Schizotypy" is a latent organization of personality related to the genetic risk for schizophrenia... more 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.
Cognitive dysfunction is central to the schizophrenia phenotype. Genetic and functional studies h... more Cognitive dysfunction is central to the schizophrenia phenotype. Genetic and functional studies have implicated Disruptedin-Schizophrenia 1 (DISC1), a leading candidate gene for schizophrenia and related psychiatric conditions, in cognitive function. Altered expression of DISC1 and DISC1-interactors has been identified in schizophrenia. Dysregulated expression of DISC1-interactome genes might, therefore, contribute to schizophrenia susceptibility via disruption of molecular systems required for normal cognitive function. Here, the blood RNA expression levels of DISC1 and DISC1-interacting proteins were measured in 63 control subjects. Cognitive function was assessed using neuropsychiatric tests and functional magnetic resonance imaging was used to assess the activity of prefrontal cortical regions during the N-back working memory task, which is abnormal in schizophrenia. Pairwise correlations between gene expression levels and the relationship between gene expression levels and cognitive function and N-back-elicited brain activity were assessed. Finally, the expression levels of DISC1, AKAP9, FEZ1, NDEL1 and PCM1 were compared between 63 controls and 69 schizophrenic subjects. We found that DISC1-interactome genes showed correlated expression in the blood of healthy individuals. The expression levels of several interactome members were correlated with cognitive performance and N-back-elicited activity in the prefrontal cortex. In addition, DISC1 and NDEL1 showed decreased expression in schizophrenic subjects compared to healthy controls. Our findings highlight the importance of the coordinated expression of DISC1-interactome genes for normal cognitive function and suggest that dysregulated DISC1 and NDEL1 expression might, in part, contribute to susceptibility for schizophrenia via disruption of prefrontal cortex-dependent cognitive functions.
remains unclear. Specifically, previous studies have failed to prove the longitudinal predictive ... more remains unclear. Specifically, previous studies have failed to prove the longitudinal predictive value of cognition in determining the final diagnoses of the first episode psychosis (FEP) samples analyzed. Methods: Eighty-three FEP patients were recruited and followedup during a 2 year follow up period after onset. Assessment included clinical interview, psychiatric evaluation (PANNS, Young Mania Scale, MADRS Depression Scale) neurocognitive (attention, processing speed, memory, language, executive functions) and functional assessment. Results: Logistic regression models revealed that executive dysfunction correctly classified patients with schizophrenia (87%), from patients with bipolar disorder (81.3%), and other psychoses (72.4%). The prediction was stable despite the inclusion of positive, negative, affective symptoms, and other cognitive tests into the model. Just Wisconsin Card Sorting Test-categories completed and percentage of perseverative errors, correctly classify up to 79.4% of patients. Discussion: These results showed that executive functioning, as measured with Wisconsin Card Sorting Test, may be a promising tool to use in basic clinical approach to FEP and schizophrenia. As far as the authors are aware, this is the first attempt to assess the longitudinal predictive value of neurocognitive performance and clinical symptoms on the clinical diagnosis after the FEP. Our results support Keefe et al´suggestion (2007, 2008), of the importance of including cognition as a part of the diagnostic criteria for schizophrenia.
Personality traits related to emotion processing are, at least in part, heritable and genetically... more Personality traits related to emotion processing are, at least in part, heritable and genetically determined. Dopamine D2 receptor signaling is involved in modulation of emotional behavior and activity of associated brain regions such as the amygdala and the prefrontal cortex. An intronic single nucleotide polymorphism within the D2 receptor gene (DRD2, rs1076560, guanine>thymine-G>T) shifts splicing of the two protein isoforms (D2 short, D2S, mainly presynaptic, and D2 long, D2L) and has been associated with modulation of memory performance and brain activity. Here, our aim was to investigate the association of DRD2 rs1076560 genotype with personality traits of emotional stability and with brain physiology during processing of emotionally relevant stimuli. DRD2 genotype and Big Five Questionnaire scores were evaluated in 134 healthy subjects demonstrating that GG subjects have reduced 'emotion control' compared with GT subjects. fMRI in a sample of 24 individuals indicated greater amygdala activity during implicit processing and greater dorsolateral prefrontal cortex (DLPFC) response during explicit processing of facial emotional stimuli in GG subjects compared with GT. Other results also demonstrate an interaction between DRD2 genotype and facial emotional expression on functional connectivity of both amygdala and dorsolateral prefrontal regions with overlapping medial prefrontal areas. Moreover, rs1076560 genotype is associated with differential relationships between amygdala/DLPFC functional connectivity and emotion control scores. These results suggest that genetically determined D2 signaling may explain part of personality traits related to emotion processing and individual variability in specific brain responses to emotionally relevant inputs.
