Original Article | Published:

Deep brain stimulation of the nucleus basalis of Meynert in Alzheimer’s dementia

Molecular Psychiatry volume 20, pages 353360 (2015) | Download Citation

Abstract

Cholinergic neurons of the medial forebrain are considered important contributors to brain plasticity and neuromodulation. A reduction of cholinergic innervation can lead to pathophysiological changes of neurotransmission and is observed in Alzheimer’s disease. Here we report on six patients with mild to moderate Alzheimer’s disease (AD) treated with bilateral low-frequency deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM). During a four-week double-blind sham-controlled phase and a subsequent 11-month follow-up open label period, clinical outcome was assessed by neuropsychological examination using the Alzheimer’s Disease Assessment Scale—cognitive subscale as the primary outcome measure. Electroencephalography and [18F]-fluoro-desoxyglucose positron emission tomography were, besides others, secondary endpoints. On the basis of stable or improved primary outcome parameters twelve months after surgery, four of the six patients were considered responders. No severe or non-transitional side effects related to the stimulation were observed. Taking into account all limitations of a pilot study, we conclude that DBS of the NBM is both technically feasible and well tolerated.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , . Atrophy of the cholinergic basal forebrain over the adult age range and in early stages of Alzheimer's disease. Biol Psychiatry 2012; 71: 805–813.

  2. 2.

    , , , , , . Nucleus basalis and thalamic control of neocortical activity in the freely moving rat. J Neurosci 1988; 8: 4007–4026.

  3. 3.

    , . Cortical map reorganization enabled by nucleus basalis activity. Science 1998; 279: 1714–1718.

  4. 4.

    , , , . Stimulation of the basal nucleus of Meynert in senile dementia of Alzheimer’s type. A preliminary report. Appl Neurophysiol 1985; 48: 216–221.

  5. 5.

    , , , , , et al. Cognitive functions in a patient with Parkinson-dementia syndrome undergoing deep brain stimulation. Arch Neurol 2009; 66: 781–785.

  6. 6.

    , , , , , et al. Changes in apraxia after deep brain stimulation of the nucleus basalis Meynert in a patient with Parkinson dementia syndrome. Mov Disord 2010; 25: 1519–1520.

  7. 7.

    , , , , , et al. Memory enhancement induced by hypothalamic/fornix deep brain stimulation. Ann Neurol 2008; 63: 119–123.

  8. 8.

    , , , , , et al. A phase I trial of deep brain stimulation of memory circuits in Alzheimer’s disease. Ann Neurol 2010; 68: 521–534.

  9. 9.

    , , , , , et al. Stimulate or degenerate: deep brain stimulation of the nucleus basalis Meynert in Alzheimer’s dementia. World Neurosurg 2012; 80: S27.e35–S27.e43.

  10. 10.

    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders-DSM IV-TR. American Psychiatric Association: Washington, DC, USA, 2000.

  11. 11.

    . International statistical classification of diseases and related health problems. Tenth revision. World Health Stat Q 1988; 41: 32–36.

  12. 12.

    , , , , , . Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34: 939–944.

  13. 13.

    , , . Atlas of the Human Brain, 3rd revised edn. Academic Press: Amsterdam, The Netherlands, 2007, p 271.

  14. 14.

    , , . The MacCAT-T: a clinical tool to assess patients’ capacities to make treatment decisions. Psychiatr Serv 1997; 48: 1415–1419.

  15. 15.

    , , , , , et al. Neurostimulation for Parkinson’s disease with early motor complications. N Engl J Med 2013; 368: 610–622.

  16. 16.

    , , , . Cholinergic innervation of cortex by the basal forebrain: cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey. J Comp Neurol 1983; 214: 170–197.

  17. 17.

    , , , , , et al. Persistence of cholinergic neurons in the basal nucleus in a brain with senile dementia of the Alzheimer’s type demonstrated by immunohistochemical staining for choline acetyltransferase. Brain Res 1983; 289: 375–379.

