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Normative modeling of brain function abnormalities in complex pathology requires a whole-brain approach
Janus R L Kobbersmed1, Chetan Gohil2, Andre Marquand3
1Department of Clinical Medicine, Center of Functionally Integrative Neuroscience, Aarhus University, Universitetsbyen 3, 8000 Aarhus C, Denmark.
Progress in Neurobiology
|March 19, 2026
Summary
This study introduces Functional Connectivity Integrative Normative Modeling (FUNCOIN) to detect brain disease biomarkers. FUNCOIN identifies abnormal brain function patterns in bipolar disorder and Parkinson's disease, outperforming localized models.
Area of Science:
- Neuroscience
- Biomarkers
- Brain Imaging
Background:
- Objective brain function biomarkers are lacking for many neurological and psychiatric disorders.
- Disease heterogeneity and spectrum presentation complicate traditional sick-healthy dichotomies.
- Normative modeling identifies abnormalities as deviations from age- and sex-matched normal brain function variation.
Purpose of the Study:
- To propose a novel whole-brain normative modeling approach for functional connectivity (FC).
- To address the limitations of localized analyses in capturing systemic brain pathology.
- To develop Functional Connectivity Integrative Normative Modeling (FUNCOIN) for enhanced biomarker discovery.
Main Methods:
- Utilized UK Biobank resting-state fMRI data from 46,000 healthy subjects.
- Applied the novel FUNCOIN whole-brain normative modeling approach.
- Trained and tested models to identify abnormal FC patterns indicative of disease.
Main Results:
- FUNCOIN identified significantly abnormal FC patterns in subjects with bipolar disorder and Parkinson's disease.
- Localized models failed to detect these widespread FC abnormalities.
- Bipolar disorder subjects showed two distinct subgroups with different FC deviations.
- Abnormal FC patterns in Parkinson's disease were detectable up to 8 years pre-diagnosis.
Conclusions:
- Whole-brain normative modeling of FC is superior to localized approaches for detecting brain disease biomarkers.
- FUNCOIN provides a sensitive method for identifying systemic brain dysfunction in neurological and psychiatric conditions.
- Early detection of Parkinson's disease may be possible through identifying abnormal FC patterns.
