Brain structural trajectories in youth at familial risk for schizophrenia or bipolar disorder according to development of psychosis spectrum symptoms

Abstract

Background: The evaluation of child and adolescent offspring of patients with schizophrenia (SzO) or bipolar disorder (BpO) may help understand changes taking place in the brain in individuals at heightened risk for disease during a key developmental period. Methods: One hundred twenty-eight individuals (33 SzO and 46 BpO, considered jointly as 'Familial High Risk' (FHR), and 49 controls) aged 6-17 years underwent clinical, cognitive and neuroimaging assessment at baseline, 2-and 4-year follow-up. Twenty FHR participants (11 SzO and 9 BpO) developed psychotic spectrum symptoms during follow-up, while 59 FHR participants did not. Magnetic resonance imaging was performed on a 3Tesla scanner; cortical surface reconstruction was applied to measure cortical thickness, surface area and grey matter volume. Results: FHR participants who developed psychotic spectrum symptoms over time showed greater time-related mean cortical thinning than those who did not and than controls. By subgroups, this effect was present in both BpO and SzO in the occipital cortex. At baseline, FHR participants who developed psychotic spectrum symptoms over time had smaller total surface area and grey matter volume than those who did not and than controls. Over time, all FHR participants showed less longitudinal decrease in surface area than controls. In those who developed psychotic spectrum symptoms over time, this effect was driven by BpO, while in those who did not, this was due to SzO, who also showed less grey matter volume reduction. Conclusion: The emergence of psychotic spectrum symptoms in FHR was indexed by smaller cross-sectional surface area and progressive cortical thinning. Relative preservation of surface area over time may signal different processes according to familial risk. These findings lay the foundation for future studies aimed at stratification of FHR youth.

Longitudinal Structural MRI Findings in Individuals at Genetic and Clinical High Risk for Psychosis: A Systematic Review

“…A number of hypothetical neurodevelopmental models may explain the diverging gray matter trajectories in HR subjects depending on clinical outcome (Figure 2). For HR subjects that do not transition, gray matter volume may initially be lower than HV, but during adolescence non-transition subjects have a slower trajectory of typical gray matter loss, allowing typically developing subjects to "catch up" to the same level of gray matter volume, as shown in the NIMH cohort and the Barcelona cohort (21,52). This infers premature gray matter loss in HR or a neurodevelopmental deficit in gray matter volume, which no longer differs from HV later on in development.…”

“…Alternatively, remitted HR subjects may retain this deficit in gray matter volume, but to a lesser extent than that seen in subjects who transition to psychosis. The former is most likely, as studies generally do not find an intermediate level of gray matter loss in remitted subjects compared to HV and transitioned subjects (17,20,28,43,44,52). Cognition may be affected in HR subjects whose brain trajectories later "normalize, " as initial gray matter deficits alongside protracted loss are associated with poor intelligence (71), which is reported to be lower in GHR groups (72).…”

“…This can bias results, particularly if the majority of the transition group are medicated whereas the non-transition group are not (41). However, in the largest study to date, reductions in cortical thickness in those who transitioned remained significant when analyses were restricted to unmedicated subjects (17), whilst another study found trend-level associations after excluding medicated subjects (52). Future studies could make use of sampling psychotic experiences in the general population, which were examined by 5 studies in this review.…”

“…Furthermore, in the anterior cingulate cortex the study reported greater volume reductions over time in the non-resilient CHR group but an increase in gyrification over time. In general, studies comparing transition and non-transition groups alongside HV found greater cortical thinning in frontal and temporal lobes, as well as the caudate and insula, which were not apparent in the non-transition group when compared to HV (17,20,28,32,43,44,52).…”

Polygenic Risk for Schizophrenia, Brain Structure and Environmental Risk in UK Biobank

“…Convergent evidence has demonstrated widespread grey matter reductions in individuals with schizophrenia, including lower cortical volume (CV), reduced cortical thickness (CT) and smaller surface area (SA) and subcortical volumes, predominantly in the frontal and temporal regions 3,[15][16][17] . Longitudinal neuroimaging studies have demonstrated progressive grey matter changes related to schizophrenia [18][19][20] as well as morphological differences that may be present prior to the onset of symptoms 20,21 . High-risk familial studies have observed brain structural alterations in unaffected relatives of patients with schizophrenia relative to controls, suggesting a genetic contribution [22][23][24] .…”