Examining Associations between Neural and Genetic Inflammatory Indices with Psychotic-Like Experiences

Research since the mid-20th century has implicated inflammation in the etiology of schizophrenia and other psychosis spectrum disorders due to increased risk for the disorder following development of specific autoimmunities (Amital & Shoenfeld, 1993; Benros et al., 2012). Additionally, individuals with psychosis spectrum disorders typically experience altered immunity through heightened concentrations of C-reactive protein (CRP) (Fond et al., 2018), IL-1𝛽 (Söderlund et al., 2009), and lymphocyte populations in cerebral spinal fluid (CSF) (Nikkilä et al., 2001). Preclinical models of T cell depletion have suggested a role mediating impairment to cognitive functions relevant to psychosis (Kipnis et al., 2004) and the classic component system may be integral to immune-mediated psychiatric disease. Allelic variants of C4 encoded in the Major Histocompatibility Complex (MHC) class III gene region have shown higher correlation with psychotic disorders compared to non-immune polygenic risk scores (PGS) (Sekar et al., 2016). Furthermore, individuals who carry the C4AL allele show a negative association with entorhinal cortex surface area which in itself has been associated with development of psychosis spectrum symptoms in adolescence (Hernandez et al., 2023). Evidence of an intersection between the peripheral immune system and the central nervous system (CNS) has increasingly gained attention and supporting data. Intriguingly, hepatic infections and autoimmune hepatitis significantly increase the risk of schizophrenia while both the C4 protein and CRP are produced in hepatocytes (Benros et al., 2012). While both CRP and C4 have been associated with psychosis, no study has provided a putative link between these inflammatory signals of hepatic origin, neuroinflammation, and psychosis. Diffusion Basis Spectrum Imaging (DBSI), a technology developed to characterize anisotropic and isotropic diffusion as a metric of neuroinflammation (Wang et al., 2011), has been used to identify elevated cellularity in post-mortem histological samples in the cingulate gyrus and hippocampus of patients diagnosed with schizophrenia (Mamah et al., 2025), suggesting that neuroinflammation in the cingulate gyrus and hippocampus may be a principal component in the neuroinflammatory axis of psychosis. Additional positron emission topography (PET) studies illuminating the coagulation of “activated” microglia in the brain through radioactive ligands targeting the Translator Protein (TSPO) receptor have further implicated the frontal lobe, temporal lobe, cerebellum, and hippocampus as putative loci of neuroinflammation in the brains of individuals experiencing psychosis (Bloomfield et al., 2016; Doorduin et al., 2009). Although these studies reported on gross anatomical disturbances by lobe, we would suggest that the primary component to this region is the ventromedial prefrontal cortex (vmPFC) given prior implication in psychotic disorders (Chai et al., 2011; Kühn & Gallinat, 2013) as well as considerable connectivity to the limbic system (Ongür & Price, 2000). The superior temporal gyrus may also be the primary region of interest within the temporal lobe given structural abnormalities associated with schizophrenia (Shenton et al., 1992). An additional study compared peripheral IL-6 expression and fractional anisotropy in white matter tracts as a measure of axonal degradation, myelination, and cellularity, and found decreased fractional anisotropy in the left cingulate gyrus as well as decreased IL-6 expression in patients experiencing first episode psychosis (Serpa et al., 2023). CRP is directly involved in the component pathway for innate immune responses, and PGS for elevated CRP have been implicated in cortical thinning in the temporal lobe and entorhinal cortex regions as well as elevated manifestation of psychopathology (Zheng et al., 2025). Lastly, despite implication of subcortical regions such as the caudate nucleus, nucleus accumbens (NAc), amygdala, thalamus, pallidum, and putamen in psychotic disorders (Gutman et al., 2021), no prior study has analyzed gray matter with respect to neuroinflammation in these subcortical regions. Of note, Mamah et al., observed increased cellularity in the thalamocortical tract in histological samples from patients diagnosed with schizophrenia (Mamah et al., 2025). Although prior studies have suggested a neuroinflammatory process in the frontal lobe, temporal lobe, entorhinal cortex, cingulate gyrus, cerebellum, and hippocampus either in the context of an active episode of psychosis or