Elsevier

Neuroscience Research

Volume 102, January 2016, Pages 29-38
Neuroscience Research

Review article
Multimodal neuroimaging as a window into the pathological physiology of schizophrenia: Current trends and issues

https://doi.org/10.1016/j.neures.2015.07.009Get rights and content

Highlights

  • Hypotheses of schizophrenia are re-examined with multimodal neuroimaging methods.

  • Further multimodal neuroimaging studies are required to conclude hypotheses.

  • Social cognitive impairments may be based on different neural abnormalities.

  • Coupled mechanism between gray and white matter abnormalities is suggested.

Abstract

Visualizing the detailed brain anatomy of individuals with schizophrenia has been made possible by recent advances in magnetic resonance imaging (MRI). Although structural MRI cannot be currently used to diagnose schizophrenia, multimodal MRI can reveal insightful information on key clinical aspects of the pathological physiology of schizophrenia. However, in this regard, the number of multimodal MRI studies is still limited and definitely required. In this review, we discuss how classical and popular theories on the pathological physiology of schizophrenia can be re-examined using neuroimaging studies, and also discuss how multimodal MRI studies may provide additional findings. The pathological hypotheses examined include the “progressive brain disease hypothesis” and “disconnection hypothesis”. This article is discussed mainly based on recent findings published by our research group.

Introduction

In research settings, a dataset consisting of multiple imaging modalities can be obtained from a single magnetic resonance imaging (MRI) scanning session, including structural, diffusion tensor, and functional MR images. Whereas MRI analysis using a single data processing method can capture a certain pathological aspect of schizophrenia, the combined application of multiple imaging modalities with multiple image processing protocols may elucidate a far more comprehensive understanding of its nature (Sui et al., 2012) (Fig. 1). Representative multi-modal MRI studies on schizophrenia offer an opportunity to reappraise common beliefs of schizophrenia pathology, yet are still limited (Table 1). In this paper, we reexamine some of the major hypotheses and beliefs from the viewpoint of neuroimaging, and discuss the future direction of multimodal MRI studies.

Section snippets

Progressive brain disease hypothesis

Schizophrenia has been considered a progressive brain disease since Emil Kraepelin first established the concept. Despite increasing evidence suggesting that clinical and cognitive outcome does not always deteriorate in individuals with schizophrenia (Bora and Murray, 2013), the concept of schizophrenia as a “progressive disease” lingers.

Evidence of global and regional progressive brain changes is apparent early in the course of schizophrenia (Kasai et al., 2003, Whitford et al., 2006).

Disconnection hypothesis

Eugen Bleuler changed the name of dementia praecox to schizophrenia, and emphasized that an essential feature of schizophrenia is the splitting of psychic functions. Specifically, he used the expressions “extreme separation of thought and affect” or “splitting of association” (Bleuler, 1911). However, because the loci of pathological connectivity have hitherto been underspecified, the idea of a “disconnection hypothesis” has not developed from an abstract concept to a testable scientific

Neural basis of social cognitive impairment

Impaired social cognition is considered one of the core factors contributing to unfavorable psychosocial functioning in schizophrenia (Penn et al., 1997, Lee et al., 2004, Brunet-Gouet and Decety, 2006, Green and Leitman, 2008). To better understand the neural underpinnings of social cognitive impairment in schizophrenia, we investigated associations between social cognitive performance and gray/white matter abnormalities in a series of studies.

As the first step, we investigated the

Gray–white matter pathological associations

Gray and white matter abnormalities of schizophrenia are well-documented in widespread brain areas (Bora et al., 2011). One reasonable understanding of these findings is to hypothesize that schizophrenia is a brain disorder in which gray and white matter pathologies develop in an intertwined manner. However, the number of studies combining structural and diffusion MRI modalities is limited (Spoletini et al., 2009, Koch et al., 2013). Thus, in a series of multimodal MRI studies, we investigated

Conclusions

This review article has discussed previously reported results and findings, mainly from our own multi-modal MRI studies. Rapidly developing MRI technologies and multi-modal combinations of them can provide biological findings that allow us to test various hypotheses that have influenced our concept of schizophrenia. The advantages of MRI are numerous, including its safety, reliability, and capacity to reflect in vivo pathophysiology, although it is still not enough to identify the core

Authors’ contribution

M.I. managed the literature search and wrote the first draft of the manuscript. J.M. also contributed to the literature search and drafting. M.H., H.T., H.F., and M.T. technically supervised interpretation of the data. All authors contributed to and have approved the final manuscript.

