Neurology -- Correspondence for Lima and Fregni, 70 (24) 2329-2337

Correspondence published:

Motor cortex stimulation for chronic pain: Systematic review and meta-analysis of the literature: William M Landau, MD, W. Thomas Thach, Jr., MD (2 October 2008)

Reply from the authors: Felipe Fregni, Moises C. Lima (2 October 2008)

Motor cortex stimulation for chronic pain: Systematic review and meta-analysis of the literature: Joe Jacob Alappat (29 August 2008)

Reply to Allapat and Sina: Felipe Fregni, Soroush Zaghi, Moises C.Lima, Felipe Fregni (29 August 2008)

Motor cortex stimulation for chronic pain: Systematic review and meta-analysis of the literature 2 October 2008

William M Landau, MD,
Washington University School of Medicine
660 S. Euclid Avenue, St. Louis, MO,
W. Thomas Thach, Jr., MD
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Re: Motor cortex stimulation for chronic pain: Systematic review and meta-analysis of the literature

landauw{at}neuro.wustl.edu William M Landau, MD, et al.

The review of the extensive literature concerning motor cortex stimulation for chronic pain is intrinsically valuable. [1] We are skeptical of the concept, but if appropriately controlled empirical studies are successful it would be encouraging. We still don’t understand the proven efficacy of electroconvulsive therapy for severe depression.
Our concern is what the authors call “the putative mechanisms of action for motor cortex stimulation in chronic pain.” They cite the entirely theoretical presumption of Holsheimer et al., “Motor cortex stimulation activates superficial layers of the motor cortex (intercortical interneurons, rather than corticospinal axons). [2] Stimulation of these fibers then conveys stimulation to different areas: 1) thalamocortical projections from ventrolateral-ventral anterior (VL-VA) thalamic nuclei, 2) collaterals of cortico-cortical projections, especially postcentral and premotor cortex, and 3) local cortical connections in parallel to the cortical layers. This activation propagates both orthodromically and antidromically and will lead to a cascade of synaptic events resulting in modulation in an extensive neural network that includes thalamic nuclei, limbic system, brainstem nuclei, and spinal cord. Indeed, invasive and noninvasive techniques are associated with activation in extensive neural networks. The exact mechanisms of such modulation (facilitation vs inhibition, or simply interference in the pain-related networks) are not yet elucidated.”
Direct electrophysiological studies in cat motor cortex demonstrated lowest threshold response by the large axial myelinated fibers situated in the lowest cortical and subcortical levels. [3] With direct recording from pyramidal tract axons, these conclusions were confirmed in the monkey with both electrical and magnetic stimulation. [4,5]
Holsheimer et al. failed to consider that the firing thresholds of very fine intracortical axons must be an order of magnitude higher than those of the large deep fibers, especially for very brief shocks and regardless of gyral/sulcal orientation in the ill-defined electrical field. However, there can be little doubt that any variety of gross motor cortex stimulation stirs up an uncontrolled volume of abnormal activity in widely dispersed brain tissue.
References:
1. Lima MC, Fregni, F. Motor cortex stimulation for chronic pain: Systematic review and meta-analysis of the literature. Neurology 2008;70:2329-2337.
2. Holsheimer J, Nguyen JP, Lefaucheur JP, Manola L. Cathodal, anodal or bifocal stimulation of the motor cortex in the management of chronic pain? Acta Neurochir Suppl 2007;97:57-66.
3. Landau WM, Bishop GH, and Clare MH. Site of excitation in stimulation of the motor cortex. J Neurophysiol 1965,28: 1206-1222.
4. Edgley SA, Eyre JA, Lemon RN, Miller S. Comparison of activation of corticospinal neurons and spinal motor neurons by magnetic and electrical transcranial stimulation in the lumbosacral cord of the anaesthetized monkey. Brain 1997;120:839-853.
5. Hern JEC, Landgren S, Phillips CG, Porter R. Selective excitation of corticofugal neurones by surface-anodal stimulation of the motor cortex. J Physiol.1962;161:73–90.
Disclosure: The authors report no disclosures.

Reply from the authors 2 October 2008

Felipe Fregni,
Harvard Medical School
330 Brookline Ave,KS 158, Boston, MA 02215,
Moises C. Lima
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Re: Reply from the authors

ffregni{at}bidmc.harvard.edu Felipe Fregni, et al.

