Publications by authors named "Teresa Popolizio"

52 Publications

Primary Epithelioid Hemangioma of the Central Nervous System: A Case Report and Review of the Literature.

J Neuropathol Exp Neurol 2021 Jan 7. Epub 2021 Jan 7.

Pathology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy.

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http://dx.doi.org/10.1093/jnen/nlaa163DOI Listing
January 2021

Balò's concentric sclerosis in a case of cocaine-levamisole abuse.

SAGE Open Med Case Rep 2020 17;8:2050313X20940532. Epub 2020 Jul 17.

Department of Diagnostic Imaging, IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.

Baló's concentric sclerosis is a rare variant of multiple sclerosis. It belongs to the group of primary inflammatory central nervous system demyelinating diseases having no clear etiology. Peculiar radiological findings on magnetic resonance imaging are alternating rings of demyelinated and myelinated axons resembling an "onion bulb." We report on a case of a patient with cocaine abuse who presented with Balò's-like acute multifocal leukoencephalopathy supported by histological and radiological findings. The abuse of cocaine and its most frequent adulterant, levamisole, may induce ischemic or hemorrhagic stroke and metabolic or multifocal inflammatory leukoencephalopathy. Only a few studies described levamisole-induced leukoencephalopathy mimicking Balò round lesions. Nevertheless, it has not yet been established the correlation between them; it might also be possible that the cocaine/levamisole addiction represents just a coincidence in some of those patients affected by Balò sclerosis disease.
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http://dx.doi.org/10.1177/2050313X20940532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370552PMC
July 2020

Imaging of cranio-cervical junction traumas.

Eur J Radiol 2020 Jun 19;127:108960. Epub 2020 Mar 19.

Neuroradiology Department, A. Cardarelli Hospital, Napoli, Italy.

The craniocervical junction (CCJ) or upper cervical spine (UCS) has anatomic features and a biomechanics completely different from the other spinal segment of the spine. Several ligaments and muscles control its motion and function and ensure the maximum mobility and the visual and auditory spatial exploration. UCS traumas represent approximately one-third of all cervical spine injuries. Most of UCS traumas results from blows to the head and sudden deceleration of the body. Thanks to the improvement of the Advanced Trauma Life Support protocols dissociative injuries of CCJ have become less lethal onsite. In other less severe but unstable injuries, patients are neurologically intact at presentation, but they may deteriorate during the stay in hospital, with important clinical and medico-legal consequences. Knowing the peculiarities of UCS is fundamental for the early detection of imaging findings that influences the patient management and outcome. The classification of UCS traumas is mechanistic. More than in any other spinal segment, fractures of CCJ bones can occur without generating instability; on the contrary highly unstable injuries may not be associated with bone fractures. An early and correct diagnosis of occipito-cervical instability may prevent secondary neurological injury. The goal of imaging is to identify which patients can benefit of surgical stabilization and prevent secondary neurologic damage. Actual helical multidetector-CT (MDCT) offers high sensitivity and specificity for bone lesions and displacements in cervical spine traumas, but magnetic resonance imaging (MRI) is increasingly being used to evaluate soft tissues and ligaments, and mainly to identify possible spinal cord injury.
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http://dx.doi.org/10.1016/j.ejrad.2020.108960DOI Listing
June 2020

The interaction between cannabis use and a CB1-related polygenic co-expression index modulates dorsolateral prefrontal activity during working memory processing.

Brain Imaging Behav 2021 Feb;15(1):288-299

Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari - 'Aldo Moro', Piazza Giulio Cesare, 11, 70124, Bari, Italy.

