Disruptions in the left frontoparietal network underlie resting state endophenotypic markers in schizophrenia

Abstract

Advances in functional brain imaging have improved the search for potential endophenotypic markers in schizophrenia. Here, we employed independent component analysis (ICA) and dynamic causal modeling (DCM) in resting state fMRI on a sample of 35 schizophrenia patients, 20 first-degree relatives and 35 control subjects. Analysis on ICA-derived networks revealed increased functional connectivity between the left frontoparietal network (FPN) and left temporal and parietal regions in schizophrenia patients (P < 0.001). First-degree relatives shared this hyperconnectivity, in particular in the supramarginal gyrus (SMG; P = 0.008). DCM analysis was employed to further explore underlying effective connectivity. Results showed increased inhibitory connections to the left angular gyrus (AG) in schizophrenia patients from all other nodes of the left FPN (P < 0.001), and in particular from the left SMG (P = 0.001). Relatives also showed a pattern of increased inhibitory connections to the left AG (P = 0.008). Furthermore, the patient group showed increased excitatory connectivity between the left fusiform gyrus and the left SMG (P = 0.002). This connection was negatively correlated to inhibitory afferents to the left AG (P = 0.005) and to the negative symptom score on the PANSS scale (P = 0.001, r = -0.51). Left frontoparietotemporal dysfunction in schizophrenia has been previously associated with a range of abnormalities, including formal thought disorder, working memory dysfunction and sensory hallucinations. Our analysis uncovered new potential endophenotypic markers of schizophrenia and shed light on the organization of the left FPN in patients and their first-degree relatives. Hum Brain Mapp 38:1741-1750, 2017. © 2017 Wiley Periodicals, Inc.

Keywords: biomarker; endophenotypes; neuroimaging; schizophrenia.

Figure 1

Location of the nodes that are part of the DCM analysis. AC: anterior cingulate, IFG: inferior frontal gyrus, AG: angular gyrus, SMG: supramarginal gyrus and OTC: occipitotemporal cortex. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 2

Profiles of networks chosen for subsequent analyses. IC corresponds to “independent component” followed by a number indicating the position of the network in regards to its capacity to explain variance in the data. Areas in red correspond to thresholded z values outputted from the independent component analysis. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 3

Clusters showing significant differences in connectivity with the LFP between A) the SZ and hMC groups and B) the RL and mHC groups. Both patients and relatives showed higher connectivity with the LFP in comparison to control in a similar region. Shown are voxels with P < 0.001 uncorrected. The colorbar corresponds to t values. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 4

Mean effective connectivity parameters for all connections and for each of the three groups in Hz. Rows correspond to sources and columns to destinations. Nonself connections were predominantly excitatory on average, with the exception of afferent connections to the left AG which were inhibitory in the patient and relative groups. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 5

Mean effective connectivity in Hz for afferent connections to the left AG. Error bars represent standard errors of the mean. Single stars correspond to P < 0.05 and double stars to P < 0.006 after correction for multiple comparisons. A two way ANOVA with afferent connection to the left AG (with exception of selfconnection) and group as factors was significant in comparison to control for both patients (P < 0.001) and relatives (P = 0.008). [Color figure can be viewed at http://wileyonlinelibrary.com]