Transdiagnostic Functional Brain Alterations Across Familial and Phenotypic Risk Samples: A Meta-Analysis

Importance: Psychiatric risk factors are often associated with multiple clinical outcomes. However, it remains unclear whether functional brain activation changes are shared across risk for mood, anxiety, and psychotic disorders. Objective: To determine which patterns of functional brain activation are shared across risk for different psychiatric disorders, defined using phenotypic (e.g., clinical) and familial risk paradigms, relative to control samples. Data Sources: PubMed and Web of Science were searched for task-based functional magnetic resonance imaging (fMRI) studies involving samples at risk for a mood, anxiety, or psychotic disorder, published between January 2000 and July 2026. Study Selection: Studies published in English, with whole brain results, comparing a high-risk sample to a control sample, with a mean age of 30 years or less, were included. Of the 5,748 studies screened, 101 met selection criteria. Data Extraction and Synthesis: Peak voxel coordinates from contrasts were extracted. Study quality was assessed using an adapted neuroimaging methods quality checklist. Peak coordinates were pooled within studies, and a random effects activation likelihood estimation meta-analysis was conducted using the Python package JALE. Main Outcomes and Measures: Statistical maps of spatial convergence in task-related brain activation were computed across risk groups and within subgroups defined by disorder risk (mood, anxiety, or psychotic disorder risk), ascertainment paradigm (phenotypic, familial), and task domain (cognitive, affective, reward). Statistical significance was assessed using permutation-based cluster-level family-wise error (cFWE) correction. Results: The studies included comprised 2534 high-risk participants and 2686 controls. Across psychosis, mood, and anxiety risk groups, there was a common area of functional activation in the left lateral prefrontal cortex (k = 319, p < 0.05 cFWE), reflecting greater activation in high-risk groups compared to controls. Approximately 30% of studies in each risk group contributed to this finding, reflecting both ascertainment paradigms and all three task types. Within the psychosis risk group, additional alterations were identified in the orbitofrontal cortex and anterior insula. Conclusions and Relevance: Increased left lateral prefrontal activation was shared across risk groups despite methodological heterogeneity. Because this region supports higher-order executive functioning and undergoes prolonged maturation, this finding may represent a shared marker of vulnerability across psychiatric risk groups.