Convergent findings indicate that cannabis use and variation in the cannabinoid CB1 receptor coding gene (CNR1) modulate prefrontal function during working memory (WM). Other results also suggest that cannabis modifies the physiological relationship between genetically induced expression of CNR1 and prefrontal WM processing. However, it is possible that cannabis exerts its modifying effect on prefrontal physiology by interacting with complex molecular ensembles co-regulated with CB1. Since co-regulated genes are likely co-expressed, we investigated how genetically predicted co-expression of a molecular network including CNR1 interacts with cannabis use in modulating WM processing in humans. Using post-mortem human prefrontal data, we first computed a polygenic score (CNR1-PCI), combining the effects of single nucleotide polymorphisms (SNPs) on co-expression of a cohesive gene set including CNR1, and positively correlated with such co-expression. Then, in an in vivo study, we computed CNR1-PCI in 88 cannabis users and 147 non-users and investigated its interaction with cannabis use on brain activity during WM. Results revealed an interaction between cannabis use and CNR1-PCI in the dorsolateral prefrontal cortex (DLPFC), with a positive relationship between CNR1-PCI and DLPFC activity in cannabis users and a negative relationship in non-users. Furthermore, DLPFC activity in cannabis users was positively correlated with the frequency of cannabis use. Taken together, our results suggest that co-expression of a CNR1-related network predicts WM-related prefrontal activation as a function of cannabis use. Furthermore, they offer novel insights into the biological mechanisms associated with the use of cannabis.
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http://dx.doi.org/10.1007/s11682-020-00256-zDOI Listing
February 2021

Assessment of lumbar disc herniaton using fractional anisotropy in diffusion tensor imaging along with conventional T2-weighted imaging.

Neuroradiol J 2020 Feb 27;33(1):24-31. Epub 2019 Nov 27.

Radiology Department, IRCCS Ospedale Casa Sollievo della Sofferenza, Italy.

Objective: To assess the usefulness of diffusion tensor imaging and its fractional anisotropy map along with conventional T2-weighted imaging in evaluating the anisotropic water diffusion variations of annulus fibres involved in herniation disc pathology.

Materials And Methods: Seventy-five patients with previous medical ethics committee approval and informed consent experiencing low back pain were selected for this prospective randomised blinded trial. Lumbar disc fractional anisotropy maps were obtained acquiring diffusion tensor sequences on a 3T machine. The matrix of nucleus pulposus and structures of annulus fibres were analysed using fractional anisotropy textural features to highlight any presence of lumbar disc herniation. Observer variability and reliability between two neuroradiologists were evaluated. The χ test, two-tailed test and linear regression analysis were used to focus differences in patients' demographic data and magnetic resonance imaging findings.

Results: Annular fissures with extrusions were identified using diffusion tensor imaging in 10 out of 17 discs (study group) previously assessed as bulging discs using conventional magnetic resonance imaging. Eighteen extrusions out of 39 (study group) disc levels were identified on diffusion tensor imaging compared to eight extrusions highlighted on T2-weighted imaging ( < 0.01). All eight (study group) disc extrusions evaluated on T2-weighted imaging showed annular fissures on diffusion tensor imaging. Seven out of 14 (study group) protrusions highlighted on T2-weighted imaging had no annular fissures on diffusion tensor imaging; thirty-six disc levels in the control group had no evidence of annular fissures on diffusion tensor imaging ( > 0.01).

Conclusions: The addition of diffusion tensor imaging sequences and fractional anisotropy mapping to a conventional magnetic resonance imaging protocol could be useful in detecting annular fissures and lumbar disc herniation.
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http://dx.doi.org/10.1177/1971400919891288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005986PMC
February 2020

Cerebral Infarcts After Coronary Angiography and Percutaneous Coronary Intervention: A Prospective Propensity-Score-Adjusted Comparison of Right Radial, Left Radial, and Femoral Approaches.

Cardiovasc Revasc Med 2020 07 12;21(7):882-887. Epub 2019 Nov 12.

Unit of Cardiology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.

Background: New cerebral infarcts (CIs) detected at magnetic resonance imaging (MRI) are reported after cardiac procedures. Clinical and procedural aspects are implicated as potential causal factors. The aim of this study was to evaluate the incidence of new CIs after coronary angiography and percutaneous coronary intervention according to the arterial access site.

Methods: 180 patients undergoing elective coronary angiography were studied with cerebral MRI the day before and the day after the procedure. Unadjusted and propensity score (PS) analyses were performed comparing the occurrence of CIs in right radial (RR), left radial (LR) and transfemoral (TF) access groups.

