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Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 2004 Apr;75(4):555–559. doi: 10.1136/jnnp.2003.018127

Motor cortex hyperexcitability to transcranial magnetic stimulation in Alzheimer's disease

L Di 1, A Oliviero 1, F Pilato 1, E Saturno 1, M Dileone 1, C Marra 1, A Daniele 1, S Ghirlanda 1, G Gainotti 1, P Tonali 1
PMCID: PMC1739006  PMID: 15026495

Abstract

Objectives: Recent transcranial magnetic stimulation (TMS) studies demonstrate that motor cortex excitability is increased in Alzheimer's disease (AD) and that intracortical inhibitory phenomena are impaired. The aim of the present study was to determine whether hyperexcitability is due to the impairment of intracortical inhibitory circuits or to an independent abnormality of excitatory circuits.

Methods: We assessed the excitability of the motor cortex with TMS in 28 patients with AD using several TMS paradigms and compared the data of cortical excitability (evaluated by measuring resting motor threshold) with the amount of motor cortex disinhibition as evaluated using the test for motor cortex cholinergic inhibition (short latency afferent inhibition) and GABAergic inhibition (short latency intracortical inhibition). The data in AD patients were also compared with that from 12 age matched healthy individuals.

Results: The mean resting motor threshold was significantly lower in AD patients than in controls. The amount of short latency afferent inhibition was significantly smaller in AD patients than in normal controls. There was also a tendency for AD patients to have less pronounced short latency intracortical inhibition than controls, but this difference was not significant. There was no correlation between resting motor threshold and measures of either short latency afferent or intracortical inhibition (r = -0.19 and 0.18 respectively, NS). In 14 AD patients the electrophysiological study was repeated after a single oral dose of the cholinesterase inhibitor rivastigmine. Resting motor threshold was not significantly modified by the administration of rivastigmine. In contrast, short latency afferent inhibition from the median nerve was significantly increased by the administration of rivastigmine.

