- p.za Giulio Cesare 11
- Johns Hopkins University, Lieber Institute for Brain Development, Department Memberadd
- Cognitive Neuroscience, FMRI, Learning and Memory (Neurosciences), Amygdala, Thalamus, Explicit Memory, and 18 moreSchizophrenia, Aggression (Psychology), ERP (Cognitive Psychology), Stroke, Alcoholism, Human Eating Behaviours, Food Science, Recognition memory, Recollection, Mediodorsal Nucleus, Neuroscience, Psychiatry, Neuropsychology, Memory (Cognitive Psychology), Gene coexpression networks, Genetics, Glutamate receptors, and Dopaminergic Neurotransmisionedit
- I believe that learning brings about change all the way from brain cells to how we define who we are. My research ask... moreI believe that learning brings about change all the way from brain cells to how we define who we are. My research asks how genetic and environmental components of human experience determine inter-individual variability. I am also interested in mental health, especially schizophrenia. Our lab tries to connect layers of biological systems from cells to brain circuits and behavior. I am looking for talented thinkers, science enthusiasts, and collaborators who seek to learn why we are who we are.
I obtained my PhD in Bochum (Germany), where I was part the Novobrain program (Marie Curie Early Stage Training) at the International Graduate School of Neuroscience & RUB Research School, with the supervision of Prof. Daum and Prof. Suchan. I received additional research training and funding by the German Academic Exchange Service (DAAD). During my postdoc at the Italian excellence campus “SISSA” (Trieste, Italy), I worked with Prof. Rumiati on how motivational salience of visual stimuli affects memory. Since May 2013 I am assistant professor at the University of Bari Aldo Moro. I am currently the Director of the lab of Brain Imaging, Networks and Data mining (https://bit.ly/2EctXJW) in the Department of Basic Medical Sciences, Neuroscience and Sense organs at the University of Bari Aldo Moro, Italy. The lab I coordinate works on the convergence of genetic risk for schizophrenia and on the associated phenotypic variability between individuals. My long-term scientific goal is to investigate the biological basis of inter-individual variability in healthy and pathological neurodevelopment.
Currently I am spending a sabbatical at the Lieber Institute for Brain Development in Baltimore funded by Horizon 2020 MSCA to train in computational genetics and data science. Check out my project here:
https://cordis.europa.eu/project/rcn/218544/enedit - Prof. Daniel R. Weinberger, MD, Prof. Alessandro Bertolino, PhD, Prof. Raffaella I. Rumiati, Prof. Boris Suchanedit
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Previous reports on brain co-expression networks, mostly applied to tissue homogenates, have utilized cluster-based strategies for assigning genes to a unique co-expression cluster. This feature is incompatible with the diversity of cell... more
Previous reports on brain co-expression networks, mostly applied to tissue homogenates, have utilized cluster-based strategies for assigning genes to a unique co-expression cluster. This feature is incompatible with the diversity of cell populations and cellular components involved. Single-cell RNA-sequencing provides a finer-grained resolution than bulk tissue when interrogating brain cell types, dynamic states, and functional processes. We uncovered co-expression patterns across different brain cell types by applying tensor decomposition to single-nucleus transcriptomes from the prefrontal cortex of male patients with depression who died by suicide. We identified a gene set differentially co-expressed in inhibitory neurons between patients and controls and enriched for genes associated with major depression and schizophrenia.
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Research Interests: Psychology and Psychosis
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Background Abnormal auditory processing of deviant stimuli, as reflected by mismatch negativity (MMN), is often reported in schizophrenia (SCZ). At present, it is still under debate whether this dysfunctional response is specific to the... more
Background Abnormal auditory processing of deviant stimuli, as reflected by mismatch negativity (MMN), is often reported in schizophrenia (SCZ). At present, it is still under debate whether this dysfunctional response is specific to the full-blown SCZ diagnosis or rather a marker of psychosis in general. The present study tested MMN in patients with SCZ, bipolar disorder (BD), first episode of psychosis (FEP), and in people at clinical high risk for psychosis (CHR). Methods Source-based MEG activity evoked during a passive auditory oddball task was recorded from 135 patients grouped according to diagnosis (SCZ, BD, FEP, and CHR) and 135 healthy controls also divided into four subgroups, age- and gender-matched with diagnostic subgroups. The magnetic MMN (mMMN) was analyzed as event-related field (ERF), Theta power, and Theta inter-trial phase coherence (ITPC). Results The clinical group as a whole showed reduced mMMN ERF amplitude, Theta power, and Theta ITPC, without any statistica...
