Connectome organization is related to longitudinal changes in general functioning, symptoms and IQ in chronic schizophrenia

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Abstract

Emerging evidence suggests schizophrenia to involve widespread alterations in the macroscale wiring architecture of the human connectome. Recent findings of attenuated connectome alterations in unaffected siblings of schizophrenia patients suggest that altered connectome organization may relate to the vulnerability to develop the disorder, but whether it relates to progression of illness after disease onset is currently unknown. Here, we examined the interaction between connectome structure and longitudinal changes in general functioning, clinical symptoms and IQ in the 3 years following MRI assessment in a group of chronically ill schizophrenia patients. Effects in patients were compared to associations between connectome organization and changes in subclinical symptoms and IQ in healthy controls and unaffected siblings of schizophrenia patients. Analyzing the patient sample revealed a relationship between structural connectivity—particularly among central ‘brain hubs’—and progressive changes in general functioning (p = 0.007), suggesting that more prominent impairments of hub connectivity may herald future functional decline. Our findings further indicate that affected local connectome organization relates to longitudinal increases in overall PANSS symptoms (p = 0.013) and decreases in total IQ (p = 0.003), independent of baseline symptoms and IQ. No significant associations were observed in controls and siblings, suggesting that the findings in patients represent effects of ongoing illness, as opposed to normal time-related changes. In all, our findings suggest connectome structure to have predictive value for the course of illness in 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).

References (85)

  • J.L. Rapoport et al.

    Childhood onset schizophrenia: support for a progressive neurodevelopmental disorder

    Int. J. Dev. Neurosci.

    (2011)
  • G. Repovs et al.

    Brain network connectivity in individuals with schizophrenia and their siblings

    Biol. Psychiatry

    (2011)
  • M. Rubinov et al.

    Complex network measures of brain connectivity: uses and interpretations

    NeuroImage

    (2010)
  • M. Senden et al.

    Rich club organization supports a diverse set of functional network configurations

    NeuroImage

    (2014)
  • P. Skudlarski et al.

    Brain connectivity is not only lower but different in schizophrenia: a combined anatomical and functional approach

    Biol. Psychiatry

    (2010)
  • A.F. Terwisscha van Scheltinga et al.

    Genetic schizophrenia risk variants jointly modulate total brain and white matter volume

    Biol. Psychiatry

    (2013)
  • M.P. Van den Heuvel et al.

    Abnormal brain wiring as a pathogenetic mechanism in schizophrenia

    Biol. Psychiatry

    (2011)
  • M.P. Van den Heuvel et al.

    Network hubs in the human brain

    Trends Cogn. Sci.

    (2013)
  • N.M.J. Van Veelen et al.

    Prefrontal lobe dysfunction predicts treatment response in medication-naive first-episode schizophrenia

    Schizophr. Res.

    (2011)
  • Q. Wang et al.

    Anatomical insights into disrupted small-world networks in schizophrenia

    NeuroImage

    (2012)
  • P. Allen et al.

    Transition to psychosis associated with prefrontal and subcortical dysfunction in ultra high-risk individuals

    Schizophr. Bull.

    (2012)
  • P. Allen et al.

    Functional outcome in people at high risk for psychosis predicted by thalamic glutamate levels and prefronto-striatal activation

    Schizophr. Bull.

    (2014)
  • American Psychiatric Association

    Diagnostical and Statistical Manual of Mental Disorders

    (2000)
  • N.C. Andreasen et al.

    The comprehensive assessment of symptoms and history (CASH): an instrument for assessing diagnosis and psychopathology

    Arch. Gen. Psychiatry

    (1992)
  • N.C. Andreasen et al.

    Remission in schizophrenia: proposed criteria and rationale for consensus

    Am. J. Psychiatry

    (2005)
  • H.E. Barder et al.

    Ten year neurocognitive trajectories in first-episode psychosis

    Front. Hum. Neurosci.

    (2013)
  • D.S. Bassett et al.

    Hierarchical organization of human cortical networks in health and schizophrenia

    J. Neurosci.

    (2008)
  • D.S. Bassett et al.

    Cognitive fitness of cost-efficient brain functional networks

    PNAS

    (2009)
  • R.V. Behere

    Dorsolateral prefontal love volume and neurological soft signs as predictors of clinical social and functional outcome in schizophrenia: a longitudinal study

    Indian J. Psychiatry

    (2013)
  • V. Bewick et al.

    Statistics review 10: further nonparametric methods

    Crit. Care

    (2004)
  • V. Cheung et al.

    A diffusion tensor imaging study of structural dysconnectivity in never-medicated, first-episode schizophrenia

    Psychol. Med.

    (2008)
  • V. Colizza et al.

    Detecting rich-club ordering in complex networks

    Nat. Phys.

    (2006)
  • G. Collin et al.

    The ontogeny of the human connectome: development and dynamic changes of brain connectivity across the life span

    Neuroscientist

    (2013)
  • G. Collin et al.

    Impaired rich club connectivity in unaffected siblings of schizophrenia patients

    Schizophr. Bull.

    (2014)
  • N.A. Crossley et al.

    The hubs of the human connectome are generally implicated in the anatomy of brain disorders

    Brain

    (2014)
  • M.R. Dauvermann et al.

    Computational neuropsychiatry—schizophrenia as a cognitive brain network disorder

    Front. Psychiatry

    (2014)
  • M.A. De Reus et al.

    Rich club organization and intermodule communication in the cat connectome

    J. Neurosci.

    (2013)
  • M.A. De Reus et al.

    Simulated rich club lesioning in brain networks: a scaffold for communication and integration?

    Front. Hum. Neurosci.

    (2014)
  • A. Fornito et al.

    Functional dysconnectivity of corticostriatal circuitry as a risk phenotype for psychosis

    JAMA Psychiatry

    (2013)
  • P. Hagmann

    From diffusion MRI to brain connectomics

    (2005)
  • L. Harriger et al.

    Rich club organization of macaque cerebral cortex and its role in network communication

    PLoS ONE

    (2012)
  • P.D. Harvey et al.

    International assessment of functional skills in people with schizophrenia

    Innov. Clin. Neurosci.

    (2011)
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    WC and MPvdH contributed equally to this work.

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