Elsevier

Brain Research Reviews

Volume 38, Issue 3, February 2002, Pages 309-327
Brain Research Reviews

Review
Transcranial magnetic stimulation and Parkinson’s disease

https://doi.org/10.1016/S0165-0173(01)00158-8Get rights and content

Abstract

While motor cortical areas are the main targets of the integrative activity of basal ganglia, their main output consists of the corticospinal system. Transcranial magnetic stimulation (TMS), a relatively new method to investigate corticospinal physiology, has been widely used to assess possible changes secondary to Parkinson’s disease (PD). The use of single- and paired-pulse TMS, two varieties of the original technique, disclosed multiple functional alterations of the corticospinal pathway. For instance, when the latter was tested at ‘rest’, or in response to somesthetic afferents, it showed excess excitability or reduced inhibition. In turn, during production of a voluntary output, its activation was defective, or inadequately modulated. One major mechanism may be a dysfunction of the interneurons mediating the level of excitation within cortical area 4. For instance, there is a shortening of the so-termed ‘central silent period’, which is a complex, TMS-induced, inhibitory phenomenon possibly mediated by activation of GABAB receptors. The so-called ‘short-interval intracortical inhibition’, which is possibly mediated by GABAA receptors, is also diminished. Levodopa restores these and other TMS alterations, thus demonstrating that cortical area 4 is sensitive to dopamine modulation. Overall, TMS has provided substantial new pathophysiological insights, which point to a central role of the primary motor cortex in the movement disorder typical of PD. Repetitive (r-)TMS, another form of TMS, has been studied as a treatment for PD motor signs. Although some reports are favorable, others are not, and have raised the problem of appropriate control experiments. Although extremely interesting, the potential therapeutic role of r-TMS in PD needs further evaluation.

Introduction

The pathophysiology of Parkinson’s disease (PD) has long fascinated generations of neurologists, who undertook multiple study approaches [66]. In the past decade, many researchers have focussed their attention on the physiological changes affecting motor cortical areas in PD. While these are the main targets of the integrative activity of basal ganglia, their main output pathway consists of the corticospinal system [80]. On this apparently simple basis, soon after transcranial electrical stimulation (TES) appeared, making studies of corticospinal physiology feasible in intact man [68], the technique was applied to PD patients. The aim was to trace the effects of the disrupted function of basal ganglia on the cortico-motoneuron connection. In fact, the classical TES study of Dick et al. [32] in three patients concluded that the cortico-motoneuron connection was normal in PD, as did the subsequent contribution of Caramia et al. [17] in five parkinsonians. However, these studies merely referred to conduction along corticospinal axons. Indeed, later, TES pulses were shown to largely bypass the cortical gray matter, which precluded information on the ‘upstream’ intracortical modulation of corticifugal activities [28], [31]. The opposite applied to the technique discovered shortly after, i.e. transcranial (electro-) magnetic stimulation (TMS) [5]. Indeed, the use of TMS in PD investigations began about 10 years ago. Then, it had become clear that TMS could provide information not only on the conductivity of corticospinal neurons, but also on other properties of the primary motor cortex, such as excitability [12]. In turn, basic evidence strongly suggested that excitability was under the influence of multiple afferences to the motor cortex itself, among which those arising from the basal ganglia [80]. Hence, a new insight arose into the pathophysiology of PD as well as of other movement disorders. In the present review, we examine separately the findings provided by single-, paired-, and repetitive-pulse TMS investigations. There are many recent reviews and monographs on the basic mechanisms, features and applications of these various forms of TMS, for instance those of Hallett [45] or Mills [69]. Yet, we shall briefly provide the unfamiliar reader with background information covering each TMS variety.