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Dynamical brain state transitions are critical for flexible working memory but the network mechanisms are incompletely understood. Here, we show that working memory performance entails brain-wide switching between activity states using a... more
Dynamical brain state transitions are critical for flexible working memory but the network mechanisms are incompletely understood. Here, we show that working memory performance entails brain-wide switching between activity states using a combination of functional magnetic resonance imaging in healthy controls and individuals with schizophrenia, pharmacological fMRI, genetic analyses and network control theory. The stability of states relates to dopamine D1 receptor gene expression while state transitions are influenced by D2 receptor expression and pharmacological modulation. Individuals with schizophrenia show altered network control properties, including a more diverse energy landscape and decreased stability of working memory representations. Our results demonstrate the relevance of dopamine signaling for the steering of whole-brain network dynamics during working memory and link these processes to schizophrenia pathophysiology.
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T (2015) Pre-stimulus BOLD-network activation modulates EEG spectral activity during working memory retention. Front. Behav. Neurosci. 9:111. doi: 10.3389/fnbeh.2015.00111 Pre-stimulus BOLD-network activation modulates EEG spectral... more
T (2015) Pre-stimulus BOLD-network activation modulates EEG spectral activity during working memory retention. Front. Behav. Neurosci. 9:111. doi: 10.3389/fnbeh.2015.00111 Pre-stimulus BOLD-network activation modulates EEG spectral activity during working memory retention
Background Genome-Wide Association Studies (GWASs) have identified several genes associated with Schizophrenia (SCZ) and exponentially increased knowledge on the genetic basis of the disease. In addition, products of GWAS genes interact... more
Background Genome-Wide Association Studies (GWASs) have identified several genes associated with Schizophrenia (SCZ) and exponentially increased knowledge on the genetic basis of the disease. In addition, products of GWAS genes interact with neuronal factors coded by genes lacking association, such that this interaction may confer risk for specific phenotypes of this brain disorder. In this regard, fragile X mental retardation syndrome-related 1 (FXR1) gene has been GWAS associated with SCZ. FXR1 protein is regulated by glycogen synthase kinase-3β (GSK3β), which has been implicated in pathophysiology of SCZ and response to antipsychotics (APs). rs496250 and rs12630592, two eQTLs (Expression Quantitative Trait Loci) of FXR1 and GSK3β, respectively, interact on emotion stability and amygdala/prefrontal cortex activity during emotion processing. These two phenotypes are associated with Negative Symptoms (NSs) of SCZ suggesting that the interaction between these SNPs may also affect NS ...
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Background Genome-Wide Association Studies (GWASs) have identified several genes associated with Schizophrenia (SCZ) and exponentially increased knowledge on the genetic basis of the disease. In addition, products of GWAS genes interact... more
Background Genome-Wide Association Studies (GWASs) have identified several genes associated with Schizophrenia (SCZ) and exponentially increased knowledge on the genetic basis of the disease. In addition, products of GWAS genes interact with neuronal factors coded by genes lacking association, such that this interaction may confer risk for specific phenotypes of this brain disorder. In this regard, fragile X mental retardation syndrome-related 1 (FXR1) gene has been GWAS associated with SCZ. FXR1 protein is regulated by glycogen synthase kinase-3β (GSK3β), which has been implicated in pathophysiology of SCZ and response to antipsychotics (APs). rs496250 and rs12630592, two eQTLs (Expression Quantitative Trait Loci) of FXR1 and GSK3β, respectively, interact on emotion stability and amygdala/prefrontal cortex activity during emotion processing. These two phenotypes are associated with Negative Symptoms (NSs) of SCZ suggesting that the interaction between these SNPs may also affect NS ...
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Patients with PD scheduled for STN-DBS were recruited. They were tested in a satiated state before surgery in on medication, and after surgery in on medication/off stimulation and on medication/on stimulation. All participants were asked... more
Patients with PD scheduled for STN-DBS were recruited. They were tested in a satiated state before surgery in on medication, and after surgery in on medication/off stimulation and on medication/on stimulation. All participants were asked to complete a self-report questionnaire about impulsiveness, a go-no-go experiment measuring the response inhibition to food items and finally, a task that evaluates hedonic and motivational aspects of food processing (liking and wanting, respectively). The preoperative and postoperative body weights were recorded. The mean body weight of patients increased postoperatively. Both reward sensitivity and impulsivity increased after surgery. The weight changes correlated positively with hedonic ratings of food items and salience/motivation towards foods in on medication/on stimulation, in particular for non-sweet foods (both high and low calorie foods). Moreover, weight changes correlated positively with false alarms for food items in the go no-go task ...
