Interhemispheric hypoconnectivity in schizophrenia: Fiber integrity and volume differences of the corpus callosum in patients and unaffected relatives

Abstract

Changes in hemispheric asymmetry and inter-hemispheric connectivity have been reported in schizophrenia. However, the genetic contribution to these alterations is still unclear. In the current study, we applied an automatic segmentation method to structural MRI and diffusion tensor imaging (DTI) data and examined volume and fiber integrity of the corpus callosum (CC), the main interhemispheric fiber tract, in 16 chronic schizophrenia (SZ) patients, matched first degree relatives and controls. SZ patients and relatives had smaller CC volumes than controls, particularly in the posterior genu, isthmus and splenium. Fractional anisotropy (FA), an indicator of fiber integrity, was reduced in patients and relatives in the whole CC, the inferior genu, the superior genu and the isthmus. Correspondingly, the mean diffusivity (MD) values of the whole CC and the isthmus were higher in patients and their unaffected relatives, indicating decreased compactness and increased intercellular space. Relatives had intermediate values in the volumetric and fiber integrity measurements between patients and controls. Lower CC volume and fiber integrity in SZ patients were associated with more severe auditory hallucinations. These results support the connectivity hypothesis of SZ (Friston, 1998) and particularly highlight the altered interhemispheric connectivity, which appears to be a genetic feature of SZ risk.

Introduction

Because of the heterogeneity of neuroanatomical changes in schizophrenia (Fletcher et al., 1999, Friston and Frith, 1995, Honea et al., 2005, Hubl et al., 2004, Lawrie et al., 2008, Rotarska-Jagiela et al., 2009, Friston, 1998) it has been proposed that the primary disease mechanism affects neuronal coordination (e.g., Uhlhaas and Singer, 2010) and connectivity rather than changes in isolated brain regions. Moreover, the role of disturbed functional connectivity in the genetic risk architecture of schizophrenia is of great interest (Esslinger et al., 2009, Esslinger et al., 2011).

Both dysfunctional interhemispheric and fronto-temporal coordination and connectivity are prominent candidate mechanisms. Aberrant fronto-temporal connectivity in SZ patients have been reported frequently (Burns et al., 2003, Lawrie and Abukmeil, 1998, Wright et al., 2000), and some researchers have suggested that frontoparietal integration may be similarly abnormal (Honey et al., 2002, Lawrie and Abukmeil, 1998, Spence et al., 1997).

Another area of central interest for the SZ spectrum is the investigation of the connections of the corpus callosum, which is the main interhemispheric commissure. Most magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) studies revealed evidences of aberrant CC structure in schizophrenia. MRI studies showed a significantly smaller volume of the CC or its subregions in SZ patients (Downhill et al., 2000, Goghari et al., 2005). Converging evidence came from post-mortem studies (Crow et al., 1989, Pierri et al., 2001) showing an association between the decreased numbers of pyramid cells in Lamina III in SZ patients, where most CC axons originate, and disturbances in the cortico-cortical connectivity. Progressive changes in CC volume and integrity in neuropsychiatric disorders can correlate with cortical atrophy changes (Hampel et al., 1998).

The volume of the CC was also reduced in first-episode SZ patients (Aydin et al., 2008) and even in high-risk individuals (Aydin et al., 2008, Walterfang et al., 2009). However, the high-risk group was defined not only by genetic risk but also on the basis of functional deficits. Thus, Chua et al. (2000) were the only group who investigated the CC size of completely healthy family members of SZ patients. They measured the volume of the mid-sagittal slice of the corpus callosum and found no difference between SZ patients, their family members and healthy controls. This finding stands out from the literature that generally reports decreased size of corpus callosum in schizophrenia, and may have been a result of the restricted imaging method (single slice measurement).

The integrity of white matter (WM) tracts can be assessed with diffusion tensor imaging (DTI), computing the fractional anisotropy (FA), which estimates the coherence of oriented structures, e.g. myelinated axons (Cercignani and Horsfield, 2001), or the mean diffusivity (MD), which is related to compactness and intercellular space (Beaulieu, 2002) and independent of fiber directionality (Basser and Roth, 2000). Most DTI studies reported decreased FA values for SZ patients in the whole or parts of the CC (Agartz et al., 2001, Ardekani et al., 2003, Buchsbaum et al., 2006, Hubl et al., 2004, Rotarska-Jagiela et al., 2008). However, some studies have not shown FA differences in the corpus callosum, e.g. in chronic patients (Voineskos et al., 2010), and in first-episode patients (Friedman et al., 2008).

Ellison-Wright and Bullmore (2009) supported the finding of FA reductions in the CC in a meta-analysis of 15 studies. They also indicated FA reduction in a number of other regions, including the left frontal deep white matter and its white matter tracts interconnecting the frontal lobe, thalamus and cingulate gyrus, and the left temporal deep white matter and its white matter tracts interconnecting the frontal lobe, insula, hippocampus-amygdala, temporal and occipital lobe. There is also evidence for increased MD values in SZ patients (Rotarska-Jagiela et al., 2008). Furthermore, studies of white matter integrity in relatives (Camchong et al., 2009, Narr et al., 2009) and high-risk individuals of schizophrenia patients reduced FA values in medial prefrontal cortex (Narr et al., 2009), the anterior limb of the internal capsule (Muñoz Maniega et al., 2008) and the superior longitudinal fasciculus (Karlsgodt et al., 2009) and increased MD values in superior temporal lobe (Narr et al., 2009).

To date, the current literature indicates that there is a network of aberrant white matter tracts, mainly in the interconnection between frontal, temporal and limbic regions, with disconnected gray matter regions which might refer to these networks. Therefore, the comparison of volume and integrity of the CC and its subregions in SZ patients, healthy first-degree relatives and controls, is of main interest in the current study. We expected differences in CC volume and fiber integrity across the three subject groups, with lowest values in patients and intermediate values in relatives. Finally, we investigated if anatomical changes in the CC were related to illness duration and severity of symptoms.