Stable signatures of schizophrenia in the cortical–subcortical–cerebellar network using fMRI of verbal working memory

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Abstract

A dysfunction in working memory (WM) is a core cognitive impairment in schizophrenia that involves the cortical–subcortical–cerebellar network. We propose that in addition to other often-referred markers, the signal reduction in the network during verbal working memory (VWM) is a stable and intrinsic indicator of illness. We presented a Sternberg VWM task to 46 patients with schizophrenia and 46 healthy controls matched on performance accuracy during functional magnetic resonance imaging (fMRI). Reduced activation was demonstrated in the thalamus, cerebellar vermis, pons and the triangular part of the inferior frontal gyrus (IFG) in the patient group. We also found a “failure of deactivation” in the default mode network (DMN) in patients as represented by a low versus high load VWM. In addition, a reduced left lateralization in the triangular and opercular parts of the IFG was observed in the patient group replicating previous “failure of lateralization” findings in schizophrenia. A comparison of long (10 to 19 years) and short (3 to 9 years) durations of illness (DoIs) demonstrated that the DoI was only associated with the activation changes in the middle frontal gyrus and lateral temporal cortex but not with the IFG-subcortico-cerebellar regions observed. These alterations were consistent with the cognitive dysmetria described in the cortical–subcortical–cerebellar network in schizophrenia. In conclusion, the combination of reduced activation in the cortical–subcortical–cerebellar network during VWM in particular, reduced deactivation in the DMN and reduced lateralization in the IFG is thought to be stable neuroimaging signatures of schizophrenia.

Introduction

Schizophrenia involves a variety of symptoms that exhibit heterogeneous manifestations across patients in neuroimaging research, which prevents tangible imaging diagnoses. Nevertheless, general imaging markers of the illness have been proposed. One of the most frequently referred features is “hypofrontality”, i.e., reduced involvement of the prefrontal cortex (Potkin et al., 2009, Thormodsen et al., 2011). Another marker, “failure of deactivation,” was uncovered during the recent advancement in neuroimaging, specifically functional magnetic resonance imaging (fMRI), and demonstrates less pronounced signal decreases during the task period in a set of brain regions known as the “default mode network (DMN)” in patients compared to controls (Pomarol-Clotet et al., 2008, Whitfield-Gabrieli et al., 2009, Pomarol-Clotet et al., 2010, Guerrero-Pedraza et al., 2012). Functional connectivity in the DMN is also altered in schizophrenia (Ongur et al., 2010). Furthermore, another marker is “failure of lateralization,” which demonstrates bilateral activation, rather than the typical leftward asymmetry during language processing (Gur et al., 1989, Crow, 1997, Sommer et al., 2001, Mitchell and Crow, 2005, Andreasen et al., 2008, Angrilli et al., 2009, Bleich-Cohen et al., 2009). In this study, we propose another signature that is closely associated with an intrinsic impairment in schizophrenia, i.e., dysfunction in working memory (WM). In addition to the previously listed markers, we investigated the effect of verbal working memory (VWM) on patients, as well as controls, and aimed to obtain stable imaging signatures of schizophrenia that will benefit clinical diagnoses.

A dysfunction in WM is a core cognitive impairment in schizophrenia (Goldman-Rakic, 1994, Conklin et al., 2000, Manoach, 2003, Lee and Park, 2005, Honey and Fletcher, 2006, Reichenberg and Harvey, 2007). WM is associated with the cortical–subcortical–cerebellar system that involves cortical areas including the inferior frontal gyrus (IFG), and subcortical regions, including the thalamus and pons, and cerebellum (Desmond et al., 1997, Chen and Desmond, 2005a, Chen and Desmond, 2005b, Passamonti et al., 2011, Strick et al., 2009); these regions were often altered in schizophrenia (Andreasen et al., 1996, Honey et al., 2005, Rusch et al., 2007, Andreasen and Pierson, 2008, Mouchet-Mages et al., 2011). We employed an established Sternberg VWM paradigm of fMRI (Desmond et al., 1997, Chen and Desmond, 2005a, Chen and Desmond, 2005b, Marvel and Desmond, 2010); a prolonged maintenance of WM in the paradigm was advantageous because it required intensive cognitive resources including parallel processing, which were altered in schizophrenia (Andreasen et al., 1998). The application of a verbal task was favorable because language includes timing processing that is deteriorated in schizophrenia (Andreasen et al., 1999, Waters and Jablensky, 2009), and it also enabled the examination of the failure of lateralization in patients. Another advantage of our paradigm was its efficiency in examining the failure of deactivation in the DMN; signal intensity changes during the baseline period contrasting to the task period were compared between patients and controls (see Supplementary materials for detailed explanation).