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AIM Alcohol use disorder (AUD) has been associated with recognition memory deficits. However, it remains unclear whether these deficits occur at the general recognition memory level or whether they selectively affect its subcomponents.... more
AIM Alcohol use disorder (AUD) has been associated with recognition memory deficits. However, it remains unclear whether these deficits occur at the general recognition memory level or whether they selectively affect its subcomponents. Evidence suggests that recognition memory deficits may vary according to the heterogeneity of memory stimuli. Our aim was to investigate stimuli pair-dependent recognition memory deficits in AUD, using a cued recall task including homogeneous and heterogeneous stimuli pairs. METHODS Twenty-three patients with AUD (days since last alcohol consumption: 11.70 ± 10.20) and 23 healthy controls (HC) underwent a neuropsychological examination tapping attention, verbal fluency, logical, working and long-term memory, and a recognition and recall task involving both homogeneous (tool-tool) and heterogeneous (tool-scene, tool-animal) stimuli pairs. Group (AUD-HC) by condition (tool-tool, tool-scene, tool-animal) ANOVAs were performed on all neuropsychological indices. RESULTS In the neuropsychological examination, AUD individuals showed deficits in delayed recall and faster reaction times compared with HC. The administration of the recognition and recall task revealed specific performance decreases in cued recall occurring in the whole sample (AUD + HC) for heterogeneous (tool-scene, tool-animal) pairs compared with homogeneous pairs. Within this pattern, AUD patients showed a lower cued recall rate than HC only for tool-animal pairs. CONCLUSIONS Our results support the existence of specific recall/recollection deficits in AUD which occurred for heterogeneous, but not for homogeneous stimuli pairs. This finding calls for further neuroimaging investigations aimed at investigating the neurobiological substrate of (i) different recognition memory subcomponents, and (ii) the processing of stimuli with different degree or type of heterogeneity.
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Schizophrenia is a chronic mental illness that is amongst the most debilitating conditions encountered in medical practice. A recent landmark schizophrenia study of the protein-coding regions of the genome identified a causal role for ten... more
Schizophrenia is a chronic mental illness that is amongst the most debilitating conditions encountered in medical practice. A recent landmark schizophrenia study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes1. This study -- and most other large-scale human genetic studies -- was mainly composed of individuals of European ancestry, and the generalizability of the findings in non-European populations is unclear. To address this gap in knowledge, we designed a custom sequencing panel based on current knowledge of the genetic architecture of schizophrenia and applied it to a new cohort of 22,135 individuals of diverse ancestries. Replicating earlier work, cases carried a significantly higher burden of rare protein-truncating variants among constrained genes (OR=1.48, p-value = 5.4 × 10−6). In meta-analyses with existing schizophrenia datasets totaling up to 35,828 cases a...
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Gene interactions can suitably be modeled as communities through weighted complex networks. However, the problem to efficiently detect these communities , eventually gaining biological insight from them, is still an open question. This... more
Gene interactions can suitably be modeled as communities through weighted complex networks. However, the problem to efficiently detect these communities , eventually gaining biological insight from them, is still an open question. This paper presents a novel data-driven strategy for community detection and tests it on the specific case study of DRD2 gene coding for the D2 dopamine receptor, which plays a prominent role in risk for Schizophrenia . We adopt a combined use of centrality and topological properties to detect an optimal network partition. We find that 21 genes belongs with our target community with probability \(P \ge 90\,\%\). The robustness of the partition is assessed with two independent methodologies: (i) fuzzy c-means and (ii) consensus analyses . We use the first one to measure how strong the membership of these genes to the DRD2 community is and the latter to confirm the stability of the detected partition. These results show an interesting reduction (\({\sim }80\,\%\)) of the target community size. Moreover, to allow this validation on different case studies, the proposed methodology is available on an open cloud infrastructure, according to the Software as a Service paradigm (SaaS).
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Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this... more
Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted ...
