Restoring Oscillatory Dynamics in Alzheimer's Disease: A Laminar Whole-Brain Model of Serotonergic Psychedelic Effects

Gendra, Lopez-Solà, Castaldo et al. — Network Neuroscience, 2025 (in press).

Why I cared. Psychedelics seem to help neurodegeneration by reshaping brain dynamics, but the “how” stayed hand-wavy. I wanted a mechanistic model that could say what the receptor actually does to the rhythms.

What we did. We built a personalised whole-brain model on a laminar neural-mass framework, fit it to multimodal data from 30 people with mild-to-moderate Alzheimer’s, and simulated serotonin-2A receptor activation by modulating the excitability of layer-5 pyramidal neurons.

What we found. That single change reproduces the signature psychedelic EEG shifts — alpha suppressed, gamma enhanced — and the size of the shift tracks where 5-HT2A receptors actually sit. The simulated EEG also became more complex and higher in entropy, as if function were being restored.

What it opened. If a laminar model can predict where and how psychedelics move the rhythms, can it pick who — and which cortex — would benefit in early Alzheimer’s, and how early that window opens?