Deep brain stimulation could help treat Alzheimer's disease

Brain stimulation could help treat Alzheimer's disease
In persons with Alzheimer's disease, the largest positive effect has been observed when stimulating the region between the fornix (green) and the bed nucleus of the stria terminalis (blue). Also shown are two brain structures—the thalamus (pink) and the hippocampus (yellow)—as well as the stimulation electrodes. Credit: Charité | Ana Sofía Ríos

Alzheimer's disease is the most common cause of dementia, but it is not easily treatable. One potential therapy is deep brain stimulation delivered by a kind of pacemaker. A team of researchers at Charité—Universitätsmedizin Berlin has found that stimulating a specific network in the brain of Alzheimer's patients reduces their symptoms. The researchers hope the findings, which appear in Nature Communications, will pave the way for further studies.

Deep brain stimulation (DBS) is a form of therapy that is already approved in Germany for treating neurological movement disorders such as Parkinson's disease and dystonia, and neuropsychiatric diseases such as obsessive-compulsive disorder.

Very thin electrodes are implanted in the patient's brain and constantly deliver mild electrical pulses to a . The electrodes remain in the brain permanently and are connected via wires that run under the skin to a pacemaker-like device implanted in the chest area. The device is used to adjust the strength and frequency of the electrical stimulation.

"Although DBS has been an established treatment for Parkinson's disease for a good 20 years now, and the costs are covered by health insurance providers, it's still not a very well-known therapy," says Prof. Andreas Horn, head of a lab that explores network-based brain stimulation at the Department of Neurology and Experimental Neurology at Campus Charité Mitte, and at Brigham and Women's Hospital and Massachusetts General Hospital, both affiliates of Harvard Medical School.

"DBS works very well in patients with Parkinson's," he says. "It improves their quality of life significantly." Since Alzheimer's is also a neurodegenerative disease, it seems likely that DBS could be used to treat this condition, too. But safe, is only possible if the precise brain regions that require stimulation are known."

The starting point for the current study, which the researchers carried out in close cooperation with multiple partners including the University of Toronto in Canada, was a random observation made within a Canadian study.

"In one patient, who was being treated for obesity, caused flashbacks—sudden memories of their childhood and adolescence," says Dr. Ana Sofía Ríos from the Department of Neurology and Experimental Neurology at Campus Charité Mitte, and the study's lead author. "This led the Canadian researchers to suspect that stimulating this brain region, which was located in the fornix, might also be suitable for treating Alzheimer's."

Researchers map deep brain stimulation target for Alzheimer's disease
Validation of tract models predictive of clinical improvements as evaluated using ADAS-cog 11. a Left: Optimal set of tracts to be modulated as calculated from the entire training cohort (N = 28 subjects), red intensity codes for R-values ranging from 0.2 to 0.6, with darker colors indicating higher R-values. Right: permutation analysis calculated on the entire training cohort (R = 0.69 at p = 0.003). b Top left: stimulation volume of a patient with top clinical improvement overlapping the tracts associated with optimal clinical improvements (calculated leaving out the subject, N = 28-1 = 27 subjects). Fibers displayed in white correspond to the portion of optimal fibers intersecting with the patient’s stimulation volume. Bottom left: Same analysis carried out with a poor-responding example patient. Right: Cross-validation within the training cohort (N = 28) using a leave-one-out design (top, R = 0.69 at p < 10−16), Spearman correlation between the degree of stimulation of positive fibertracts (aggregated R-scores under each E-field) and clinical improvements, and within-fold analysis, reporting root mean square error (RMS) and median absolute error (MAE). The boxplot displays the interquartile range in the box with the median percentual absolute predicted error as a vertical line, whiskers extend to 1.5 times the interquartile range, outlier points outside of this range are plotted (bottom). The two example patients are marked in the correlation plot with circles. c Optimal tracts calculated from the entire training cohort (as shown in panel a, N = 28) were used to cross-predict outcomes in N = 18 patients of the hold-out cohort (R = 0.45, p = 0.031). Left: two example cases from the hold-out cohort are shown, a top responding patient’s stimulation volume with corresponding connected (white) optimal fibers defined by the training cohort; and a poor-responding patient’s stimulation volume with corresponding connected (white) fibers. The two example patients are marked in the correlation plot with circles. Right: Spearman correlation between the degree of stimulating positively correlated tracts from the training cohort by the hold-out cohort and clinical improvements of the latter, gray shaded areas represent 95% confidence intervals. Fiber tracts and example stimulation volumes were superimposed on slices of a 100-µm, 7T brain scan in MNI 152 space. Credit: Nature Communications (2022). DOI: 10.1038/s41467-022-34510-3

To investigate this further, researchers working at seven international centers as part of a multicenter study implanted electrodes in the same area of the fornix in participants with mild Alzheimer's disease. "Unfortunately, most patients showed no improvement in their symptoms. But a handful of participants benefited considerably from the treatment," says Dr. Ríos. "In the present study, we wanted to find the root cause of these differences, so we compared the exact position of the electrodes in each participant."

Prof. Horn's research group has specialized in analyzing high-resolution magnetic resonance images of the brain and combining these with computer models to precisely pinpoint the optimal locations for DBS. "One of the main challenges is that every brain is different—and that's really important for accurately planting the electrodes," says Prof. Horn. "When electrodes are placed even a few millimeters off target, it could lead to a lack of benefit for the patient."

This was what happened for most of the study participants. But Prof. Horn and his team were able to use imaging data to determine the exact position of the electrodes in the patients that profited from the procedure. "The optimal site seems to be the intersection of two fiber bundles—the fornix and stria terminalis—that connect regions deep in the brain. Both structures have been linked to memory function," says Prof. Horn.

Further are needed before DBS can be approved and used to treat Alzheimer's disease. The present results are an important next step in the process. "If our data make it possible to place electrodes more precisely in neurosurgical studies trialing DBS in Alzheimer's patients, that would be fantastic," says Prof. Horn. "We desperately need an effective therapy that alleviates the symptoms of this disease—and DBS is very promising."

Going forward, the Horn laboratory will conduct further studies to investigate and define other neural networks in the brain that could be useful in treating dementia. Their work will include examining areas of lesions and identifying target regions for both DBS and other methods of neurostimulation.

More information: Ana Sofía Ríos et al, Optimal deep brain stimulation sites and networks for stimulation of the fornix in Alzheimer's disease, Nature Communications (2022). DOI: 10.1038/s41467-022-34510-3

Journal information: Nature Communications

Citation: Deep brain stimulation could help treat Alzheimer's disease (2022, December 14) retrieved 25 March 2023 from
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