Deep-brain stimulation (DBS) has become widely used for the treatment of Parkinson's disease, and researchers are now hoping to use it for other diseases, including Alzheimer's (AD). Two years ago, researchers led by Andres Lozano, University of Toronto, Ontario, Canada, claimed that DBS of the fornix area heightened glucose metabolism and caused possible cognitive benefits in a small pilot study of AD. A separate analysis of the same data, published in the May 7 Neuron, suggests that that DBS improved functional connectivity, too, and that the surgery may exert the greatest cognitive benefit in those in the earliest stages of AD.

"The study is an exciting advancement in the development of a treatment for the cognitive and neuropsychiatric symptoms of AD," wrote Michele York, Baylor College of Medicine, Houston, Texas, to ARF in an e-mail. However, it is still in its early days, cautioned York, who was not involved in this study. "This avenue of research will require a large, well-controlled, and thoroughly described investigation ... prior to it being offered as a therapeutic intervention."

In 2010, Lozano's group implanted electrodes near the fornix—the fiber bundle that connects the hippocampus and hypothalamus—in six patients diagnosed with AD. After one year of stimulation with the electrodes, positron emission tomography scans using the radiotracer [18F]-2-deoxy-2-fluoro-D-glucose (FDG-PET) indicated that certain brain structures used more glucose at rest than they had before, meaning those regions were consuming more sugar and being more active (see ARF related news story on Laxton et al., 2010). In typical AD patients, glucose metabolism falls as the disease progresses, so this hinted at some improvement. Hippocampal volume also declined more slowly than expected in AD, or even grew a bit, as presented at the Society for Neuroscience meeting in 2011. A manuscript on those results is in preparation, said Smith.

In the current paper, first author Gwenn Smith, Johns Hopkins University, Baltimore, Maryland, and colleagues reanalyzed the FDG-PET data for five of those patients (one of the six was tested on a different scanner and was excluded from these analyses). The authors first looked for a correlation between baseline glucose use, improvement in glucose metabolism, and cognitive scores. All patients showed revved-up glucose metabolism after one year of DBS, but metabolism perked up more in those who started the study with the highest initial glucose use. These same high-baseline individuals either raised their scores on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), or at least declined less than expected in AD. This means that baseline glucose use might eventually predict the benefits of DBS, the authors wrote.

"That suggests the circuits you are targeting need to be in pretty good shape to be sustained; if they're already broken, DBS is not going to mend them," said Paul Frankland, University of Toronto, who was not involved with this study. In previous collaboration with Lozano, Frankland reported that spatial memory improved after DBS stimulation of the entorhinal cortex in wild-type mice (see ARF related news story). Another paper suggested that DBS applied in the fornix region overcomes memory impairment in rats (see Hescham et al., 2012), and Frankland will soon publish results that suggest similar benefits of DBS in AD mouse models.

The researchers further report that the structures with heightened glucose metabolism comprised two separate neural networks that showed strengthened functional connectivity. One was a frontal-temporal-parietal-striatal-thalamic network, the other a frontal-temporal-parietal-occipital-hippocampal network. Their glucose use rose simultaneously. "This shows a contrast with what we know about the course of Alzheimer's disease," said Smith. Previous studies have reported that functional connectivity breaks down over the course of AD (see ARF related news story on Sperling et al., 2009; Allen et al., 2007, and Damoiseaux et al., 2012). What mechanisms might underlie the apparent benefit of DBS? Candidates include neurogenesis and heightened neurotransmitter or neurotrophic factor release, the authors wrote. Future molecular imaging studies could be used to determine which is responsible.

Smith and her coauthors acknowledge that this is a tiny sample of patients without placebo controls. They are planning more rigorous clinical trials for people in early stages of AD. "In Alzheimer's, we are so anxious to find treatments that work," she said. "We want to be very careful. Before making any claims about using DBS on a larger scale or how effective it is, we really need to see more data." Other recent studies have suggested that reducing the brain's activity with pharmacologic agents may be a treatment for patients diagnosed with mild cognitive impairment (see ARF related news story and ARF news story). In Smith's, view, the two ideas are not at odds with each other, since each is targeting a different stage of the disease—hyperactivity in MCI and hypoactivity in AD.—Gwyneth Dickey Zakaib

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  1. Dr. Lozano’s study demonstrating increased cerebral glucose metabolism one year following deep-brain stimulation for Alzheimer’s disease is an exciting advancement in the development of a treatment for the cognitive and neuropsychiatric symptoms of AD. The findings of a relationship between improvements in outcome (although minor) and increased metabolism strengthens the researchers' argument that a larger study is needed to further evaluate the efficacy of this intervention. It should be noted that in this very small sample, the patients were younger and less cognitively impaired than the majority of AD patients seen in clinical populations. However, as a proof-of-concept and tolerability study, these findings provide the impetus needed for further investigation. This avenue of research will require a large, well-controlled, and thoroughly described investigation with both short- and long-term safety and efficacy outcomes in a sample that can be generalized to a wider AD population prior to it being offered as a therapeutic intervention.