three fMRI studies to investigate the interaction between the CEN, default-mode and the salience ... more three fMRI studies to investigate the interaction between the CEN, default-mode and the salience networks in patients with schizophrenia and healthy volunteers. Methods: 20 patients with DSM-IV schizophrenia and 20 age, gender and parental socio-occupational status matched controls participated in the study after providing informed consent. The subjects performed two functional tasks (n-back memory task and auditory oddball task) and data was also acquired when the subjects were in resting state for 5 minutes, with eyes closed. Functional MR Imaging was performed on a 3 Tesla Philips MR device employing echo-planar (EPI) acquisition (TE / TR 35 / 2100 ms; 64 × 64 matrix, voxel size 3.25 × 3.25 × 3.25; 35 slices). Images were reoriented, realigned, coregistered, spatially normalized and smoothed using SPM5 (http://www.fil.ion.ucl.ac.uk/spm). The smoothed images from all the subjects were subjected to Independent Component Analysis (ICA) using the GIFT software (http://icatb.sourceforge.net) to decompose the data into 20 spatially independent components. The resulting components were subjected to visual inspection and correlation with apriori masks created in MRIcron. The correlation between the networks were tested using the Functional Network Connectivity software (Jafri et al., 2008). Results: Both in the two functional tasks and the resting stage, the three components correlating to the CEN, DMN and salience networks were clearly identified in the combined group ICA. Separate group ICA of the patients and controls also led to identification of the three networks in each group. The time courses of the three components showed that the CEN, and Salience components were correlated with active tasks in the functional tasks, and the DMN was anticorrelated with the tasks. The functional connectivity analysis showed the complex interplay differences between patients with schizophrenia and controls. Discussion: The three networks (CEN, DMN and Salience networks) were clearly identifiable using model-free ICA analysis in both functional tasks and the resting stage for both groups, which suggests that three networks are key to information processing in both resting and active states of brain activity. The complex interplay between the three networks that is aberrant in schizophrenia may explain the 'disconnection' resulting in the diverse range of symptoms in schizophrenia. References
resting-state. Midline default network areas, including the medial prefrontal cortex and posterio... more resting-state. Midline default network areas, including the medial prefrontal cortex and posterior cingulate cortex, are implicated in self-referential and social cognitive tasks, and individuals at ultrahigh risk (UHR) for psychosis were recently reported to have selfdisturbances and deficits in social cognition and functioning. Thus, the DMN has its potential to reveal the neural substrates of selfreferential and social cognitive information processing in UHR subjects. In this study, we investigated resting-state DMN and TRN functional connectivity in UHR subjects and healthy controls. Methods: Twenty UHR subjects and 20 matched healthy controls underwent fMRI while resting quietly. We selected bilateral posterior cingulate cortex (Brodmann area 23) as a seed region and reconstructed the intrinsic organization in the UHR subjects and healthy controls on the basis of fMRI time series correlation (also known as functional connectivity). Between-group comparison of the DMN and TRN was restricted to regions belonging to the intrinsic networks of control group. Additionally, we also conducted between-group region of interest (ROI)-based connectivity analyses on areas in which UHR subjects showed altered connectivities, within a priori selected anatomical ROIs. Results: Default mode and task-related areas were observed in regions previously associated with the DMN and TRN for both groups. Default mode areas included the posterior/anterior cingulate, medial prefrontal and lateral parietal cortices, and inferior/ superior temporal gyri, whereas task-related areas included the dorsolateral prefrontal and middle temporal cortex, supplementary motor area, and frontal eye field. Compared to healthy controls, UHR subjects exhibited hyperconnectivity within the default network regions and reduced anti-correlations between the posterior cingulate cortex and task-related areas. Between-group ROI analysis also confirmed these findings. Discussion: Our findings suggest that abnormal hyperconnectivity of the default areas in UHR subjects might be related with clinical features of UHR subjects like disturbance of self-perception and heightened social anxiety. Neurodevelopmental and anatomical alterations of cortical midline structure might underlie altered intrinsic networks in UHR subjects. We also speculate that reduced anti-correlation between two networks might be related with impaired neurocognitive function in UHR subjects, which might be mediated by weaker task-induced deactivation of the DMN.
