Neuroimaging as a Window Into the Pathophysiological Mechanisms of Schizophrenia

Abstract

Schizophrenia is a complex neuropsychiatric disorder with a diverse clinical phenotype that has a substantial personal and public health burden. To advance the mechanistic understanding of the illness, neuroimaging can be utilized to capture different aspects of brain pathology in vivo, including brain structural integrity deficits, functional dysconnectivity, and altered neurotransmitter systems. In this review, we consider a number of key scientific questions relevant in the context of neuroimaging studies aimed at unraveling the pathophysiology of schizophrenia and take the opportunity to reflect on our progress toward advancing the mechanistic understanding of the illness. Our data is congruent with the idea that the brain is fundamentally affected in the illness, where widespread structural gray and white matter involvement, functionally abnormal cortical and subcortical information processing, and neurometabolic dysregulation are present in patients. Importantly, certain brain circuits appear preferentially affected and subtle abnormalities are already evident in first episode psychosis patients. We also demonstrated that brain circuitry alterations are clinically relevant by showing that these pathological signatures can be leveraged for predicting subsequent response to antipsychotic treatment. Interestingly, dopamine D2 receptor blockers alleviate neural abnormalities to some extent. Taken together, it is highly unlikely that the pathogenesis of schizophrenia is uniform, it is more plausible that there may be multiple different etiologies that converge to the behavioral phenotype of schizophrenia. Our data underscore that mechanistically oriented neuroimaging studies must take non-specific factors such as antipsychotic drug exposure or illness chronicity into consideration when interpreting disease signatures, as a clear characterization of primary pathophysiological processes is an imperative prerequisite for rational drug development and for alleviating disease burden in our patients.

Salience network glutamate and brain connectivity in medication-naïve first episode patients – A multimodal magnetic resonance spectroscopy and resting state functional connectivity MRI study

“…Consistent with its role in neuroenergetics ( Shulman et al, 2014 , Singh, 2012 ), recent studies have revealed that cortical glutamate appears to play an important role in modulating the blood-oxygen level-dependent (BOLD) signal ( Enzi et al, 2012 , Kraguljac and Lahti, 2021 ) as well as the functional connectivity between brain regions ( Kraguljac et al, 2017 , Tomasi et al, 2013 ). In addition, a review of combined MRS/fMRI studies in healthy subjects concluded that there was evidence that cortical glutamate was not only correlated with the BOLD signal within the measured voxels, but also with regions distant from the voxel ( Duncan et al, 2014 ).…”

Neuro-Immune Aspects of Schizophrenia with Severe Negative Symptoms: New Diagnostic Markers of Disease Phenotype

“…Neuroimaging contributes a lot to the identification of clinically significant biological processes in schizophrenia and provides the opportunity to study specifics of the brain pathology in vivo, including structural brain abnormalities, impaired functional connectivity, and neurotransmitter systems disorders [18]. In many patients with schizophrenia, there are structural, functional, and metabolic disorders in the frontal lobe, yet the mechanisms underlying these changes are not yet fully understood [18][19][20].…”

Incidence rate of psychiatric disorders in 2020: The pivotal role played by SARS-CoV-2 infection

“…Interestingly, psychotic disorders showed the largest change in incidence rates in those with COVID-19 in both the present study and in Taquet et al [ 21 ]. While all psychiatric disorders are linked to stress, this pathophysiological connection is stronger for anxiety/depressive disorders than for psychotic disorders, where mechanisms affecting the brain structure and function seem to play a major role [ 36 ]. This might suggest that mechanisms elicited by SARS-CoV-2 infection, e.g., vascular dysfunction and neuroinflammation, could contribute to the development of new (or exacerbation of ongoing) mental/behavioral health symptoms, subsequently contributing to a diagnosis of psychiatric disorders.…”