Restoring Oscillatory Dynamics in Alzheimer’s Disease: A Laminar Whole-Brain Model of Serotonergic Psychedelic Effects
Jan C. Gendra, Edmundo Lopez-Sola, Francesca Castaldo, Èlia Lleal-Custey, Roser Sanchez-Todo, Jakub Vohryzek, Ricardo Salvador, Ralph G. Andrzejak, Giulio Ruffini, The Alzheimer’s Disease Neuroimaging Initiative
bioRxiv (Cold Spring Harbor Laboratory) December 16, 2024 preprint DOI: 10.1101/2024.12.15.628565 via OpenAlex
Summary
AI-generated from the abstractClassical serotonergic psychedelics may help treat neurodegenerative disorders like Alzheimer's disease by altering pathological brain dynamics. Using multimodal neuroimaging data from thirty subjects with mild to moderate Alzheimer's disease, a personalized whole-brain model based on a laminar neural mass framework simulated the effects of serotonin 2A receptor activation. Modulating the excitability of layer 5 pyramidal neurons reproduced hallmark EEG changes seen under psychedelics, including alpha power suppression and gamma power enhancement. These spectral shifts correlated strongly with regional serotonin 2A receptor distribution. Simulated EEG also showed increased complexity and entropy, suggesting restored network function, offering mechanistic insights into potential therapeutic effects in early Alzheimer's disease.
Study at a glance
| Characteristics | Observational cohort with computational modeling |
|---|---|
| Sample size | 30 |
| Population | Subjects diagnosed with mild to moderate Alzheimer's disease |
| Topics | Serotonin |
| Keywords | Neuroscience Disease Dynamics music Laminar flow |
| Citations | 7 |
| Key finding | Simulated serotonin 2A receptor activation reproduces EEG changes (alpha suppression, gamma enhancement) that correlate with receptor distribution and suggest restored network function in Alzheimer's disease. |
Abstract
Abstract Classical serotonergic psychedelics show promise in addressing neurodegenerative disorders such as Alzheimer’s disease by modulating pathological brain dynamics. However, the precise neurobiological mechanisms underlying their effects remain elusive. This study introduces a personalized whole-brain model built upon a laminar neural mass framework to elucidate these effects. Using multimodal neuroimaging data from thirty subjects diagnosed with mild to moderate Alzheimer’s disease, we simulate the impact of serotonin 2A receptor activation, characteristic of psychedelics, on cortical dynamics. By modulating the excitability of layer 5 pyramidal neurons, our models reproduce hallmark changes in EEG power spectra observed under psychedelics, including alpha power suppression and gamma power enhancement. These spectral shifts are shown to correlate strongly with the regional distribution of serotonin 2A receptors. Furthermore, simulated EEG reveals increased complexity and entropy, suggesting restored network function. These findings underscore the potential of serotonergic psychedelics to reestablish healthy oscillatory dynamics in the prodromal and early phases of Alzheimer’s disease and offer mechanistic insights into their potential therapeutic effects in neurodegenerative disorders.