Characterizing white matter changes in chronic schizophrenia: A free-water imaging multi-site study
Introduction
Diffusion-tensor imaging (DTI) studies in patients with chronic schizophrenia have typically focused on a diffusion index termed fractional anisotropy (FA), which quantifies the directionality of water diffusion (Mori and Zhang, 2006). FA reductions in schizophrenia patients, compared to healthy controls, are typically interpreted as reflecting white matter degeneration. Tract-based spatial statistics (TBSS) has been the most commonly used approach to study white matter changes across the whole brain. The results of previous studies have been somewhat inconsistent. Whereby some TBSS studies report reduced FA in chronic schizophrenia in several regions across the brain (Asami et al., 2014), specifically the frontal and temporal regions (Scheel et al., 2013), others have failed to find any FA changes associated with schizophrenia (Clark et al., 2012).
Voxel-based morphometry (VBM) and tractography studies add even further variability to the findings in chronic schizophrenia: VBM studies report reduced FA in the left uncinate fasciculus (Kitiş et al., 2011), the bilateral inferior fronto-occipital fasciculus, the superior longitudinal fasciculus and the genu of the right internal capsule (Nakamura et al., 2012), as well as the left posterior radiata (Cui et al., 2011). Tractography studies report reduced FA in chronic schizophrenia in the arcuate fasciculus (Catani et al., 2011, McCarthy-Jones et al., 2015), the anterior limb of the internal capsule (Rosenberger et al., 2012), the anterior commissure (Choi et al., 2011), the inferior occipito-frontal fasciculus (Oestreich et al., 2015), and the cingulum bundle, uncinate fasciculus and fornix (Kunimatsu et al., 2012). Yet a tractography study by Boos et al. (2013) that investigated a subset of individual white matter tracts did not find any significant FA reductions in chronic schizophrenia patients compared to their healthy siblings or healthy controls. A possible explanation for these inconsistent results across DTI studies is the large variability in data acquisition, processing and analysis protocols (Kubicki et al., 2007).
One of the major limitations of previous DTI studies is the assumption that altered FA equates to structural changes of white matter itself, which can be biased by several factors. Noise in the diffusion-weighted signals refers to the fact that even in a perfectly isotropic medium, the three eigenvalues will never be exactly identical, which introduces a bias into the FA measures (Jones and Cercignani, 2010). The robustness of FA also depends on the number of sampling orientations used and their distribution (Jones and Cercignani, 2010). FA in a given region may further be influenced by factors such as axon diameter, packing density (Takahashi et al., 2002), or membrane permeability (i.e., reduced boundary effectiveness; Jones et al., 2013).
FA measurements are also biased by partial volume with extracellular free-water (Alexander et al., 2007). Free-water is defined as water molecules that are not restricted or hindered by surrounding tissue and therefore diffuses freely and isotropically in the extracellular space (Pasternak et al., 2009). When different tissue types are captured in one voxel, such as diffusion along white matter tracts and free-water in the extracellular space surrounding those white matter tracts, the DTI indices are no longer tissue-specific but instead represent the weighted average of both compartments. Free-water is predominantly present in the cerebrospinal fluid (CSF), which is why CSF contamination is a major problem for fibers in close proximity to the ventricles, such as the cingulum, fornix, and parts of the corpus callosum (Papadakis et al., 2002, Chou et al., 2005, Concha et al., 2005). However, recent studies suggest that varying levels of free-water in the tissue itself, may also account for variability between subjects. In order to remove this confound, Pasternak et al. (2009) developed a technique termed free-water imaging. This enables the differentiation between alterations in the tissue itself as measured by free-water corrected fractional anisotropy (FAT) and extracellular changes as measure by the fractional volume of free-water (FW; Pasternak et al., 2009).
A recent study by Pasternak et al. (2015) used free-water imaging to examine white matter degeneration (measured by FAT) and extracellular volume (measured by FW) in 29 chronic schizophrenia patients compared to healthy controls, and compared these changes to previously documented abnormalities in FAT and FW in first-episode schizophrenia patients (Pasternak et al., 2012b). The study revealed that chronic schizophrenia patients exhibited more widespread reductions in FAT relative to the first-episode patients, but more circumscribed increases in FW. Specifically, decreased FAT was observed in the corona radiata bilaterally, splenium and genu of the corpus callosum, bilateral thalamic radiation, bilateral superior longitudinal fasciculus, and the left external capsule. The more widespread reductions in FAT in chronic schizophrenia patients compared with first-episode patients suggested a progressive deterioration of white matter structures in the later stages of schizophrenia, which could indicate a neurodegenerative illness progression of schizophrenia (Pasternak et al., 2015). On the other hand, since the extracellular volume is expected to increase during neuroinflammatory states, the less extensive FW abnormalities found in the chronic patients relative to the first-episode schizophrenia patients suggests that neuroinflammation may play a larger role in the early stages of schizophrenia relative to later, chronic stages of schizophrenia (Pasternak et al., 2012b, Pasternak et al., 2015). The present study aimed to validate the pattern of findings reported by Pasternak et al. (2015) in an independent, substantially larger, and multi-site sample. That is, we predicted to find relatively circumscribed regions of FW abnormalities but more widespread regions of FAT abnormalities in patients with chronic schizophrenia, relative to healthy controls.
