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. 2025 May 29:16:1587296.
doi: 10.3389/fneur.2025.1587296. eCollection 2025.

A Hybrid Digital-4E Strategy for comorbid migraine and depression: a medical hypothesis on an AI-driven, neuroadaptive, and exposome-aware approach

Parisa Gazerani  1
Affiliations

A Hybrid Digital-4E Strategy for comorbid migraine and depression: a medical hypothesis on an AI-driven, neuroadaptive, and exposome-aware approach

Parisa Gazerani. Front Neurol. .

Abstract

Objective: The co-occurrence of migraines and depression presents a critical clinical challenge, affecting up to 50% of individuals with either condition. This comorbidity leads to greater disability, higher healthcare costs, and poorer treatment outcomes than either disorder alone. Despite a bidirectional pathophysiological relationship, current models remain static and fragmented, treating each condition separately. This paper proposes a Hybrid Digital-4E Strategy, deployed on an AI-driven neuroadaptive digital health platform, integrating closed-loop therapy, digital phenotyping, and exposome tracking to enable real-time, personalized care.

Methods: Grounded in the 4E cognition framework (Embodied, Embedded, Enactive, and Extended cognition), this strategy reconceptualizes migraine-depression as an interactive system rather than two separate conditions. The platform integrates real-time biomarker tracking, neuromorphic AI, and precision environmental analytics to dynamically optimize treatment. Adaptive chronotherapy, brain-computer interfaces (BCIs), and virtual reality (VR)-based neuroplasticity training further enhance intervention precision.

Conclusion: A closed-loop, AI-driven neuroadaptive system could improve outcomes by enabling early detection, real-time intervention, and precision care tailored to individual neurophysiological and environmental profiles. Addressing AI bias, data privacy, and clinical validation is crucial for implementation. If validated, this Hybrid Digital-4E Strategy could redefine migraine-depression management, paving the way for precision neuropsychiatry.

Keywords: 4E cognition; AI-driven therapy; closed-loop systems; digital health; exposome; migraine-depression comorbidity; neuroadaptive; precision medicine.

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Conflict of interest statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
A conceptual diagram of the Hybrid Digital-4E Strategy for the management of comorbid migraine and depression.
See this image and copyright information in PMC

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References

    1. Amiri P, Kazeminasab S, Nejadghaderi SA, Mohammadinasab R, Pourfathi H, Araj-Khodaei M, et al. Migraine: a review on its history, global epidemiology, risk factors, and comorbidities. Front Neurol. (2021) 12:800605. doi: 10.3389/fneur.2021.800605 - DOI - PMC - PubMed
    1. Lv X, Xu B, Tang X, Liu S, Qian JH, Guo J, et al. The relationship between major depression and migraine: a bidirectional two-sample Mendelian randomization study. Front Neurol. (2023) 14:1143060. doi: 10.3389/fneur.2023.1143060, PMID: - DOI - PMC - PubMed
    1. Al Ghadeer HA, Al Salman SA, Alshakhs ZM, Alghanim JH, Alneamah AA, Almazyadi HS, et al. Migraine headache and the risk of depression. Cureus. (2022) 14:e31081. doi: 10.7759/cureus.31081, PMID: - DOI - PMC - PubMed
    1. Viudez-Martínez A, Torregrosa AB, Navarrete F, García-Gutiérrez MS. Understanding the biological relationship between migraine and depression. Biomol Ther. (2024) 14:163. doi: 10.3390/biom14020163, PMID: - DOI - PMC - PubMed
    1. Altamura C, Corbelli I, de Tommaso M, Di Lorenzo C, Di Lorenzo G, Di Renzo A, et al. Pathophysiological bases of comorbidity in migraine. Front Hum Neurosci. (2021) 15:640574. doi: 10.3389/fnhum.2021.640574, PMID: - DOI - PMC - PubMed

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