Mediation of Developmental Risk Factors for Psychosis by White Matter Microstructure in Young Adults With Psychotic Experiences

Abstract

IMPORTANCE White matter (WM) abnormalities have been identified in schizophrenia at the earliest stages of the disorder. Individuals in the general population with psychotic experiences (PEs) may show similar changes, suggesting dysfunction due to aberrant neurodevelopment. Studying such people is a powerful means of understanding the nature of neurodevelopmental problems without the confound of clinical management and allows other potential risk factors associated with the schizophrenia spectrum to be taken into account. OBJECTIVES To compare WM microstructure and myelination in young adults with and without PEs identified from a population-based cohort using diffusion and relaxometry magnetic resonance imaging and to quantify potential mediating effects of WM on several known risk factors for psychosis. DESIGN, SETTING, AND PARTICIPANTS In this case-control study, participants were drawn from the UK Avon Longitudinal Study of Parents and Children. Psychotic experiences were assessed using a semistructured interview. Magnetic resonance imaging was carried out at age 20 years in 123 participants who had PEs and 124 individuals serving as controls. Participants with PEs were subdivided into those with operationally defined suspected PEs, definite PEs, and psychotic disorder. MAIN OUTCOMES AND MEASURES Diffusion tensor magnetic resonance imaging and relaxometry-derived myelin water fractions were used to measure WM microstructure and myelination, respectively. Differences in quantitative WM indices were assessed using tract-based spatial statistics. A binary model and a continuum-like ordinal model of PEs were tested. RESULTS Among the 123 participants who had PEs (mean [SE] age, 20.01 [0.004] years), 37 were male and 86 were female. Among the 124 controls (mean [SE] age, 20.11 [0.004] years), 49 were male and 76 were female. Fractional anisotropy in left frontomedial WM was significantly reduced in individuals with PEs (Montreal Neurological Institute [MNI] coordinates, −18, 37, −2; P = .0046). The ordinal model identified a similar but more widespread effect, with a corresponding increase in radial diffusivity (MNI coordinates, −15, 29, 21; P = .0042). Low birth weight (ρ = −0.155; P = .015) and childhood IQ (ρ = −0.188; P = .003) were associated with the presence of PEs. Results of mediation analysis were consistent with the association between birth weight (21.1% mediation effect; P = 6.20 × 10 −3) and childhood IQ (7.9% mediation effect; P = .041) and by PEs being mediated by fractional anisotropy changes in these regions. CONCLUSIONS AND RELEVANCE The results of the study imply the presence of abnormal WM microstructure in young adults with PEs. The results are consistent with the hypothesis that neurodevelopmental factors cause alterations in the cellular composition of WM circuits critical to higher cognitive function. Such alterations may first manifest in childhood as reduced IQ and later contribute to PEs in early adulthood.

Complement pathway changes at age 12 are associated with psychotic experiences at age 18 in a longitudinal population-based study: evidence for a role of stress

“…Previous studies based on the ALSPAC cohort, a prospective general population cohort based in the Bristol area in South West England, have shown subgroups of subjects who developed psychotic disorder (PD) and psychotic experiences (PEs) [24] at age 18. These groups showed alterations in cortical white matter microstructure [25], working memory [26], and raised inflammatory markers in childhood [12] in subjects with PE at age 18. We recently used discovery methods to compare the plasma proteome of age 12 subjects who developed psychotic disorder at age 18 and we found evidence implicating some protein members of the complement pathway at age 12 in subjects with PD at age 18 [27].…”

Bad wrap: Myelin and myelin plasticity in health and disease

“…White matter abnormalities are diffuse in subjects with schizophrenia, with globally decreased levels of fractional anisotropy (FA) and increased radial diffusivity (RD) (Chavarria‐Siles et al, ; Reid et al, ), proxy measures for myelin integrity. Deficits are evident diffusely in frontomedial white matter tracts (Drakesmith et al, ), orbitofrontal cortex, posterior parietal cortex (Green et al, ), arcuate fasciculus, cingulum bundle, and inferior longitudinal fasciculus (Oestreich et al, ; Seitz et al, ). The apparently more global disruptions to white matter in schizophrenia compared to other neuropsychiatric disorders are consistent with the more severe and complex nature of dysfunction in schizophrenia.…”

Deficits in Neurite Density Underlie White Matter Structure Abnormalities in First-Episode Psychosis

“…Disrupted white matter structure is likely to precede the onset of FEP (2). In adolescent cohorts within the general population, alterations in white matter structure associated with a psychotic experience can be observed before diagnosis of a mental health condition (3,10). This suggests that an aberrant neurodevelopmental risk state, centered on a structural vulnerability that compromises functional connectivity, can predispose to psychotic symptoms, which in some individuals may progress to a diagnosed disorder.…”

“…Correspondingly, structural abnormalities in white matter tracts across the brain are observed in postmortem studies (7) and in vivo noninvasive imaging using diffusion-weighted magnetic resonance imaging (MRI) (2,8,9). It is likely that white matter changes are present even before the experience of active symptoms at the onset of firstepisode psychosis (FEP), preceding pharmacological treatment with neuroleptic medications (2,3,10).…”