Results: New CIs were observed in 14 patients (7.8% of the total sample, one with neurological sequelae). CIs were detected in 15.5% vs 4.9% vs 3.3% of RR, LR and TF groups, respectively (p = .026). In PS adjusted analyses, the RR approach was associated with more CIs compared with the TF approach (odds ratio [OR] estimate from logistic regression adjusted by PS quartiles: 0.158; 95% confidence interval: 0.031 to 0.814; p = .027) and the LR approach (OR: 0.266; 95% confidence interval: 0.066 to 1.080; p = .064). In a secondary analysis, a comparison of RR vs non-RR approach (TF + LR) was performed, showing that post-procedural CIs were more frequent in the RR group (OR: 0.170; 95% confidence interval: 0.050 to 0.574; p = .004).

Conclusions: Our study suggests that the RR approach may be associated with a higher rate of new CIs after coronary angiography compared with LR and TF approaches.
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http://dx.doi.org/10.1016/j.carrev.2019.11.010DOI Listing
July 2020

Multivariate patterns of gray matter volume in thalamic nuclei are associated with positive schizotypy in healthy individuals.

Psychol Med 2020 07 30;50(9):1501-1509. Epub 2019 Jul 30.

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

Background: Previous models suggest biological and behavioral continua among healthy individuals (HC), at-risk condition, and full-blown schizophrenia (SCZ). Part of these continua may be captured by schizotypy, which shares subclinical traits and biological phenotypes with SCZ, including thalamic structural abnormalities. In this regard, previous findings have suggested that multivariate volumetric patterns of individual thalamic nuclei discriminate HC from SCZ. These results were obtained using machine learning, which allows case-control classification at the single-subject level. However, machine learning accuracy is usually unsatisfactory possibly due to phenotype heterogeneity. Indeed, a source of misclassification may be related to thalamic structural characteristics of those HC with high schizotypy, which may resemble structural abnormalities of SCZ. We hypothesized that thalamic structural heterogeneity is related to schizotypy, such that high schizotypal burden would implicate misclassification of those HC whose thalamic patterns resemble SCZ abnormalities.

Methods: Following a previous report, we used Random Forests to predict diagnosis in a case-control sample (SCZ = 131, HC = 255) based on thalamic nuclei gray matter volumes estimates. Then, we investigated whether the likelihood to be classified as SCZ (π-SCZ) was associated with schizotypy in 174 HC, evaluated with the Schizotypal Personality Questionnaire.

Results: Prediction accuracy was 72.5%. Misclassified HC had higher positive schizotypy scores, which were correlated with π-SCZ. Results were specific to thalamic rather than whole-brain structural features.

Conclusions: These findings strengthen the relevance of thalamic structural abnormalities to SCZ and suggest that multivariate thalamic patterns are correlates of the continuum between schizotypy in HC and the full-blown disease.
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http://dx.doi.org/10.1017/S0033291719001430DOI Listing
July 2020

Imaging of cervical spine traumas.

Eur J Radiol 2019 Aug 7;117:75-88. Epub 2019 May 7.

Department of Neuroradiology, A.O.R.N. Cardarelli, Naples, Italy.

Spinal traumas represent a significant proportion of muscle-skeletal injuries worldwide. Spinal injuries involve a complex structure with components having different traumatic susceptibility and variable healing capabilities. The interaction of numerous variables at time of trauma creates a great variety of lesions which makes challenging the creation and comparison of homogeneous groups, with difficulties in classifying spinal lesions, in assessing their instability, and in defining the indication and outcome of different treatment strategies. The evolution of concepts on instability has accompanied that of traumas classification schemes and treatment strategies. The assessment of instability in a spinal injury is actually crucial in front of newer surgical techniques and hardwares. Despite a long history of attempts to classify spinal traumas, it remains some degree of controversy in describing imaging data and a wide variety of treatment strategies. Acute cervical spine injuries affect from 1.9% to 4.6% of subjects reporting a blunt trauma, and up to 5.9% of multiple-injured patients. Most of spinal cord injuries are a consequence of unstable fractures of the cervical spine. An accurate and early diagnosis is mandatory to prevent neurological damage in unstable fractures. Classic and newer classifications are primarily based on features identifiable by using conventional imaging and CT scan, which are the most available modalities at most trauma centers. Even though multidetector-CT remains superior in assessing with high accuracy bone injuries, MRI is the most sensitive modality for detecting soft tissues injuries and spinal cord damage.
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http://dx.doi.org/10.1016/j.ejrad.2019.05.007DOI Listing
August 2019

Thalamic connectivity measured with fMRI is associated with a polygenic index predicting thalamo-prefrontal gene co-expression.