We thank Drs. Landau and Thach for their comments. We agree that the mechanisms of cortical stimulation for the treatment of pain are poorly understood.
The mechanisms vary across the different techniques of motor cortex stimulation including repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS) and epidural stimulation. Currently, little can be inferred from their mechanisms of action. In addition, as Landau and Thach point out, even the effects of electroconvulsive therapy (ECT) for the treatment of depression are unclear.
We also agree that different cortical layers have different threshold responses. However, because some of the techniques such as tDCS induce a modulation in a large cortical area [6], we discussed the network effects of such activation rather than the local effects. This was also pointed out by Drs. Landau and Thach.
Our main point is that stimulation of motor cortex leads to activation of a large neural network associated with pain control. [7] We hope that the clinical evidence demonstrated in our meta-analysis will encourage future research on the mechanisms of action of this approach for pain treatment and optimize its clinical effects.
References
6. Lang N, Siebner HR, Ward NS, et al. How does transcranial DC stimulation of the primary motor cortex alter regional neuronal activity in the human brain? Eur J Neurosci 2005;22:495-504.
7. Garcia-Larrea L, Peyron R, Mertens P, et al. Electrical stimulation of motor cortex for pain control: a combined PET-scan and electrophysiological study. Pain 1999;83:259-273.
Disclosure: The authors report no disclosures.

Motor cortex stimulation for chronic pain: Systematic review and meta-analysis of the literature 29 August 2008

Joe Jacob Alappat,
Department of Neurology
Ibn Sina Hospital Safat, Kuwait
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Re: Motor cortex stimulation for chronic pain: Systematic review and meta-analysis of the literature

joealappat{at}yahoo.com Joe Jacob Alappat

I read this interesting review by Lima and Fregni. [1] Motor cortical stimulation—especially invasive—can have significant beneficial effects on chronic pain. However, stimulations of any kind on the cortex, especially the motor cortex and thalamus, are known to precipitate seizures. [2]
From this study involving a novel modality of cortical stimulation, we would expect data on occurrence of seizures in the study populations. There are other studies where the effect of low-frequency electric stimulation had inhibitory effects on epileptic activity. [3]
It would have been ideal if the authors discussed epilepsy episodes as well, since seizures could be one of the major limiting side effects of this procedure.
References
1. Lima MC Fregni F. Motor cortex stimulation for chronic pain: Systemic review and meta-analysis of the literature. Neurology 2008;70:2329-2337.
2. Rosa MA, Picarelli H, et al. Accidental seizure with repetitive transcranial magnetic stimulation. J ECT. 2006 Dec;22:265-266.
3. Yamamoto J, Ikeda A et al Low-frequency electric cortical stimulation has an inhibitory effect on epileptic focus in mesial temporal lobe epilepsy.Epilepsia. 2002;43:491-495.
Disclosures: The authors report no disclosures.

Reply to Allapat and Sina 29 August 2008

Felipe Fregni,
Harvard Medical School
330 Brookline Ave., KS 452, Boston, MA 02215,
Soroush Zaghi, Moises C.Lima, Felipe Fregni
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Re: Reply to Allapat and Sina

ffregni{at}bidmc.harvard.edu Felipe Fregni, et al.

We thank Drs. Allapat and Sina for their comments.
Because repetitive transcranial magnetic stimulation (rTMS) can increase cortical excitability, this method of noninvasive brain stimulation can indeed induce seizures, especially when the stimulation is applied at high frequency for long durations with short intervals between the trains of stimulation. Low-frequency rTMS has an antiepileptic effect. [4]
Allapat and Sina mention that our review lacks a discussion of the seizure-inducing profile of the invasive and noninvasive forms of motor cortex stimulation. Although it is true that the most common site of stimulation for the induction of seizure is the motor cortex, cases of unintentionally induced seizures are rare.
Rosa et al. identified only eight cases of accidental seizure in their review. [5] Our personal review of 140 relevant articles (updated through Feb 2008) of correct application of rTMS has yielded five cases in which convulsion was reported: two patients with depression; one with bipolar disorder; one with multiple sclerosis; and one healthy volunteer with a family history of epilepsy. No cases of convulsion or seizure-like activity were reported in any of the articles that we cited in our review. [1]
Rosa et al. and Wasserman provide a review of seizures and other adverse effects associated with rTMS. [5,6] Nevertheless, numerous studies and expert opinions suggest that the induction of seizures can be avoided by careful consideration of the Summary of Guidelines for rTMS proposed in Wasserman. [6] The safety guidelines specify the variables such as stimulus intensity, train duration and frequency that are recommended to avoid seizures.
Despite this, the induction of seizure is still possible as shown by our review of accidental cases and remains the greatest safety concern in the application of rTMS. We would also urge increased reporting of this adverse effect.
References
4. Fregni F, Otachi PT, Do Valle A, et al. A randomized clinical trial of repetitive transcranial magnetic stimulation in patients with refractory epilepsy. Ann Neurol. 2006;60:447-455.
5. Rosa MA, Odebrecht M, Rigonatti SP, Marcolin MA. Transcranial magnetic stimulation: review of accidental seizures. Rev. Bras. Psiquiatr. [online]. 2004, 26(2)[cited 2008-07-30],131-134.
6. Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Electroencephalogr Clin Neurophysiol 1998;108:1-16.
Disclosures: The authors report no disclosures.