Conclusions: The change in threshold did not seem to correlate with dysfunction of inhibitory intracortical cholinergic and GABAergic circuits, nor with the central cholinergic activity. We propose that the hyperexcitability of the motor cortex is caused by an abnormality of intracortical excitatory circuits.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alagona G., Bella R., Ferri R., Carnemolla A., Pappalardo A., Costanzo E., Pennisi G. Transcranial magnetic stimulation in Alzheimer disease: motor cortex excitability and cognitive severity. Neurosci Lett. 2001 Nov 13;314(1-2):57–60. doi: 10.1016/s0304-3940(01)02288-1. [DOI] [PubMed] [Google Scholar]
  2. Bartus R. T. On neurodegenerative diseases, models, and treatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp Neurol. 2000 Jun;163(2):495–529. doi: 10.1006/exnr.2000.7397. [DOI] [PubMed] [Google Scholar]
  3. Bisgaard C., Jensen A. S. Iatrogenic cutaneous implantation metastasis from exfoliated rectal adenocarcinoma cells. Case report. Acta Chir Scand. 1989 Feb;155(2):137–138. [PubMed] [Google Scholar]
  4. Carlesimo G. A., Caltagirone C., Gainotti G. The Mental Deterioration Battery: normative data, diagnostic reliability and qualitative analyses of cognitive impairment. The Group for the Standardization of the Mental Deterioration Battery. Eur Neurol. 1996;36(6):378–384. doi: 10.1159/000117297. [DOI] [PubMed] [Google Scholar]
  5. Choi B. H., Holt J. T., McDonald J. V. Occult malignant astrocytoma of pons with extracranial metastasis to bone prior to craniotomy. Acta Neuropathol. 1981;54(4):269–273. doi: 10.1007/BF00696999. [DOI] [PubMed] [Google Scholar]
  6. Conti F., Weinberg R. J. Shaping excitation at glutamatergic synapses. Trends Neurosci. 1999 Oct;22(10):451–458. doi: 10.1016/s0166-2236(99)01445-9. [DOI] [PubMed] [Google Scholar]
  7. Dawson T. P. Pancytopaenia from a disseminated anaplastic oligodendroglioma. Neuropathol Appl Neurobiol. 1997 Dec;23(6):516–520. doi: 10.1111/j.1365-2990.1997.tb01330.x. [DOI] [PubMed] [Google Scholar]
  8. Dewar J. M., Dady P. J., Balakrishnan V. Metastatic astrocytoma. Aust N Z J Med. 1985 Dec;15(6):745–747. [PubMed] [Google Scholar]
  9. Di Lazzaro V., Oliviero A., Meglio M., Cioni B., Tamburrini G., Tonali P., Rothwell J. C. Direct demonstration of the effect of lorazepam on the excitability of the human motor cortex. Clin Neurophysiol. 2000 May;111(5):794–799. doi: 10.1016/s1388-2457(99)00314-4. [DOI] [PubMed] [Google Scholar]
  10. Di Lazzaro V., Oliviero A., Profice P., Pennisi M. A., Di Giovanni S., Zito G., Tonali P., Rothwell J. C. Muscarinic receptor blockade has differential effects on the excitability of intracortical circuits in the human motor cortex. Exp Brain Res. 2000 Dec;135(4):455–461. doi: 10.1007/s002210000543. [DOI] [PubMed] [Google Scholar]
  11. Di Lazzaro V., Oliviero A., Profice P., Pennisi M. A., Pilato F., Zito G., Dileone M., Nicoletti R., Pasqualetti P., Tonali P. A. Ketamine increases human motor cortex excitability to transcranial magnetic stimulation. J Physiol. 2003 Jan 17;547(Pt 2):485–496. doi: 10.1113/jphysiol.2002.030486. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Di Lazzaro V., Oliviero A., Profice P., Saturno E., Pilato F., Insola A., Mazzone P., Tonali P., Rothwell J. C. Comparison of descending volleys evoked by transcranial magnetic and electric stimulation in conscious humans. Electroencephalogr Clin Neurophysiol. 1998 Oct;109(5):397–401. doi: 10.1016/s0924-980x(98)00038-1. [DOI] [PubMed] [Google Scholar]
  13. Di Lazzaro V., Restuccia D., Oliviero A., Profice P., Ferrara L., Insola A., Mazzone P., Tonali P., Rothwell J. C. Effects of voluntary contraction on descending volleys evoked by transcranial stimulation in conscious humans. J Physiol. 1998 Apr 15;508(Pt 2):625–633. doi: 10.1111/j.1469-7793.1998.625bq.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Di Lazzaro Vincenzo, Oliviero A., Tonali P. A., Marra C., Daniele A., Profice P., Saturno E., Pilato F., Masullo C., Rothwell J. C. Noninvasive in vivo assessment of cholinergic cortical circuits in AD using transcranial magnetic stimulation. Neurology. 2002 Aug 13;59(3):392–397. doi: 10.1212/wnl.59.3.392. [DOI] [PubMed] [Google Scholar]
  15. Ferreri Florinda, Pauri Flavia, Pasqualetti Patrizio, Fini Rita, Dal Forno Gloria, Rossini Paolo Maria. Motor cortex excitability in Alzheimer's disease: a transcranial magnetic stimulation study. Ann Neurol. 2003 Jan;53(1):102–108. doi: 10.1002/ana.10416. [DOI] [PubMed] [Google Scholar]