Cortical and subcortical dopamine D2 receptor (DRD2) signaling has been implicated in cognitive p... more Cortical and subcortical dopamine D2 receptor (DRD2) signaling has been implicated in cognitive processes, including working memory, attention and executive functions. The aim of this study was to investigate the association of cognition with three frequent DRD2 SNPs, two intronic SNPs, respectively SNP19 (rs#1076560)(G/T) and SNP17 (rs#2283265)(G/T), which affect mRNA splicing, and SNP2 in the promoter region (rs#12364283)(T/C) affecting total mRNA expression. Methods: We recruited a large sample of healthy subjects (N=77-119) matched for socio-demographic variables across the three DRD2 SNPs. All subjects underwent a set of neuropsychological tests assessing working memory (N-back), sustained attention (CPT), executive function (WCST), cognitive flexibility (TMT A-B), and memory (WMS). Behavioral performance was evaluated in terms of accuracy and reaction time. Moreover, all raw scores were transformed to z scores to calculate the composite score using the mean of z scores for each subject. Results: ANOVA demonstrated a significant main effect of DRD2 SNP19 on composite score (p<0.05). ANOVAs of the different tests indicated that G/G homozygotes perform better than T allele carriers at 1back and 2back. We also observed a significant association between DRD2 SNP2 and cognitive flexibility (p<0.05). Homozygotes T/T were faster than T/C while performing the TMT B. No significant effect was found for SNP17. Conclusions: Genetic variation in DRD2 seems to affect several cognitive processes, including working memory and cognitive flexibility. Our results may suggest that these variants provide risk to psychiatric disorders associated with these cognitive deficits. References [1] Y.
Up to ten percent of patients affected with schizophrenia commit suicide and thus suicide represe... more Up to ten percent of patients affected with schizophrenia commit suicide and thus suicide represents the major contributor to the increased mortality of people suffering from schizophrenia. Alterations in the serotonin (5-HT) system have been related to impulsive aggression and suicidal behavior. Genetic variations in the serotonin ionotropic receptor subunits (HTR3A and HTR3B) genes, positioned in tandem on chromosome 11q23.2, have been shown to be associated with psychiatric disorders. Methods: To determine the association between suicide attempt in 231 schizophrenia patients, we performed haplotype analysis in the genomic regions of HTR3A and HTR3B using 16 polymorphisms. Results: The SNP rs1176744 Ser129Tyr yielded evidence of association with suicide attempts in schizophrenia (p=0.0107) employing a multidimensionality reduction analysis. On the other hand the haplotype analysis was not significant. Conclusions: Our results suggest an important role for HTR3B in suicide attempts in schizophrenia and also exclude the interaction between these two subunits in conferring risk for suicide attempts using two different statistical strategies
Rationale Pharmacological stimulation of D2 receptors modulates prefrontal neural activity associ... more 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.
BackgroundAbnormalities in hippocampal–parahippocampal (H-PH) function are prominent features of ... more BackgroundAbnormalities in hippocampal–parahippocampal (H-PH) function are prominent features of schizophrenia and have been associated with deficits in episodic memory. However, it remains unclear whether these abnormalities represent a phenotype related to genetic risk for schizophrenia or whether they are related to disease state.MethodWe investigated H-PH-mediated behavior and physiology, using blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI), during episodic memory in a sample of patients with schizophrenia, clinically unaffected siblings and healthy subjects.ResultsPatients with schizophrenia and unaffected siblings displayed abnormalities in episodic memory performance. During an fMRI memory encoding task, both patients and siblings demonstrated a similar pattern of reduced H-PH engagement compared with healthy subjects.ConclusionsOur findings suggest that the pathophysiological mechanism underlying the inability of patients with schizophren...
Background: Variation of the gene coding for D2 receptors (DRD2) has been associated with risk fo... more Background: Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known.
