schizophrenic subjects compared to healthy controls. Our findings highlight the importance of the coordinated expression of DISC1-interactome genes for normal cognitive function and suggest that dysregulated DISC1 and NDEL1 expression might, in part, contribute to susceptibility for schizophrenia via disruption of prefrontal cortex-dependent cognitive functions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0099892PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4062455PMC
July 2015

DRD2/CHRNA5 interaction on prefrontal biology and physiology during working memory.

PLoS One 2014 12;9(5):e95997. Epub 2014 May 12.

IRCCSS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy; Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, Aldo Moro University, Bari, Italy; pRED, NORD DTA, F. Hoffman-La Roche Ltd., Basel, Switzerland.

Background: Prefrontal behavior and activity in humans are heritable. Studies in animals demonstrate an interaction between dopamine D2 receptors and nicotinic acetylcholine receptors on prefrontal behavior but evidence in humans is weak. Therefore, we hypothesize that genetic variation regulating dopamine D2 and nicotinic acetylcholine receptor signaling impact prefrontal cortex activity and related cognition. To test this hypothesis in humans, we explored the interaction between functional genetic variants in the D2 receptor gene (DRD2, rs1076560) and in the nicotinic receptor α5 gene (CHRNA5, rs16969968) on both dorsolateral prefrontal cortex mediated behavior and physiology during working memory and on prefrontal gray matter volume.

Methods: A large sample of healthy subjects was compared for genotypic differences for DRD2 rs1076560 (G>T) and CHNRA5 rs16969968 (G>A) on prefrontal phenotypes, including cognitive performance at the N-Back task, prefrontal physiology with BOLD fMRI during performance of the 2-Back working memory task, and prefrontal morphometry with structural MRI.

Results: We found that DRD2 rs1076560 and CHNRA5 rs16969968 interact to modulate cognitive function, prefrontal physiology during working memory, and prefrontal gray matter volume. More specifically, CHRNA5-AA/DRD2-GT subjects had greater behavioral performance, more efficient prefrontal cortex activity at 2Back working memory task, and greater prefrontal gray matter volume than the other genotype groups.

Conclusions: The present data extend previous studies in animals and enhance our understanding of dopamine and acetylcholine signaling in the human prefrontal cortex, demonstrating interactions elicited by working memory that are modulated by genetic variants in DRD2 and CHRNA5.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095997PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018353PMC
January 2015

DRD2 genotype predicts prefrontal activity during working memory after stimulation of D2 receptors with bromocriptine.

Psychopharmacology (Berl) 2014 Jun 15;231(11):2361-70. Epub 2014 Jan 15.

Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari "Aldo Moro", Bari, 70124, Italy.

Rationale: Pharmacological stimulation of D2 receptors modulates prefrontal neural activity associated with working memory (WM) processing. The T allele of a functional single-nucleotide polymorphism (SNP) within DRD2 (rs1076560 G > T) predicts reduced relative expression of the D2S receptor isoform and less efficient neural cortical responses during WM tasks.

Objective: We used functional MRI to test the hypothesis that DRD2 rs1076560 genotype interacts with pharmacological stimulation of D2 receptors with bromocriptine on prefrontal responses during different loads of a spatial WM task (N-Back).

Methods: Fifty-three healthy subjects (38 GG and 15 GT) underwent two 3-T functional MRI scans while performing the 1-, 2- and 3-Back versions of the N-Back WM task. Before the imaging sessions, either bromocriptine or placebo was administered to all subjects in a counterbalanced order. A factorial repeated-measures ANOVA within SPM8 (p < 0.05, family-wise error corrected) was used.

Results: On bromocriptine, GG subjects had reduced prefrontal activity at 3-Back together with a significant decrement in performance, compared with placebo. On the other hand, GT subjects had lower activity for the same level of performance at 1-Back but a trend for reduced behavioral performance in the face of unchanged activity at 2-Back.

Conclusions: These results indicate that bromocriptine stimulation modulates prefrontal activity in terms of disengagement or of efficiency depending on DRD2 genotype and working memory load.
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http://dx.doi.org/10.1007/s00213-013-3398-9DOI Listing
June 2014

Mirtazapine add-on improves olanzapine effect on negative symptoms of schizophrenia.

