Altered integrity of the right arcuate fasciculus as a trait marker of schizophrenia: a sibling study using tractography-based analysis of the whole brain

Abstract

Trait markers of schizophrenia aid the dissection of the heterogeneous phenotypes into distinct subtypes and facilitate the genetic underpinning of the disease. The microstructural integrity of the white matter tracts could serve as a trait marker of schizophrenia, and tractography-based analysis (TBA) is the current method of choice. Manual tractography is time-consuming and limits the analysis to preselected fiber tracts. Here, we sought to identify a trait marker of schizophrenia from among 74 fiber tracts across the whole brain using a novel automatic TBA method. Thirty-one patients with schizophrenia, 31 unaffected siblings and 31 healthy controls were recruited to undergo diffusion spectrum magnetic resonance imaging at 3T. Generalized fractional anisotropy (GFA), an index reflecting tract integrity, was computed for each tract and compared among the three groups. Ten tracts were found to exhibit significant differences between the groups with a linear, stepwise order from controls to siblings to patients; they included the right arcuate fasciculus, bilateral fornices, bilateral auditory tracts, left optic radiation, the genu of the corpus callosum, and the corpus callosum to the bilateral dorsolateral prefrontal cortices, bilateral temporal poles, and bilateral hippocampi. Posthoc between-group analyses revealed that the GFA of the right arcuate fasciculus was significantly decreased in both the patients and unaffected siblings compared to the controls. Furthermore, the GFA of the right arcuate fasciculus exhibited a trend toward positive symptom scores. In conclusion, the right arcuate fasciculus may be a candidate trait marker and deserves further study to verify any genetic association.

Keywords: diffusion spectrum imaging; endophenotype; schizophrenia; tractography; trait marker.

Figure 1

Illustration of the six steps of the TBAA. LDDMM, large deformation diffeomorphic metric mapping; DSI, diffusion spectrum imaging; SST, study‐specific template; GFA, generalized fractional anisotropy.

Figure 2

Three‐dimensional fiber tracking of the 10 tracts. (a) Right arcuate fasciculus: ROIs, R STG and R IFG oper. (b) Left fornix: ROIs, L MB and L HP. (c) Right fornix: ROIs, R MB and R HP. (d) Left auditory tract: ROIs, L Th, and L AC. (e) Right auditory tract: ROIs, R Th, and R AC. (f) Left optic radiation: ROIs, L Th, and L SOG. (g) The genu of the corpus callosum: ROIs, R OFG, and L OFG. (h) The corpus callosum to the bilateral DLPFC: ROIs, R DLPFC, and L DLPFC. (i) The corpus callosum to the bilateral temporal poles: ROIs, R TP, and L TP. (j) The corpus callosum to the bilateral hippocampi: ROIs, R HP, and L HP. ROIs, regions of interest; R, right; L, left; STG, superior temporal gyrus; IFG oper, the opercular portion of the inferior frontal gyrus; MB, mammillary body; Th, thalamus; AC: auditory cortex; HP, hippocampus; SOG, superior occipital gyrus; CC, corpus callosum; OFG, orbital frontal gyrus; DLPFC, dorsal lateral prefrontal gyrus; TP, temporal pole.