Schizotypy" is a latent organization of personality related to the genetic risk for schizophrenia... more 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.
Cognitive dysfunction is central to the schizophrenia phenotype. Genetic and functional studies h... more Cognitive dysfunction is central to the schizophrenia phenotype. Genetic and functional studies have implicated Disruptedin-Schizophrenia 1 (DISC1), a leading candidate gene for schizophrenia and related psychiatric conditions, in cognitive function. Altered expression of DISC1 and DISC1-interactors has been identified in schizophrenia. Dysregulated expression of DISC1-interactome genes might, therefore, contribute to schizophrenia susceptibility via disruption of molecular systems required for normal cognitive function. Here, the blood RNA expression levels of DISC1 and DISC1-interacting proteins were measured in 63 control subjects. Cognitive function was assessed using neuropsychiatric tests and functional magnetic resonance imaging was used to assess the activity of prefrontal cortical regions during the N-back working memory task, which is abnormal in schizophrenia. Pairwise correlations between gene expression levels and the relationship between gene expression levels and cognitive function and N-back-elicited brain activity were assessed. Finally, the expression levels of DISC1, AKAP9, FEZ1, NDEL1 and PCM1 were compared between 63 controls and 69 schizophrenic subjects. We found that DISC1-interactome genes showed correlated expression in the blood of healthy individuals. The expression levels of several interactome members were correlated with cognitive performance and N-back-elicited activity in the prefrontal cortex. In addition, DISC1 and NDEL1 showed decreased expression in schizophrenic subjects compared to healthy controls. Our findings highlight the importance of the coordinated expression of DISC1-interactome genes for normal cognitive function and suggest that dysregulated DISC1 and NDEL1 expression might, in part, contribute to susceptibility for schizophrenia via disruption of prefrontal cortex-dependent cognitive functions.
remains unclear. Specifically, previous studies have failed to prove the longitudinal predictive ... more remains unclear. Specifically, previous studies have failed to prove the longitudinal predictive value of cognition in determining the final diagnoses of the first episode psychosis (FEP) samples analyzed. Methods: Eighty-three FEP patients were recruited and followedup during a 2 year follow up period after onset. Assessment included clinical interview, psychiatric evaluation (PANNS, Young Mania Scale, MADRS Depression Scale) neurocognitive (attention, processing speed, memory, language, executive functions) and functional assessment. Results: Logistic regression models revealed that executive dysfunction correctly classified patients with schizophrenia (87%), from patients with bipolar disorder (81.3%), and other psychoses (72.4%). The prediction was stable despite the inclusion of positive, negative, affective symptoms, and other cognitive tests into the model. Just Wisconsin Card Sorting Test-categories completed and percentage of perseverative errors, correctly classify up to 79.4% of patients. Discussion: These results showed that executive functioning, as measured with Wisconsin Card Sorting Test, may be a promising tool to use in basic clinical approach to FEP and schizophrenia. As far as the authors are aware, this is the first attempt to assess the longitudinal predictive value of neurocognitive performance and clinical symptoms on the clinical diagnosis after the FEP. Our results support Keefe et al´suggestion (2007, 2008), of the importance of including cognition as a part of the diagnostic criteria for schizophrenia.
Personality traits related to emotion processing are, at least in part, heritable and genetically... more Personality traits related to emotion processing are, at least in part, heritable and genetically determined. Dopamine D2 receptor signaling is involved in modulation of emotional behavior and activity of associated brain regions such as the amygdala and the prefrontal cortex. An intronic single nucleotide polymorphism within the D2 receptor gene (DRD2, rs1076560, guanine>thymine-G>T) shifts splicing of the two protein isoforms (D2 short, D2S, mainly presynaptic, and D2 long, D2L) and has been associated with modulation of memory performance and brain activity. Here, our aim was to investigate the association of DRD2 rs1076560 genotype with personality traits of emotional stability and with brain physiology during processing of emotionally relevant stimuli. DRD2 genotype and Big Five Questionnaire scores were evaluated in 134 healthy subjects demonstrating that GG subjects have reduced 'emotion control' compared with GT subjects. fMRI in a sample of 24 individuals indicated greater amygdala activity during implicit processing and greater dorsolateral prefrontal cortex (DLPFC) response during explicit processing of facial emotional stimuli in GG subjects compared with GT. Other results also demonstrate an interaction between DRD2 genotype and facial emotional expression on functional connectivity of both amygdala and dorsolateral prefrontal regions with overlapping medial prefrontal areas. Moreover, rs1076560 genotype is associated with differential relationships between amygdala/DLPFC functional connectivity and emotion control scores. These results suggest that genetically determined D2 signaling may explain part of personality traits related to emotion processing and individual variability in specific brain responses to emotionally relevant inputs.
