Effective Connectivity Between the Orbitofrontal Cortex and the Precuneus Differentiates Major Psychiatric Disorders: Results from a Transdiagnostic Spectral DCM Study

Under embargo until: 2022-11-24Background & Objective: We have previously identified aberrant connectivity of the left precuneus, ventrolateral prefrontal cortex, anterior cingulate cortex, and anterior insula in patients with either a paranoid (schizophrenia), or a depressive syndrome (both unipolar and bipolar). In the current study, we attempted to replicate and expand these findings by including a healthy control sample and separating the patients in a depressive episode into two groups: unipolar and bipolar depression. We hypothesized that the connections between those major nodes of the resting state networks would demonstrate different patterns in the three patient groups compared to the healthy subjects. Methods: Resting-state functional MRI was performed on a sample of 101 participants, of which 26 patients with schizophrenia (current psychotic episodes), 24 subjects with Bipolar Disorder (BD), 33 with Major Depressive Disorder (MDD) (both BD and MDD patients were in a current depressive episode), and 21 healthy controls. Spectral Dynamic Causal Modeling was used to calculate the coupling values between eight regions of interest, including the anterior precuneus (PRC), anterior hippocampus, anterior insula, angular gyrus, lateral Orbitofrontal Cortex (OFC), middle frontal gyrus, planum temporale, and anterior thalamus. Results & Conclusion: We identified disturbed effective connectivity from the left lateral orbitofrontal cortex to the left anterior precuneus that differed significantly between unipolar depression, where the influence was inhibitory, and bipolar depression, where the effect was excitatory. A logistic regression analysis correctly classified 75% of patients with unipolar and bipolar depression based solely on the coupling values of this connection. In addition, patients with schizophrenia demonstrated negative effective connectivity from the anterior PRC to the lateral OFC, which distinguished them from healthy controls and patients with major depression. Future studies with unmedicated patients will be needed to establish the replicability of our findings.acceptedVersio

Pharmaco-Magnetic Resonance as a Tool for Monitoring the Medication-Related Effects in the Brain May Provide Potential Biomarkers for Psychotic Disorders

The neurodegenerative and neurodevelopmental hypotheses represent the basic etiological framework for the origin of schizophrenia. Additionally, the dopamine hypothesis, adopted more than two decades ago, has repeatedly asserted the position of dopamine as a pathobiochemical substrate through the action of psychostimulants and neuroleptics on the mesolimbic and mesocortical systems, giving insight into the origin of positive and negative schizophrenic symptoms. Meanwhile, cognitive impairments in schizophrenia remain incompletely understood but are thought to be present during all stages of the disease, as well as in the prodromal, interictal and residual phases. On the other hand, observations on the effects of NMDA antagonists, such as ketamine and phencyclidine, reveal that hypoglutamatergic neurotransmission causes not only positive and negative but also cognitive schizophrenic symptoms. This review aims to summarize the different hypotheses about the origin of psychoses and to identify the optimal neuroimaging method that can serve to unite them in an integral etiological framework. We systematically searched Google scholar (with no concern to the date published) to identify studies investigating the etiology of schizophrenia, with a focus on impaired central neurotransmission. The complex interaction between the dopamine and glutamate neurotransmitter systems provides the long-needed etiological concept, which combines the neurodegenerative hypothesis with the hypothesis of impaired neurodevelopment in schizophrenia. Pharmaco-magnetic resonance imaging is a neuroimaging method that can provide a translation of scientific knowledge about the neural networks and the disruptions in and between different brain regions, into clinically applicable and effective therapeutic results in the management of severe psychotic disorders

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

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

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

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