Brain Struct Funct 2019 Apr 6;224(3):1331-1344. Epub 2019 Feb 6.

Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Piazza Giulio Cesare, 11, 70124, Bari, Italy.

The functional connectivity between thalamic medio-dorsal nucleus (MD) and cortical regions, especially the dorsolateral prefrontal cortex (DLPFC), is implicated in attentional processing and is anomalous in schizophrenia, a brain disease associated with polygenic risk and attentional deficits. However, the molecular and genetic underpinnings of thalamic connectivity anomalies are unclear. Given that gene co-expression across brain areas promotes synchronous interregional activity, our aim was to investigate whether coordinated expression of genes relevant to schizophrenia in MD and DLPFC may reflect thalamic connectivity anomalies in an attention-related network including the DLPFC. With this aim, we identified in datasets of post-mortem prefrontal mRNA expression from healthy controls a gene module with robust overrepresentation of genes with coordinated MD-DLPFC expression and enriched for schizophrenia genes according to the largest genome-wide association study to date. To link this gene cluster with imaging phenotypes, we computed a Polygenic Co-Expression Index (PCI) combining single-nucleotide polymorphisms predicting module co-expression. Finally, we investigated the association between PCI and thalamic functional connectivity during attention through fMRI Independent Component Analysis in 265 healthy participants. We found that PCI was positively associated with connectivity strength of a thalamic region overlapping with the MD within an attention brain circuit. These findings identify a novel association between schizophrenia-related genes and thalamic functional connectivity. Furthermore, they highlight the association between gene expression co-regulation and brain connectivity, such that genes with coordinated MD-DLPFC expression are associated with coordinated activity between the same brain regions. We suggest that gene co-expression is a plausible mechanism underlying biological phenotypes of schizophrenia.
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http://dx.doi.org/10.1007/s00429-019-01843-7DOI Listing
April 2019

Isolated fungus ball in sphenoid sinus: tips and pitfalls of hyperintense lesions.

BJR Case Rep 2018 10;4(2):20170081. Epub 2018 Jan 10.

Department of Hemathology and Medical Oncology, Unit of Pathology, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Puglia, Italy.

Isolated sphenoid sinus fungus ball is a very rare condition. CT is the most used imaging investigation for diagnosis. In some cases, MRI may provide further information to evaluate the extracompartmental invasion. We report the case of an elderly female patient who presented with headache and a soft tissue mass filling the right sphenoid sinus on CT, misdiagnosed as simple sinusitis. After 1 year, with recrudescence of symptoms, brain MRI showed a hyperintense soft tissue mass on  weighted images within the right sphenoidal sinus; a new CT examination revealed calcifications within the mass. Surgical histological examination showed fungus ball. Fungal ball should be included in the differential diagnosis of hyperintense lesions in the sphenoid sinus.
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http://dx.doi.org/10.1259/bjrcr.20170081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159120PMC
January 2018

Transcriptomic context of is associated with prefrontal activity and behavior during working memory.

Proc Natl Acad Sci U S A 2018 05 7;115(21):5582-5587. Epub 2018 May 7.

Institute of Psychiatry, Bari University Hospital, 70124 Bari, Italy.

Dopamine D receptor (DR) signaling shapes prefrontal cortex (PFC) activity during working memory (WM). Previous reports found higher WM performance associated with alleles linked to greater expression of the gene coding for DRs (). However, there is no evidence on the relationship between genetic modulation of expression in PFC and patterns of prefrontal activity during WM. Furthermore, previous studies have not considered that DRs are part of a coregulated molecular environment, which may contribute to DR-related prefrontal WM processing. Thus, we hypothesized a reciprocal link between a coregulated (i.e., coexpressed) molecular network including and PFC activity. To explore this relationship, we used three independent postmortem prefrontal mRNA datasets (total = 404) to characterize a coexpression network including Then, we indexed network coexpression using a measure (polygenic coexpression index--PCI) combining the effect of single nucleotide polymorphisms (SNPs) on coexpression. Finally, we associated the -PCI with WM performance and related brain activity in independent samples of healthy participants (total = 371). We identified and replicated a coexpression network including , whose coexpression was correlated with -PCI. We also found that -PCI was associated with lower PFC activity and higher WM performance. Behavioral and imaging results were replicated in independent samples. These findings suggest that genetically predicted expression of and of its coexpression partners stratifies healthy individuals in terms of WM performance and related prefrontal activity. They also highlight genes and SNPs potentially relevant to pharmacological trials aimed to test cognitive enhancers modulating signaling.
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http://dx.doi.org/10.1073/pnas.1717135115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003490PMC
May 2018

Isolated pons involvement in Posterior Reversible Encephalopathy Syndrome: Case report and review of the literature.

eNeurologicalSci 2017 Mar 28;6:51-54. Epub 2016 Nov 28.