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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... more
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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Genome-Wide-Association studies have involved miR-137 in schizophrenia. However, the biology underlying this statistical evidence is unclear. Statistical polygenic risk for schizophrenia is associated with working memory, while other... more
Genome-Wide-Association studies have involved miR-137 in schizophrenia. However, the biology underlying this statistical evidence is unclear. Statistical polygenic risk for schizophrenia is associated with working memory, while other biological evidence involves miR-137 in emotion processing. We investigated the function of miR-137 target schizophrenia risk genes in humans.We identified a prefrontal co-expression pathway of schizophrenia-associated miR-137 targets and validated the association with miR-137 expression in neuroblastoma cells. Alleles predicting greater co-expression of this pathway were associated with greater prefrontal activation during emotion processing in two independent cohorts of healthy volunteers (N1=222; N2=136). Statistical polygenic risk for schizophrenia was instead associated with prefrontal activation during working memory.A co-expression pathway links miR-137 and its target genes to emotion processing and risk for schizophrenia. Low prefrontal miR-137 ...
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BACKGROUND Schizophrenia risk is associated with both genetic and environmental risk factors. Furthermore, cognitive abnormalities are established core characteristics of schizophrenia. We aim to assess whether a classification approach... more
BACKGROUND Schizophrenia risk is associated with both genetic and environmental risk factors. Furthermore, cognitive abnormalities are established core characteristics of schizophrenia. We aim to assess whether a classification approach encompassing risk factors, cognition, and their associations can discriminate patients with schizophrenia (SCZs) from healthy control subjects (HCs). We hypothesized that cognition would demonstrate greater HC-SCZ classification accuracy and that combined gene-environment stratification would improve the discrimination performance of cognition. METHODS Genome-wide association study-based genetic, environmental, and neurocognitive classifiers were trained to separate 337 HCs from 103 SCZs using support vector classification and repeated nested cross-validation. We validated classifiers on independent datasets using within-diagnostic (SCZ) and cross-diagnostic (clinically isolated syndrome for multiple sclerosis, another condition with cognitive abnormalities) approaches. Then, we tested whether gene-environment multivariate stratification modulated the discrimination performance of the cognitive classifier in iterative subsamples. RESULTS The cognitive classifier discriminated SCZs from HCs with a balanced accuracy (BAC) of 88.7%, followed by environmental (BAC = 65.1%) and genetic (BAC = 55.5%) classifiers. Similar classification performance was measured in the within-diagnosis validation sample (HC-SCZ BACs, cognition = 70.5%; environment = 65.8%; genetics = 49.9%). The cognitive classifier was relatively specific to schizophrenia (HC-clinically isolated syndrome for multiple sclerosis BAC = 56.7%). Combined gene-environment stratification allowed cognitive features to classify HCs from SCZs with 89.4% BAC. CONCLUSIONS Consistent with cognitive deficits being core features of the phenotype of SCZs, our results suggest that cognitive features alone bear the greatest amount of information for classification of SCZs. Consistent with genes and environment being risk factors, gene-environment stratification modulates HC-SCZ classification performance of cognition, perhaps providing another target for refining early identification and intervention strategies.
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Previous studies have indicated a link between socio-emotional processing and the oxytocin receptor. In this regard, a single nucleotide polymorphism in the oxytocin receptor coding gene ( OXTR rs2268493) has been linked with lower social... more
Previous studies have indicated a link between socio-emotional processing and the oxytocin receptor. In this regard, a single nucleotide polymorphism in the oxytocin receptor coding gene ( OXTR rs2268493) has been linked with lower social functioning, increased risk for autism spectrum disorders (ASDs) and with post-mortem OXTR mRNA expression levels. Indeed, the levels of expression of OXTR in brain regions involved in emotion processing are also associated with maternal care. Furthermore, maternal care has been associated with emotional correlates. Taken together, these previous findings suggest a possible combined effect of rs2268493 and maternal care on emotion-related brain phenotypes. A crucial biological mechanism subtending emotional processing is the amygdala–dorsolateral prefrontal cortex (DLPFC) functional connection. On this basis, our aim was to investigate the interaction between rs2268493 and maternal care on amygdala–DLPFC effective connectivity during emotional evaluation. We characterized through dynamic causal modeling (DCM) patterns of amygdala–DLPFC effective connectivity during explicit emotion processing in healthy controls (HC), profiled based on maternal care and rs2268493 genotype. In the whole sample, right top-down DLPFC-to-amygdala pattern was the most likely directional model of effective connectivity. This pattern of connectivity was the most likely for all rs2268493/maternal care subgroups, except for thymine homozygous (TT)/low maternal care individuals. Here, a right bottom-up amygdala-to-DLPFC was the most likely directional model. These results suggest a gene by environment interaction mediated by the oxytocin receptor on biological phenotypes relevant to emotion processing.
