title: Mediation of Developmental Risk Factors for Psychosis by White Matter Microstructure in Young Adults With Psychotic Experiences.
abstract: OBJECTIVE
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff, Wales2Neuroscience and Mental Health Research Institute, School of Medicine, Cardiff University, Cardiff, Wales.
authors.forename: Mark
authors.initials: M
authors.lastname: Drakesmith
authors.affiliation: Institute of Psychiatry, Psychology, and Neuroscience, King's College London, DeCrespigny Park, London, England.
authors.forename: Anirban
authors.initials: A
authors.lastname: Dutt
authors.affiliation: Institute of Psychiatry, Psychology, and Neuroscience, King's College London, DeCrespigny Park, London, England.
authors.forename: Leon
authors.initials: L
authors.lastname: Fonville
authors.affiliation: Neuroscience and Mental Health Research Institute, School of Medicine, Cardiff University, Cardiff, Wales4Centre for Academic Mental Health, School of Social and Community Medicine, University of Bristol, Bristol, England.
authors.forename: Stanley
authors.initials: S
authors.lastname: Zammit
authors.affiliation: Institute of Psychiatry, Psychology, and Neuroscience, King's College London, DeCrespigny Park, London, England5Department of Psychiatry, Icahn School of Medicine, Mount Sinai Hospital, New York, New York.
authors.forename: Abraham
authors.initials: A
authors.lastname: Reichenberg
authors.affiliation: Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff, Wales.
authors.forename: C John
authors.initials: CJ
authors.lastname: Evans
authors.affiliation: Division of Psychiatry, Faculty of Brain Sciences, University College London, Maple House, London, England.
authors.forename: Glyn
authors.initials: G
authors.lastname: Lewis
authors.affiliation: Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff, Wales2Neuroscience and Mental Health Research Institute, School of Medicine, Cardiff University, Cardiff, Wales.
authors.forename: Derek K
authors.initials: DK
authors.lastname: Jones
authors.affiliation: Institute of Psychiatry, Psychology, and Neuroscience, King's College London, DeCrespigny Park, London, England.
authors.forename: Anthony S
authors.initials: AS
authors.lastname: David
mesh_terms: D016880:Anisotropy; D016022:Case-Control Studies; D015986:Confounding Factors, Epidemiologic; D038524:Diffusion Magnetic Resonance Imaging; D056324:Diffusion Tensor Imaging; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D011618:Psychotic Disorders / Q000473:pathology*; D012307:Risk Factors; D057566:Self Report; D006113:United Kingdom; D014888:Wechsler Scales; D066127:White Matter / Q000473:pathology / Q000648:ultrastructure*; D055815:Young Adult