Nonlinear Response of the Anterior Cingulate and Prefrontal Cortex in Schizophrenia as a Function of Variable Attentional Control

Blasi, Giuseppe; Taurisano, Paolo; Papazacharias, Apostolos; Caforio, Grazia; Romano, Raffaella; Lobianco, Luciana; Fazio, Leonardo; Giorgio, Annabella Di; Latorre, Valeria; Sambataro, Fabio; Popolizio, Teresa; Nardini, Marcello; Mattay, Venkata S.; Weinberger, Daniel R.; Bertolino, Alessandro

doi:10.1093/cercor/bhp146

Cited by 30 publications

(29 citation statements)

References 40 publications

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“…This relationship was not evident in DRD2 GT/AKT1 A carrier individuals whose activity in anterior cingulate dropped off from the intermediate to the higher level of attentional control. This pattern of response is strongly reminiscent of the results we have recently reported in patients with schizophrenia, in whom a similar drop of cingulate responses was present at the high attentional control load (17).…”

Section: Discussionsupporting

confidence: 85%

“…The relationship between increasing load of attentional control and activity in anterior cingulate is linear, increasing from lower to higher loads (14,17). This relationship was not evident in DRD2 GT/AKT1 A carrier individuals whose activity in anterior cingulate dropped off from the intermediate to the higher level of attentional control.…”

Section: Discussionmentioning

confidence: 93%

“…Seventy-three healthy subjects (Table 1) were enrolled to evaluate the association of DRD2 rs1076560 and AKT1 rs1130233 with brain activity during VAC processing. All subjects underwent fMRI while performing the VAC task, which elicits increasing demand for attentional control and which was identical to that published in previous studies (14,15,17,20). This task allows investigation of brain activity during three levels of attentional control (low, intermediate, high), which were obtained manipulating both the relative directions of arrows with different sizes and the related cue words (SI Materials and Methods).…”

Section: Methodsmentioning

confidence: 99%

“…Consistent with these models, previous data have suggested that attentional behavior is affected by D2 genetic variation (15). Furthermore, deficits in attentional processing are centrally implicated in schizophrenia (16,17). In fact, patients with schizophrenia performing attentional tasks have abnormal activity in the cingulate cortex, a brain region tightly linked to attentional processing (14) and modulated by D2 receptors (18,19), as well as by genetic variants possibly affecting D1/D2 ratio stimulation (10,20).…”

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confidence: 99%

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DRD2/AKT1interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia

Blasi

Napolitano

Ursini

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The D2/AKT1/GSK-3β signaling pathway has been involved in the downstream intracellular effects of dopamine, in the pathophysiology of cognitive deficits and related brain activity in schizophrenia, as well as in response to treatment with antipsychotics. Polymorphisms in the D2 (DRD2 rs1076560) and AKT1 (AKT1 rs1130233) genes have been associated with their respective protein expression and with higher-order cognition and brain function, including attention. Given the strong potential for their relationship, we investigated the interaction of these polymorphisms on multiple molecular and in vivo phenotypes associated with this signaling pathway. We measured AKT1 and GSK-3β proteins and phosphorylation in human peripheral blood mononuclear cells, functional MRI cingulate response during attentional control, behavioral accuracy during sustained attention, and response to 8 wk of treatment with olanzapine in a total of 190 healthy subjects and 66 patients with schizophrenia. In healthy subjects, we found that the interaction between the T allele of DRD2 rs1076560 and the A allele of AKT1 rs1130233 was associated with reduced AKT1 protein levels and reduced phosphorylation of GSK-3β, as well as with altered cingulate response and reduced behavioral accuracy during attentional processing. On the other hand, interaction of these two alleles was associated with greater improvement of Positive and Negative Syndrome Scale scores in patients with schizophrenia after treatment with olanzapine. The present results indicate that these functional polymorphisms are epistatically associated with multiple phenotypes of relevance to schizophrenia. Our results also lend support to further investigation of this downstream molecular pathway in the etiology and treatment of this disorder.A large series of experimental data indicate that dopamine D2 receptors and schizophrenia are tightly related. First, these receptors are privileged targets of antipsychotic drugs, which antagonize their activity (1). Second, previous reports have suggested association between psychosis and relatively greater D2 density in striatum, even though change is moderate (2). Third, clinical symptoms and cognitive deficits have been associated with abnormal D2 signaling (3-12). The relationship between D2 receptors and cognitive deficits in schizophrenia is also supported by previous models postulating that relatively excessive D2 signaling may lead to lower cortical signal-to-noise ratio and reduced filtering of information, as well as blocking of distracting inputs (10-12). These brain processes contribute to different higherorder cognitive functions and are strongly involved in top-down modulation of attention (13,14). Consistent with these models, previous data have suggested that attentional behavior is affected by D2 genetic variation (15). Furthermore, deficits in attentional processing are centrally implicated in schizophrenia (16,17). In fact, patients with schizophrenia performing attentional tasks have abnormal activity in the cingulate cortex, a ...