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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... more
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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Functional-Magnetic-Imaging (fMRI) is widely adopted to investigate neurophysiological correlates of emotion processing (EP). However, studies have reported that scanning procedures in neuroimaging protocols may increase or cause anxiety... more
Functional-Magnetic-Imaging (fMRI) is widely adopted to investigate neurophysiological correlates of emotion processing (EP). However, studies have reported that scanning procedures in neuroimaging protocols may increase or cause anxiety and psychological distress related with the scanning, thus inducing peripheral cortisol release. These phenomena may in turn impact on brain EP. Additionally, previous findings have indicated that inter-individual differences in stress-response intensity are mediated by levels of Emotional Stability (ES), a personality trait that has been associated with brain activity during EP, especially in amygdala and prefrontal cortex (PFC). The aim of this study was to investigate the interaction between indices of stress related to anticipation of fMRI scanning and levels of ES on amygdala and PFC activity during EP. With this aim, fifty-five healthy volunteers were characterized for trait ES. Furthermore, salivary cortisol levels at baseline and soon before fMRI scanning were measured as an index of stress related to scanning anticipation. During fMRI, participants performed an explicit EP task. We found that variation in salivary cortisol (Δc) interacts with ES on left amygdala and PFC activity during EP. More in details, in the context of a higher ES, the greater the Δc, the lower the activity in left amygdala and PFC. In the context of lower ES, the opposite Δc-brain activity relationship was found. Our results suggest that the stressful potential of fMRI interacts with personality traits in modulating brain activity during EP. These findings should be taken into account when interpreting neuroimaging studies especially exploring brain physiology during EP.
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Dynamical brain state transitions are critical for flexible working memory but the network mechanisms are incompletely understood. Here, we show that working memory entails brain-wide switching between activity states. The stability of... more
Dynamical brain state transitions are critical for flexible working memory but the network mechanisms are incompletely understood. Here, we show that working memory entails brain-wide switching between activity states. The stability of states relates to dopamine D1 receptor gene expression while state transitions are influenced by D2 receptor expression and pharmacological modulation. Schizophrenia patients show altered network control properties, including a more diverse energy landscape and decreased stability of working memory representations.
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Gene co-expression networks are relevant to functional and clinical translation of schizophrenia (SCZ) risk genes. We hypothesized that SCZ risk genes may converge into coexpression pathways which may be associated with gene regulation... more
Gene co-expression networks are relevant to functional and clinical translation of schizophrenia (SCZ) risk genes. We hypothesized that SCZ risk genes may converge into coexpression pathways which may be associated with gene regulation mechanisms and with response to treatment in patients with SCZ. We identified gene co-expression networks in two prefrontal cortex post-mortem RNA sequencing datasets (total N=688) and replicated them in four more datasets (total N=227). We identified and replicated (all p-values<.001) a single module enriched for SCZ risk loci (13 risk genes in 10 loci). In silico screening of potential regulators of the SCZ risk module via bioinformatic analyses identified two transcription factors and three miRNAs associated with the risk module. To translate post-mortem information into clinical phenotypes, we identified polymorphisms predicting co-expression and combined them to obtain an index approximating module co-expression (Polygenic Co-expression Index: PCI). The PCI-co-expression association was successfully replicated in two independent brain transcriptome datasets (total N=131; all p-values<.05). Finally, we tested the association between the PCI and short-term treatment response in two independent samples of patients with SCZ treated with olanzapine (total N=167). The PCI was associated with treatment response in the positive symptom domain in both clinical cohorts (all p-values<.05). In summary, our findings in a large sample of human post-mortem prefrontal cortex show that coexpression of a set of genes enriched for schizophrenia risk genes is relevant to treatment response. This co-expression pathway may be co-regulated by transcription factors and miRNA associated with it.
