Elsevier

Schizophrenia Research

Volume 184, June 2017, Pages 73-81
Schizophrenia Research

Functional brain networks in treatment-resistant schizophrenia

https://doi.org/10.1016/j.schres.2016.12.008Get rights and content

Abstract

Introduction

Up to 20% of individuals with schizophrenia show minimal or no response to medication and are considered to have ‘treatment-resistant’ schizophrenia (TRS). Unlike early and established schizophrenia, few studies have investigated resting-state functional connectivity (rs-FC) in TRS. Here, we test for disruptions in FC and altered efficiency of functional brain networks in a well-characterized cohort of TRS patients.

Methods

Resting-state functional magnetic resonance imaging was used to investigate functional brain networks in 42 TRS participants prescribed clozapine (30 males, mean age = 41.3(10)) and 42 healthy controls (24 males, mean age = 38.4(10)). Graph analysis was used to characterize between-group differences in local and global efficiency of functional brain network organization as well as the strength of FC.

Results

Global brain FC was reduced in TRS patients (p = 0.0001). Relative to controls, 3.4% of all functional connections showed reduced strength in TRS (p < 0.001), predominantly involving fronto-temporal, fronto-occipital and temporo-occipital connections. Global efficiency was reduced in TRS (p = 0.0015), whereas local efficiency was increased (p = 0.0042).

Conclusions

TRS is associated with widespread reductions in rs-FC and altered network topology. Increased local functional network efficiency coupled with decreased global efficiency suggests that hub-to-hub connections are preferentially affected in TRS. These findings further our understanding of the neurobiological impairments in TRS.

Introduction

Schizophrenia is a severe and chronically debilitating psychiatric disorder, with a two to three-fold increase in early mortality compared with the general population (Saha et al., 2007). Although use of first and second generation antipsychotics has significantly improved treatment response and quality of life for many individuals with schizophrenia, symptoms persist for up to one third of affected individuals, despite trialing various types of antipsychotic medications. This population has been termed “treatment resistant” (i.e., TRS). Currently clozapine is the only evidence-based atypical antipsychotic that has been found effective in ameliorating psychotic symptoms in TRS (Asenjo Lobos et al., 2010). However, clozapine is effective in only a fraction of patients, as up to 70% of TRS individuals do not respond (Papetti et al., 2007). Consequently, TRS is one of the greatest therapeutic challenges, with patients often suffering a more severe and chronic form of the disorder than those who respond to antipsychotic treatment (Bolonna and Kerwin, 2005). Many clinicians have posited that TRS may in fact be more accurately understood as a distinct subtype of schizophrenia, as opposed to being a chronic illness phase (Farooq et al., 2013, Lee et al., 2015). This notion has been supported by recent findings of differences in dopamine concentrations in the limbic and associative striatal subdivisions and glutamate levels in the anterior cingulate cortex between treatment-responsive schizophrenia and TRS groups (Demjaha et al., 2014, Demjaha et al., 2012). The relation between striatal dopamine and disrupted functional connectivity remains unclear in schizophrenia, however elevated dopamine levels may worsen the signal-to-noise ratio of spontaneous brain activity in the striatum, leading to a reduction in functional connectivity between striatum and frontal regions (Sorg et al., 2013). Despite the clinical relevance of TRS, few neuroimaging studies have focused on this population.

The theory of ‘dysconnectivity’ between spatially separated brain systems is one of the most prominent and widely researched hypotheses in schizophrenia (Friston and Frith, 1995, Zalesky et al., 2011, Zalesky et al., 2015). Findings however are inconsistent, with reports of both increased resting-state functional connectivity (rs-FC) (Jafri et al., 2008, Lui et al., 2010, Sorg et al., 2013, Whitfield-Gabrieli et al., 2009) and decreased rs-FC (Bluhm et al., 2007, Bluhm et al., 2009, Camchong et al., 2011, Gavrilescu et al., 2010, Hoptman et al., 2010, Liang et al., 2006, Meda et al., 2012, Ongur et al., 2010, Rotarska-Jagiela et al., 2010, Vercammen et al., 2010, Zhou et al., 2007, Zhou et al., 2008). Few studies have used functional imaging to investigate rs-FC in individuals with TRS. Using independent component analysis, one study found that TRS individuals with auditory-verbal hallucinations (AVH) showed reduced rs-FC between the left temporo-parietal junction and right Broca's area and anterior cingulate cortex (Vercammen et al., 2010). A later study also investigated AVH in TRS and found an increase in connectivity between bilateral temporal regions and a decrease in connectivity within the cingulate cortex (Wolf et al., 2011). These studies however, had relatively small samples (n = 27, n = 10) and explored connectivity predominantly in the context of AVH (Vercammen et al., 2010, Wolf et al., 2011). The most recent study by White et al. (2016) found reduced FC between the ventral striatum and substantia nigra in TRS compared with non-TRS patients, indicating there may be fundamental differences in network properties (reduced FC) between treatment-responsive and TRS patients.