Section snippets
Participants
The data for this study was provided by the Australian Schizophrenia Research Bank. The original data collection process is outlined in detail elsewhere (Loughland et al., 2010). In short, patients with schizophrenia were recruited from treatment settings such as hospitals, mental health services, community services and a media campaign. Healthy individuals were also recruited through the media campaign. Clinical assessment officers (CAO), who were either registered or intern psychologists,
Results
Schizophrenia patients and healthy controls did not differ on age [F(1467) = 0.323, p < 0.570] but differed significantly on gender [χ2(1) = 29.16, p < 0.001] and handedness [χ2(2) = 9.654, p = 0.008]. Data on illness duration was available for 160 schizophrenia patients (years: M = 15.10, SD = 9.80). Data on duration of antipsychotic drug use was available for 266 patients (years: M = 4.30, SD = 2.96) and information on typical (n = 19) or atypical (n = 244) antipsychotic drug use was available for 263 schizophrenia
Discussion
This study investigated free-water corrected fractional anisotropy (FAT) and extracellular free-water (FW) in ROIs across the whole brain in a large sample of chronic schizophrenia patients compared to healthy controls. Reduced FAT was observed in the schizophrenia group compared to healthy controls in the posterior thalamic radiation bilaterally, the anterior limb of the internal capsule bilaterally, and both the genu and body of the corpus callosum. While a main effect for group was observed
Role of funding source
This study was supported by the Schizophrenia Research Institute using data from the Australian Schizophrenia Research Bank, funded by NHMRC Enabling Grant (No. 386500) held by V Carr, U Schall, R Scott, A Jablensky, BMowry, PMichie, S Catts, F Henskens and C Pantelis (Chief Investigators), and the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation, as well the Schizophrenia Research Institute, using an infrastructure grant from the NSW Ministry of Health. Thomas Whitford
Contributors
Lena Oestreich designed the study, performed the pre-processing of the data and the TBSS analysis, performed the statistical analysis and wrote the first draft of the manuscript. Dominick Newell, Amanda Lyall, Peter Savadjiev and Sylvain Bouix assisted with the pre-processing of the data and the ENIGMA-TBSS analysis. Zora Kikinis assisted with the design of the study and the interpretation of the results. Thomas Whitford and Simon McCarthy-Jones assisted with the statistical analysis and
Conflict of interest
None of the authors have any conflicts of interest to declare.
Acknowledgements
This study was supported by the Australian Schizophrenia Research Bank, which is supported by the National Health and Medical Research Council of Australia, the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation and the Schizophrenia Research Institute. This work is part of Lena Oestreich's doctorate thesis (PhD).
References (51)
- et al.
Diffusion tensor imaging of the brain
Neurotherapeutics
(2007) - et al.
Cerebral white matter abnormalities and their associations with negative but not positive symptoms of schizophrenia
Psychiatry Res.
(2014) - et al.
Tract-based diffusion tensor imaging in patients with schizophrenia and their non-psychotic siblings
Eur. Neuropsychopharmacol.
(2013) - et al.
Altered integrity of perisylvian language pathways in schizophrenia: relationship to auditory hallucinations
Biol. Psychiatry
(2011) - et al.
Diffusion tensor imaging of anterior commissural fibers in patients with schizophrenia
Schizophr. Res.
(2011) - et al.
White matter integrity, language, and childhood onset schizophrenia
Schizophr. Res.
(2012) - et al.
Assessment of white matter abnormalities in paranoid schizophrenia and bipolar mania patients
Psychiatry Res.
(2011) - et al.
A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors
Schizophr. Res.
(2005) - et al.
Multi-site genetic analysis of diffusion images and voxelwise heritability analysis: a pilot project of the ENIGMA DTI working group
NeuroImage
(2013) - et al.
