White Matter Integrity According to the Stage of Mental Disorder in Youth

Highlights

• Change in white matter integrity is associated with stage of mental illness in young people.

• Those at later stages of illness showed reduced corpus callosum fractional anisotropy

• Reduced fractional anisotropy is significantly associated with poor set shifting

• Neuroanatomical biomarkers may have applications for mental disorder clinical staging

Abstract

The present study investigated differences in white matter (WM) integrity between 96 young people with affective and/or psychotic symptoms classified at an early stage of mental disorder (i.e. ‘attenuated syndrome’; stage 1b), 85 young people classified at a more advanced stage of mental disorder (i.e. ‘discrete disorder’; stage 2), and 81 demographically matched healthy controls using diffusion tensor imaging. The relationship between WM integrity (indexed by fractional anisotropy; FA) across the tracts and neuropsychological functioning was also investigated. A significant reduction in FA was identified in those with more advanced disorder in the body of the corpus callosum. Clinical stage groups were associated with significant neuropsychological impairment, which was significantly greater in those with discrete disorders. Compared to those in the earlier stage of disorder, participants at the later clinical stage showed decreased FA in the body of the corpus callosum that was associated with worse performance in attentional set formation maintenance, shifting and flexibility. These results provide further support for clinical staging of mental disorder and highlight the potential for utilising neuroanatomical biomarkers to support the classification of stages of mental disorder in the future.

Introduction

Recent research has investigated the use of clinical staging as an adjunct to traditional diagnostic tools for psychiatric disorders. Clinical staging is commonly used in medical practice to classify the progression of disease, but has only received recent attention as an adjunctive tool to formal diagnoses of mental disorder (McGorry et al., 2006). Adapting clinical staging for psychiatry has been recommended due to its utility in evaluating young people with emerging psychiatric disorders (Hickie et al., 2013b; McGorry et al., 2006). Youth is recognised as a critical period for mental disorder, with approximately 75% of psychiatric disorders developing prior to the age of 24 (Kessler et al., 2005). Furthermore, a greater duration between the onset of mental disorder and the provision of treatment corresponds with reduced intervention efficacy (Drancourt et al., 2013; Korczak and Goldstein, 2009; Marshall et al., 2005). As such, facilitating early intervention in young people may improve the prognosis and reduce the burden of psychiatric disorders (Correll et al., 2018; Lagopoulos et al., 2013; McGorry et al., 2011). The classification of mental disorder is an important antecedent to treatment, as it informs both practitioners and patients whether and when intervention is required, enables clinicians to predict the likely trajectory of individuals’ mental health and provides a guide to treatment efficacy (Craddock and Mynors-Wallis, 2018; Kendell and Jablensky, 2003; Scott, 2002). Thus, frameworks that assist with the classification of psychiatric disorders in young people, such as clinical staging, are particularly pertinent.

Traditional diagnostic tools such as the Diagnostic and Statistical Manual of Mental Disorders – 5^th Ed (DSM-5; American Psychiatric Association, 2013) focus on the classification of established psychiatric disorders and thus have limited utility in young people with emerging psychiatric disorders (Hickie et al., 2013b). Young people often present with ‘attenuated syndromes’ – combinations of subthreshold affective and/or psychotic symptoms not specific to a single disorder (Lewinsohn et al., 2004; Lim et al., 2015; Scott et al., 2013). These syndromes are associated with significant, ongoing socio-occupational impairment (Iorfino et al., 2018; Lee et al., 2013) and indicate an increased likelihood of developing a discrete psychiatric disorder (Fergusson et al., 2005; Iorfino et al., 2019). Clinical staging can be used to differentiate between earlier, milder stages of disorder and later stages characterised by progression, chronicity, and impairment (Hickie et al., 2019; Hickie et al., 2013a; Iorfino et al., 2019; McGorry et al., 2006). Thus, a transdiagnostic clinical staging model intended to classify stages of mental illness in young people with affective and psychotic syndromes has been developed (Hickie et al., 2013a; McGorry et al., 2006). Subsequent research investigated the distinction between ‘attenuated syndromes’ (stage 1b) and ‘discrete disorders’ (stage 2) in this model utilising neuropsychological measures (Hermens et al., 2013; Tickell et al., 2017) and neuroimaging (Eggins et al., 2018; Lagopoulos et al., 2013; Lagopoulos et al., 2012). Collectively, these studies have demonstrated that attenuated and discrete stages of disorder are characterised by worse neuropsychological performance, reduced grey matter volume, and compromised white matter (WM) integrity compared to healthy controls, and that these deficits are significantly greater at the more advanced discrete disorder stage compared to the earlier attenuated syndrome stage.

Disorganised WM due to demyelination and/or loss of axons, or excessive myelination, dense axonal packing, and reduced neural branching has been recognised as an important biomarker of psychiatric disorders (Feldman et al., 2010; Thomason and Thompson, 2011). Diffusion tensor imaging (DTI) is a contemporary application of MRI that enables in vivo analysis of WM integrity. Measurement of water diffusivity along WM tracts can be used to determine fractional anisotropy (FA), which is considered a proxy measure for WM integrity (Soares et al., 2013). Significant FA abnormalities are consistently reported across studies examining psychotic, depressive, and bipolar disorders, although abnormal WM tracts vary substantially between studies and are not specific to individual disorders (Heng et al., 2010; Hermens et al., 2019; Kanaan et al., 2005; Sexton et al., 2009). The majority of research investigating WM at early stages of mental disorder has focused on subthreshold psychotic syndromes. These studies suggest that FA is significantly reduced at early stages compared to controls (Samartzis et al., 2014), but significantly increased at early stages compared to those with schizophrenia (Carletti et al., 2012). One recent study by Vulser et al. (2018) found that individuals with subthreshold depressive symptoms at 14 years had significantly reduced FA across WM tracts compared to controls. These results suggest that early stages of mental disorder are associated with impaired WM, although further research is required to further characterise the observed changes. Transdiagnostic approaches that investigate WM integrity according to the stage of mental illness may be beneficial because of the non-specific nature of of impaired tract integrity across disorders and phenotypical variability of mental disorder.

Using DTI, Lagopoulos et al. (2013) compared WM integrity between 74 young people classified at stage 1b, 69 patients classified at stage 2 or stage 3 (‘recurrent or persistent disorder’), and 39 healthy controls. The clinical groups had significantly reduced FA in the anterior corona radiata when compared to controls, and this reduction was significantly more severe at stage 2 than stage 1b. These findings provide evidence for neuroanatomically distinct stages of mental disorder characterised by differing levels of WM disruption. However, as Lagopoulos et al. (2013) was the first study to compare WM at different stages of mental disorder transdiagnostically, these results require replication. Additionally, it is important to determine whether differences in WM integrity at different stages of disorder correspond with other neurobiological correlates of mental disorder that vary according to clinical stage, such as neuropsychological functioning. Accordingly, the present study aimed to investigate differences between WM integrity in a transdiagnostic group of young people at the attenuated syndrome and discrete disorder stages of mental disorder. Additionally, the study sought to investigate whether impairments in WM integrity and neuropsychological cognitive functioning were associated with the different stages of mental disorder. It was hypothesised that both attenuated syndromes and discrete disorders would be characterised by reduced FA in WM tracts compared to controls, that FA would be further reduced at the discrete disorder stage, and that progressive WM disruption would be associated with progressive impairment to neuropsychological functioning at each stage of mental disorder.