  18. 18.

    , . Nucleus basalis (Ch4) and cortical cholinergic innervation in the human brain: observations based on the distribution of acetylcholinesterase and choline acetyltransferase. J Comp Neurol 1988; 275: 216–240.

  19. 19.

    , , , , , . Cell loss and shrinkage in the nucleus basalis Meynert complex in Alzheimer’s disease. Neurobiol Aging 1990; 11: 3–13.

  20. 20.

    , . NGF receptor gene expression is decreased in the nucleus basalis in Alzheimer’s disease. Exp Neurol 1989; 106: 222–236.

  21. 21.

    , , , , , et al. Reduction of basal forebrain cholinergic system parallels cognitive impairment in patients at high risk of developing Alzheimer’s disease. Cereb Cortex 2010; 20: 1685–1695.

  22. 22.

    , , , , , et al. Preservation of nucleus basalis neurons containing choline acetyltransferase and the vesicular acetylcholine transporter in the elderly with mild cognitive impairment and early Alzheimer’s disease. J Comp Neurol 1999; 411: 693–704.

  23. 23.

    , , . Mechanisms of deep brain stimulation. Mov Disord 2002; 17(Suppl 3): S73–S74.

  24. 24.

    , , . Stimulation of the nucleus basalis of Meynert increases acetylcholine release in the cerebral cortex in rats. Neurosci Lett 1989; 98: 45–50.

  25. 25.

    , , , , , et al. Patients’ expectations of deep brain stimulation, and subjective perceived outcome related to clinical measures in Parkinson’s disease: a mixed-method approach. J Neurol Neurosurg Psychiatry 2013; 84: 1273–1281.

  26. 26.

    , . Acquisition and retention of gestures by apraxic patients. Brain Cogn 1984; 3: 426–437.

  27. 27.

    . Matching and imitation of hand and finger postures in patients with damage in the left or right hemispheres. Neuropsychologia 1999; 37: 559–566.

  28. 28.

    , , . Assessing the nutritional status of the elderly: The Mini Nutritional Assessment as part of the geriatric evaluation. Nutr Rev 1996; 54(1 Pt 2): S59–S65.

  29. 29.

    , , , , . Objective assessment of the degree of dementia by means of EEG. Neuropsychobiology 2003; 48: 19–26.

  30. 30.

    , . What is the clinically relevant change on the ADAS-Cog? J Neurol Neurosurg Psychiatry 2012; 83: 171–173.

  31. 31.

    , , , , , et al. Long-term progression of Alzheimer’s disease in patients under antidementia drugs. Alzheimers Dement 2011; 7: 579–592.

  32. 32.

    , , , , , et al. Longitudinal change of biomarkers in cognitive decline. Arch Neurol 2011; 68: 1257–1266.

  33. 33.

    , , . A longitudinal EEG study of mild senile dementia of Alzheimer type: changes at 1 year and at 2.5 years. Electroencephalogr Clin Neurophysiol 1985; 61: 101–112.

  34. 34.

    , , , , , et al. Memory enhancement and deep-brain stimulation of the entorhinal area. N Engl J Med 2012; 366: 502–510.

  35. 35.

    , , , . Induction of c-Fos expression by electrical stimulation of the nucleus basalis magnocellularis. Neurosci Lett 2009; 449: 137–141.

  36. 36.

    , , . Expression of the CD15 epitope in the human magnocellular basal forebrain system. Histochem J 1992; 24: 902–909.

  37. 37.

    , , , . Basal forebrain stimulation induces NGF secretion in ipsilateral parietal cortex via nicotinic receptor activation in adult, but not aged rats. Neurosci Res 2009; 63: 122–128.

  38. 38.

    , , , , , et al. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med 2005; 11: 551–555.

Download references

Acknowledgements

This study was supported by grants from the Marga and Walter Boll foundation and Medtronic Europe SARL.

