Altered cortical network dynamics: A potential intermediate phenotype for schizophrenia and association with ZNF804A

Context: Studies have shown patterns of abnormal dorsolateral prefrontal cortex (DLPFC) functional connectivity with other brain areas in schizophrenia and association of these patterns with a putative susceptibility gene (ZNF804A). However, whether these patterns are trait phenomena linked to genetic risk for illness is unclear. Objective: To test the hypotheses that altered DLPFC connectivity is (1) a familial, likely heritable feature of genetic risk for schizophrenia, (2) a novel intermediate phenotype independent of altered DLPFC engagement, and (3) selectively modulated by a polymorphism in ZNF804A. Design: Cross-sectional case-control study using blood oxygen level-dependent functional magnetic resonance imaging during a working memory task and genotyping of rs1344706 in ZNF804A. Setting: Research center. Participants: A total of 402 subjects (153 cognitively normal controls, 171 healthy siblings of patients with schizophrenia, and 78 patients). Main Outcome Measures: Task-independent and task-dependent physiologic coupling between the DLPFC and other brain "target" regions investigated with (1) seeded connectivity and (2) psychophysiological interaction analysis. Results: Siblings and patients showed greater DLPFC" in-efficiency" than controls. Abnormal DLPFC functional coupling with the hippocampus and, to a lesser degree, the rest of the prefrontal cortex, was observed in patients and siblings when compared with controls using both connectivity analyses. Prefrontal activation and connectivity measures within siblings did not correlate, implying that they were independent phenomena. The ZNF804A genotype significantly modulated DLPFC coupling with the hippocampus and prefrontal cortex but not DLPF Cactivity in the control group. Similarly, ZNF804A genotype modulated right DLPFC-hippocampal formation coupling in siblings and patients. Conclusions: Coupling between the DLPFC and hippocampus is compromised in siblings of patients with schizophrenia and is independent of DLPFC engagement. The selective association with a single-nucleotide polymorphism in ZNF804A suggests that this intermediate phenotype proxies a distinct neural system mechanism related to genetic risk for schizophrenia and the biology of this gene

Seeking Optimal Region-Of-Interest (ROI) Single-Value Summary Measures for fMRI Studies in Imaging Genetics.

A data-driven hypothesis-free genome-wide association (GWA) approach in imaging genetics studies allows screening the entire genome to discover novel genes that modulate brain structure, chemistry, and function. However, a whole brain voxel-wise analysis approach in such genome-wide based imaging genetic studies can be computationally intense and also likely has low statistical power since a stringent multiple comparisons correction is needed for searching over the entire genome and brain. In imaging genetics with functional magnetic resonance imaging (fMRI) phenotypes, since many experimental paradigms activate focal regions that can be pre-specified based on a priori knowledge, reducing the voxel-wise search to single-value summary measures within a priori ROIs could prove efficient and promising. The goal of this investigation is to evaluate the sensitivity and reliability of different single-value ROI summary measures and provide guidance in future work. Four different fMRI databases were tested and comparisons across different groups (patients with schizophrenia, their siblings, vs. normal control subjects; across genotype groups) were conducted. Our results show that four of these measures, particularly those that represent values from the top most-activated voxels within an ROI are more powerful at reliably detecting group differences and generating greater effect sizes than the others

Altered hippocampal-parahippocampal function during stimulus encoding:A potential indicator of genetic liability for schizophrenia

IMPORTANCE Declarative memory-the ability to learn, store, and retrieve information-has been consistently reported to be altered in schizophrenia, and hippocampal-parahippocampal dysfunction has been implicated in this deficit. To elucidate the possible role of genetic risk factors in such findings, it is necessary to study healthy relatives of patients with schizophrenia who carry risk-associated genes but not the confounding factors related to the disorder. OBJECTIVE To investigate whether altered brain responses, particularly in the hippocampus and parahippocampus, during the encoding phase of a simple declarative memory task are also observed in unaffected siblings who are at increased genetic risk for schizophrenia. DESIGN, SETTING, AND PARTICIPANTS Functional magnetic resonance imaging was used with a simple visual declarative memory paradigm to test for differences in neural activation across normal control participants, patients with schizophrenia, and their healthy siblings. This study was conducted at a research center and included a total of 308 participants (181 normal control participants, 65 healthy siblings, and 62 patients with schizophrenia); all participants were white of European ancestry. MAIN OUTCOMES AND MEASURES All participants completed a declarative memory task involving incidental encoding of neutral visual scenes interleaved with crosshair fixation while undergoing functional magnetic resonance imaging. Differences in hippocampus and parahippocampus activation and coupling across groups and correlations with accuracy were analyzed. Analyses were repeated in pairwise-matched samples. RESULTS Both patients with schizophrenia and their healthy siblings showed reduced parahippocampal activation (bilaterally) and hippocampal-parietal (BA 40) coupling during the encoding of novel stimuli when compared with normal control participants. There was a significant positive correlation between parahippocampal activation during encoding and the visual-memory score. CONCLUSIONS AND RELEVANCE These results suggest that altered hippocampal-parahippocampal function during encoding is an intermediate biologic phenotype related to increased genetic risk for schizophrenia. Therefore, measuring hippocampal-parahippocampal function with neuroimaging represents a potentially useful approach to understanding genetic mechanisms that confer risk for schizophrenia

Group mean plots for two NBack datasets.

<p>(a) The split dataset PTs vs. NCs; and (b) the Sibling dataset, PTs vs. SIBs vs. NCs. Selected ROI summary measures (mean, mean of voxels above <i>p</i> = 0.05 threshold, peak, and peak-correlated voxels) were used to extract single-value summaries from three types of ROIs in right DLPFC. * <i>p</i> < 0.05; ** <i>p</i> < 0.01. Error bars represent standard errors.</p

Results summary.

<p>We (a) combined the results of the two-sample <i>t</i> tests by averaging the effect sizes from dataset 1 and 4 together; and (b) combined the one-way ANOVA results by averaging the effect sizes from dataset 2 and 3. The horizontal lines in (a) represent the medium effect size (0.50) for Cohen’s d and the lines in (b) represent the small effect size for Omega squared (0.01).</p

Group difference results from the voxel-wise analysis within anatomical ROIs.

<p>Group difference results from the voxel-wise analysis within anatomical ROIs.</p

The generalizability of the ROI single value summary measures is further examined across three datasets.

<p>(a) The NBack Sibling dataset, PTs vs. SIBs vs. NCs, one-way ANOVA; (b) the NBack COMT dataset, Val/Val vs. Val/Met vs. Met/Met, one-way ANOVA; and (c) the Flanker dataset, NCs vs. PTs, <i>t</i> test.</p