The use of operational diagnostic criteria has become standard in psychiatric diagnosis, seemingly reducing the importance of traditional psychopathology, which describes psychiatric signs and symptoms and considers their underlying pathology. However, findings from neuroscientific research on the mechanisms of psychosis (a state characterized by delusions, hallucinations, and ego disturbances) often align with concepts in psychopathology. This symposium reexamined the psychopathology of psychosis from neuroscientific perspectives, including MRI, EEG, and computational approaches. The author focused on aberrant salience caused by heightened midbrain‐striatal dopamine activity and its relation to the tendency to form delusions. We also explored the domain specificity of salience in delusions, hallucinations, and ego disturbances, and found that, contrary to conventional theories, the dorsal striatum plays a more significant role than the ventral striatum in aberrant salience. This approach aims to reconstruct and advance the psychopathology of psychosis from a neuroscientific standpoint.

View full abstract

The infiltration of “Fremdheit” in patients’ whole experience‐field including self‐experience and perceptual experience is specific in schizophrenia. This symptom is called the “Entfremdungselrebnis”. Then, otherness which emerges in psychotic symptoms in schizophrenia is primarily some “fremde Mächte”, not the real other people. Patients experience being “gemacht” (made) in Ich‐störung, and being “gestellt” (staged) in Wahnwahrnehmung by some “fremde Mächte”. The infiltration of “Fremdheit” is extremely abstract formal aspect of psychotic symptoms of schizophrenia, and this could be a clue for linkage between psychopathology and neuroscience. In order to prove mechanisms of the “Entfremdungselrebnis”, we have studied psychopathology of schizophrenia from the standpoint of abnormal Sense of Agency (SoA) . We developed original experimental settings where temporal or spatial biases were introduced in order to evaluate the SoA. Several neurophysiological and theoretical studies have suggested that aberrancy may be due to temporal delays in sensory‐motor prediction signals. Moreover, we have established a methodology: agency tuning to intervene learning (updating) mechanisms of the internal prediction model under the delayed prediction signals using original application as a cognitive rehabilitation for schizophrenia.

View full abstract

Computational psychiatry offers a novel perspective on understanding the pathophysiology of psychosis. This review focuses on the predictive processing framework, one of the most influential computational theories of the brain, to explore the abnormalities in prediction, prediction error, and prediction precision that underlie psychotic symptoms. Hallucinations and delusions, key features of psychosis, are hypothesized to result from hierarchical interactions among these factors. Using a neuro‐robotics experimental framework, studies have empirically examined how disruptions in prediction, prediction error, and precision can contribute to the formation of psychotic symptoms. These experiments replicated behaviors and experiences analogous to schizophrenia, providing insights into the mechanisms driving the disorder. Furthermore, this review highlights the importance of biological non‐specificity（multifinality）and heterogeneity（equifinality）in psychosis pathophysiology. Non‐specificity refers to the phenomenon where the same biological factor leads to distinct symptoms, while heterogeneity describes how different biological factors produce similar symptoms. These concepts underscore the necessity of moving beyond a single causal pathway to consider multiple interacting mechanisms. Understanding these dynamics may pave the way for integrative approaches to the diagnosis and treatment of psychosis, contributing to a more unified and comprehensive understanding of its pathophysiological basis.

View full abstract

Mismatch negativity (MMN) is a well known EEG index that is a useful in investigating the pathophysiology of schizophrenia. Previous studies repeatedly reported that MMN amplitude is reduced in patients with schizophrenia, and associated with clinical symptoms such as cognitive function, negative symptom, and functional outcomes. There are two types of MMN : duration MMN (dMMN) , which is obtained by changing the duration of the sound of the deviant stimulus, and frequency MMN (fMMN) , which is obtained by changing the frequency of the sound. It is known that in the early stages of schizophrenia, such as early post‐onset schizophrenia and ultra‐high risk for psychosis, dMMN and fMMN differ in the clinical stage of their amplitude reduction and the way they are related to clinical symptoms. In recent years, some studies reported the mechanism, and estimated sources of MMN in schizophrenia. Since MMN is also an index that can be measured in animals, prior studies using monkeys reported detailed results on the source and mechanism of MMN. The results of these studies greatly contributed to the elucidation of the pathophysiology of schizophrenia. It is expected that the development of new treatment methods targeting MMN will be promoted in both clinical and basic research in the future.

View full abstract

Mismatch negativity is an event‐related potential that includes deviance detection (DD) and is frequently interpreted within a predictive coding framework. The DD component, but not the adaptation component, of auditory duration mismatch negativity (dMMN) is reduced in patients with schizophrenia. However, the neural basis for deviance detection was unknown. Recently, we conducted one‐photon and two‐photon calcium imaging of the primary and higher‐order (lateral belt and parabelt) auditory cortex in awake common marmosets, and clearly found DD, but not response adaptation, in a dMMN paradigm. Rostral parabelt (RPB) neurons showed the strongest DD without response during tone presentation. DD‐related signaling in the RPB spread over the primary auditory cortex (A1) and lateral belt. DD in A1 required RPB activation, and optogenetic activation of RPB enhanced the A1 response to the standard tone stimulation. Our results suggest that pure prediction error signals are generated in a subset of RPB neurons and spread backward similar to backpropagation, indicating the essence of dMMN. This review outlines this study.

View full abstract

Mismatch negativity (MMN) is a negative event‐related potential (ERP) component observed in response to a rare stimulus embedded within a sequence of regular stimuli. It is considered to reflect the brain’s pre‐attentive mechanism for detecting deviations. MMN has been studied predominantly in the auditory system, and reductions in MMN responses have been observed in certain psychiatric disorders, including schizophrenia, emphasizing its potential contribution to understanding disease pathology and advancing biomarker research. Rodent models, which share similar neuroanatomical structures with humans, have played an important role in elucidating the mechanisms underlying MMN and in advancing our knowledge of these disorders, owing to the relative ease of brain activity recording, genetic manipulation, and other experimental approaches. Recent technological advances, such as calcium imaging and molecular biology tools, enable detailed analyses of specific neuronal circuit components and associated molecular bases. These developments have furthered our understanding of the neural activities involved in deviance detection and are expected to contribute to the elucidation of psychiatric disease pathology.

View full abstract