Section snippets

Single pulse-TMS (s-TMS)

s-TMS was originally developed by Barker et al. [5]. Serial capacitors discharge through a wire coil a high peak (∼5000 A) and a very brief (∼100 μs) electrical pulse. This generates a magnetic field that, by changing rapidly, can induce weak electrical currents in conductive structures neighboring (1.5–2 cm) the coil, such as the cerebral cortex. Activation of corticospinal neurons occurs, which finally leads to a muscle twitch in one or more adjacent muscles (the ‘target’ muscles), depending

Paired pulse TMS (p-TMS)

Table 4 details the main p-TMS studies in PD. The methodology of p-TMS dates back to the early 1990s. It is capable of studying a number of physiological phenomena, such as ipsilateral intracortical excitability [58], transcallosal inhibition [38] or cerebellar inhibition [105]. With respect to PD, most studies have dealt with ipsilateral intracortical excitability, at short and sometimes long interstimulus intervals (ISIs). Two stimuli are delivered to the motor cortex through the same coil,

Repetitive TMS (r-TMS)

Table 5 provides details about the main r-TMS studies in PD. Magnetic pulses can be delivered to brain structures in a repetitive fashion through specific devices. The rate of repetition is of fundamental importance as to the physiologic effect. Slow r-TMS is below a frequency of 1 Hz, while rapid-rate r-TMS is above 1 Hz. Other important variables are the number of pulses, the duration of the trains, their repetitions, and the stimulus intensity. Contrary to s- and p-TMS, r-TMS, especially in

Patients

To date, s-TMS analyses have been carried out in about 430 PD patients. d-TMS studies have involved about 70 PD sufferers, while about 125 have been subject to r-TMS procedures, the vast majority of whom for therapeutic purposes. Overall, the mean patient age was 65 years (range 40–75). Homogeneously throughout the studies, patients prevailed of the akineto-rigid type, and their Hohen and Yahr stage [49] was generally II–III. On the contrary, the diagnostic procedures were seldom specified.

Conclusions

Overall, the most consistent results obtained by TMS studies in PD were of the pathophysiological type. Multiple alterations of the motor cortical function, as tested by TMS, emerged. Particularly, excess excitability or reduced inhibition, especially when at ‘rest’, or in response to somesthetic afference. In turn, cortical activation proved defective, or inadequately modulated, when a voluntary output was to be produced. Motor cortical hypoexcitability emerged when studies focussed on

Acknowledgements

We are very grateful to Cristoforo Comi, MD, and Marilena Poletto MD, for their help in collecting references for an early draft of the present paper.

References (123)

  • P.H. Ellaway et al.

    The relation between bradykinesia and excitability of the motor cortex assessed using transcranial magnetic stimulation in normal and parkinsonian subjects

    Electroencephalogr. Clin. Neurophysiol.

    (1995)
  • P. Fuhr et al.

    Spinal motor neuron excitability during the silent period after cortical stimulation

    Electroencephalogr. Clin. Neurophysiol.

    (1991)
  • R. Hanajima et al.

    Ipsilateral cortico-cortical inhibition of the motor cortex in various neurological disorders

    J. Neurol. Sci.

    (1996)
  • B.A. Haug et al.

    Silent period revives as a valuable diagnostic tool with transcranial magnetic stimulation

    Electroencephalogr. Clin. Neurophysiol.

    (1992)
  • R.H. Kandler et al.

    Abnormalities of central motor conduction in Parkinson’s disease

    J. Neurol. Sci.

    (1990)
  • J. Mally et al.

    Improvement in Parkinsonian symptoms after repetitive transcranial magnetic stimulation

    J. Neurol. Sci.

    (1999)
  • L. Manfredi et al.

    Increased cortical inhibition induced by apomorphine in patients with Parkinson’s disease

    Neurophysiol. Clin.

    (1998)
  • J.W. Mink

    The basal ganglia: focused selection and inhibition of competing activity

    Prog. Neurobiol.

    (1996)
  • K. Nakashima et al.

    Shortened silent period produced by magnetic cortical stimulation in patients with Parkinson’s disease

    J. Neurol. Sci.

    (1995)
  • J.A. Obeso et al.

    Pathophysiology of the basal ganglia in Parkinson’s disease

    Trends Neurosci.

    (2000)
  • A. Pascual-Leone et al.

    Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression

    Lancet

    (1996)
  • P.M. Rossini et al.

    Pre-movement facilitation of motor-evoked potentials in man during transcranial stimulation of the central motor pathways

    Brain Res.

    (1988)
  • P.M. Rossini et al.

    Brain excitability and long latency muscular arm responses: non-invasive evaluation in healthy and parkinsonian subjects

    Electroencephalogr. Clin. Neurophysiol.

    (1991)
  • P.M. Rossini et al.

    Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee

    Electroencephalogr. Clin. Neurophysiol.

    (1994)
  • H.R. Siebner et al.

    Repetitive transcranial magnetic stimulation causes a short-term increase in the duration of the cortical silent period in patients with Parkinson’s disease

    Neurosci. Lett.

    (2000)
  • H.R. Siebner et al.

    Short-term motor improvement after sub-threshold 5-Hz repetitive transcranial magnetic stimulation of the primary motor hand area in Parkinson’s disease

    J. Neurol. Sci.

    (2000)
  • A.P. Strafella et al.

    Effects of chronic levodopa and pergolide treatment on cortical excitability in Parkinson’s disease: a transcranial magnetic stimulation study

    Clin. Neurophysiol.

    (2000)
  • G. Abbruzzese et al.

    Assessment of motor neuron excitability in parkinsonian rigidity by the F wave

    J. Neurol.

    (1985)
  • G. Abbruzzese et al.

    Sensory and motor evoked potentials in multiple system atrophy: a comparative study with Parkinson’s disease

    Mov. Disord.

    (1997)
  • P. Ashby et al.

    Neurophysiological effects of stimulation through electrodes in the human subthalamic nucleus

    Brain

    (1999)
  • A. Berardelli et al.

    Cortical inhibition in Parkinson’s disease. A study with paired magnetic stimulation

    Brain

    (1996)
  • A. Berardelli et al.

    Effects of repetitive cortical stimulation on the silent period evoked by magnetic stimulation

    Exp. Brain Res.

    (1999)
  • C.A. Bloxham et al.

    Reaction times and attention in Parkinson’s disease

    J. Neurol. Neurosurg. Psychiatry

    (1987)
  • T.C. Britton et al.

    Modulation of postural wrist tremors by magnetic stimulation of the motor cortex in patients with Parkinson’s disease or essential tremor and in normal subjects mimicking tremor

    Ann. Neurol.

    (1993)
  • M.P. Caligiuri et al.

    Sensorimotor disinhibition in Parkinson’s disease: effects of levodopa

    Ann. Neurol.

    (1992)
  • R. Cantello et al.

    Parkinson’s disease rigidity: magnetic motor evoked potentials in a small hand muscle

    Neurology

    (1991)
  • R. Cantello et al.

    Magnetic brain stimulation: the silent period after the motor evoked potential

    Neurology

    (1992)
  • R. Cantello et al.

    Pathophysiology of Parkinson’s disease rigidity. Role of corticospinal motor projections

  • R. Cantello et al.

    Cortical excitability in cryptogenic localization-related epilepsy: interictal transcranial magnetic stimulation studies

    Epilepsia

    (2000)
  • R. Chen et al.

    Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation

    Neurology

    (1997)
  • R. Chen et al.

    Time course of corticospinal excitability in reaction time and self-paced movements

    Ann. Neurol.

    (1998)
  • R. Chen et al.

    Effects of internal globus pallidus stimulation on motor cortex excitability

    Neurology

    (2001)
  • C. Civardi, R. Cantello, P. Asselmann, J.C. Rothwell, Transcranial magnetic stimulation can be used to test connections...
  • R. Cunnington et al.

    Effects of magnetic stimulation over supplementary motor area on movement in Parkinson’s disease

    Brain

    (1996)
  • N.J. Davey et al.

    Effects of antipsychotic medication on electromyographic responses to transcranial magnetic stimulation of the motor cortex in schizophrenia

    J. Neurol. Neurosurg. Psychiatry

    (1997)
  • B.L. Day et al.

    Motor cortex stimulation in intact man. II. Multiple descending volleys

    Brain

    (1987)
  • B.L. Day et al.

    Electric and magnetic stimulation of human motor cortex: surface EMG and single motor unit responses

    J. Physiol. (London)

    (1989)
  • P.J. Delwaide et al.

    Conditioning transcranial cortical stimulation (TCCS) by exteroceptive stimulation in parkinsonian patients

  • P.J. Delwaide et al.

    Projections from basal ganglia to tegmentum: a subcortical route for explaining the pathophysiology of Parkinson’s disease signs?

    J. Neurol.

    (2000)
  • J.P.R. Dick et al.

    The corticomotoneurone connection is normal in Parkinson disease

    Nature

    (1984)
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