An Integrated Hypothesis on Neurobiological and Environmental Mechanisms in Psychosis

Đinh Thiên anh © 2025 Creative Commons BY-NC-ND 4.0 This essay is linked with: https://zenodo.org/records/16966779 Bài luận này được liên kết với: https://zenodo.org/records/16966779 Note: The entirety of the following content is presented as theoretical assumptions and proposed research directions, rather than scientifically proven conclusions. The mechanisms and models described are inferential, based on existing data and literature, aiming to construct a theoretical framework and propose methods for empirical validation. Note: The Default Mode Network (DMN) is presented merely as a representative example in this thesis on the definition of the 'thinking stream' (Vietnamese: Dòng nghĩ). In fact, all other functional networks—including the Salience Network, the Central Executive Network, motor and sensory networks, among others—contribute to sustaining this continuous electrochemical activity, each in its own specific way. Academic Summary — An Integrated Hypothesis on Neural and Environmental Mechanisms in Psychotic Disorders Purpose and Nature of the PaperThis paper proposes an integrated theoretical framework in which psychosis is explained as an endogenous narrative mechanism driven by the dominance of the Default Mode Network (DMN/PCC), combined with dysregulation of cognitive control systems and neurotransmission, within the context of interactions among environmental factors, stress, and genetic predispositions—rather than merely as a consequence of organic brain damage or psychedelic substance use. Core Hypothesis:Schizophrenia is conceptualized as the brain’s strategy to "escape from reality": when external information becomes overwhelming or unprocessable (e.g., trauma, social isolation), the DMN/PCC generates a continuous endogenous narrative (a “locked” stream of thought) to maintain coherence; meanwhile, the PFC/ACC (reality-monitoring system) is impaired, preventing updates to the narrative, leading to delusions, hallucinations, and dissociative symptoms. Theoretical Framework — Neural and Cognitive Mechanisms Stream of Thought : A spontaneously generated stream of thought produced by the DMN; when disorganized, it becomes a monotonous, compulsive “narrative.” Relevant Networks : DMN/PCC (story generation), PFC & ACC (monitoring and conflict detection), TPJ/AG (self-other distinction, semantic processing), insula/amygdala (interoception — linking emotion to the narrative). Dyscoordination among these systems results in the “DMN dominance — frontal lobe hypofunction” state characteristic of psychosis. Hypothesis on Neurotransmitters and Neuroendocrine MechanismsThe author integrates multiple biological axes: mesolimbic dopamine is activated in response to narrative content, assigning salience and value; norepinephrine, cortisol, endorphins, serotonin, and oxytocin are described as responding to the narrative content (threat/reward/social aspects) rather than solely reacting to external stimuli; glutamate, GABA, acetylcholine (ACh), and the PCC are considered modulators or amplifiers of the “endogenous world.” Validation of the Proposal — Primary MethodsThe paper proposes operationalizing the endogenous narrative into observable and measurable indices by integrating: natural language processing (NLP) to encode narrative content; physiological measures (heart rate variability [HRV], electrodermal activity [EDA], facial electromyography [EMG]); neuroimaging techniques (EEG, fNIRS, fMRI/rs-fMRI to assess DMN/PCC activity and PFC/ACC connectivity); magnetic resonance spectroscopy (MRS)/positron emission tomography (PET) to examine glutamate, GABA, and dopaminergic receptors; diffusion tensor imaging (DTI) to assess white matter integrity; assays of cytokines, cortisol, prolactin, serotonin, and oxytocin; and genetic analyses (GWAS/polygenic risk scores [PRS], Mendelian randomization subgrouping). The study design includes longitudinal cohorts (prodromal → acute → post-treatment) and interventional trials. Sample Criteria & Confounding Factor ControlThe study recommends excluding cases related to potent psychoactive substances, organic brain damage, or rare genetic mutations (e.g., 22q11.2 deletion), focusing instead on “endogenous” psychosis arising from gene-environment interactions; controlling for BMI, medication, smoking, acute infections, sleep quality, pollution, nutrition, etc. Clinical Significance & Proposed InterventionsIf validated, this framework would shift treatment from mere symptom suppression (pharmacotherapy) toward narrative restructuring (narrative therapy, cognitive-behavioral therapy [CBT] focusing on belief systems), social interventions (enhancing social connectivity to modulate oxytocin/serotonin), and methods to enhance PFC/ACC function (non-invasive brain stimulation, cognitive training). Creative interventions and flow induction are also proposed as protective strategies. Limitations & Nature of the Hypothesis:This work is clearly a theoretical proposal and research direction—not a collection of scientifically established conclusions. Many causal relationships remain inferential; some variables (e.g., acetylcholine and certain neurotransmitters) are difficult to measure directly in humans. Longitudinal, multimodal, and causal analyses (e.g., Mendelian randomization) are necessary for validation. Brief Conclusion:The paper presents a compelling interdisciplinary model suggesting that psychotic disorders may result from an endogenous narrative stream driven by DMN/PCC dominance amid impaired cognitive monitoring and gene-environment interactions. It further advocates for a multimodal research program to validate this model and translate it into clinical interventions.