Neurology Unit, Department of Medicine, Research Center "Casa Sollievo della Sofferenza", San Giovanni Rotondo, FG, Italy.

Background: Posterior Reversible Encephalopathy Syndrome (PRES) is a clinical-radiological syndrome, usually reversible and with a favorable prognosis, which recognizes a variety of etiologies and clinical patterns and is likely due to an impairment in cerebral blood flow autoregulation. It is typically characterized by subcortical, predominantly parieto-occipital, vasogenic brain oedema in patients with acute-subacute neurological symptoms. Infratentorial oedema on neuroimaging has been mostly described in association with the typical supratentorial pattern and seldom as isolated.

Case Report: We report a case of PRES with isolated pons involvement on MRI. A woman affected by Turner syndrome, epilepsy, slight mental deficiency, obesity and hypothyroidism, experienced a progressive gait and standing impairment, worsening in the last 2 weeks. At admission blood pressure was 220/110 mmHg. Brain MRI showed a wide FLAIR signal hyperintensity on T2-weighted sequences affecting the entire pons, without contrast enhancement. Clonidine, doxazosine, furosemide and telmisartan were effective in restoring normal blood pressure. Pons hyperintensity completely resolved on MRI 3 weeks later, together with return to normal neurological examination.

Conclusions: Though isolated infratentorial involvement in PRES recognizes several causes, hypertension, which is a common feature in Turner syndrome, would have played a key role in our case with solely pons MRI T2-hyperintensity.
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http://dx.doi.org/10.1016/j.ensci.2016.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721558PMC
March 2017

Familial Risk and a Genome-Wide Supported DRD2 Variant for Schizophrenia Predict Lateral Prefrontal-Amygdala Effective Connectivity During Emotion Processing.

Schizophr Bull 2018 06;44(4):834-843

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

The brain functional mechanisms translating genetic risk into emotional symptoms in schizophrenia (SCZ) may include abnormal functional integration between areas key for emotion processing, such as the amygdala and the lateral prefrontal cortex (LPFC). Indeed, investigation of these mechanisms is also complicated by emotion processing comprising different subcomponents and by disease-associated state variables. Here, our aim was to investigate the relationship between risk for SCZ and effective connectivity between the amygdala and the LPFC during different subcomponents of emotion processing. Thus, we first characterized with dynamic causal modeling (DCM) physiological patterns of LPFC-amygdala effective connectivity in healthy controls (HC) during implicit and explicit emotion processing. Then, we compared DCM patterns in a subsample of HC, in patients with SCZ and in healthy siblings of patients (SIB), matched for demographics. Finally, we investigated in HC association of LPFC-amygdala effective connectivity with a genome-wide supported variant increasing genetic risk for SCZ and possibly relevant to emotion processing (DRD2 rs2514218). In HC, we found that a "bottom-up" amygdala-to-LPFC pattern during implicit processing and a "top-down" LPFC-to-amygdala pattern during explicit processing were the most likely directional models of effective connectivity. Differently, implicit emotion processing in SIB, SCZ, and HC homozygous for the SCZ risk rs2514218 C allele was associated with decreased probability for the "bottom-up" as well as with increased probability for the "top-down" model. These findings suggest that task-specific anomaly in the directional flow of information or disconnection between the amygdala and the LPFC is a good candidate endophenotype of SCZ.
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http://dx.doi.org/10.1093/schbul/sbx128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007415PMC
June 2018

[PRES (Posterior Reversible Encephalopathy Syndrome): potential complication of hypertensive crisis. Case report and literature review].

G Ital Nefrol 2017 Apr;34(2):100-109

Struttura Complessa di Nefrologia e Dialisi IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Foggia, Italia.