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ABSTRACT As a result of neuro‐vascular coupling, the functional effects of antipsychotics in human brain have been investigated in both healthy and clinical populations using haemodynamic markers such as regional Cerebral Blood Flow... more
ABSTRACT As a result of neuro‐vascular coupling, the functional effects of antipsychotics in human brain have been investigated in both healthy and clinical populations using haemodynamic markers such as regional Cerebral Blood Flow (rCBF). However, the relationship between observed haemodynamic effects and the pharmacological action of these drugs has not been fully established. Here, we analysed Arterial Spin Labelling (ASL) rCBF data from a placebo‐controlled study in healthy volunteers, who received a single dose of three different D2 receptor (D2R) antagonists and tested the association of the main effects of the drugs on rCBF against normative population maps of D2R protein density and gene‐expression data. In particular, we correlated CBF changes after antipsychotic administration with non‐displaceable binding potential (BPND) template maps of the high affinity D2‐antagonist Positron Emission Tomography (PET) ligand [18F]Fallypride and with brain post‐mortem microarray mRNA expression data for the DRD2 gene from the Allen Human Brain Atlas (ABA). For all antipsychotics, rCBF changes were directly proportional to brain D2R densities and DRD2 mRNA expression measures, although PET BPND spatial profiles explained more variance as compared with mRNA profiles (PET R2 range=0.20–0.60, mRNA PET R2 range 0.04–0.20, pairwise‐comparisons all pcorrected<0.05). In addition, the spatial coupling between &Dgr;CBF and D2R profiles varied between the different antipsychotics tested, possibly reflecting differential affinities. Overall, these results indicate that the functional effects of antipsychotics as measured with rCBF are tightly correlated with the distribution of their target receptors in striatal and extra‐striatal regions. Our results further demonstrate the link between neurotransmitter targets and haemodynamic changes reinforcing rCBF as a robust in‐vivo marker of drug effects. This work is important in bridging the gap between pharmacokinetic and pharmacodynamics of novel and existing compounds.
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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 ().... more
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...
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Numerous genetic and environmental factors contribute to psychiatric disorders and other brain disorders. Common risk factors likely converge on biological pathways regulating the optimization of brain structure and function across the... more
Numerous genetic and environmental factors contribute to psychiatric disorders and other brain disorders. Common risk factors likely converge on biological pathways regulating the optimization of brain structure and function across the lifespan. Here, using structural magnetic resonance imaging and machine learning, we estimated the gap between brain age and chronological age in 36,891 individuals aged 3 to 96 years, including individuals with different brain disorders. We show that several disorders are associated with accentuated brain aging, with strongest effects in schizophrenia, multiple sclerosis and dementia, and document differential regional patterns of brain age gaps between disorders. In 16,269 healthy adult individuals, we show that brain age gap is heritable with a polygenic architecture overlapping those observed in common brain disorders. Our results identify brain age gap as a genetically modulated trait that offers a window into shared and distinct mechanisms in di...
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It has been proposed that the conceptual knowledge of food and its putative subdivision into natural (i.e., fruit/vegetables) and transformed (i.e., food that underwent thermic or non-thermic processing) may follow the living/non-living... more
It has been proposed that the conceptual knowledge of food and its putative subdivision into natural (i.e., fruit/vegetables) and transformed (i.e., food that underwent thermic or non-thermic processing) may follow the living/non-living distinction. In the present study, we investigated whether the advantage for living things compared to non-living things observed in episodic memory (the so-called animacy effect) extends to natural foods and transformed foods respectively. We pursued this issue in two experiments. In Experiment 1, we measured episodic memory for natural and transformed foods in young participants. In Experiment 2, we enrolled dementia-free centenarians, patients with Alzheimer's disease (DAT), Progressive primary aphasia (PPA), and healthy controls whose episodic memory was also tested for living/non-living things. Results showed that young participants had better recognition memory for transformed foods compared to natural foods. This difference disappeared in centenarians and patients. However, centenarians and PPA exhibited enhanced levels of false alarms (FA) with natural food, and DAT patients with both natural and transformed food. As far as the living/non-living distinction is concerned, the episodic memory for the living category appears more resilient to the decline compared to the non-living category in patients, particularly those with PPA. In conclusion, our study shows that transformed food is better remembered than natural food, suggesting that it is more salient and possibly relevant from an evolutionary perspective. The natural/transformed distinction appears susceptible to erosion only in the presence of a high degree of episodic memory impairment. These results offer novel insight on episodic memory of food, and also extend the current knowledge on the animacy effect in episodic memory.
