Changes in patterns of age-related network connectivity are associated with risk for schizophrenia

Abstract

Alterations in fMRI-based brain functional network connectivity (FNC) are associated with schizophrenia (SCZ) and the genetic risk or subthreshold clinical symptoms preceding the onset of SCZ, which often occurs in early adulthood. Thus, age-sensitive FNC changes may be relevant to SCZ risk-related FNC. We used independent component analysis to estimate FNC from childhood to adulthood in 9,236 individuals. To capture individual brain features more accurately than single-session fMRI, we studied an average of three fMRI scans per individual. To identify potential familial risk-related FNC changes, we compared age-related FNC in first-degree relatives of SCZ patients mostly including unaffected siblings (SIB) with neurotypical controls (NC) at the same age stage. Then, we examined how polygenic risk scores for SCZ influenced risk-related FNC patterns. Finally, we investigated the same risk-related FNC patterns in adult SCZ patients (oSCZ) and young individuals with subclinical psychotic symptoms (PSY). Age-sensitive risk-related FNC patterns emerge during adolescence and early adulthood, but not before. Young SIB always followed older NC patterns, with decreased FNC in a cerebellar-occipitoparietal circuit and increased FNC in two prefrontal-sensorimotor circuits when compared to young NC. Two of these FNC alterations were also found in oSCZ, with one exhibiting reversed pattern. All were linked to polygenic risk for SCZ in unrelated individuals (R² varied from 0.02 to 0.05). Young PSY showed FNC alterations in the same direction as SIB when compared to NC. These results suggest that age-related neurotypical FNC correlates with genetic risk for SCZ and is detectable with MRI in young participants.

Keywords: familial risk; functional network connectivity; neurodevelopment; polygenic risk; schizophrenia.

Fig. 1.

Chart describing the outline of this study including (A) the multisession fMRI protocol, (B) the individual-level FNC matrices determination through the application of the MOO-ICAR Algorithm [Du et al. (41)] on each fMRI session, (C) the group analysis on (1) the age-related FNC, (2) the familial risk–related FNC and, subsequently, the clinical risk–related FNC, (3) the SCZ-related FNC, (4) the genetic analysis PRS × FNC across groups within cohorts, and (5) the meta-analysis on the association PRS × FNC across cohorts.

Fig. 2.

Connectome plot showing the differences between yNC and oNC on FNC estimated on multiple fMRI sessions among age-related IC pairs resulted from the consensus across the LIBD, UNIBA1, and UNIBA2 cohorts. The 17 IC pairs included in the cerebellar (CB, N = 2), cognitive control (CC, N = 7), default mode (DM, N = 4), sensorimotor (SM, N = 2), subcortical (SC, N = 2), and visual (VI, N = 5) networks. Blue lines represent decreased FNC in oNC compared with yNC, whereas red lines represent increased FNC in oNC compared with yNC.

Fig. 3.

Brain sections depicting the (A) cerebellar–occipitoparietal circuit and the (B) medial and (C) dorsolateral PFC circuits. Boxplots showing differences on averaged FNC across sessions among risk-related IC pairs comparing all groups, i.e., cNC, yNC, oNC, cSIB/FHR, ySIB, oSIB, cPSY, yPSY, and oSCZ. Significant differences in each of the three cohorts are indicated with asterisks. Different colors represent different groups: cNC (red), cSIB/FHR (orange), cPSY (light orange), yNC (dark yellow), ySIB (yellow), yPSY (light green), oNC (green), oSIB (dark green), and oSCZ (blue).

Fig. 4.

Plots showing the association between polygenic risk for SCZ and FNC across sessions related to (A) the cerebellar–occipitoparietal circuit; (B) the medial PFC–sensorimotor circuit; and (C) the dorsolateral PFC–sensorimotor circuit. The threshold pFDR < 0.05 was considered on meta-analytic mixed-effect-model-derived P values extracted across cohorts (C.I. 0.95), accounting for multiple comparisons via Benjamini–Hochberg. Significant associations are reported in red.