Neurology -- Correspondence for Däuper et al., 59 (5) 700-706

Correspondence published:

Reply to Letter to the Editor: Jens D Rollnik, J Dauper and C Schrader (29 October 2002)

Effects of subthalamic nucleus (STN) stimulation on motor cortex excitability: Tobias Loddenkemper, Christoph Kellinghaus and Hans O Luders (29 October 2002)

Reply to Letter to the Editor 29 October 2002

Jens D Rollnik
Medical School of Hannover Germany,
J Dauper and C Schrader
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Re: Reply to Letter to the Editor

Rollnik.Jens{at}MH-Hannover.de Jens D Rollnik, et al.

We appreciate the critical comments on our paper “Effects of subthalamic nucleus (STN) stimulation on motor cortex excitability.” [1] The authors of the letter have several concerns that we would like to address.
Methodology. We agree that age has a substantial influence on motor cortex excitability. We will publish a paper focusing on this issue in the near future. [3] We have examined two different age groups in this study using paired-pulse TMS (3 vs. 13 ms inter-stimulus interval) and found that intracortical inhibition was significantly greater in older subjects. [3] This result, however, is different from previous reports [4] suggesting a decrease of intracortical inhibition with ongoing age. This might be explained by different stimulation techniques. While our group has administered monophasic magnetic stimuli, Peinemann et al. [4] used biphasic stimulation. Thus, it is not questionable that age has an impact on motor cortex excitability. Although the main focus of our paper [1] was a comparison of different stimulation/medication conditions among PD patients (and not a comparison of PD and healthy subjects), the control group in our study was of comparable age (mean age 56 years). Most clinical neurophysiologists would agree that motor evoked potentials (MEP) are subject to considerable data variation, regardless all efforts to keep coil position and angle constant. As described in our paper [1], we have performed five trials for each condition (3 ms vs. 13 ms, stimulation/medication on vs. off) and calculated mean values. This procedure has been used in other publications as well. [3, 5] The problem of poor cooperation in PD patients has been addressed in our paper extensively. [1] However, we found that EMG activity among akinetic- rigid PD patients (only little tremor) was moderate and did not differ significantly from healthy controls. Further, another study confirmed that the ECR and FCR muscles can be fairly well relaxed in PD patients. [6] As far as L-dopa effects on intracortical inhibition are concerned, the authors also found a reduced ICI in patients while on dopaminergic medication. [6]
Results: This issue has been addressed in the discussion section of our paper in detail. [1] We just would like to point out the fact that our experimental protocol and the sample of PD patients were different from previous studies, [2] possibly accounting for different findings.
Discussion: We are thankful for their additional suggestions. However, at this stage all explanations are rather hypothetical; an open discussion on this matter would be appreciated.
References:
1. Däuper J, Peschel T, Schrader C, Kohlmetz C, Joppich G, Nager W et al. Effects of subthalamic nucleus (STN) stimulation on motor cortex excitability. Neurology 2002;59:700-706.
2. Cunic D, Roshan L. Khan FI, Lozano AM, Lang AE, Chen R. Effects of subthalamic nucleus stimulation on motor cortex excitability in Parkinson’s disease. Neurology 2002;58:1665-1672.
3. Kossev AR, Schrader C, Däuper J, Dengler R, Rollnik JD. Increased intracortical inhibition in middle-aged humans; a study using paired-pulse transcranial magnetic stimulation. Neurosci Lett 2002, in press.
4. Peinemann A, Lehner C, Conrad B, Siebner HR. Age-related decrease in paired-pulse intracortical inhibition in the human primary motor cortex. Neurosci Lett 2001; 313:33-36.
5. Siggelkow S, Kossev A, Moll C, Dengler R, Rollnik JD: Impaired sensorimotor integration in cervical dystonia – a study using TMS and muscle vibration. J Clin Neurophysiol 2002;19: 232-239.
6. Lewis GN, Byblow WD. Altered sensorimotor integration in Parkinson's disease. Brain 2002;125: 2089-2099.

