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Mechanisms of Disease: basic-research-driven investigations in humans—the case of hyperkinetic disorders

Nature Clinical Practice Neurology volume 3, pages 572–580 (2007)Cite this article

Abstract

Recent studies have revealed that animal models of Huntington's disease and levodopa-induced dyskinesia show similar changes in corticostriatal transmission. In both conditions, corticostriatal long-term potentiation (LTP) is abnormally stable, causing persistent inhibition of the output nuclei of the basal ganglia, and involuntary movements. This finding has led to speculation that interventions that interfere with the maintenance of corticostriatal LTP might be useful as antidyskinetic treatments. One approach that is known to reduce cortical hyperexcitability in human disorders is the delivery of a long train of low-frequency (∼1 Hz) stimulation using repetitive transcranial magnetic stimulation. This stimulation protocol is remarkably similar to that used in brain slices to reverse previously induced LTP, and consequently it has been used in patients with Huntington's disease or levodopa-induced dyskinesia to try to interfere with the abnormal corticostriatal plasticity postulated to underlie the motor disturbances in these conditions. Clear antidyskinetic effects of stimulation have been obtained in both disorders, without significant side effects. These findings could have implications for the treatment of hyperkinetic disorders in the clinic, and they illustrate how basic neuroscience can generate predictions to be tested in patients.

Key Points

  • Defective corticostriatal depotentiation occurs in rodent models of Huntington's disease and levodopa-induced dyskinesia

  • The persistence of corticostriatal long-term potentiation (LTP) in these disorders might cause hyperkinetic manifestations by unbalancing basal ganglia pathways

  • Repetitive transcranial magnetic stimulation is a noninvasive tool for investigating LTP, long-term depression and depotentiation in humans

  • Brief and repeated trains of high-frequency stimulation induce LTP and long-term depression in experimental animals and in humans, whereas long trains of low-frequency stimulation cause depotentiation

  • Long trains of low-frequency repetitive transcranial magnetic stimulation have been used to successfully treat hyperkinetic manifestations in Huntington's disease and levodopa-induced dyskinesia

  • Basic neurophysiology can generate predictions to be tested in human subjects

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Figure 1: Schematic representation of basal ganglia circuits in normal conditions, and in Huntington's disease and levodopa-induced dyskinesia.
Figure 2: Corticostriatal long-term potentiation and depotentiation in control conditions and in models of Huntington's disease and levodopa-induced dyskinesia.
Figure 3: Continuous low-frequency repetitive transcranial magnetic stimulation of the supplementary motor area.

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Acknowledgements

This work was supported by grants awarded by the Italian Ministero dell'Università e della Ricerca to DC, by the Ministero della Salute to DC, and by the Agenzia Spaziale Italiana to GB.

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Authors and Affiliations

  1. D Centonze is Assistant Professor of Neurology at the University of Tor Vergata and Head of the Laboratory of Experimental Neurophysiology at the University of Tor Vergata and at the Fondazione Santa Lucia at the European Center for Brain Research (CERC),

    Diego Centonze

  2. G Bernardi is Full Professor of Neurology and Chairman of the Department of Clinical Neuroscience at the University of Tor Vergata, and Scientific Director of the Fondazione Santa Lucia, CERC,

    Giorgio Bernardi

  3. G Koch is a Clinical Neurologist at the University of Tor Vergata, and Head of the Laboratory of Brain Stimulation at the Fondazione Santa Lucia Hospital, Rome, Italy.,

    Giacomo Koch

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  1. Diego Centonze
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Correspondence to Diego Centonze.

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Centonze, D., Bernardi, G. & Koch, G. Mechanisms of Disease: basic-research-driven investigations in humans—the case of hyperkinetic disorders. Nat Rev Neurol 3, 572–580 (2007). https://doi.org/10.1038/ncpneuro0617

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