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Complex network analysis has become a gold standard to investigate functional connectivity in the human brain. Popular approaches for quantifying functional coupling between fMRI time series are linear zero-lag correlation methods;... more
Complex network analysis has become a gold standard to investigate functional connectivity in the human brain. Popular approaches for quantifying functional coupling between fMRI time series are linear zero-lag correlation methods; however, they might reveal only partial aspects of the functional links between brain areas. In this work, we propose a novel approach for assessing functional coupling between fMRI time series and constructing functional brain networks. A phase space framework is used to map couples of signals exploiting their cross recurrence plots (CRPs) to compare the trajectories of the interacting systems. A synchronization metric is extracted from the CRP to assess the coupling behavior of the time series. Since the functional communities of a healthy population are expected to be highly consistent for the same task, we defined functional networks of task-related fMRI data of a cohort of healthy subjects and applied a modularity algorithm in order to determine the ...
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Metabolic abnormalities and peripheral inflammation have been increasingly reported in patients at the onset of psychosis and associated with important physical health disorders and increased mortality. However, the impact of an abnormal... more
Metabolic abnormalities and peripheral inflammation have been increasingly reported in patients at the onset of psychosis and associated with important physical health disorders and increased mortality. However, the impact of an abnormal metabolic-inflammatory status on the psychiatric outcome of these patients has not yet been investigated. The aims of this study were 1) to explore whether, in a sample of patients at their first episode of psychosis (FEP), an overall metabolic-inflammatory status may be measured, by combining metabolic and inflammatory variables in metabolic-inflammatory factors; 2) to explore the association between these factors and clinical outcome at 1-year follow-up (FU), in terms of symptoms severity and treatment response. In this longitudinal study we recruited 42 FEP patients and 46 healthy controls (HC) matched with patients for age, gender and ethnicity. At baseline (T1) we measured high sensitivity C-reactive protein (hsCRP) as biomarker of inflammation...
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Research on brain disorders with a strong genetic component and complex heritability, such as schizophrenia, has led to the development of brain transcriptomics. This field seeks to gain a deeper understanding of gene expression, a key... more
Research on brain disorders with a strong genetic component and complex heritability, such as schizophrenia, has led to the development of brain transcriptomics. This field seeks to gain a deeper understanding of gene expression, a key factor in exploring further research issues. Our study focused on how genes are associated amongst each other. In this perspective, we have developed a novel data-driven strategy for characterizing genetic modules, i.e., clusters of strongly interacting genes. The aim was to uncover a pivotal community of genes linked to a target gene for schizophrenia. Our approach combined network topological properties with information theory to highlight the presence of a pivotal community, for a specific gene, and to simultaneously assess the information content of partitions with the Shannon's entropy based on betweenness. We analyzed the publicly available BrainCloud dataset containing post-mortem gene expression data and focused on the Dopamine D2 receptor...
Research Interests:
The use of polygenic risk scores has become a practical translational approach to investigating the complex genetic architecture of schizophrenia, but the link between polygenic risk scores and pathophysiological components of this... more
The use of polygenic risk scores has become a practical translational approach to investigating the complex genetic architecture of schizophrenia, but the link between polygenic risk scores and pathophysiological components of this disorder has been the subject of limited research. We investigated in healthy volunteers whether schizophrenia polygenic risk score predicts hippocampal activity during simple memory encoding, which has been proposed as a risk-associated intermediate phenotype of schizophrenia. We analysed the relationship between polygenic risk scores and hippocampal activity in a discovery sample of 191 unrelated healthy volunteers from the USA and in two independent replication samples of 76 and 137 healthy unrelated participants from Europe and the USA, respectively. Polygenic risk scores for each individual were calculated as the sum of the imputation probability of reference alleles weighted by the natural log of odds ratio from the recent schizophrenia genome-wide ...
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Dopamine D2 receptors (D2Rs) contribute to the inverted U-shaped relationship between dopamine signaling and prefrontal function. Genetic networks from post-mortem human brain revealed 84 partner genes co-expressed with DRD2. Moreover,... more
Dopamine D2 receptors (D2Rs) contribute to the inverted U-shaped relationship between dopamine signaling and prefrontal function. Genetic networks from post-mortem human brain revealed 84 partner genes co-expressed with DRD2. Moreover, eight functional single nucleotide polymorphisms combined into a polygenic co-expression index (PCI) predicted co-expression of this DRD2 network and were associated with prefrontal function in humans. Here, we investigated the non-linear association of the PCI with behavioral and Working Memory (WM) related brain response to pharmacological D2Rs stimulation. Fifty healthy volunteers took part in a double-blind, placebo-controlled, functional MRI (fMRI) study with bromocriptine and performed the N-Back task. The PCI by drug interaction was significant on both WM behavioral scores (P = 0.046) and related prefrontal activity (all corrected P < 0.05) using a polynomial PCI model. Non-linear responses under placebo were reversed by bromocriptine admini...
