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

Methods
In a randomized, clinical intervention-trial (FOCUS), UHR-individuals aged 18–40 years were assigned to treatment as usual (TAU) or TAU plus cognitive remediation (CR) for 20 weeks. CR comprised 20 x 2-hour sessions of neurocognitive and social-cognitive training (SCIT). Primary outcome was whole brain fractional anisotropy (FA) derived from diffusion weighted imaging. Secondary outcomes pertained to regions of interest analyses. Planned post-hoc analyses explored dose-response effects of CR on WM. Main analyses of treatment effect of CR on primary and secondary outcomes were conducted using linear mixed models, assessing the interaction of timepoint by group (CR and TAU). Analyses were conducted according to the intention-to-treat principle.

Results
111 UHR-individuals and 59 healthy controls were included. Attrition-rate was 30% at 6 months post-treatment follow-up. The CR group completed a mean of 12 hours of neurocognitive training.

We found no effect of CR on whole-brain or regional FA. Planned post-hoc analyses revealed significant time*group (high- and low-attendance to CR) interactions in left superior corona radiata (p<0.01), left cingulum cingulate gyrus (P=0.03), and right superior longitudinal fasciculus (P<0,01), corrected. Specifically, when compared to UHR-individuals with high attendance (UHR-high >12 hours), those with low attendance (UHR-low <12 hours) had more co-morbid diagnoses, larger recreational smoking (nicotine and cannabis), more depressive and negative symptoms, and had significantly lower global FA at baseline, and showed a significant increase in FA after treatment. Furthermore, UHR-low displayed large effect-size (ES) improvements on depressive and negative symptoms, and moderate to large ES improvements in several cognitive functions (verbal fluency, verbal working memory, and processing speed). In contrast, UHR-high displayed large ES improvements in UHR-symptoms, and moderate ES improvement on social and occupational functioning.

Discussion
Contradicting our main hypothesis, we found no effect of CR on whole-brain or regional FA after six months. This may be explained by both the low number of neurocognitive training sessions and the attrition rate. The average of 12 hours of neurocognitive training is considerably lower than the recommended dosage of 25–30 hours necessary for cognitive improvements. The continuous need to develop feasible interventions and enhance adherence is stressed.

Nevertheless, non-specific treatment may improve WM-integrity in UHR-individuals with lower global baseline FA in those with more severe psychopathology. The UHR-low subgroup exhibited improvements with large ES in levels of depressive and negative symptoms, as well as cognitive functions. We speculate, whether our results reflect that UHR-individuals with higher baseline FA (approaching the healthy controls), present with a preserved structural capacity for increased demands and new learning, while UHR-individuals characterized by lower FA at baseline may be more amendable to neuroplastic treatment-effects. The results support the value of subgrouping in a clinically heterogenous UHR-population, which also applies to examining WM integrity.