Posterior reversible encephalopathy syndrome (PRES) is a clinical-radiological syndrome, usually reversible, characterized by vasogenic oedema in cerebral posterior regions in patients with autoimmune diseases, nephropathies, hypertensive crisis, eclampsia and exposure to cytotoxic drugs. The main symptoms are: headache, nausea, vomiting, seizures, visual disturbance and altered consciousness. Complications as cerebral hemorrhage and recurrences are rare. We describe a case of a 65 years old woman, affected by chronic kidney disease, recently exacerbated, diabetes and hypertension in treatment, who showed an heterogeneous clinical presentation with vomiting, headache, blurred vision and impaired consciousness during an episode of acute hypertension. After an adjustement of the antihypertensive treatment we observed a regression of symptoms in one week. FLAIR sequences on MRI showed cerebral bilateral vasogenic oedema in posterior regions, typical for PRES. This case was suggestive for PRES and a prompt adjustement of the antihypertensive treatment was critical for clinical recovery. Brain MRI was crucial for diagnosis. It is important for clinicians to recognize PRES as a possible complication of renal disease and hypertensive crisis.
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April 2017

Adult-onset pure tic disorder after post-traumatic hypoxic lesions of the globus pallidus.

Parkinsonism Relat Disord 2017 01 18;34:75-76. Epub 2016 Nov 18.

Center for Neurodegenerative Disease, University of Salerno-CEMAND, Salerno, Italy.

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http://dx.doi.org/10.1016/j.parkreldis.2016.11.007DOI Listing
January 2017

Prefrontal Activity and Connectivity with the Basal Ganglia during Performance of Complex Cognitive Tasks Is Associated with Apathy in Healthy Subjects.

PLoS One 2016 31;11(10):e0165301. Epub 2016 Oct 31.

Bari University Hospital-Psychiatry Unit, 70124, Bari, Italy.

Objective: Convergent evidence indicates that apathy affects cognitive behavior in different neurological and psychiatric conditions. Studies of clinical populations have also suggested the primary involvement of the prefrontal cortex and the basal ganglia in apathy. These brain regions are interconnected at both the structural and functional levels and are deeply involved in cognitive processes, such as working memory and attention. However, it is unclear how apathy modulates brain processing during cognition and whether such a modulation occurs in healthy young subjects. To address this issue, we investigated the link between apathy and prefrontal and basal ganglia function in healthy young individuals. We hypothesized that apathy may be related to sub-optimal activity and connectivity in these brain regions.

Methods: Three hundred eleven healthy subjects completed an apathy assessment using the Starkstein's Apathy Scale and underwent fMRI during working memory and attentional performance tasks. Using an ROI approach, we investigated the association of apathy with activity and connectivity in the DLPFC and the basal ganglia.

Results: Apathy scores correlated positively with prefrontal activity and negatively with prefrontal-basal ganglia connectivity during both working memory and attention tasks. Furthermore, prefrontal activity was inversely related to attentional behavior.

Conclusions: These results suggest that in healthy young subjects, apathy is a trait associated with inefficient cognitive-related prefrontal activity, i.e., it increases the need for prefrontal resources to process cognitive stimuli. Furthermore, apathy may alter the functional relationship between the prefrontal cortex and the basal ganglia during cognition.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165301PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087839PMC
June 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

What Impact does An Angry Context have Upon Us? The Effect of Anger on Functional Connectivity of the Right Insula and Superior Temporal Gyri.

Front Behav Neurosci 2016 6;10:109. Epub 2016 Jun 6.

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

Being in a social world requires an understanding of other people that is co-determined in its meaning by the situation at hand. Therefore, we investigated the underlying neural activation occurring when we encounter someone acting in angry or joyful situation. We hypothesized a dynamic interplay between the right insula, both involved in mapping visceral states associated with emotional experiences and autonomic control, and the bilateral superior temporal gyri (STG), part of the "social brain", when facing angry vs. joyful situations. Twenty participants underwent a functional magnetic resonance imaging (fMRI) scanning session while watching video clips of actors grasping objects in joyful and angry situations. The analyses of functional connectivity, psychophysiological interaction (PPI) and dynamic causal modeling (DCM), all revealed changes in functional connectivity associated with the angry situation. Indeed, the DCM model showed that the modulatory effect of anger increased the ipsilateral forward connection from the right insula to the right STG, while it suppressed the contralateral one. Our findings reveal a critical role played by the right insula when we are engaged in angry situations. In addition, they suggest that facing angry people modulates the effective connectivity between these two nodes associated, respectively, with autonomic responses and bodily movements and human-agent motion recognition. Taken together, these results add knowledge to the current understanding of hierarchical brain network for social cognition.
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http://dx.doi.org/10.3389/fnbeh.2016.00109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893496PMC
July 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

Cerebral Hypoperfusion in Hereditary Coproporphyria (HCP): A Single Photon Emission Computed Tomography (SPECT) Study.

