White matter changes in psychosis risk relate to development and are not impacted by the transition to psychosis

Abstract

Subtle alterations in white matter microstructure are observed in youth at clinical high risk (CHR) for psychosis. However, the timing of these changes and their relationships to the emergence of psychosis remain unclear. Here, we track the evolution of white matter abnormalities in a large, longitudinal cohort of CHR individuals comprising the North American Prodrome Longitudinal Study (NAPLS-3). Multi-shell diffusion magnetic resonance imaging data were collected across multiple timepoints (1-5 over 1 year) in 286 subjects (aged 12-32 years): 25 CHR individuals who transitioned to psychosis (CHR-P; 61 scans), 205 CHR subjects with unknown transition outcome after the 1-year follow-up period (CHR-U; 596 scans), and 56 healthy controls (195 scans). Linear mixed effects models were fitted to infer the impact of age and illness-onset on variation in the fractional anisotropy of cellular tissue (FA T ) and the volume fraction of extracellular free water (FW). Baseline measures of white matter microstructure did not differentiate between HC, CHR-U and CHR-P individuals. However, age trajectories differed between the three groups in line with a developmental effect: CHR-P and CHR-U groups displayed higher FA T in adolescence, and 4% lower FA T by 30 years of age compared to controls. Furthermore, older CHR-P subjects (20+ years) displayed 4% higher FW in the forceps major (p < 0.05). Prospective analysis in CHR-P did not reveal a significant impact of illness onset on regional FA T or FW, suggesting that transition to psychosis is not marked by dramatic change in white matter microstructure. Instead, clinical high risk for psychosisregardless of transition outcome-is characterized by subtle age-related white matter changes that occur in tandem with development.

White matter microstructure and the clinical risk for psychosis: A diffusion tensor imaging study of individuals with basic symptoms and at ultra-high risk

“…Finding a reliable biomarker or at least achieving some biomarker-informed improvement in prognostic accuracy could revolutionize early recognition and intervention. There is an ongoing discussion of whether the transition may be marked by dramatic changes in WM microstructure or rather follows a more subtle pattern ( Di Biase et al, 2021 ).…”

The iPSC perspective on schizophrenia

“…Considering the gradual development of myelin, deficient production and misplacement of oligodendrocytes in the brain could lead to uneven myelination and strengthening of axonal pathways in schizophrenia. In general, the current evidence suggests that schizophrenia is associated with persistent developmental alterations in brain connectivity that could be caused by aberrant axonal pathfinding or myelination [74,75]. However, these changes could also arise from remodeling of connections later in adolescence, particularly in somatosensory and prefrontal cortices [103].…”

“…In support of the early developmental origin of these alterations, individuals with familial risk for ASD have been found to display a caudal shift in thalamocortical wiring in infancy [72], whereas toddlers with high risk for schizophrenia reportedly exhibit hypoconnectivity in the thalamo-PFC tract [73]. Longitudinal studies have observed alterations in brain white matter tracts in individuals at high risk for psychosis persisting from childhood to adulthood, with no dramatic changes associated with transition to psychosis [74,75] (Box 2). Thus, the risk for psychosis appears to be linked to developmentally established structural alterations in brain connectivity.…”

Psychosis spectrum illnesses as disorders of prefrontal critical period plasticity

“…If dysregulated or “hyperplastic” critical period processes are occurring in early phases of illness, they are happening concurrently with dynamic macro-scale structural brain changes that signal a devolving cortex, consistent with over-exuberant synaptic sculpting as the brain attempts to shape its representations to an environment with unreliable statistics and/or is responding to increased stress and inflammation. High-risk individuals who develop psychosis have greater rates of cortical atrophy and reductions in the fractional anisotropy of white matter than those who don’t over the one-year period prior to onset of illness [ 161 , 162 ]. In animal models, sensory deprivation, sensory noise, deleterious environments, and social isolation all impact cortical integrity and myelination [ 163 ].…”