Changes in negative symptoms are linked to white matter changes in superior longitudinal fasciculus in individuals at ultra-high risk for psychosis

Abstract 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.

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Patterns of white matter microstructure in individuals at ultra-high-risk for psychosis: associations to level of functioning and clinical symptoms

Psychological Medicine ◽

10.1017/s0033291717001210 ◽

2017 ◽

Vol 47 (15) ◽

pp. 2689-2707 ◽

Cited By ~ 16

Author(s):

K. Krakauer ◽

B. H. Ebdrup ◽

B. Y. Glenthøj ◽

J. M. Raghava ◽

D. Nordholm ◽

...

Keyword(s):

White Matter ◽

High Risk ◽

Negative Symptoms ◽

Clinical Symptoms ◽

Diffusion Tensor ◽

Mental States ◽

Brain Regions ◽

Level Of Functioning ◽

Ultra High Risk ◽

The Cross

BackgroundIndividuals at ultra-high-risk (UHR) for psychosis present with emerging symptoms and decline in functioning. Previous univariate analyses have indicated widespread white matter (WM) aberrations in multiple brain regions in UHR individuals and patients with schizophrenia. Using multivariate statistics, we investigated whole brain WM microstructure and associations between WM, clinical symptoms, and level of functioning in UHR individuals.MethodsForty-five UHR individuals and 45 matched healthy controls (HCs) underwent magnetic resonance diffusion tensor imaging (DTI) at 3 Tesla. UHR individuals were assessed with the Comprehensive Assessment of At-Risk Mental States, Scale for the Assessment of Negative Symptoms, and Social and Occupational Functioning Assessment Scale. Partial least-squares correlation analysis (PLSC) was used as statistical method.ResultsPLSC group comparisons revealed one significant latent variable (LV) accounting for 52% of the cross-block covariance. This LV indicated a pattern of lower fractional anisotropy (FA), axial diffusivity (AD), and mode of anisotropy (MO) concomitant with higher radial diffusivity (RD) in widespread brain regions in UHR individuals compared with HCs. Within UHR individuals, PLSC revealed five significant LVs associated with symptoms and level of functioning. The first LV accounted for 31% of the cross-block covariance and indicated a pattern where higher symptom score and lower level of functioning correlated to lower FA, AD, MO, and higher RD.ConclusionsUHR individuals demonstrate complex brain patterns of WM abnormalities. Despite the subtle psychopathology of UHR individuals, aberrations in WM appear associated with positive and negative symptoms as well as level of functioning.

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White matter microstructure in ultra-high risk and first episode schizophrenia: A prospective study

Psychiatry Research Neuroimaging ◽

10.1016/j.pscychresns.2015.11.003 ◽

2016 ◽

Vol 247 ◽

pp. 42-48 ◽

Cited By ~ 14

Author(s):

Silvia Rigucci ◽

Giulia Santi ◽

Valentina Corigliano ◽

Annamaria Imola ◽

Camilla Rossi-Espagnet ◽

...

Keyword(s):

White Matter ◽

High Risk ◽

Prospective Study ◽

First Episode ◽

White Matter Microstructure ◽

Ultra High Risk ◽

A Prospective Study ◽

First Episode Schizophrenia

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Investigating Cognitive and Clinical Predictors of Real-Life Functioning, Functional Capacity, and Quality of Life in Individuals at Ultra-High Risk for Psychosis

Schizophrenia Bulletin Open ◽

10.1093/schizbullopen/sgaa027 ◽

2020 ◽

Vol 1 (1) ◽

Author(s):

Louise Birkedal Glenthøj ◽

Tina Dam Kristensen ◽

Christina Wenneberg ◽

Carsten Hjorthøj ◽

Merete Nordentoft

Keyword(s):

Quality Of Life ◽

Social Skills ◽

High Risk ◽

Functional Capacity ◽

Processing Speed ◽

Negative Symptoms ◽

Role Functioning ◽

Functional Impairments ◽

Ultra High Risk

Abstract A substantial proportion of individuals at ultra-high risk (UHR) for psychosis show long-term functional impairments, which may have profound consequences for the individual and society. Finding predictors of these functional impairments is critical to inform on the individual’s functional prognosis and potentially develop targeted interventions. This study used data from 91 UHR individuals participating in a randomized, clinical trial, that were followed up at 12 months, to elucidate on clinical, neuro- and social-cognitive predictors of UHR individuals’ functional outcome in the domains of social- and role functioning, quality of life, and functional capacity. The proportion of UHR individuals showing a poor social- and role outcome at 12-month follow-up was 50% and 63%, respectively. Worse social outcome was predicted by higher levels of negative symptoms, reduced processing speed, and impaired baseline social functioning explaining 52% of the variance. Worse role outcome was predicted by impaired role functioning at baseline, explaining 25% of the variance. Quality of life impairments were predicted by better theory of mind explaining 4% of the variance, and functional capacity social skills deficits were predicted by impaired baseline social skills explaining 20% of the variance. Our findings indicate that processing speed and negative symptoms may contribute to social- and role-functioning deficits, and while aspects of social cognition may also relate to social- and role functioning, baseline-functional impairments seem to be a strong contributor to persistent impairments in functioning and quality of life. If replicated, our findings suggest the need for future studies investigating the effect of pro-functional interventions targeting baseline functioning and targeted cognitive domains in UHR.

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