Research Interests:
Research Interests:
Visual recognition of objects may rely on different features depending on the category to which they belong. Recognizing natural objects, such as fruits and plants, weighs more on their perceptual attributes, whereas recognizing man-made... more
Visual recognition of objects may rely on different features depending on the category to which they belong. Recognizing natural objects, such as fruits and plants, weighs more on their perceptual attributes, whereas recognizing man-made objects, such as tools or vehicles, weighs more upon the functions and actions they enable. Edible objects are perceptually rich but also prepared for specific functions, therefore it is unclear how perceptual and functional attributes affect their recognition. Two event-related potentials experiments investigated: (i) whether food categorization in the brain is differentially modulated by sensory and functional attributes, depending on whether the food is natural or transformed; (ii) whether these processes are modulated by participants&amp;amp;amp;amp;amp;amp;amp;amp;#39; body mass index. In experiment 1, healthy normal-weight participants were presented with a sentence (prime) and a photograph of a food. Primes described either a sensory feature (&amp;amp;amp;amp;amp;amp;amp;amp;#39;It tastes sweet&amp;amp;amp;amp;amp;amp;amp;amp;#39;) or a functional feature (&amp;amp;amp;amp;amp;amp;amp;amp;#39;It is suitable for a wedding party&amp;amp;amp;amp;amp;amp;amp;amp;#39;) of the food, while photographs depicted either a natural (e.g., cherry) or a transformed food (e.g., pizza). Prime-feature pairs were either congruent or incongruent. This design aimed at modulating N400-like components elicited by semantic processing. In experiment 1, N400-like amplitude was significantly larger for transformed food than for natural food with sensory primes, and vice versa with functional primes. In experiment 2, underweight and obese women performed the same semantic task. We found that, while the N400-like component in obese participants was modulated by sensory-functional primes only for transformed food, the same modulation was found in underweight participants only for natural food. These findings suggest that the level of food transformation interacts with participants&amp;amp;amp;amp;amp;amp;amp;amp;#39; body mass index in modulating food perception and the underlying brain processing.
Research Interests:
A possible role of reward sensitivity and impulsivity in weight gain after deep brain stimulation. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is safe procedure to treat Parkinson's disease (PD) that however may expose... more
A possible role of reward sensitivity and impulsivity in weight gain after deep brain stimulation. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is safe procedure to treat Parkinson's disease (PD) that however may expose patients to non-motor effects [1]. In particular it has been shown that after the implant patients suddenly increase in weight. However, the exact mechanism of this weight gain has not yet been identified [2,3]. Since these changes seem to be modulated by STN-DBS [4-6], we aimed at evaluating the role of reward sensitivity and impulsivity in weight gain after DBS. Patients with PD scheduled for STN-DBS were recruited. They were tested in a satiated state before surgery in on medication, and after surgery in on medication/off stimulation and on medication/on stimulation. All participants were asked to complete a self-report questionnaire about impulsiveness, a go-no-go experiment measuring the response inhibition to food items and finally, a task that evaluates hedonic and motivational aspects of food processing (liking and wanting, respectively). The preoperative and postoperative body weights were recorded. The mean body weight of patients increased postoperatively. Both reward sensitivity and impulsivity increased after surgery. The weight changes correlated positively with hedonic ratings of food items and salience/motivation towards foods in on medication/on stimulation, in particular for non-sweet foods (both high and low calorie foods). Moreover, weight changes correlated positively with false alarms for food items in the go no-go task in on medication/on stimulation. Finally, weight changes correlated negatively with motor impulsiveness in the pre surgical condition and positively with changes in motor impulsiveness after surgery. Our results confirm that STN-DBS expose patients to the risk of weight gain. Moreover, they suggest that postoperative weight gain may be related to changes in food reward sensitivity and in inhibitory control. Both these aspects have been recognized to play an important role in eating behaviors.