DBS Update: Attempting to Stimulate Memory in Alzheimer’s

Series - Deep-Brain Stimulation: Surgical Relief for Parkinson's and Beyond:

Researchers are sliding electrodes into the brains of people with Alzheimer disease, hoping to awaken memories and stave off disease-induced forgetfulness. In the August 4 Annals of Neurology online, a team led by Andres Lozano at Toronto Western Hospital report on a small deep-brain stimulation (DBS) trial. They write that the therapy was safe and was able to alter brain metabolism.

DBS can quell the symptoms of Parkinson disease and is under investigation for a variety of conditions, including Huntington disease, pain, epilepsy, and Tourette syndrome (see ARF four-part news story on advances in this treatment technique). Lozano and colleagues first discovered its effect on memory when they stimulated the hypothalamus of an obese man. They were hoping to curb his appetite, but instead induced a flashback to a 30-year-old memory (Hamani et al., 2008).

Now, Lozano, first author Adrian Laxton, and colleagues have completed a Phase 1 trial on six participants with early Alzheimer’s. The physicians were successful in their primary goal—to show the treatment is safe—as none of the six suffered serious adverse effects.

Further, the scientists looked for evidence that the stimulation was increasing brain activity. Alzheimer disease dampens glucose metabolism in the temporal and parietal regions, so Laxton and the other researchers used positron emission tomography (PET) to examine metabolism after DBS. Changes occurred within one month of starting stimulation, with metabolism going up in both the temporal and parietal areas.

The researchers also examined the subjects for evidence of altered cognition. Standard measures such as the Mini-Mental State Examination (MMSE) and the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) do not decrease linearly or regularly, so it is difficult to speculate how much decline the participants would have experienced without DBS. With no placebo control participants for comparison, the study was not able to clearly demonstrate cognitive effects. The researchers suggest that a few participants seemed to benefit, though, in that their scores improved or declined more slowly than might be expected.

Lozano and colleagues, satisfied with their results, are now planning a multicenter Phase 2 trial. The technique is currently approved by the FDA for Parkinson disease, essential tremor, and dystonia.—Amber Dance

Comments

  1. It is quite interesting that stimulation of the fornix/hypothalamus influences memory, with notable effects on FDG-PET activity in the regions of abnormality in AD. With the success of DBS for Parkinson's, this approach is clearly feasible. Of course, much more work is required to determine whether DBS can produce clinically meaningful benefits in AD, mild cognitive impairment, or other amnestic disorders. But Andres Lozano and his colleagues should be applauded for this novel and intriguing approach.

    View all comments by Paul Aisen

  2. I have studied Alzheimer disease (AD) since 1978, and since about 1980, I have seen some new ideas for treating AD nearly every month. Of these, five have been FDA approved and have modest benefits for patients (some improvement in cognition and behavior, and changing the course of the disease by a few months). I am sure that 300 good ideas have failed in this time, and there is nothing on the horizon that looks like it will stop AD.

    This study of brain stimulation does not distinguish itself from other failed approaches at this point. The rationale for how this treatment would stop the development of senile plaques and neurofibrillary tangles is missing. The idea of stimulating the "default mode network" is also weak. The idea of stimulating the fornix is admirable, but I think it is a little too much wishful thinking to really conceive that this would help to stop Alzheimer pathology or improve memory in a dementia patient. If this approach could be shown to diminish amyloid deposition in the brain (even in a few locations), lower CSF tau, and show long-term improvement or even maintenance of cognitive and behavioral function, then it could be a tremendous advance.

    There is a problem with the results of this study. The presented results do not show any clear benefit, and there is little attempt to correct the effects of the stimulation on the ADAS and MMSE for severity and age. These are important factors that need to be addressed. Evidence of beneficial effect on relevant biomarkers is becoming more important for accepting therapeutic interventions, and long-term demonstrations of clinical improvement, with careful control for specific ApoE genotypes, are also needed.

    In summary, I think it was good that this study was done, but it remains to be seen whether it will have promise for the future.

    View all comments by John (Wes) Ashford

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References

News Citations

  1. Deep-Brain Stimulation: Decade of Surgical Relief, Not Just for PD

Paper Citations

  1. Hamani C, McAndrews MP, Cohn M, Oh M, Zumsteg D, Shapiro CM, Wennberg RA, Lozano AM. Memory enhancement induced by hypothalamic/fornix deep brain stimulation. Ann Neurol. 2008 Jan;63(1):119-23. PubMed.

Further Reading

Papers

  1. Soriano-Mas C, Redolar-Ripoll D, Aldavert-Vera L, Morgado-Bernal I, Segura-Torres P. Post-training intracranial self-stimulation facilitates a hippocampus-dependent task. Behav Brain Res. 2005 May 7;160(1):141-7. PubMed.
  2. Freund HJ, Kuhn J, Lenartz D, Mai JK, Schnell T, Klosterkoetter J, Sturm V. Cognitive functions in a patient with Parkinson-dementia syndrome undergoing deep brain stimulation. Arch Neurol. 2009 Jun;66(6):781-5. PubMed.
  3. Aybek S, Lazeyras F, Gronchi-Perrin A, Burkhard PR, Villemure JG, Vingerhoets FJ. Hippocampal atrophy predicts conversion to dementia after STN-DBS in Parkinson's disease. Parkinsonism Relat Disord. 2009 Aug;15(7):521-4. PubMed.

Primary Papers

  1. Laxton AW, Tang-Wai DF, McAndrews MP, Zumsteg D, Wennberg R, Keren R, Wherrett J, Naglie G, Hamani C, Smith GS, Lozano AM. A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease. Ann Neurol. 2010 Oct;68(4):521-34. PubMed.

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