More recently, in conjunction with measures of FC strength, graph theoretical methods have been applied to functional magnetic resonance imaging (fMRI) data in an attempt to understand the topology of brain networks. Two such measures that address the question of functional network organization are global and local efficiency. The efficiency of a brain network is inversely related to the number of intermediate regions that must be traversed for a pair of brain regions to communicate with each other. A directly connected pair of regions can communicate most efficiently since they do not utilize any intermediate regions. However, many pairs of brain regions are not directly connected, and thus communication between such regions is via a path that traverses one or more intermediate regions. The greater the number of intermediate regions traversed, the less efficient communication becomes, due to increasing energy requirements and potential signal dispersion (Bullmore and Sporns, 2012, Fornito et al., 2016). A reduction in brain network efficiency in patients may indicate a bias in the trade-off between metabolic costs and topology (Rubinov and Sporns, 2010, Wang et al., 2010).

Here, we characterized the connectivity and efficiency of whole-brain functional networks inferred from rs-fMRI in a group of individuals with TRS, compared to healthy controls. We also investigated whether a relationship between network connectivity and topology and symptomatology/functioning is evident. In light of previous research and the chronicity of the present sample, we hypothesize that the TRS group will show widespread reduced rs-FC, predominantly between frontal-temporal regions and topological abnormalities in the form of reduced global efficiency compared with controls. We also hypothesize that these abnormalities will correlate with symptom severity and functioning in the TRS group.

Section snippets

Participants

Forty-two treatment resistant schizophrenia (TRS) individuals (mean age 41.3 ± 10.0, 30 males) were recruited from inpatient and outpatient clinics in Melbourne, Australia. TRS was defined as at least two unsuccessful trials of two or more different antipsychotic types and currently taking clozapine (Kane et al., 1988, Suzuki et al., 2012).

Inclusion criteria for the TRS group were a diagnosis of schizophrenia, currently prescribed and taking clozapine and aged 18–65 years. Forty-two healthy

Results

Demographic information is shown in Table 1.

Discussion

This study explored whole-brain resting-state functional connectivity (FC), and the efficiency of whole-brain networks in patients with schizophrenia who have not responded to antipsychotic treatment (treatment-resistant schizophrenia; TRS). We found widespread reductions in FC in the TRS group at the whole-brain level, particularly implicating temporal, occipital and frontal regions with follow-up analyses showing the subregions predominantly involved to be Heschl's gyri, cuneus and

Contributors

Author Zalesky designed the functional connectivity protocol and was imperative to the methodology and analysis of the neuroimaging data. Author Seguin assisted in the design and execution of the graph theory section. Author Pantelis, author Phassouliotis and author Everall were imperative to the design, recruitment and execution of the study. Author Whittle, author Bousman and author Bartholomeusz assisted in the statistical design of the study. Author Ganella performed all the neuroimaging

Funding body agreements and policies

The authors acknowledge the financial support of the Cooperative Research Centre (CRC) for Mental Health which is an Australian Government Initiative. EG was supported by the University of Melbourne Ronald John Gleghorn Bursary and CRC for Mental Health PhD top-up scholarship. CAB was supported by University of Melbourne Ronald Phillip Griffith Fellowship and Brain and Behavior Research Foundation (NARSAD) Young Investigator Award (20526). CP was supported by NHMRC Senior Principal Research

Conflict of interest

The authors declare they have no conflicts of interest.

Acknowledgements

We thank the research assistants Annabel Burnside and Courtney Purdie who recruited the participants for this study and Despina Ganella who assisted with the preparation and proof-reading of the manuscript. We would also like to thank Chester Kang for IT support.

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