Conflict of interest

The authors declare no conflicts of interest.

Acknowledgements

This work was supported by Grant-in-Aid for Scientific Research on Innovative Areas (23118004; Adolescent Mind & Self-Regulation), Grant-in-Aid for Scientific Research A (15H01690), Grant-in-Aid for Scientific Research B (15H04893) and Grant-in-Aid for Scientific Research C (26461767) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. This work was also supported by research grant from Schizophrenia Research Group, sponsored by Astellas Pharma Inc.

References (65)

  • H. Fujiwara et al.

    Anterior cingulate pathology and social cognition in schizophrenia: a study of gray matter, white matter and sulcal morphometry

    NeuroImage

    (2007)
  • L.A. Glantz et al.

    Apoptotic mechanisms and the synaptic pathology of schizophrenia

    Schizophr. Res.

    (2006)
  • K. Koch et al.

    Disrupted white matter connectivity is associated with reduced cortical thickness in the cingulate cortex in schizophrenia

    Cortex

    (2013)
  • M. Kubota et al.

    Age-related cortical thinning in schizophrenia

    Schizophr. Res.

    (2011)
  • A.M. Michael et al.

    Does function follow form?.: methods to fuse structural and functional brain images show decreased linkage in schizophrenia

    NeuroImage

    (2010)
  • J. Miyata et al.

    Reduced white matter integrity correlated with cortico-subcortical gray matter deficits in schizophrenia

    Schizophr. Res.

    (2009)
  • J. Miyata et al.

    Interfrontal commissural abnormality in schizophrenia: tractography-assisted callosal parcellation

    Schizophr. Res.

    (2007)
  • J. Miyata et al.

    Reduced white matter integrity as a neural correlate of social cognition deficits in schizophrenia

    Schizophr. Res.

    (2010)
  • J. Moriya et al.

    Gray and white matter volumetric and diffusion tensor imaging (DTI) analyses in the early stage of first-episode schizophrenia

    Schizophr. Res.

    (2010)
  • R.G. Schlosser et al.

    White matter abnormalities and brain activation in schizophrenia: a combined DTI and fMRI study

    Schizophr. Res.

    (2007)
  • J.H. Seok et al.

    White matter abnormalities associated with auditory hallucinations in schizophrenia: a combined study of voxel-based analyses of diffusion tensor imaging and structural magnetic resonance imaging

    Psychiatry Res.

    (2007)
  • P. Skudlarski et al.

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

    Biol. Psychiatry

    (2010)
  • I. Spoletini et al.

    Reduced fronto-temporal connectivity is associated with frontal gray matter density reduction and neuropsychological deficit in schizophrenia

    Schizophr. Res.

    (2009)
  • G. Sugranyes et al.

    Multimodal analyses identify linked functional and white matter abnormalities within the working memory network in schizophrenia

    Schizophr. Res.

    (2012)
  • J. Sui et al.

    Discriminating schizophrenia and bipolar disorder by fusing fMRI and DTI in a multimodal CCA+ joint ICA model

    NeuroImage

    (2011)
  • N.E. Van Haren et al.

    Confounders of excessive brain volume loss in schizophrenia

    Neurosci. Biobehav. Rev.

    (2013)
  • N.E. van Haren et al.

    Progressive brain volume loss in schizophrenia over the course of the illness: evidence of maturational abnormalities in early adulthood

    Biol. Psychiatry

    (2008)
  • T.J. Whitford et al.

    Progressive grey matter atrophy over the first 2–3 years of illness in first-episode schizophrenia: a tensor-based morphometry study

    NeuroImage

    (2006)
  • M. Yamada et al.

    Social cognition and frontal lobe pathology in schizophrenia: a voxel-based morphometric study

    NeuroImage

    (2007)
  • A. Amad et al.

    The multimodal connectivity of the hippocampal complex in auditory and visual hallucinations

    Mol. Psychiatry

    (2014)
  • N.C. Andreasen et al.

    Relapse duration, treatment intensity, and brain tissue loss in schizophrenia: a prospective longitudinal MRI study

    Am. J. Psychiatry

    (2013)
  • E. Bleuler

    Dementia Praecox oder Gruppe der Schizophrenien

    (1911)
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