    View all comments by Michele York
  2. Since the end of the 1980s, deep-brain stimulation (DBS) has substantially expanded the therapeutically possibilities of treating Parkinson’s disease (1). DBS refers to a complex neuromodulative procedure, which implies the stereotactical implantation of two electrodes into defined target structures of the brain. The success story told by DBS in the field of movement disorders, the minimally invasive surgery and the rare and usually very minor side effects, suggest that the ambitions of applying DBS to other neurological and psychiatric indications will be more quickly fulfilled in the future (2). And indeed, in the last three years two groups (3-6) (see also http://clinicaltrials.gov/ct2/show/NCT01094145) employed DBS has been used with the aim of improving cognitive abilities in patients with dementia.

    Despite many years of experience with DBS, the therapeutic mechanisms are not yet completely understood. There are various actions being discussed, since, on the neuronal level, excitatory and inhibitory mechanisms are assumed to play a part (7). In the case of applying DBS to Alzheimer’s dementia there is hope that the cognitive abilities of the patients can be stabilized and ideally neuroprotective effects promoted—for example through the induction of NGF-synthesis (8) or changes in cerebral blood supply. This recent investigation by Smith and colleagues seems to support those hypothesis concerning the working mechanism of DBS. Patients with mild to moderate AD were treated with DBS in the fornix and demonstrated, after one year of stimulation, increased cerebral metabolism in cortical-subcortical and cortical-hippocampal regions. The increased metabolism correlated positively with global cognition, memory functioning, and quality of life. The published results encourage further research into this field to evaluate the efficacy of DBS in patients with AD.

    References:

    . Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet. 1991 Feb 16;337(8738):403-6. PubMed.

    . Deep brain stimulation for psychiatric disorders. Dtsch Arztebl Int. 2010 Feb;107(7):105-13. PubMed.

    . Increased Cerebral Metabolism After 1 Year of Deep Brain Stimulation in Alzheimer Disease. Arch Neurol. 2012 May 7; PubMed.

    . A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease. Ann Neurol. 2010 Oct;68(4):521-34. PubMed.

    . Cognitive functions in a patient with Parkinson-dementia syndrome undergoing deep brain stimulation. Arch Neurol. 2009 Jun;66(6):781-5. PubMed.

    . Changes in apraxia after deep brain stimulation of the nucleus basalis Meynert in a patient with Parkinson dementia syndrome. Mov Disord. 2010 Jul 30;25(10):1519-20. PubMed.

    . How does deep brain stimulation work? Present understanding and future questions. J Clin Neurophysiol. 2004 Jan-Feb;21(1):40-50. PubMed.

    . Stimulate or Degenerate: Deep Brain Stimulation of the Nucleus Basalis Meynert in Alzheimer Dementia. World Neurosurg. 2012 Dec 12; PubMed.

    View all comments by Jens Kuhn

References

News Citations

  1. DBS Update: Attempting to Stimulate Memory in Alzheimer’s
  2. Does Deep-Brain Stimulation Spark Neurogenesis, Enhance Learning?
  3. BOLD New Look—Aβ Linked to Default Network Dysfunction
  4. Epilepsy Drug Calms the Hippocampus, Aids Memory
  5. Needs Salt: Reduced Sodium Channel Linked to Seizures in AD Model

Paper Citations

  1. . A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease. Ann Neurol. 2010 Oct;68(4):521-34. PubMed.
  2. . Deep brain stimulation of the forniceal area enhances memory functions in experimental dementia: The role of stimulation parameters. Brain Stimul. 2012 Feb 23; PubMed.
  3. . Amyloid deposition is associated with impaired default network function in older persons without dementia. Neuron. 2009 Jul 30;63(2):178-88. PubMed.
  4. . Reduced hippocampal functional connectivity in Alzheimer disease. Arch Neurol. 2007 Oct;64(10):1482-7. PubMed.
  5. . Functional connectivity tracks clinical deterioration in Alzheimer's disease. Neurobiol Aging. 2012 Apr;33(4):828.e19-30. PubMed.

External Citations

  1. presented

Further Reading

Papers

  1. . Deep brain stimulation: current and future clinical applications. Mayo Clin Proc. 2011 Jul;86(7):662-72. PubMed.
  2. . Disrupting abnormal electrical activity with deep brain stimulation: is epilepsy the next frontier?. Neurosurg Focus. 2010 Aug;29(2):E7. PubMed.

Primary Papers

  1. . Increased Cerebral Metabolism After 1 Year of Deep Brain Stimulation in Alzheimer Disease. Arch Neurol. 2012 May 7; PubMed.