Deep Brain Stimulation Influences Brain Structure in Alzheimer's 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: Alzheimer's disease; Deep brain stimulation; Fornix; Hippocampus; MRI; Volume.

Conflict of interest statement

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.

Copyright © 2015 Elsevier Inc. All rights reserved.

Figures

Figure 1

Hippocampal volume changes after one year of continuous fornix DBS and associated cognitive change. (A) Relative changes in mean (i.e., average of right and left) hippocampal volume for each patient after one year of fornix DBS. Unexpectedly, patients 1 and 4 demonstrated hippocampal enlargement (*). (B) ADAS-Cog score changes for each patient following one year of DBS. Patients 1 and 4, who showed evidence of hippocampal enlargement, also showed the best preservation of cognitive function at one year. (C) There was no significant correlation between change in ADAS-Cog score and hippocampal volume at the group-wide level, though patient #6 (marked with a box) appeared to be an outlier, showing relative preservation of ADAS-Cog score despite considerable hippocampal volume loss. (D) When patient 6 was excluded, there was a nearly significant correlation between change in ADAS-Cog score and hippocampal volume.

Figure 2

Relationship between hippocampal, fornix, and mammillary body volume change in response to fornix DBS. (A) Relative changes in mean (i.e., average of right and left) fornix volume for each patient after one year of fornix DBS. (B) Relative changes in mean (i.e., average of right and left) mammillary body (MB) volume for each patient after one year of fornix DBS. (C) Hippocampal volume change and fornix volume change are highly correlated. (D) Hippocampal volume change and mammillary body volume change are also highly correlated. Taken together, the results in (C) and (D) support the notion of a circuit-wide neuroprotective effect of DBS in AD.

Figure 3

Volume changes in the hippocampus, fornix, and mammillary bodies in patient 4 after three years of continuous fornix DBS. (A) Hippocampal volume is well-preserved at three years in patient 4. (B) and (C) Volumes of the fornix and mammillary bodies are also well-preserved three years after initial DBS implantation in patient 4. These results may argue for a durable neuroprotective effect of fornix DBS in some patients with AD.

Figure 4

Change in hippocampal metabolism after one year of fornix DBS. (A) Hippocampal glucose metabolism (normalized by pontine glucose metabolism) increased following one year of fornix DBS in patients 1 and 4, in whom we also observed increases in hippocampal volume. (B) Across all patients, hippocampal glucose metabolism tracked hippocampal volume change over one year, implying that any favorable effects of fornix DBS against neurodegeneration may depend on its ability to successfully enhance metabolism within the AD-affected hippocampus.

Figure 5

Brain-wide structural effects of fornix DBS in AD assessed using deformation-based morphometry (DBM). Representative axial brain slices showing representative clusters of volume increase across all patients following one year of fornix DBS. Many significant clusters were identified, particularly in several regions typically atrophied in AD (see Table 2).

Figure 6

Comparison of baseline hippocampal volume and hippocampal atrophy rate between fornix DBS and matched AD patients. (A) Baseline hippocampal volume was no different between DBS and matched AD patients. (B) % mean hippocampal atrophy over one year was significantly greater in the matched AD group compared to the DBS group (*P < 0.05).

Figure 7

Brain-wide structural changes in matched AD patients assessed using deformation-based morphometry (DBM). Representative axial brain slices showing representative clusters of volume decrease over one year across a group of 25 AD patients from the ADNI database. Several significant clusters of volume loss were identified, in regions known to be atrophic in AD (see Table 4). Clusters of ventricular enlargement were observed bilaterally, consistent with brain-wide atrophy in AD (not shown). Unlike AD DBS patients, no intraparenchymal clusters of volume increase were seen.