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Dopaminergic therapy selectively amplifies hallucination susceptibility in patients with Parkinson's disease with cortico-striatal hyperconnectivity

Bernasconi, F.; Stampacchia, S.; Burget, L.; Potheegadoo, J.; Maradan, M.; Habiby Alaoui, S.; Catalano Chiuve, S.; Van De Ville, D.; Krack, P.; Fleury, V.; Blanke, O.

2026-09-03 neurology
10.64898/2026.09.01.26361921 medRxiv
Show abstract

Dopamine replacement therapy (DRT) alleviates motor symptoms in Parkinson's disease (PD) but can trigger hallucinations in a subset of patients, yet the neural basis of this selective vulnerability is unknown. Hallucinations are among the most disabling non-motor symptoms of PD, linked to social isolation, dementia and institutionalization. Using a validated robotic paradigm to induce and quantify hallucinations in real-time, combined with resting-state fMRI in a crossover On/Off DRT design, we studied patients with PD with (PD-H) and without (PD-nH) hallucinations. DRT selectively amplified sensitivity to robot-induced hallucinations in patients with pre-existing hallucinatory phenotype (PD-H, but not PD-nH) and was accompanied by cortico-striatal and large-scale network hyperconnectivity. Rather than supporting a uniform hallucinogenic effect of dopamine in PD, these findings indicate that DRT interacts with an intrinsic neural vulnerability that varies in patients. Prospective studies will establish whether this pharmacological-behavioural signature identifies patients at risk before clinical hallucinations emerge.

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