Endocr Metab Immune Disord Drug Targets 2016 ;16(1):39-46

Interdisciplinary Department of Medicine, Section of Internal Medicine, Geriatrics, Endocrinology and Rare Diseases, University of Bari "Aldo Moro", Bari, Italy.

Background: Hereditary Coproporphyria (HCP) is characterized by abdominal pain, neurologic symptoms and psychiatric disorders, even if it might remain asymptomatic. The pathophysiology of both neurologic and psychiatric symptoms is not fully understood. Therefore, aiming to evaluate a possible role of brain blood flow disorders, we have retrospectively investigated cerebral perfusion patterns in Single Photon Emission Computed Tomography (SPECT) studies in HCP patients.

Materials & Methods: We retrospectively evaluated the medical records of patients diagnosed as being affected by HCP. A total of seven HCP patients had been submitted to brain perfusion SPECT study with 99mTc-Exametazime (hexamethylpropyleneamine oxime, HMPAO) or with its functionally equivalent 99mTc-Bicisate (ECD or Neurolite) according with common procedures. In 3 patients the scintigraphic study had been repeated for a second time after the first evaluation at 3, 10 and 20 months, respectively. All the studied subjects had been also submitted to an electromyographic and a Magnetic Resonance Imaging (MRI) study of the brain.

Results: Mild to moderate perfusion defects were detected in temporal lobes (all 7 patients), frontal lobes (6 patients) and parietal lobes (4 patients). Occipital lobe, basal ganglia and cerebellar involvement were never observed. In the three subjects in which SPECT study was repeated, some recovery of hypo-perfused areas and appearance of new perfusion defects in other brain regions have been found. In all patients electromyography resulted normal and MRI detected few unspecific gliotic lesions only in one patient. Discussion & Conclusions: Since perfusion abnormalities were usually mild to moderate, this can probably explain the normal pattern observed at MRI studies. Compared to MRI, SPECT with 99mTc showed higher sensitivity in HCP patients. Changes observed in HCP patients who had more than one study suggest that transient perfusion defects might be due to a brain artery spasm possibly leading to psychiatric and neurologic symptomatology, as already observed in patients affected by acute intermittent porphyria. This observation, if confirmed by other well designed studies aiming to demonstrate a direct link between artery spasm, perfusion defects and related symptoms could lead to improvements in HCP treatments.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5171194PMC
http://dx.doi.org/10.2174/1871530316666151218151101DOI Listing
April 2017

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

Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics.

Neuropsychopharmacology 2015 Jun 7;40(7):1600-8. Epub 2015 Jan 7.

1] Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy [2] pRED, NORD DTA, F. Hoffman-La Roche Ltd., Basel, Switzerland.

Dopamine D2 and serotonin 5-HT2A receptors contribute to modulate prefrontal cortical physiology and response to treatment with antipsychotics in schizophrenia. Similarly, functional variation in the genes encoding these receptors is also associated with these phenotypes. In particular, the DRD2 rs1076560 T allele predicts a lower ratio of expression of D2 short/long isoforms, suboptimal working memory processing, and better response to antipsychotic treatment compared with the G allele. Furthermore, the HTR2A T allele is associated with lower 5-HT2A expression, impaired working memory processing, and poorer response to antipsychotics compared with the C allele. Here, we investigated in healthy subjects whether these functional polymorphisms have a combined effect on prefrontal cortical physiology and related cognitive behavior linked to schizophrenia as well as on response to treatment with second-generation antipsychotics in patients with schizophrenia. In a total sample of 620 healthy subjects, we found that subjects with the rs1076560 T and rs6314 T alleles have greater fMRI prefrontal activity during working memory. Similar results were obtained within the attentional domain. Also, the concomitant presence of the rs1076560 T/rs6314 T alleles also predicted lower behavioral accuracy during working memory. Moreover, we found that rs1076560 T carrier/rs6314 CC individuals had better responses to antipsychotic treatment in two independent samples of patients with schizophrenia (n=63 and n=54, respectively), consistent with the previously reported separate effects of these genotypes. These results indicate that DRD2 and HTR2A genetic variants together modulate physiological prefrontal efficiency during working memory and also modulate the response to antipsychotics. Therefore, these results suggest that further exploration is needed to better understand the clinical consequences of these genotype-phenotype relationships.
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http://dx.doi.org/10.1038/npp.2015.5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915265PMC
June 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

