No Effects of Cognitive Remediation on Cerebral White Matter in Individuals at Ultra-High Risk for Psychosis-A Randomized Clinical Trial

Tina D Kristensen, Bjørn H Ebdrup, Carsten Hjorthøj, René C W Mandl, Jayachandra M Raghava, Jens Richardt M Jepsen, Birgitte Fagerlund, Louise B Glenthøj, Christina Wenneberg, Kristine Krakauer, Christos Pantelis, Birte Y Glenthøj, Merete Nordentoft, Tina D Kristensen, Bjørn H Ebdrup, Carsten Hjorthøj, René C W Mandl, Jayachandra M Raghava, Jens Richardt M Jepsen, Birgitte Fagerlund, Louise B Glenthøj, Christina Wenneberg, Kristine Krakauer, Christos Pantelis, Birte Y Glenthøj, Merete Nordentoft

Abstract

Background: Individuals at ultra-high risk for psychosis (UHR) present with subtle alterations in cerebral white matter (WM), which appear to be associated with clinical and functional outcome. The effect of cognitive remediation on WM organization in UHR individuals has not been investigated previously.

Methods: In a randomized, clinical trial, UHR individuals aged 18 to 40 years were assigned to treatment as usual (TAU) or TAU plus cognitive remediation for 20 weeks. Cognitive remediation comprised 20 x 2-h sessions of neurocognitive and social-cognitive training. Primary outcome was whole brain fractional anisotropy derived from diffusion weighted imaging, statistically tested as an interaction between timepoint and treatment group. Secondary outcomes were restricted to five predefined region of interest (ROI) analyses on fractional anisotropy, axial diffusivity, radial diffusivity and mean diffusivity. For significant timepoint and treatment group interactions within these five ROIs, we explored associations between longitudinal changes in WM and cognitive functions/clinical symptoms. Finally, we explored dose-response effects of cognitive remediation on WM.

Results: A total of 111 UHR individuals were included. Attrition-rate was 26%. The cognitive remediation group completed on average 12 h of neurocognitive training, which was considerably lower than per protocol. We found no effect of cognitive remediation on whole-brain FA when compared to treatment as usual. Secondary ROI analyses revealed a nominal significant interaction between timepoint*treatment of AD in left medial lemniscus (P=0.016) which did not survive control for multiple comparisons. The exploratory test showed that this change in AD correlated to improvements of mental flexibility in the cognitive remediation group (p=0.001). We found no dose-response effect of neurocognitive training on WM.

Conclusions: Cognitive remediation comprising 12 h of neurocognitive training on average did not improve global or regional WM organization in UHR individuals. Further investigations of duration and intensity of cognitive training as necessary prerequisites of neuroplasticity-based changes are warranted.

Clinical trial registration: ClinicalTrials.gov, identifier NCT02098408.

Keywords: clinical trial; cognition; cognitive remediation; diffusion-weighted imaging; ultra-high risk for psychosis; white matter.

Copyright © 2020 Kristensen, Ebdrup, Hjorthøj, Mandl, Raghava, Jepsen, Fagerlund, Glenthøj, Wenneberg, Krakauer, Pantelis, Glenthøj and Nordentoft.

Figures

Figure 1
Figure 1
Flowchart of the FOCUS trial. CR, cognitive remediation; MRI, magnetic resonance imaging; TAU, treatment as usual; UHR, ultra-high risk.
Figure 2
Figure 2
Boxplots illustrating the development of mean whole brain fractional anisotropy at baseline and 26 weeks follow-up for UHR individuals allocated to cognitive remediation versus treatment as usual are displayed. Error bars indicate the 95% confidence intervals. Note that the y-axis has been altered to enhance visual display. CR, cognitive remediation; TAU, treatment as usual; UHR, ultra-high risk.
Figure 3
Figure 3
The scatterplots illustrate the exploratory correlations between changes in left medial lemniscus axial diffusivity and changes in mental flexibility (CANTAB IED total errors adjusted) in UHR individuals allocated to cognitive remediation versus treatment as usual are displayed. Error-bars indicate the 95% confidence intervals. Note that the y-axis has been altered to enhance visual display. The correlations have been tested with and without outliers, which were included due to no effect on the result. Numerical results are reported in detail in Supplementary Table S4. CANTAB, Cambridge neuropsychological test automated battery; CR, cognitive remediation; IED, intra-extra dimensional set-shifting; TAU, treatment as usual; UHR, ultra-high risk.

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