Applying dimensional psychopathology: transdiagnostic prediction of executive cognition using brain connectivity and inflammatory biomarkers

Abstract

Background The association between executive dysfunction, brain dysconnectivity, and inflammation is a prominent feature across major psychiatric disorders (MPDs), schizophrenia, bipolar disorder, and major depressive disorder. A dimensional approach is warranted to delineate their mechanistic interplay across MPDs. Methods This single site study included a total of 1543 participants (1058 patients and 485 controls). In total, 1169 participants underwent diffusion tensor and resting-state functional magnetic resonance imaging (745 patients and 379 controls completed the Wisconsin Card Sorting Test). Fractional anisotropy (FA) and regional homogeneity (ReHo) assessed structural and functional connectivity, respectively. Pro-inflammatory cytokine levels [interleukin (IL)-1β, IL-6, and tumor necrosis factor-α] were obtained in 325 participants using blood samples collected with 24 h of scanning. Group differences were determined for main measures, and correlation and mediation analyses and machine learning prediction modeling were performed. Results Executive deficits were associated with decreased FA, increased ReHo, and elevated IL-1β and IL-6 levels across MPDs, compared to controls. FA and ReHo alterations in fronto-limbic-striatal regions contributed to executive deficits. IL-1β mediated the association between FA and cognition, and IL-6 mediated the relationship between ReHo and cognition. Executive cognition was better predicted by both brain connectivity and cytokine measures than either one alone for FA-IL-1β and ReHo-IL-6. Conclusions Transdiagnostic associations among brain connectivity, inflammation, and executive cognition exist across MPDs, implicating common neurobiological substrates and mechanisms for executive deficits in MPDs. Further, inflammation-related brain dysconnectivity within fronto-limbic-striatal regions may represent a transdiagnostic dimension underlying executive dysfunction that could be leveraged to advance treatment.

Acute rapamycin treatment reveals novel mechanisms of behavioral, physiological, and functional dysfunction in a maternal inflammation mouse model of autism and sensory over-responsivity

“…There is evidence in the literature that supports the theory that these functional brain alterations that we have observed in the MIR model are induced by maternal inflammation and sustained by the chronic inflammation in the offspring. For example, neuro-inflammation has been increasingly recognized as a factor contributing to atypical functional connectivity patterns and network abnormalities [283][284][285][286][287][288][289] . Neuro-inflammation can affect synaptic function by modulating the release of neurotransmitters, altering receptor expression, and ion channel function which impacts long-term potentiation and long-term depression 72,86,[290][291][292][293][294][295] .…”

Clinical Value of Inflammatory and Neurotrophic Biomarkers in Bipolar Disorder: A Systematic Review and Meta-Analysis

“…Recent studies have also evaluated non-coding RNA expression, sexual hormones, oxidative stress (uric acid, bilirubin, albumin) and metabolic biomarkers (metabolic syndrome, overweight/obesity, thyroid and liver function) in predicting BD and suicidality in individuals with bipolar disorder [ 94 , 95 , 96 , 97 , 98 ]. In addition, big data of cerebral blood flow and structural and functional connectivity using magnetic resonance imaging are becoming useful tools for actual practice in psychiatry [ 99 , 100 ]. By gathering all this information and using multivariable logistic regression, it could be possible to construct a model to predict BD.…”

Characterizing the distinct imaging phenotypes, clinical behavior, and genetic vulnerability of brain maturational subtypes in mood disorders

“…This is not completely surprising because studies have mainly used nosology that differentiates mood disorders according to clinical symptoms in the lack of any objective biomarker, although the clinical diagnostic system, Diagnostic and Statistical Manual of Mental Disorders, has already dramatically revolutionized the psychiatry field. While long proposed as distinguishable diagnostic categories, MDD and BD share substantial key attributes as implicated by complementary sources of evidence from neuroimaging, histological, and genetic studies (Brambilla, Perez, Barale, Schettini, & Soares, 2003;O'Donovan & Owen, 2016;Sheline, 2003;Wei et al, 2020Wei et al, , 2023Xia et al, 2019). This suggests a broader continuum between MDD and BD than previously assumed.…”