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 Wolk; Anna 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

doi:10.1038/s41467-022-34510-3

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

Nat Commun. 2022 Dec 14;13(1):7707. doi: 10.1038/s41467-022-34510-3.

Authors

Ana Sofía Ríos¹, Simón Oxenford¹, Clemens Neudorfer¹, Konstantin Butenko¹, Ningfei Li¹, Nanditha Rajamani¹, Alexandre Boutet^{2

3

4}, Gavin J B Elias^{2

3}, Jurgen Germann^{2

3}, Aaron Loh^{2

3}, Wissam Deeb^{5

6}, Fuyixue Wang^{7

8}, Kawin Setsompop^{7

8

9}, Bryan Salvato¹⁰, Leonardo Brito de Almeida¹¹, Kelly D Foote¹¹, Robert Amaral¹², Paul B Rosenberg¹³, David F Tang-Wai^{3

14}, David A Wolk¹⁵, Anna D Burke¹⁶, Stephen Salloway^{17

18}, Marwan N Sabbagh¹⁶, M Mallar Chakravarty^{12

19

20}, Gwenn S Smith¹³, Constantine G Lyketsos¹³, Michael S Okun¹¹, William S Anderson²¹, Zoltan Mari^{21

22}, Francisco A Ponce¹⁶, Andres M Lozano^{2

3}, Andreas Horn^{23

24

25}

Affiliations

¹ Movement Disorder and Neuromodulation Unit, Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
² Division of Neurosurgery, Department of Surgery, University Health Network and University of Toronto, Toronto, ON, M5T2S8, Canada.
³ Krembil Research Institute, University of Toronto, Toronto, ON, M5T2S8, Canada.
⁴ Joint Department of Medical Imaging, University of Toronto, Toronto, ON, M5T1W7, Canada.
⁵ UMass Chan Medical School, Department of Neurology, Worcester, MA, 01655, USA.
⁶ UMass Memorial Health, Department of Neurology, Worcester, MA, 01655, USA.
⁷ Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA.
⁸ Harvard-MIT Health Sciences and Technology, MIT, Cambridge, MA, USA.
⁹ Department of Radiology, Stanford University, Stanford, CA, USA.
¹⁰ University of Florida Health Jacksonville, Jacksonville, FL, USA.
¹¹ Norman Fixel Institute for Neurological Diseases, Departments of Neurology and Neurosurgery, University of Florida, Gainesville, FL, USA.
¹² Cerebral Imaging Centre, Douglas Research Centre, Montreal, QC, Canada.
¹³ Department of Psychiatry and Behavioral Sciences and Richman Family Precision Medicine Center of Excellence, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹⁴ Department of Medicine, Division of Neurology, University Health Network and University of Toronto, Toronto, ON, M5T2S8, Canada.
¹⁵ Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
¹⁶ Barrow Neurological Institute, Phoenix, AZ, USA.
¹⁷ Department of Psychiatry and Human Behavior and Neurology, Alpert Medical School of Brown University, Providence, RI, USA.
¹⁸ Memory & Aging Program, Butler Hospital, Providence, USA.
¹⁹ Department of Psychiatry, McGill University, Montreal, QC, Canada.
²⁰ Biological and Biomedical Engineering, McGill University, Montreal, QC, Canada.
²¹ Johns Hopkins School of Medicine, Baltimore, MD, USA.
²² Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.
²³ Movement Disorder and Neuromodulation Unit, Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. ahorn1@bwh.harvard.edu.
²⁴ Center for Brain Circuit Therapeutics, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA. ahorn1@bwh.harvard.edu.
²⁵ Departments of Neurology and Neurosurgery, Massachusetts General Hospital, Boston, MA, USA. ahorn1@bwh.harvard.edu.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / therapy
Brain / diagnostic imaging
Deep Brain Stimulation*
Fornix, Brain / diagnostic imaging
Fornix, Brain / physiology
Humans
Randomized Controlled Trials as Topic
Thalamus

Abstract

Publication types

MeSH terms

Grants and funding