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

Ana Sofía Ríos, Movement Disorder and Neuromodulation Unit, Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Simón Oxenford, Movement Disorder and Neuromodulation Unit, Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Clemens Neudorfer, Movement Disorder and Neuromodulation Unit, Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Konstantin Butenko, Movement Disorder and Neuromodulation Unit, Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Ningfei Li, Movement Disorder and Neuromodulation Unit, Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Nanditha Rajamani, Movement Disorder and Neuromodulation Unit, Department of Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Alexandre Boutet, Division of Neurosurgery, Department of Surgery, University Health Network and University of Toronto, Toronto, ON, M5T2S8, Canada.
Gavin J. Elias, Division of Neurosurgery, Department of Surgery, University Health Network and University of Toronto, Toronto, ON, M5T2S8, Canada.
Jurgen Germann, Division of Neurosurgery, Department of Surgery, University Health Network and University of Toronto, Toronto, ON, M5T2S8, Canada.
Aaron Loh, Division of Neurosurgery, Department of Surgery, University Health Network and University of Toronto, Toronto, ON, M5T2S8, Canada.
Wissam Deeb, UMass Chan Medical School, Department of Neurology, Worcester, MA, 01655, USA.
Fuyixue Wang, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA.
Kawin Setsompop, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA.
Bryan Salvato, University of Florida Health Jacksonville, Jacksonville, FL, USA.
Leonardo Brito Almeida, Norman Fixel Institute for Neurological Diseases, Departments of Neurology and Neurosurgery, University of Florida, Gainesville, FL, USA.
Kelly D. Foote, Norman Fixel Institute for Neurological Diseases, Departments of Neurology and Neurosurgery, University of Florida, Gainesville, FL, USA.
Robert Amaral, Cerebral Imaging Centre, Douglas Research Centre, Montreal, QC, Canada.
Paul B. Rosenberg, Department of Psychiatry and Behavioral Sciences and Richman Family Precision Medicine Center of Excellence, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
David F. Tang-Wai, Krembil Research Institute, University of Toronto, Toronto, ON, M5T2S8, Canada.
David A. Wolk, Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
Anna D. Burke, Barrow Neurological Institute, Phoenix, AZ, USA.
Stephen Salloway, Department of Psychiatry and Human Behavior and Neurology, Alpert Medical School of Brown University, Providence, RI, USA.
Marwan N. Sabbagh, Barrow Neurological Institute, Phoenix, AZ, USA.
M Mallar Chakravarty, Cerebral Imaging Centre, Douglas Research Centre, Montreal, QC, Canada.
Gwenn S. Smith, Department of Psychiatry and Behavioral Sciences and Richman Family Precision Medicine Center of Excellence, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Constantine G. Lyketsos, Department of Psychiatry and Behavioral Sciences and Richman Family Precision Medicine Center of Excellence, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Michael S. Okun, Norman Fixel Institute for Neurological Diseases, Departments of Neurology and Neurosurgery, University of Florida, Gainesville, FL, USA.
William S. Anderson, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Zoltan Mari, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Francisco A. Ponce, Barrow Neurological Institute, Phoenix, AZ, USA.
Andres M. Lozano, Division of Neurosurgery, Department of Surgery, University Health Network and University of Toronto, Toronto, ON, M5T2S8, Canada.
Andreas Horn, 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.

Document Type

Article

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.

Medical Subject Headings

Humans; Alzheimer Disease (therapy); Brain (diagnostic imaging); Deep Brain Stimulation; Fornix, Brain (diagnostic imaging, physiology); Thalamus; Randomized Controlled Trials as Topic

Publication Date

12-14-2022

Publication Title

Nature communications

E-ISSN

2041-1723

Volume

13

Issue

1

First Page

7707

PubMed ID

36517479

Digital Object Identifier (DOI)

10.1038/s41467-022-34510-3

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