Mapping Psychosis Through a Multiscale Lens
The key to understanding psychosis may lie not in a single symptom or brain region, but in the complex interplay between our biology, cognition, and lived experience.
Psychosis remains one of the most misunderstood conditions in mental health, often reduced to dramatic portrayals of hallucinations and breaks from reality. In truth, it represents a heterogeneous collection of biological and behavioral alterations that evolve over time, affecting how individuals think, feel, and navigate the world 1 . The condition carries substantial personal and societal costs, ranking among the leading causes of disability worldwide 1 .
Traditional approaches have struggled to capture the full complexity of psychosis, often examining symptoms or brain function in isolation. However, a revolutionary framework called multiscale neuroscience offers a new perspective, conceptualizing mental illness as arising from aberrant interactions across and within multiple biopsychosocial scales 1 .
This article explores how researchers are leveraging this framework to propose a comprehensive disease progression model of psychosis, revealing how hippocampal-cortical dysconnectivity can cascade through cognitive processes to ultimately impact daily functioning.
Examining interactions across biological, cognitive, and functional domains to understand psychosis progression.
The hippocampus functions as a crucial hub whose connectivity impacts multiple aspects of psychosis.
Multiscale neuroscience represents a paradigm shift in how we study mental disorders. Rather than focusing exclusively on one level of analysis, this approach examines how processes across different scales interact over time 1 .
It acknowledges that changes at the biological level can influence cognitive function, which in turn affects symptoms and real-world functioning, creating feedback loops that can either worsen or improve outcomes 1 .
The hippocampus, a seahorse-shaped structure deep within the brain, has long been recognized for its role in memory formation. However, recent research has revealed its broader significance in psychosis 3 .
The hippocampus functions as a crucial hub within brain networks, with its connections to other cortical regions supporting not just memory but also social and cognitive processes 3 .
Psychosis manifests across multiple dimensions:
These dimensions are not isolated—research consistently shows they interact in complex ways .
Changes at one level cascade through other domains, creating complex progression pathways
To address the heterogeneity of psychosis and test their multiscale progression model, researchers employed an innovative machine-learning algorithm called Subtype and Stage Inference (SuStaIn) 1 .
The study sampled data from two cross-sectional datasets of first- and multi-episode psychosis, resulting in a sample of 163 patients and 119 non-clinical controls 1 .
The analysis revealed three distinct patient subtypes with different impairment profiles and disease trajectories:
| Subtype | Impairment Profile | Clinical Presentation |
|---|---|---|
| Subtype 0 | Normal-range performance on all variables | Minimal impairments across biological, cognitive, and functional measures |
| Subtype 1 | Lower episodic memory, social cognition, functional outcome, and higher negative symptoms | Prominent cognitive and functional impairments with significant negative symptoms |
| Subtype 2 | Lower hippocampal-cortical connectivity and episodic memory | Primary neurological and memory impairments |
Perhaps most intriguing were the different progression sequences identified for Subtype 1 and Subtype 2. For Subtype 2, the progression followed the predicted multiscale model, beginning with hippocampal dysconnectivity. However, Subtype 1 showed a different pattern, beginning with episodic memory impairments and ending with hippocampal dysconnectivity 1 .
Initial cognitive impairments in memory function
Difficulties in understanding social cues and interactions
Development of motivational and emotional deficits
Impairment in real-world functioning
Altered brain connectivity emerges later in progression
Initial alterations in brain network connectivity
Cognitive impairments follow neurological changes
Social processing difficulties emerge
Impact on daily functioning
Clinical symptoms manifest later in progression
"While the hippocampus seems to play a central role in leading the disease progression in Subtype 2, there might be other factors responsible for leading the progression in Subtype 1" .
Modern psychosis research relies on a diverse array of methodological tools and approaches.
| Tool/Resource | Function | Application in Psychosis Research |
|---|---|---|
| Structural MRI | Visualizes brain anatomy and connectivity | Measures hippocampal volume and cortical connectivity |
| Resting-state fMRI | Assesses functional brain connectivity | Evaluates hippocampal-cortical network integrity |
| Graph Theory Analysis | Quantifies network properties | Calculates participation coefficient of hippocampal circuitry |
| SuStaIn Algorithm | Identifies subtypes and progression patterns | Models heterogeneous disease trajectories |
| MATRICS Consensus Battery | Standardized cognitive assessment | Evaluates multiple cognitive domains affected in psychosis |
| Functional Outcome Measures | Assesses real-world functioning | Measures occupational and social functioning |
Advanced imaging techniques to visualize brain structure and function
Machine learning algorithms to identify patterns and progression
Standardized measures for cognitive, clinical, and functional evaluation
Recent follow-up research has already begun extending these findings across neuroimaging modalities. A 2025 study examining resting-state functional MRI found similar progression patterns, suggesting these trajectories are robust across different measurement techniques 2 6 . Importantly, this research also indicated that different imaging modalities might provide complementary information 2 .
The identification of distinct psychosis subtypes with different progression trajectories supports a precision psychiatry approach that moves beyond one-size-fits-all treatments.
The multiscale approach to psychosis represents a fundamental shift in how we understand severe mental illness. By examining how processes across biological, cognitive, and functional domains interact over time, researchers are beginning to unravel the heterogeneity that has long complicated both treatment and research.
The path forward lies in continuing to map these multiscale interactions, developing increasingly sophisticated models that can capture the dynamic nature of psychosis, and translating these insights into personalized interventions that address the unique progression pathways of each individual.