Highlights
- •We examined structural brain changes following DBS of the fornix in AD.
- •In 2 of 6 AD patients, fornix DBS reversed hippocampal atrophy at one year.
- •Across all 6 AD patients, fornix DBS preserved volume in several brain regions.
- •DBS may influence the natural course of brain atrophy in neurodegenerative disease.
Abstract
Background
Deep Brain Stimulation (DBS) is thought to improve the symptoms of selected neurological
disorders by modulating activity within dysfunctional brain circuits. To date, there
is no evidence that DBS counteracts progressive neurodegeneration in any particular
disorder.
Objective/Hypothesis
We hypothesized that DBS applied to the fornix in patients with Alzheimer's Disease
(AD) could have an effect on brain structure.
Methods
In six AD patients receiving fornix DBS, we used structural MRI to assess one-year
change in hippocampal, fornix, and mammillary body volume. We also used deformation-based
morphometry to identify whole-brain structural changes. We correlated volumetric changes
to hippocampal glucose metabolism. We also compared volumetric changes to those in
an age-, sex-, and severity-matched group of AD patients (n = 25) not receiving DBS.
Results
We observed bilateral hippocampal volume increases in the two patients with the best
clinical response to fornix DBS. In one patient, hippocampal volume was preserved
three years after diagnosis. Overall, mean hippocampal atrophy was significantly slower
in the DBS group compared to the matched AD group, and no matched AD patients demonstrated
bilateral hippocampal enlargement. Across DBS patients, hippocampal volume change
correlated strongly with hippocampal metabolism and with volume change in the fornix
and mammillary bodies, suggesting a circuit-wide effect of stimulation. Deformation-based
morphometry in DBS patients revealed local volume expansions in several regions typically
atrophied in AD.
Conclusion
We present the first in-human evidence that, in addition to modulating neural circuit
activity, DBS may influence the natural course of brain atrophy in a neurodegenerative
disease.
Keywords
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Article Info
Publication History
Published online: December 03, 2014
Accepted:
November 29,
2014
Received in revised form:
November 25,
2014
Received:
August 11,
2014
Footnotes
Funding disclosures: T.S. is supported by a Canadian Institutes of Health Research (CIHR) fellowship award ( #234784 ). A.W.L. received support from the Surgeon Scientist Program, Department of Surgery, University of Toronto , and the Neurosurgical Research and Education Foundation of the American Association of Neurological Surgeons. A.M.L. is a Canada Research Chair in Neuroscience and is supported by the R.R. Tasker Chair in Functional Neurosurgery. Additional support was provided by the Dana Foundation and Krembil Neuroscience Discovery Fund .
Conflicts of interest: A.M.L. is a consultant to Medtronic, St Jude, and Boston Scientific. A.M.L. serves on the scientific advisory board of Ceregene, Codman, Neurophage, Aleva and Alcyone Life Sciences. A.M.L. is co-founder of Functional Neuromodulation Inc. and holds intellectual property in the field of Deep Brain Stimulation. All other authors declare no relevant conflicts.
Authorship contributions: T.S., A.W.L., and A.M.L. conceived and designed the study. T.S. supervised all data collection and analysis, and drafted most of the manuscript. M.M.C. collected deformation-based morphometry data, performed neuroimaging data quality control, and wrote part of the Methods. A.B., M.L., and T.O. collected and analyzed MRI volumetric data. A.W.L., D.F.T-W. and M.P.M performed and analyzed clinical assessments. C.I.W. and G.S.S. collected and analyzed PET data and wrote part of the Methods. All authors contributed to critically revising the manuscript, and approved the final version before submission.
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