Author information

Author notes

    • J Kuhn
    •  & K Hardenacke

    Shared first authorship.

    • H-J Freund
    •  & V Sturm

    Shared senior authorship.

Affiliations

  1. Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany

    • J Kuhn
    • , K Hardenacke
    • , T Gruendler
    • , C Bartsch
    •  & J Klosterkötter
  2. Department of Functional Neurosurgery and Stereotaxy, University of Cologne, Cologne, Germany

    • D Lenartz
    • , C P Bührle
    •  & V Sturm
  3. Faculty of Economics, Otto-von-Guericke University Magdeburg, Magdeburg, Germany

    • T Gruendler
  4. Center for Behavioral Brain Sciences, Magdeburg, Germany

    • T Gruendler
    •  & M Ullsperger
  5. Institute of Psychology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany

    • M Ullsperger
  6. Department of Neuroanatomy, University of Düsseldorf, Düsseldorf, Germany

    • J K Mai
    •  & H-J Freund
  7. Institute of Neuroscience and Medicine, Research Centre Juelich, Juelich, Germany

    • K Zilles
    • , A Bauer
    •  & A Matusch
  8. University Hospital of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany

    • K Zilles
  9. Department of Neurology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany

    • A Bauer
  10. University of Cologne, Department of Geriatrics and St. Marien-Hospital, Cologne, Germany

    • R-J Schulz
    •  & M Noreik
  11. University of Cologne, Department for Radiology, Cologne, Germany

    • D Maintz
  12. University of Cologne, Research Unit Ethics, Institute for the History of Medicine and Medical Ethics, Cologne, Germany

    • C Woopen
  13. LVR Clinic Cologne, Department of Gerontopsychiatry, Cologne, Germany

    • P Häussermann
  14. University of Cologne, Institute of Medical Statistics, Informatics and Epidemiology, Cologne, Germany

    • M Hellmich
  15. Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Göttingen, Germany

    • J Wiltfang
  16. Department of Stereotaxy and Functional Neurosurgery, Klinikum Merheim, Cologne, Germany

    • M Maarouf

Authors

  1. Search for J Kuhn in:

  2. Search for K Hardenacke in:

  3. Search for D Lenartz in:

  4. Search for T Gruendler in:

  5. Search for M Ullsperger in:

  6. Search for C Bartsch in:

  7. Search for J K Mai in:

  8. Search for K Zilles in:

  9. Search for A Bauer in:

  10. Search for A Matusch in:

  11. Search for R-J Schulz in:

  12. Search for M Noreik in:

  13. Search for C P Bührle in:

  14. Search for D Maintz in:

  15. Search for C Woopen in:

  16. Search for P Häussermann in:

  17. Search for M Hellmich in:

  18. Search for J Klosterkötter in:

  19. Search for J Wiltfang in:

  20. Search for M Maarouf in:

  21. Search for H-J Freund in:

  22. Search for V Sturm in:

Competing interests

Jens Kuhn has occasionally received honoraria from AstraZeneca, Lilly, Lundbeck and Otsuka Pharma for lecturing at conferences and financial support to travel. He received financial support for studies from Medtronic Europe SARL (Meerbusch, Germany).

Doris Lenartz and Juergen K. Mai received financial assistance for travel to congresses from Medtronic Europe SARL. Mohammad Maarouf has occasionally received honoraria from Medtronic Europe SARL for lecturing at conferences and consulting. Volker Sturm disclosed financial support for studies and travel to congresses, and lecture fees from Medtronic Europe SARL and Advanced Neuromodulation Systems INC. He is also a co-holder of patents on desynchronized brain stimulation and shareholder of ANM-GmbH Juelich, a company that intends to develop new stimulators.

The remaining authors declare no conflict of interest.

Corresponding author

Correspondence to J Kuhn.

Supplementary information

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/mp.2014.32

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

Further reading