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

Recurrent glioblastoma multiforme versus radiation injury: a multiparametric 3-T MR approach.

Radiol Med 2014 Aug 10;119(8):616-24. Epub 2014 Jan 10.

Dipartimento di Medicina e Scienze per la Salute, Università del Molise, Via De Sanctis snc, 86100, Campobasso, Italy,

Objective: The discrimination between recurrent glioma and radiation injury is often a challenge on conventional magnetic resonance imaging (MRI). We verified whether adding and combining proton MR spectroscopic imaging ((1)H-MRSI), diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) information at 3 Tesla facilitate such discrimination.

Materials And Methods: Twenty-nine patients with histologically verified high-grade gliomas, who had undergone surgical resection and radiotherapy, and had developed new contrast-enhancing lesions close to the treated tumour, underwent MRI, (1)H-MRSI, DWI and PWI at regular time intervals. The metabolite ratios choline (Cho)/normal( n )Cho n , N-acetylaspartate (NAA)/NAA n , creatine (Cr)/Cr n , lactate/lipids (LL)/LL n , Cho/Cr n , NAA/Cr n , Cho/NAA, NAA/Cr and Cho/Cr were derived from (1)H-MRSI; the apparent diffusion coefficient (ADC) from DWI; and the relative cerebral blood volume (rCBV) from PWI.

Results: In serial MRI, recurrent gliomas showed a progressive enlargement, and radiation injuries showed regression or no modification. Discriminant analysis showed that discrimination accuracy was 79.3 % when considering only the metabolite ratios (predictor, Cho/Cr n ), 86.2 % when considering ratios and ADC (predictors, Cho/Cr n and ADC), 89.7 % when considering ratios and rCBV (predictors, Cho/Cr n , Cho/Cr and rCBV), and 96.6 % when considering ratios, ADC and rCBV (predictors, Cho/Cho n , ADC and rCBV).

Conclusions: The multiparametric 3-T MR assessment based on (1)H-MRSI, DWI and PWI in addition to MRI is a useful tool to discriminate tumour recurrence/progression from radiation effects.
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http://dx.doi.org/10.1007/s11547-013-0371-yDOI Listing
August 2014

Effects of emotional contexts on cerebello-thalamo-cortical activity during action observation.

PLoS One 2013 26;8(9):e75912. Epub 2013 Sep 26.

Swiss Center for Affective Sciences (CISA), University of Geneva, Geneva, Switzerland.

Several studies investigated the neural and functional mechanisms underlying action observation in contexts with objects. However, actions seen in everyday life are often embedded in emotional contexts. The neural systems integrating emotion cues in action observation are still poorly understood. Previous findings suggest that the processing of both action and emotion information recruits motor control areas within the cerebello-thalamo-cortical pathways. It is therefore hard to determine whether social emotional contexts influence action processing via a direct modulation of motor representations coding for the observed action or via the affective state and implicit motor preparedness elicited in observers in response to emotional contexts. Here we designed a novel fMRI task to identify neural networks engaged by the affective appraisal of a grasping action seen in two different emotional contexts, while keeping the action kinematics constant. Results confirmed that observing the same acts of grasping but in different emotional contexts modulated activity in supplementary motor area, ventrolateral thalamus, anterior cerebellum. Moreover, changes in functional connectivity between left supplementary motor area and parahippocampus in different emotional contexts suggested a direct neural pathway through which emotional contexts may drive the neural motor system. Taken together, these findings shed new light on the malleability of motor system as a function of emotional contexts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0075912PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784399PMC
July 2014

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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