Optimal deep brain stimulation sites and networks for stimulation of the fornix in Alzheimer’s disease

Ana Sofía Ríos, Simón Oxenford, Clemens Neudorfer, Konstantin Butenko, Ningfei Li, Nanditha Rajamani, Alexandre Boutet, Gavin J.B. Elias, Jurgen Germann, Aaron Loh, Wissam Deeb, Fuyixue Wang, Kawin Setsompop, Bryan Salvato, Leonardo Brito de Almeida, Kelly D. Foote, Robert Amaral, Paul B. Rosenberg, David F. Tang-Wai, David A. WolkAnna D. Burke, Stephen Salloway, Marwan N. Sabbagh, M. Mallar Chakravarty, Gwenn S. Smith, Constantine G. Lyketsos, Michael S. Okun, William S. Anderson, Zoltan Mari, Francisco A. Ponce, Andres M. Lozano, Andreas Horn

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27 Scopus citations


Deep brain stimulation (DBS) to the fornix is an investigational treatment for patients with mild Alzheimer’s Disease. Outcomes from randomized clinical trials have shown that cognitive function improved in some patients but deteriorated in others. This could be explained by variance in electrode placement leading to differential engagement of neural circuits. To investigate this, we performed a post-hoc analysis on a multi-center cohort of 46 patients with DBS to the fornix (NCT00658125, NCT01608061). Using normative structural and functional connectivity data, we found that stimulation of the circuit of Papez and stria terminalis robustly associated with cognitive improvement (R = 0.53, p < 0.001). On a local level, the optimal stimulation site resided at the direct interface between these structures (R = 0.48, p < 0.001). Finally, modulating specific distributed brain networks related to memory accounted for optimal outcomes (R = 0.48, p < 0.001). Findings were robust to multiple cross-validation designs and may define an optimal network target that could refine DBS surgery and programming.

Original languageEnglish (US)
Article number7707
JournalNature communications
Issue number1
StatePublished - Dec 2022
Externally publishedYes

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