  16. Figueroa Patricio, Lupton Jason R., Remington Todd, Olding Michael, Jones Robert V., Sekhar Laligam N., Sulica Virginia I. Cutaneous metastasis from an intracranial glioblastoma multiforme. J Am Acad Dermatol. 2002 Feb;46(2):297–300. doi: 10.1067/mjd.2002.104966. [DOI] [PubMed] [Google Scholar]
  17. Fisher R. J., Nakamura Y., Bestmann S., Rothwell J. C., Bostock H. Two phases of intracortical inhibition revealed by transcranial magnetic threshold tracking. Exp Brain Res. 2002 Jan 25;143(2):240–248. doi: 10.1007/s00221-001-0988-2. [DOI] [PubMed] [Google Scholar]
  18. Francis P. T., Palmer A. M., Snape M., Wilcock G. K. The cholinergic hypothesis of Alzheimer's disease: a review of progress. J Neurol Neurosurg Psychiatry. 1999 Feb;66(2):137–147. doi: 10.1136/jnnp.66.2.137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kemp John A., McKernan Ruth M. NMDA receptor pathways as drug targets. Nat Neurosci. 2002 Nov;5 (Suppl):1039–1042. doi: 10.1038/nn936. [DOI] [PubMed] [Google Scholar]
  20. Kennedy J. S., Polinsky R. J., Johnson B., Loosen P., Enz A., Laplanche R., Schmidt D., Mancione L. C., Parris W. C., Ebert M. H. Preferential cerebrospinal fluid acetylcholinesterase inhibition by rivastigmine in humans. J Clin Psychopharmacol. 1999 Dec;19(6):513–521. doi: 10.1097/00004714-199912000-00005. [DOI] [PubMed] [Google Scholar]
  21. Kim Jeong E., Kim Chae-Yong, Kim Dong G., Jung Hee-Won. Implantation metastasis along the stereotactic biopsy tract in anaplastic astrocytoma: a case report. J Neurooncol. 2003 Feb;61(3):215–218. doi: 10.1023/a:1022581526527. [DOI] [PubMed] [Google Scholar]
  22. Kujirai T., Caramia M. D., Rothwell J. C., Day B. L., Thompson P. D., Ferbert A., Wroe S., Asselman P., Marsden C. D. Corticocortical inhibition in human motor cortex. J Physiol. 1993 Nov;471:501–519. doi: 10.1113/jphysiol.1993.sp019912. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Liepert J., Bär K. J., Meske U., Weiller C. Motor cortex disinhibition in Alzheimer's disease. Clin Neurophysiol. 2001 Aug;112(8):1436–1441. doi: 10.1016/s1388-2457(01)00554-5. [DOI] [PubMed] [Google Scholar]
  24. McKhann G., Drachman D., Folstein M., Katzman R., Price D., Stadlan E. M. 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 Jul;34(7):939–944. doi: 10.1212/wnl.34.7.939. [DOI] [PubMed] [Google Scholar]
  25. Moghaddam B., Adams B., Verma A., Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci. 1997 Apr 15;17(8):2921–2927. doi: 10.1523/JNEUROSCI.17-08-02921.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Pasquier B., Pasquier D., N'Golet A., Panh M. H., Couderc P. Extraneural metastases of astrocytomas and glioblastomas: clinicopathological study of two cases and review of literature. Cancer. 1980 Jan 1;45(1):112–125. doi: 10.1002/1097-0142(19800101)45:1<112::aid-cncr2820450121>3.0.co;2-9. [DOI] [PubMed] [Google Scholar]
  27. Pennisi Giovanni, Alagona Giovanna, Ferri Raffaele, Greco Salvatore, Santonocito Domenico, Pappalardo Alessandra, Bella Rita. Motor cortex excitability in Alzheimer disease: one year follow-up study. Neurosci Lett. 2002 Sep 6;329(3):293–296. doi: 10.1016/s0304-3940(02)00701-2. [DOI] [PubMed] [Google Scholar]
  28. Rosenfeld J. V., Murphy M. A., Chow C. W. Implantation metastasis of pineoblastoma after stereotactic biopsy. Case report. J Neurosurg. 1990 Aug;73(2):287–290. doi: 10.3171/jns.1990.73.2.0287. [DOI] [PubMed] [Google Scholar]
  29. Tokimura H., Di Lazzaro V., Tokimura Y., Oliviero A., Profice P., Insola A., Mazzone P., Tonali P., Rothwell J. C. Short latency inhibition of human hand motor cortex by somatosensory input from the hand. J Physiol. 2000 Mar 1;523(Pt 2):503–513. doi: 10.1111/j.1469-7793.2000.t01-1-00503.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ziemann U., Lönnecker S., Steinhoff B. J., Paulus W. Effects of antiepileptic drugs on motor cortex excitability in humans: a transcranial magnetic stimulation study. Ann Neurol. 1996 Sep;40(3):367–378. doi: 10.1002/ana.410400306. [DOI] [PubMed] [Google Scholar]
  31. de Carvalho M., de Mendonça A., Miranda P. C., Garcia C., Luís M. L. Magnetic stimulation in Alzheimer's disease. J Neurol. 1997 May;244(5):304–307. doi: 10.1007/s004150050091. [DOI] [PubMed] [Google Scholar]

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