three fMRI studies to investigate the interaction between the CEN, default-mode and the salience ... more three fMRI studies to investigate the interaction between the CEN, default-mode and the salience networks in patients with schizophrenia and healthy volunteers. Methods: 20 patients with DSM-IV schizophrenia and 20 age, gender and parental socio-occupational status matched controls participated in the study after providing informed consent. The subjects performed two functional tasks (n-back memory task and auditory oddball task) and data was also acquired when the subjects were in resting state for 5 minutes, with eyes closed. Functional MR Imaging was performed on a 3 Tesla Philips MR device employing echo-planar (EPI) acquisition (TE / TR 35 / 2100 ms; 64 × 64 matrix, voxel size 3.25 × 3.25 × 3.25; 35 slices). Images were reoriented, realigned, coregistered, spatially normalized and smoothed using SPM5 (http://www.fil.ion.ucl.ac.uk/spm). The smoothed images from all the subjects were subjected to Independent Component Analysis (ICA) using the GIFT software (http://icatb.sourceforge.net) to decompose the data into 20 spatially independent components. The resulting components were subjected to visual inspection and correlation with apriori masks created in MRIcron. The correlation between the networks were tested using the Functional Network Connectivity software (Jafri et al., 2008). Results: Both in the two functional tasks and the resting stage, the three components correlating to the CEN, DMN and salience networks were clearly identified in the combined group ICA. Separate group ICA of the patients and controls also led to identification of the three networks in each group. The time courses of the three components showed that the CEN, and Salience components were correlated with active tasks in the functional tasks, and the DMN was anticorrelated with the tasks. The functional connectivity analysis showed the complex interplay differences between patients with schizophrenia and controls. Discussion: The three networks (CEN, DMN and Salience networks) were clearly identifiable using model-free ICA analysis in both functional tasks and the resting stage for both groups, which suggests that three networks are key to information processing in both resting and active states of brain activity. The complex interplay between the three networks that is aberrant in schizophrenia may explain the 'disconnection' resulting in the diverse range of symptoms in schizophrenia. References
resting-state. Midline default network areas, including the medial prefrontal cortex and posterio... more resting-state. Midline default network areas, including the medial prefrontal cortex and posterior cingulate cortex, are implicated in self-referential and social cognitive tasks, and individuals at ultrahigh risk (UHR) for psychosis were recently reported to have selfdisturbances and deficits in social cognition and functioning. Thus, the DMN has its potential to reveal the neural substrates of selfreferential and social cognitive information processing in UHR subjects. In this study, we investigated resting-state DMN and TRN functional connectivity in UHR subjects and healthy controls. Methods: Twenty UHR subjects and 20 matched healthy controls underwent fMRI while resting quietly. We selected bilateral posterior cingulate cortex (Brodmann area 23) as a seed region and reconstructed the intrinsic organization in the UHR subjects and healthy controls on the basis of fMRI time series correlation (also known as functional connectivity). Between-group comparison of the DMN and TRN was restricted to regions belonging to the intrinsic networks of control group. Additionally, we also conducted between-group region of interest (ROI)-based connectivity analyses on areas in which UHR subjects showed altered connectivities, within a priori selected anatomical ROIs. Results: Default mode and task-related areas were observed in regions previously associated with the DMN and TRN for both groups. Default mode areas included the posterior/anterior cingulate, medial prefrontal and lateral parietal cortices, and inferior/ superior temporal gyri, whereas task-related areas included the dorsolateral prefrontal and middle temporal cortex, supplementary motor area, and frontal eye field. Compared to healthy controls, UHR subjects exhibited hyperconnectivity within the default network regions and reduced anti-correlations between the posterior cingulate cortex and task-related areas. Between-group ROI analysis also confirmed these findings. Discussion: Our findings suggest that abnormal hyperconnectivity of the default areas in UHR subjects might be related with clinical features of UHR subjects like disturbance of self-perception and heightened social anxiety. Neurodevelopmental and anatomical alterations of cortical midline structure might underlie altered intrinsic networks in UHR subjects. We also speculate that reduced anti-correlation between two networks might be related with impaired neurocognitive function in UHR subjects, which might be mediated by weaker task-induced deactivation of the DMN.