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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DRD2/AKT1interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia

Blasi

Napolitano

Ursini

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…The anterior part of the cingulate gyrus is a key region in sustained attention, cognitive control and error processing [72][73][74] . An altered function of ACC has been consistently reported in both schizophrenic patients and unaffected relatives [75,76] during attentional control [77] conflict/error monitoring [78][79][80][81] , working memory [82][83][84] and semantic [85] tasks. The posterior part of the cingulate gyrus is usu-…”

Section: Discussionmentioning

confidence: 96%

Sustained attention in psychosis: Neuroimaging findings

Sepede¹

2014

WJR

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To provide a systematic review of scientific literature on functional magnetic resonance imaging (fMRI) studies on sustained attention in psychosis. We searched PubMed to identify fMRI studies pertaining sustained attention in both affective and non-affective psychosis. Only studies conducted on adult patients using a sustained attention task during fMRI scanning were included in the final review. The search was conducted on September 10 th , 2013. 15 fMRI studies met our inclusion criteria: 12 studies were focused on Schizophrenia and 3 on Bipolar Disorder Type Ⅰ (BDI). Only half of the Schizophrenia studies and two of the BDI studies reported behavioral abnormalities, but all of them evidenced significant functional differences in brain regions related to the sustained attention system. Altered functioning of the insula was found in both Schizophrenia and BDI, and therefore proposed as a candidate trait marker for psychosis in general. On the other hand, other brain regions were differently impaired in affective and non-affective psychosis: alterations of cingulate cortex and thalamus seemed to be more common in Schizophrenia and amygdala dysfunctions in BDI. Neural correlates of sustained attention seem to be of great interest in the study of psychosis, highlighting differences and similarities between Schizophrenia and BDI. Key words: Sustained attention; Affective psychosis; Non-affective psychosis; Schizophrenia; Bipolar disorder; Functional magnetic resonance imaging; Insula Core tip: In the present paper, we systematically reviewed functional magnetic resonance imaging studies investigating sustained attention in affective and nonaffective psychosis. We found that differences between cases (patients, unaffected relatives of psychotic probands) and controls in terms of functional activation of sustained attention system structures were detectable even when the groups performed comparably. In particular, the insular cortex seems to be a trait marker for psychosis in general, whereas other regions (thalamus, cingulate cortex, amygdala) seem to be differently impaired in affective and non-affective psychosis.

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Converging Evidence for the Association of Functional Genetic Variation in the Serotonin Receptor 2a Gene With Prefrontal Function and Olanzapine Treatment

et al. 2013

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Nonlinear Response of the Anterior Cingulate and Prefrontal Cortex in Schizophrenia as a Function of Variable Attentional Control

Cited by 30 publications

References 40 publications

DRD2/AKT1interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia

DRD2/AKT1interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia

Sustained attention in psychosis: Neuroimaging findings

Converging Evidence for the Association of Functional Genetic Variation in the Serotonin Receptor 2a Gene With Prefrontal Function and Olanzapine Treatment

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