J Clin Psychopharmacol 2013 Dec;33(6):810-2

Group of Psychiatric Neuroscience, Department of Neuroscience and Sense Organs, University of Bari Bari, Italy IRCCS "Casa Sollievo della Sofferenza" San Giovanni Rotondo (FG), Italy Group of Psychiatric Neuroscience Department of Neuroscience and Sense Organs University of Bari Bari, Italy Group of Psychiatric Neuroscience, Department of Neuroscience and Sense Organs, University of Bari Bari, Italy and IRCCS "Casa Sollievo della Sofferenza" San Giovanni Rotondo (FG), Italy Group of Psychiatric Neuroscience Department of Neuroscience and Sense Organs University of Bari Bari, Italy Eli Lilly Italia S.p.A., Sesto Fiorentino, Florence, Italy Group of Psychiatric Neuroscience, Department of Neuroscience and Sense Organs, University of Bari Bari, Italy and IRCCS "Casa Sollievo della Sofferenza" San Giovanni Rotondo (FG), Italy

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http://dx.doi.org/10.1097/JCP.0b013e3182a4ec77DOI Listing
December 2013

Converging evidence for the association of functional genetic variation in the serotonin receptor 2a gene with prefrontal function and olanzapine treatment.

JAMA Psychiatry 2013 Sep;70(9):921-30

Group of Psychiatric Neuroscience, Department of Neuroscience and Sense Organs, Aldo Moro University, Bari, Italy.

Importance: Serotonin (5-hydroxytryptamine) receptor 2a (5-HT2AR) signaling is important for modulation of corticostriatal pathways and prefrontal activity during cognition. Furthermore, newer antipsychotic drugs target 5-HT2AR. A single-nucleotide polymorphism in the 5-HT2AR gene (HTR2A rs6314, C>T; OMIM 182135) has been weakly associated with differential 5-HT2AR signaling and with physiologic as well as behavioral effects.

Objective: To use a hierarchical approach to determine the functional effects of this single-nucleotide polymorphism on 5-HT2AR messenger RNA and protein expression, on prefrontal phenotypes linked with genetic risk for schizophrenia, and on treatment with olanzapine.

Design: In silico predictions, in vitro, and case-control investigations.

Setting: Academic and clinical facilities.

Participants: The postmortem study included 112 brains from healthy individuals; the in vivo investigation included a total sample of 371 healthy individuals and patients with schizophrenia. EXPOSURES Patients received olanzapine monotherapy for 8 weeks.

Main Outcomes And Measures: In silico predictions, messenger RNA, and protein expression in postmortem human prefrontal cortex and HeLa cells, functional magnetic resonance imaging prefrontal activity and behavior during working memory and attention in healthy individuals, and response to an 8-week trial of olanzapine treatment in patients with schizophrenia.

Results: Bioinformatic analysis predicted that rs6314 alters patterns of splicing, with possible effects on HTR2A expression. Moreover, the T allele was associated with reduced prefrontal messenger RNA expression in postmortem prefrontal cortex, with reduced protein expression in vitro, inefficient prefrontal blood oxygen level-dependent functional magnetic resonance imaging response during working memory and attentional control processing, and impaired working memory and attention behavior, as well as with attenuated improvement in negative symptoms after olanzapine treatment.

Conclusions And Relevance: Our results suggest that HTR2A rs6314 affects 5-HT2AR expression and functionally contributes to genetic modulation of known endophenotypes of schizophrenia-like higher-level cognitive behaviors and related prefrontal activity, as well as response to treatment with olanzapine.
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http://dx.doi.org/10.1001/jamapsychiatry.2013.1378DOI Listing
September 2013

Association of GSK-3β genetic variation with GSK-3β expression, prefrontal cortical thickness, prefrontal physiology, and schizophrenia.

Am J Psychiatry 2013 Aug;170(8):868-76

Group of Psychiatric Neuroscience, Department of Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.

OBJECTIVE Glycogen synthase kinase 3β (GSK-3β) is an enzyme implicated in neurodevelopmental processes with a broad range of substrates mediating several canonical signaling pathways in the brain. The authors investigated the association of variation in the GSK-3β gene with a series of progressively more complex phenotypes of relevance to schizophrenia, a neurodevelopmental disorder with strong genetic risk. METHOD Based on computer predictions, the authors investigated in humans the association of GSK-3β functional variation with 1) GSK-3β mRNA expression from postmortem prefrontal cortex, 2) GSK-3β and β-catenin protein expression from peripheral blood mononuclear cells (PBMCs), 3) prefrontal imaging phenotypes, and 4) diagnosis of schizophrenia. RESULTS Consistent with predictions, the TT genotype of a single-nucleotide polymorphism in GSK-3β (rs12630592) was associated with reduced GSK-3β mRNA from postmortem prefrontal cortex. Furthermore, this genotype was associated with GSK-3β protein expression and kinase activity, as well as with downstream effects on β-catenin expression in PBMCs. Finally, the TT genotype was associated with attenuated functional MRI prefrontal activity, reduced prefrontal cortical thickness, and diagnosis of schizophrenia. CONCLUSIONS These results suggest that GSK-3β variation is implicated in multiple phenotypes relevant to schizophrenia.
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http://dx.doi.org/10.1176/appi.ajp.2012.12070908DOI Listing
August 2013
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