Diagnostic Task Specific Activations in Functional MRI and Aberrant Connectivity of Insula with Middle Frontal Gyrus Can Inform the Differential Diagnosis of Psychosis

Abstract

We constructed a novel design integrating the administration of a clinical self-assessment scale with simultaneous acquisition of functional Magnetic Resonance Imaging (fMRI), aiming at cross-validation between psychopathology evaluation and neuroimaging techniques. We hypothesized that areas demonstrating differential activation in two groups of patients (the first group exhibiting paranoid delusions in the context of paranoid schizophrenia—SCH—and second group with a depressive episode in the context of major depressive disorder or bipolar disorder—DEP) will have distinct connectivity patterns and structural differences. Fifty-one patients with SCH (n = 25) or DEP (n = 26) were scanned with three different MRI sequences: a structural and two functional sequences—resting-state and task-related fMRI (the stimuli represent items from a paranoid-depressive self-evaluation scale). While no significant differences were found in gray matter volumes, we were able to discriminate between the two clinical entities by identifying two significant clusters of activations in the SCH group—the left Precuneus (PreCu) extending to the left Posterior Cingulate Cortex (PCC) and the right Angular Gyrus (AG). Additionally, the effective connectivity of the middle frontal gyrus (MFG), a part of the Dorsolateral Prefrontal Cortex (DLPFC) to the Anterior Insula (AI), demonstrated a significant difference between the two groups with inhibitory connection demonstrated only in SCH. The observed activations of PreCu, PCC, and AG (involved in the Default Mode Network DMN) might be indirect evidence of the inhibitory connection from the DLPFC to AI, interfering with the balancing function of the insula as the dynamic switch in the DMN. The findings of our current study might suggest that the connectivity from DLPFC to the anterior insula can be interpreted as evidence for the presence of an aberrant network that leads to behavioral abnormalities, the manifestation of which depends on the direction of influence. The reduced effective connectivity from the AI to the DLPFC is manifested as depressive symptoms, and the inhibitory effect from the DLPFC to the AI is reflected in the paranoid symptoms of schizophrenia.

In schizophrenia, chronic fatigue syndrome- and fibromyalgia-like symptoms are driven by breakdown of the paracellular pathway with increased zonulin and immune activation-associated neurotoxicity

“…Interestingly, the combined impact of leaky gut, immune activation and natural IgM biomarkers was more important than that of neurotoxicity indices, although the MITOTOX index comprising the neurotoxic cytokines/chemokines and TRYCATs coupled with LPS and the oxidative stress damage was strongly associated with the physiosomatic symptoms. Previously, we have discussed that the symptomatome, G-CoDe, Qol-phenome, and the BCPS-worsening index are significantly associated with indices of increased neurotoxicity as indicated by increased levels of neurotoxic cytokines including IL-6, TNF-α, CCL11, MIP-1, increased levels of neurotoxic TRYCATs, including PA, XA, and 3HK, and signs of oxidative/chlorinative stress as indicated by increased LOOH, MDA, and AOPP levels (Maes et al, 2020a;2021b).…”

“…CCL11 was not included in this index to allow for the additional effects of this . chemokine; and d) the MITOTOX index was computed as zTNF-α + zIL-6 + zCCL11 + zTRYCAT ratio + zLOOH + zMDA + zAOPP + zIgA LPS (Maes et al, 2020a;2021b).…”

“…Moreover, it is important to note that the plasma levels of Hp, which is an acute phase protein (APP), are significantly increased in schizophrenia in conjunction with other acute phase proteins and complement factors, including C3C (Maes et al, 1997). As such, part of the immune-inflammatory and oxidative stress responses in schizophrenia (Maes et al, 1997;2021b) may be explained by an increased Hp-2 gene frequency, increased zonulin levels and accompanying leaky gut (Maes et al, 2001;2019a).…”

“…CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) which lead to aberrations in neuroplasticity and connectivity especially in the salience network (anterior insula and anterior cingulate cortex), amygdala, the prefronto-striato-thalamic, prefrontoparietal, prefronto-temporal, and dorsolateral prefrontal cortex Orellana and Slachevsky, 2013;Maes et al, 2020a;2021b;Stoyanov and Maes, 2021;Stoyanov et al, 2021).…”

Implications from translational cross-validation of clinical assessment tools for diagnosis and treatment in psychiatry

“…Copyright ©The Author(s) 2021. Published by MDPI[ 32 ].…”