a historical diagnosis of schizophrenia, no study has directly attempted measurement of lymphocyte activity and has either consisted exclusively of ex-vivo samples or used radioactive ligands binding to microglia which is a relatively non-specific method (Gao et al., 2023). Lastly, no study has comprehensively considered subcortical features such as the thalamus, amygdala, NAc, caudate nucleus, putamen, and pallidum, as will be done in the present study. Psychotic symptoms exist along a spectrum and cut across psychiatric disorders with incompletely understood pathophysiology. Psychotic-like experiences (PLEs) offer early identification and stratification of individuals experiencing symptoms on this spectrum. Although a metric such as PLEs persists in viewing these disorders through the macroscopic perspective of a spectrum, PLEs offer early insights towards the future development of disease within this range of disorders. Significantly distressing PLEs in young adolescents have previously been shown to have an association with PGS for schizophrenia (Karcher, Paul, et al., 2022) and are associated with a family history of psychotic disorders as well as a range of mild impairments in functioning, cognition, and neural metrics (Karcher, Loewy, et al., 2022). Adolescents who report significantly distressing PLEs also show a higher index of regional vulnerability in cortical thickness typically observed in adults diagnosed with schizophrenia as measured by magnetic resonance imaging (MRI) (Karcher et al., 2023). Early recognition in treatment and research is especially critical for psychosis spectrum disorders as immediate and consistent intervention to psychotic episodes reduces lifetime periods of relapse (Bogers, 2025) which carry deleterious functional consequences and reduced overall likelihood of remission (Howes et al., 2021; Lin et al., 2021) as well as contested neurodegenerative effects (Anderson et al., 2014). Although elevated CRP PGS have revealed increased risk for cortical thinning, no study has illustrated a neuroinflammatory component to this progression. Recent development in diffusion MRI techniques has shown effective utility for measurement of neuroinflammatory processes through methods such as Restriction Spectrum Imaging (RSI). RSI separates the diffusion-weighted MRI signal into isotropic and anisotropic signals within voxels and stratifies the isotropic signal into restricted, hindered, and freely diffusing water mobility. Restricted diffusion is the putative indicator of cellular barriers preventing water movement, in contrast to the hindered movement of water through the tortuosity of extracellular space. Contrasting these metrics, freely diffused space represents the absence of hindrance to water movement and may be an indicator of vasogenic edema. Combination of restricted and hindered diffusion offers proportional measurements which may further be used to identify the relative diffusivity of a given voxel as an approximation of cellularity as has been done previously in the ABCD study (Adise et al., 2025; Bottenhorn et al., 2024; Rapuano et al., 2020). As the proportion of restricted diffusion rises, it is expected that this is due to a local aggregation of cell bodies which may represent microglial clustering and lymphocyte infiltration. No prior research has revealed a specific inflammatory mediator in the development of psychosis. Although prior studies utilizing diffusion through DWI or DBSI as discussed above, or non-diffusion metrics such as radioactive ligand tracing have explored the relationship between neuroinflammation and psychosis, none have utilized RSI or used restricted diffusion to analyze gray matter and none have compared these metrics to early signs of developing psychopathology such as PLEs. In the present study, we approach the polygenic-neuroinflammatory-psychiatric axis and consider the relationship between CRP PGS and significantly distressing PLEs and how neuroinflammation assessed by RSI mediates this dynamic in the Adolescent Brain Cognitive Development (ABCD) study. We expect that higher PGS for heightened CRP expression will be associated with significantly distressing adolescent PLEs at ages 12-13. If higher CRP activity does correlate with more distressing PLEs, we expect that this influence will involve inflammation in the brain and therefore expect that higher indices of neuroinflammation in the vmPFC, superior temporal gyrus, cingulate gyrus, entorhinal cortex, cerebellum, thalamus, hippocampus, amygdala, NAc, caudate nucleus, pallidum, and putamen as assessed by restricted and hindered isotropy through RSI will mediate this effect.