Effects of subthalamic nucleus (STN) stimulation on motor cortex excitability 29 October 2002

Tobias Loddenkemper
The Cleveland Clinic Foundation Cleveland OH,
Christoph Kellinghaus and Hans O Luders
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Re: Effects of subthalamic nucleus (STN) stimulation on motor cortex excitability

Loddent{at}ccf.org Tobias Loddenkemper, et al.

We agree with Däuper et al., [1] that STN stimulation may modulate cortical excitability. [2] However, Däuper et al.’s [1] study raises several concerns related to methodology, results and discussion.
Methodology. Information on the age of the control group is not provided – age, however, is a crucial factor for motor evoked potentials. For a valid comparison the age group of the controls should be matched with the age of the patients. Besides, the reproducibility of the total voltage time integral may be questionable, considering the intertrial variability (Figure 1 in their article), [1] and considering that only a few trials were averaged (possibly preselected from more trials by an unblinded observer). Movement of coil position and angle against the individual’s vertex may also have increased data variability. Moreover, patients with predominantly akinetic-rigid PD are not able to cooperate as well as controls in silent period (SP) studies requiring maintenance of a constant muscle tone. [3] Consequently, the SP is frequently interrupted by small amounts of EMG in patients with PD. [4]
Results. Previous studies suggest that STN stimulation restores intracortical inhibition (ICI) similar to the effect of dopaminergic drugs, [3, 5] and has no effect on the SP. [3] In contrast to these results, Däuper et al. did not report restoration of ICI by dopaminergic drugs alone, but ICI was reduced with stimulation “on”/medication “on” in the same amount as with stimulation”off”/medication”off” (Figure 2 in their article). [1] Different stimulation paradigms only partially explain these inconsistent results.
Discussion. Finally, in the discussion of their results the authors raise the question “How can the increase of the SP during stimulator “on” be explained?” [1] Modulation of other indirect connections not mentioned in Däuper et al.’s manuscript, [1] like disinhibition of the dorsal midbrain anticonvulsant zone via the substantia nigra, may also influence motor excitability. [2] Furthermore, high frequency stimulation does not only inhibit STN neurons, but simultaneously excites axons within the STN. [2] Antidromic activation of cortico-subthalamic collaterals of the pyramidal tract may lead to cortical modulation (for example via retrograde activation of collaterals to cortical GABA-ergic basket cells) as well as spinal modulation (via nigro-spinal pathways or via collaterals to spinal alpha-motoneurons and activation of Renshaw cells). This could also explain a modulation of intracortical and spinal inhibitory mechanisms by STN stimulation.
References
1. Däuper J, Peschel T, Schrader C, Kohlmetz C, Joppich G, Nager W et al. Effects of subthalamic nucleus (STN) stimulation on motor cortex excitability. Neurology 2002;59:700-706.
2. Loddenkemper T, Pan A, Neme S, Baker KB, Rezai AR, Dinner DS et al. Deep brain stimulation in epilepsy. J Clin Neurophysiol 2001; 18:514- 532.
3. Cunic D, Roshan L, Khan FI, Lozano AM, Lang AE, Chen R. Effects of subthalamic nucleus stimulation on motor cortex excitability in Parkinson's disease. Neurology 2002; 58:1665-1672.
4. Cantello R, Gianelli M, Bettucci D, Civardi C, De Angelis MS, Mutani R. Parkinson's disease rigidity: magnetic motor evoked potentials in a small hand muscle. Neurology 1991; 41:1449-1456.
5. Pierantozzi M, Palmieri MG, Mazzone P, Marciani MG, Rossini PM, Stefani A et al. Deep brain stimulation of both subthalamic nucleus and internal globus pallidus restores intracortical inhibition in Parkinson's disease paralleling apomorphine effects: a paired magnetic stimulation study. Clin Neurophysiol 2002; 113:108-113.