Association of rs1006737 in CACNA1C with alterations in prefrontal activation and fronto-hippocampal connectivity.

BACKGROUND: Genome-wide association studies have identified the rs1006737 single nucleotide polymorphism (SNP) in the CACNA1C gene as a susceptibility locus for schizophrenia and bipolar disorder. On the neural systems level this association is explained by altered functioning of the dorsolateral prefrontal cortex (DLPFC) and the hippocampal formation (HF), brain regions also affected by mental illness. In the present study we investigated the association of rs1006737 genotype with prefrontal activation and fronto-hippocampal connectivity. METHODS: We used functional magnetic resonance imaging to measure neural activation during an n-back working memory task in 94 healthy subjects. All subjects were genotyped for the SNP rs1006737. We tested associations of the rs1006737 genotype with changes in working-memory-related DLPFC activation and functional integration using a seed region functional connectivity approach. RESULTS: Rs1006737 genotype was associated with altered right-hemispheric DLPFC activation. The homozygous A (risk) group showed decreased activation compared to G-allele carriers. Further, the functional connectivity analysis revealed a positive association of fronto-hippocampal connectivity with rs1006737 A alleles. CONCLUSIONS: We did not replicate the previous findings of increased right DLPFC activation in CACNA1C rs1006737 A homozygotes. In fact, we found the opposite effect, thus questioning prefrontal inefficiency as rs1006737 genotype-related intermediate phenotype. On the other hand, our results indicate that alterations in the functional coupling between the prefrontal cortex and the medial temporal lobe could represent a neural system phenotype that is mediated by CACNA1C rs1006737 and other genetic susceptibility loci for schizophrenia and bipolar disorder.

Partial support for ZNF804A genotype-dependent alterations in prefrontal connectivity.

Genome-wide association studies identified the single nucleotide polymorphism rs1344706 in ZNF804A as a common risk-variant for schizophrenia and bipolar disorder. Whereas the molecular function of ZNF804A is yet unclear, recent imaging genetics studies have started to characterize the neural systems architecture linking rs1344706 genotype to psychosis. Carring rs1344706 risk-alleles was associated with a decrease in functional connectivity within the dorsolateral prefrontal cortices (DLPFCs) as well as an increase in connectivity between the DLPFC and the hippocampal formation (HF) in the context of a working memory task. The present study aimed at replicating these findings in an independent sample of 94 healthy subjects. Subjects were genotyped for rs1344706 and performed a working memory task during functional magnetic resonance imaging. Results indicate no support for a decrease of functional coupling between the bilateral DLPFCs at higher ZNF804A risk status. However, the current data show the previously described alteration in functional coupling between the right DLPFC and the HFs, albeit with weaker effects. Decoupled by default, the functional connectivity between the right DLPFC and anterior HFs increased with the number of rs1344706 risk alleles. The present data support fronto-hippocampal dysconnectivity as intermediate phenotype linking rs1344706 genotype to psychosis. We discuss the issues in replicating the interhemispheric DLPFC coupling in light of the effect sizes rs1344706 genotype has on brain function, concluding that further independent replication studies are fundamentally needed to ascertain the role of rs1344706 in the functional integration of neural systems.

Determination of crossed language dominance: dissociation of language lateralization within the temporoparietal cortex.

'Crossed language dominance' is a rare form of language lateralization, characterized by a dissociation of anterior and posterior language regions. We present the case of a healthy subject whose language lateralization pattern, as assessed by functional magnetic resonance imaging, is reliably characterized as crossed language dominance based on a word generation task, but typical left-lateralized when a semantic decision task is applied. A single language task is therefore not sufficient to characterize language lateralization, at least not for subjects with rare forms of language dominance. In the pre-surgical diagnostic of language lateralization, several language tasks tapping into different aspects of language functions should be applied.

Test-Retest Reliability of fMRI Brain Activity during Memory Encoding.

The mechanisms underlying hemispheric specialization of memory are not completely understood. Functional magnetic resonance imaging (fMRI) can be used to develop and test models of hemispheric specialization. In particular for memory tasks however, the interpretation of fMRI results is often hampered by the low reliability of the data. In the present study we therefore analyzed the test-retest reliability of fMRI brain activation related to an implicit memory encoding task, with a particular focus on brain activity of the medial temporal lobe (MTL). Fifteen healthy subjects were scanned with fMRI on two sessions (average retest interval 35 days) using a commonly applied novelty encoding paradigm contrasting known and unknown stimuli. To assess brain lateralization, we used three different stimuli classes that differed in their verbalizability (words, scenes, fractals). Test-retest reliability of fMRI brain activation was assessed by an intraclass-correlation coefficient (ICC), describing the stability of inter-individual differences in the brain activation magnitude over time. We found as expected a left-lateralized brain activation network for the words paradigm, a bilateral network for the scenes paradigm, and predominantly right-hemispheric brain activation for the fractals paradigm. Although these networks were consistently activated in both sessions on the group level, across-subject reliabilities were only poor to fair (ICCs ≤ 0.45). Overall, the highest ICC values were obtained for the scenes paradigm, but only in strongly activated brain regions. In particular the reliability of brain activity of the MTL was poor for all paradigms. In conclusion, for novelty encoding paradigms the interpretation of fMRI results on a single subject level is hampered by its low reliability. More studies are needed to optimize the retest reliability of fMRI activation for memory tasks.

Functional connectivity analyses in imaging genetics: considerations on methods and data interpretation.

Functional magnetic resonance imaging (fMRI) can be combined with genotype assessment to identify brain systems that mediate genetic vulnerability to mental disorders ("imaging genetics"). A data analysis approach that is widely applied is "functional connectivity". In this approach, the temporal correlation between the fMRI signal from a pre-defined brain region (the so-called "seed point") and other brain voxels is determined. In this technical note, we show how the choice of freely selectable data analysis parameters strongly influences the assessment of the genetic modulation of connectivity features. In our data analysis we exemplarily focus on three methodological parameters: (i) seed voxel selection, (ii) noise reduction algorithms, and (iii) use of additional second level covariates. Our results show that even small variations in the implementation of a functional connectivity analysis can have an impact on the connectivity pattern that is as strong as the potential modulation by genetic allele variants. Some effects of genetic variation can only be found for one specific implementation of the connectivity analysis. A reoccurring difficulty in the field of psychiatric genetics is the non-replication of initially promising findings, partly caused by the small effects of single genes. The replication of imaging genetic results is therefore crucial for the long-term assessment of genetic effects on neural connectivity parameters. For a meaningful comparison of imaging genetics studies however, it is therefore necessary to provide more details on specific methodological parameters (e.g., seed voxel distribution) and to give information how robust effects are across the choice of methodological parameters.