White matter integrity, fiber count, and other fallacies: the do's and don'ts of diffusion MRI
NeuroImage
(2013)
Principles of diffusion tensor imaging and its applications to basic neuroscience research
Neuron
Interhemispheric hypoconnectivity in schizophrenia: fiber integrity and volume differences of the corpus callosum in patients and unaffected relatives
NeuroImage
A review of diffusion tensor imaging studies in schizophrenia
J. Psychiatr. Res.
Tract-specific analysis of white matter integrity disruption in schizophrenia
Psychiatry Res.
White matter alterations associated with suicide in patients with schizophrenia or schizophreniform disorder
Psychiatry Res.
Fractional anisotropy and radial diffusivity: diffusion measures of white matter abnormalities in the anterior limb of the internal capsule in schizophrenia
Schizophr. Res.
Reduced integrity of the left arcuate fasciculus is specifically associated with hallucinations in the auditory verbal modality in schizophrenia
Schizophr. Res.
Stereotaxic white matter atlas based on diffusion tensor imaging in an ICBM template
NeuroImage
Reduced white matter fractional anisotropy and clinical symptoms in schizophrenia: a voxel-based diffusion tensor imaging study
Psychiatry Res.
Human brain white matter atlas: identification and assignment of common anatomical structures in superficial white matter
NeuroImage
The extent of diffusion MRI markers of neuroinflammation and white matter deterioration in chronic schizophrenia
Schizophr. Res.
Characterizing white matter changes in cigarette smokers via diffusion tensor imaging
Drug Alcohol Depend.
Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data
NeuroImage
Corpus callosum abnormalities and their association with psychotic symptoms in patients with schizophrenia
Biol. Psychiatry
Predicting inter-hemispheric transfer time from the diffusion properties of the corpus callosum in healthy individuals and schizophrenia patients: a combined ERP and DTI study
NeuroImage
Cited by (52)
Lower fractional anisotropy without evidence for neuro-inflammation in patients with early-phase schizophrenia spectrum disorders
2024, Schizophrenia ResearchCitation Excerpt :This method demonstrated group-level increases of EFW, especially in patients with early-phase SSD compared to healthy controls (HC) (Chang et al., 2021; Guo et al., 2020; Lyall et al., 2017; Pasternak et al., 2012). In chronically ill patients, EFW increases were not observed (Gurholt et al., 2020; Oestreich et al., 2017). The hypothesis that EFW increases are associated with immune dysregulation is supported by DWI studies that find significant correlations with clinical markers of inflammation (i.e. peripheral cytokines and glutathione levels in brain) (Di Biase et al., 2021; Lesh et al., 2019; Rodrigue et al., 2019).
Free water alterations in different inflammatory subgroups in schizophrenia
2024, Brain, Behavior, and ImmunityFree-Water Diffusion Magnetic Resonance Imaging Differentiates Suicidal Ideation From Suicide Attempt in Treatment-Resistant Depression
2023, Biological Psychiatry: Cognitive Neuroscience and NeuroimagingTransdiagnostic In Vivo Magnetic Resonance Imaging Markers of Neuroinflammation
2022, Biological Psychiatry: Cognitive Neuroscience and NeuroimagingCitation Excerpt :Given the accumulating evidence for a role of inflammation in depression (68), further FW investigations in larger, more diverse depression samples supplemented with inflammation markers derived from blood or CSF are required before ultimate conclusions as to the usefulness of FW imaging to detect neuroinflammatory processes in depressive disorders can be drawn. Several studies found evidence for increased extracellular FW in the absence of large-scale microstructural changes in patients with first-episode schizophrenia (Figure 4) (60,64), with the reverse pattern reported in chronic schizophrenia (61,62,66). This is consistent with the view that the early stages of schizophrenia are marked by neuroinflammation rather than substantial changes in underlying neuronal architecture, which manifest in later illness stages (60).
Transdiagnostic role of glutamate and white matter damage in neuropsychiatric disorders: A Systematic Review
2022, Journal of Psychiatric ResearchDiffusion MRI derived free-water imaging measures in patients with schizophrenia and their non-psychotic siblings
2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Our study demonstrates that FW abnormalities in patients more likely to reflect clinical phenotypes of schizophrenia than an expression of pre-existing (genetic) risk for the illness. Previous studies suggested that free-water accumulation may change with disease progression, from being widespread in the first-episode (Lyall et al., 2018; Pasternak et al., 2012) to more confined in the chronic stage (Oestreich et al., 2017; Pasternak et al., 2015). Patients recruited in our current study have a relatively short median duration of illness of 4 years.
- 1
Joint senior authorship.