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Original Investigation |

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

Mark Drakesmith, PhD1,2; Anirban Dutt, MD3; Leon Fonville, MSc3; Stanley Zammit, PhD2,4; Abraham Reichenberg, PhD3,5; C. John Evans, PhD1; Glyn Lewis, PhD6; Derek K. Jones, PhD1,2; Anthony S. David, MD3
[+] Author Affiliations
1Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff, Wales
2Neuroscience and Mental Health Research Institute, School of Medicine, Cardiff University, Cardiff, Wales
3Institute of Psychiatry, Psychology, and Neuroscience, King's College London, DeCrespigny Park, London, England
4Centre for Academic Mental Health, School of Social and Community Medicine, University of Bristol, Bristol, England
5Department of Psychiatry, Icahn School of Medicine, Mount Sinai Hospital, New York, New York
6Division of Psychiatry, Faculty of Brain Sciences, University College London, Maple House, London, England
JAMA Psychiatry. 2016;73(4):396-406. doi:10.1001/jamapsychiatry.2015.3375.
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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.

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Figure 1.
Tract-Based Spatial Statistics Results for Binary Classification of Psychotic Experiences (PEs)

A, Significant effects of PEs on fractional anisotropy (FA) using the binary classification of PEs. Regions of significant effect are shown in red; blue lines indicate position of axial sections shown in the sagittal plane. B, Mean (SE) of FA values in significant region of interest (ROI), with binary classification of PEs. L indicates left; MNI, Montreal Neurological Institute; and R, right.

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Figure 2.
Tract-Based Spatial Statistics Results for Ordinal Classification of Psychotic Experiences (PEs) and Changes in Effect Size When Covarying for Risk Factors

A, Regions of significant effects of PEs on fractional anisotropy (FA) and radial diffusivity (RD) inferred using the ordinal classification of PEs. Negative effects on FA are shown in red; positive effects of RD, in blue; and overlap between the 2 effects, in purple. Additional overlap with mean diffusivity (MD) is shown in cyan. Blue lines indicate position of axial sections shown in the sagittal plane. B, Mean (SE) of FA in the significant region of interest (ROI), with ordinal classification of PEs. C, Mean (SE) of RD in the significant ROI, with ordinal classification of PEs. D, Estimated change in effect size in significant ROIs where FA significantly correlates with PEs when covarying for risk factors (numbered bar labels correspond to those given in Table 2). E, Estimated change in effect size in significant ROIs where RD significantly correlates with PEs when covarying for risk factors. L indicates left; MNI, Montreal Neurological Institute; and R, right.

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Figure 3.
Results of Voxelwise Mediation Analysis

A-B, Mediation effects for which there is evidence in regions of the tract-based spatial statistics skeleton. C, Regions on the white matter skeleton where fractional anisotropy (FA) significantly mediates the association between childhood IQ and psychotic experiences (PEs). L indicates left; R, right.

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