Connectome organization is related to longitudinal changes in general functioning, symptoms and IQ in chronic schizophrenia
Introduction
Schizophrenia's etiology has long since been related to alterations in the wiring architecture of the brain's network (Stephan et al., 2009, Rubinov and Bassett, 2011, Van den Heuvel and Kahn, 2011, Fornito et al., 2012, Van den Heuvel and Fornito, 2014, Wheeler and Voineskos, 2014). A comprehensive map of the white matter pathways connecting disparate areas of the human brain is referred to as the macroscale connectome (Hagmann, 2005, Sporns et al., 2005). Emerging evidence on connectome structure in schizophrenia suggests disease-related changes to include affected neural communication, aberrant local organization and modular structure and a less central position of brain hubs (Bassett et al., 2008, Lynall et al., 2010, Skudlarski et al., 2010, Van den Heuvel et al., 2010). These putative brain hubs have been suggested to reside in multimodal association areas of the cortex, to participate in complex and diverse neuronal communication (Rubinov and Bullmore, 2013, Van den Heuvel and Sporns, 2013, De Reus and Van den Heuvel, 2014, Senden et al., 2014) and to be mutually connected into a core collective referred to as a ‘rich club’ (Van den Heuvel and Sporns, 2011, Van den Heuvel et al., 2012). The white matter pathways comprising this central communication system have been suggested to be disproportionally affected in schizophrenia (Van den Heuvel et al., 2013). Moreover, unaffected siblings of patients to show similar, though attenuated, effects (Collin et al., 2014). Such findings of connectome alterations in first-degree relatives (Repovs et al., 2011, Fornito et al., 2013, Collin et al., 2014), who are at increased genetic risk for schizophrenia but lack the potential impact of (untreated) psychosis (Cahn et al., 2009) and psychotropic medication (Nejad et al., 2012, Vita et al., 2012), have led to the hypothesis that affected connectome organization might be reflective of an inherited neurodevelopmental vulnerability to the disorder (Collin and Van den Heuvel, 2013, Skudlarski et al., 2013, Van den Heuvel and Fornito, 2014).
Cross-sectional investigations of brain network organization in relation to illness severity in schizophrenia have suggested global and local network efficiency to be related to severity of both positive (Wang et al., 2012) and negative (Yu et al., 2011, Wang et al., 2012) symptoms. In addition, reduced levels of functional network cost-efficiency have been associated with poorer working memory performance (Bassett et al., 2009). An open question regarding connectome abnormalities in schizophrenia (Dauvermann et al., 2014)—altered hub connectivity in particular (Van den Heuvel and Kahn, 2011)—is whether, and if so how, alterations in macroscale connectome wiring relate to illness progression and outcome. Persistent symptoms (Lieberman, 1999) and real-world deficits in areas such as employment (Harvey and Velligan, 2011) and everyday living (Harvey et al., 2009, Leifker et al., 2009) are common in patients, but prognosis at the individual level is heterogeneous (Schultz and Andreasen, 1999). Relating connectome architecture to progression of illness and functional deficits might inform prognostic estimations. In this longitudinal study, a group of schizophrenia patients, investigated previously in two cross-sectional connectome studies (Van den Heuvel et al., 2013, Collin et al., 2014), was reassessed after 3 years follow-up. Changes over time in general and intellectual functioning and clinical symptoms were evaluated and related to connectome structure at baseline. Particular emphasis was placed on examining the predictive value of measures of connectome topology (e.g., clustering, global efficiency and rich club organization) in terms of illness progression in the 3 years following MRI assessment.
Section snippets
Participants
A sample of 30 schizophrenia patients, from a total sample of 40 patients of whom diffusion-weighted imaging data were examined previously as part of two studies on connectome architecture in patients (Van den Heuvel et al., 2013) and their unaffected siblings (Collin et al., 2014), were included in the current study. Longitudinal data on functional outcome, IQ and symptomatology at 3-year follow-up were examined in relation to connectome structure. In addition, from the baseline sample
Clinical measurements at time of scan acquisition and follow-up
Out of the original forty patients in our previous investigations (Van den Heuvel et al., 2013, Collin et al., 2014), thirty were reassessed after 3 years (T-FU) and ten were lost to follow-up (see Supplementary material for details). There were no significant differences in clinical or MRI measures between subjects that were lost to follow-up, relative to those reevaluated at T-FU (Supplementary material).
On average, patients showed more clinical symptoms as measured by PANSS total symptoms at
Discussion
Structural connectome wiring was examined in relation to longitudinal changes in general and intellectual functioning and clinical symptoms in 3 years following MRI assessment in a cohort of chronically ill schizophrenia patients. Examining patients' functioning over time revealed more severely affected wiring of the connectome—especially concerning rich club connections—to precede a progressive decrease in functional performance over time, while relative sparing of these connections preceded
Role of funding source
The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Contributors
Authors WC and JdN were responsible for data collection. Authors GC and MPvdH designed the study and analyzed the data. Author GC wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.
Conflict of interest
The authors report no conflict of interest.
Acknowledgments
Dr. M.P. van den Heuvel is supported by a VENI (no. 451-12-001) grant from the Netherlands Organization for Scientific Research (NWO).
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WC and MPvdH contributed equally to this work.