One clinical concern in seeking stable signatures of schizophrenia is the duration of illness (DoI) (Premkumar et al., 2008, Elsabagh et al., 2009, Tanskanen et al., 2010). A long-term DoI may include side effects of the prolongation, which are independent of the illness. However, it is less well known to what extent the DoI affects WM-related activation. We extracted short and long DoI groups from our patient subjects to compare their activation.

Using whole-brain fMRI, we expected to observe lowered activation in the cortical–subcortical–cerebellar network and other indicators of illness in an all-in-one manner using the VWM paradigm. If these alterations were specific to the illness, the DoI would not affect these alterations. Taken together, these observations contributed to the characterization of schizophrenia and the attainment of stable diagnostic signatures of the illness.

Section snippets

Participants

Forty-six outpatients diagnosed with schizophrenia (SZ, DoI  1 year, 23 females, 23 males) and 46 healthy volunteers (CT) matched for age, gender and performance accuracy were examined with obtaining written informed consent (Table 1). The protocol was approved by the University Hospital Institutional Review Board in adherence with the Declaration of Helsinki. All patients were diagnosed by the attending psychiatrists in the Department of Psychiatry at the National Taiwan University Hospital as

Behavioral data

As participants were matched on task performance, neither the RT nor the accuracy was significantly different between patients and controls (Table 1) or between the long and short DoIs (Table 2).

Image data

The VWM contrast, i.e., high > low WM loads, yielded activation typically observed during VWM, including the IFG, intraparietal cortex, thalamus and cerebellum (Fig. 2). These areas are key regions of the cortical–subcortical–cerebellar network. A group comparison (CT > SZ) revealed a greater activation in

Promising signatures of schizophrenia

We confirmed previously proposed signatures of schizophrenia, i.e., a reduced activation in the cortical–subcortical–cerebellar network, a “failure of deactivation” in the DMN and a “failure of lateralization” in the posterior IFG. We demonstrated that the DoI did not affect these changes in general. Thus, these changes were independent of the DoI and viable as stable WM-related markers of schizophrenia.

Reductions in the cortical–subcortical–cerebellar network were particularly pronounced in

Role of the funding source

  • 1.

    Schizophrenia Project undertaken at the National Taiwan University Hospital.

    • Grant numbers: NTU97HM00273: National Taiwan University

      • NSC100-3112-B-002-016, NSC99-3112-B-002-030 (98HD017): National Science Council, Taiwan

      • NHRI-EX101-10145NI: National Health Research Institute, Taiwan

  • 2.

    Contributions from SHA Chen were in part supported by Tier2 Academic Research Fund (MOE2011-T2-1-031), Ministry of Education, Singapore.

The funding above was used for the machine usage charge, reward to subjects,

Contributors

Kayako Matsuo participated in all the MRI data collections and performed all the analysis and main interpretation of the data and wrote the draft of the manuscript.

Shen-Hsing Annabel Chen conceptualized and designed the fMRI experimental design and substantially determined the directions of the experiment, interpretation and discussion.

Chih-Min Liu has a principal responsibility in the interpretation of the results in regard to the clinical aspect of schizophrenia as a representative of the

Conflict of interest

We have no conflict of interest in regard to this study.

Acknowledgments

This study was supported by the Schizophrenia Project undertaken at the National Taiwan University Hospital (NTU97HM00273). It was also supported by the National Science Council, Taiwan (NSC100-3112-B-002-016, NSC99-3112-B-002-030 (98HD017)) and the National Health Research Institute, Taiwan (NHRI-EX101-10145NI). Contributions from SHA Chen were in part supported by Tier2 Academic Research Fund (MOE2011-T2-1-031), Ministry of Education, Singapore. We would like to specifically express our

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