Cortical and subcortical dopamine D2 receptor (DRD2) signaling has been implicated in cognitive p... more Cortical and subcortical dopamine D2 receptor (DRD2) signaling has been implicated in cognitive processes, including working memory, attention and executive functions. The aim of this study was to investigate the association of cognition with three frequent DRD2 SNPs, two intronic SNPs, respectively SNP19 (rs#1076560)(G/T) and SNP17 (rs#2283265)(G/T), which affect mRNA splicing, and SNP2 in the promoter region (rs#12364283)(T/C) affecting total mRNA expression. Methods: We recruited a large sample of healthy subjects (N=77-119) matched for socio-demographic variables across the three DRD2 SNPs. All subjects underwent a set of neuropsychological tests assessing working memory (N-back), sustained attention (CPT), executive function (WCST), cognitive flexibility (TMT A-B), and memory (WMS). Behavioral performance was evaluated in terms of accuracy and reaction time. Moreover, all raw scores were transformed to z scores to calculate the composite score using the mean of z scores for each subject. Results: ANOVA demonstrated a significant main effect of DRD2 SNP19 on composite score (p<0.05). ANOVAs of the different tests indicated that G/G homozygotes perform better than T allele carriers at 1back and 2back. We also observed a significant association between DRD2 SNP2 and cognitive flexibility (p<0.05). Homozygotes T/T were faster than T/C while performing the TMT B. No significant effect was found for SNP17. Conclusions: Genetic variation in DRD2 seems to affect several cognitive processes, including working memory and cognitive flexibility. Our results may suggest that these variants provide risk to psychiatric disorders associated with these cognitive deficits. References [1] Y.
Up to ten percent of patients affected with schizophrenia commit suicide and thus suicide represe... more Up to ten percent of patients affected with schizophrenia commit suicide and thus suicide represents the major contributor to the increased mortality of people suffering from schizophrenia. Alterations in the serotonin (5-HT) system have been related to impulsive aggression and suicidal behavior. Genetic variations in the serotonin ionotropic receptor subunits (HTR3A and HTR3B) genes, positioned in tandem on chromosome 11q23.2, have been shown to be associated with psychiatric disorders. Methods: To determine the association between suicide attempt in 231 schizophrenia patients, we performed haplotype analysis in the genomic regions of HTR3A and HTR3B using 16 polymorphisms. Results: The SNP rs1176744 Ser129Tyr yielded evidence of association with suicide attempts in schizophrenia (p=0.0107) employing a multidimensionality reduction analysis. On the other hand the haplotype analysis was not significant. Conclusions: Our results suggest an important role for HTR3B in suicide attempts in schizophrenia and also exclude the interaction between these two subunits in conferring risk for suicide attempts using two different statistical strategies
Rationale Pharmacological stimulation of D2 receptors modulates prefrontal neural activity associ... more 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.
BackgroundAbnormalities in hippocampal–parahippocampal (H-PH) function are prominent features of ... more BackgroundAbnormalities in hippocampal–parahippocampal (H-PH) function are prominent features of schizophrenia and have been associated with deficits in episodic memory. However, it remains unclear whether these abnormalities represent a phenotype related to genetic risk for schizophrenia or whether they are related to disease state.MethodWe investigated H-PH-mediated behavior and physiology, using blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI), during episodic memory in a sample of patients with schizophrenia, clinically unaffected siblings and healthy subjects.ResultsPatients with schizophrenia and unaffected siblings displayed abnormalities in episodic memory performance. During an fMRI memory encoding task, both patients and siblings demonstrated a similar pattern of reduced H-PH engagement compared with healthy subjects.ConclusionsOur findings suggest that the pathophysiological mechanism underlying the inability of patients with schizophren...
Background: Variation of the gene coding for D2 receptors (DRD2) has been associated with risk fo... more Background: Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known.
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Papers by Barbara Gelao