The effects of a DTNBP1 gene variant on attention networks: an fMRI study

<p>Abstract</p> <p>Background</p> <p>Attention deficits belong to the main cognitive symptoms of schizophrenia and come along with altered neural activity in previously described cerebral networks. Given the high heritability of schizophrenia the question arises if impaired function of these networks is modulated by susceptibility genes and detectable in healthy risk allele carriers.</p> <p>Methods</p> <p>The present event-related fMRI study investigated the effect of the single nucleotide polymorphism (SNP) rs1018381 of the <it>DTNBP1 </it>(dystrobrevin-binding protein 1) gene on brain activity in 80 subjects while performing the attention network test (ANT). In this reaction time task three domains of attention are probed simultaneously: alerting, orienting and executive control of attention.</p> <p>Results</p> <p>Risk allele carriers showed impaired performance in the executive control condition associated with reduced neural activity in the left superior frontal gyrus [Brodmann area (BA) 9]. Risk allele carriers did not show alterations in the alerting and orienting networks.</p> <p>Conclusions</p> <p>BA 9 is a key region of schizophrenia pathology and belongs to a network that has been shown previously to be involved in impaired executive control mechanisms in schizophrenia. Our results identified the impact of <it>DTNBP1 </it>on the development of a specific attention deficit via modulation of a left prefrontal network.</p

Inefficient DMN Suppression in Schizophrenia Patients with Impaired Cognitive Function but not Patients with Preserved Cognitive Function

Previous studies have observed reduced suppression of the default mode network (DMN) during cognitive tasks in schizophrenia, suggesting inefficient DMN suppression is critical for the cognitive deficits of schizophrenia. Cognitive function in schizophrenia patients, however, varies from relatively intact to severely impaired. This study, which compared the DMN suppression patterns between first-episode schizophrenia patients with (SZ-Imp) and without (SZ-Pre) impaired cognitive function, may provide further insight into the role of DMN dysfunction in cognitive deficits of schizophrenia. Independent component analysis (ICA) was applied to resting-state fMRI data to identify the DMN in each subject, and then general linear modeling based on the task-fMRI data was used to examine the different DMN activation patterns between groups. We observed that the SZ-Imp group, but not the SZ-Pre group, showed reduced suppression in the medial prefrontal cortex and posterior cingulated cortexPrevious studies have observed reduced suppression of the default mode network (DMN) when compared to the healthy controls (HC) group. Moreover, less DMN suppression was associated with poorer task performance in both HC and patient groups. Our findings provide the first direct evidence that disrupted DMN activity only exists in schizophrenia patients with impaired cognitive function, supporting the specific neuro-pathological role of inefficient DMN suppression in cognitive deficits of first-episode schizophrenia

Schizophrenia-like Cognitive, Trait and DNA Markers in Regular Cannabis Users

Rationale: Converging evidence suggests that cannabis use can induce psychosis and is a distinct risk factor for schizophrenia. Taken together with the effects of Tetrahydrocannabinol (THC) on neural systems, dopamine and endocannabinoids it is likely that cannabis use may also produce sub- clinical psychosis-linked changes in a much larger number of regular recreational users; observable in schizophrenia-sensitive assessments. Use of the drug by individuals with genetic risk factors for schizophrenia appears to magnify the chances of pathology, and so changes in recreational users with one or more of these genetic markers may be more evident or pronounced. Method: 50 cannabis users and 50 non cannabis users were assessed in each of two studies. Study one assessed selective attention in the Latent Inhibition (LI) and Kamin Blocking (KB) paradigms and examined schizophrenia-linked traits using the short form of the Schizotypal Personality Questionnaire (the SPQ-B; Raine and Benishay, 1995). Study two assessed executive control (using an Anti-Saccade Test), decision-making (using the Iowa Gambling Task), and selective/sustained attention and inhibitory control (Continuous Performance Test). Study two included additional personality measures to explore paranoia, emotional processing, ambivalence and impulsivity. Across both studies, the relative contribution of seven genetic risk markers in five candidate genes for schizophrenia (DAOA, COMT, NRG1, FAAH and CNR1) were assessed. Key Results: Cannabis use was associated with abolished latent inhibition and significantly riskier decision making, especially in those who used the drug more frequently. Cannabis users reported significantly higher scores for psychosis-linked personality traits and there was a dose-response effect with heavier users experiencing more of these schizotypal traits. Some key trends existed in the genotyping data for the cannabis group. The psychosis-risk C allele in the NRG1 gene was linked to higher SPQ-B scores and more errors on the AST; and was also associated with longer use of cannabis. Cannabis users without the protective three-way T-G-G haplotype COMT gene had higher scores for the SPQ-B disorganised thinking subscale than users with the protective haplotype. Discussion: The data in this thesis suggests that cannabis users are showing differences in brain inhibitory function and decision-making akin to previous research with schizophrenic patients, their first degree relatives and high schizotypy scorers. Exposure to THC may contribute to changes in individuals by pushing them further along a schizophrenia-spectrum resulting in the display of more psychotic-like traits and cognitive dysfunction at sub-clinical levels. These preliminary findings need expansion and replication, particularly with regards to the COMT three-way haplotype