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he Editor:We read with interest the paper by Pierelli et al. [9] thatlores, through a paired associative stimulation (PAS) paradigm,ibitory (LTD-like) and facilitatory (LTP-like) mechanisms of cor-l plasticity in migraine patients. The PAS technique works bypling sensory and motor stimuli at precise intervals and is ablenduce plastic changes in motor cortex that depend on the inter-

used: 10 ms (PAS 10), generally inducing inhibition [LTD-like]25 ms (PAS 25) inducing facilitation. In analogy to what has

n found in experimental animals, PAS has been demonstratede mediated by NMDA receptors, as pretreatment with dextro-

thorphan (a NMDA antagonist) is able to abolish its plasticcts in human beings.

In their study, Pierelli et al. [9] showed that PAS 10, which usu-has LTD-like effects in normal subjects, induced instead facil-

ory responses in migraineurs, whereas PAS 25, which normallyuces facilitatory LTP-like effects, failed to show significantentiation in the same patients. The response to PAS 10 inients is in agreement with the paradoxical facilitatory responsehe inhibitory rTMS paradigm (1-Hz frequency) that we firsterved in the primary visual cortex and then confirmed in thetor cortex [1,2,5]. This finding was interpreted as caused by auced efficiency of inhibitory circuits in analogy to models ofctional deafferentation, where down-regulation of inhibitoryuits occurs and facilitatory responses can be induced by-frequency stimulation. In support of such an explanation, wefound reduced short latency intracortical inhibition (SICI), an

ective measure of cortical inhibition, in motor cortex of migrai-rs [2]. In contrast, Pierelli et al. [9] based their interpretation onence about homeostatic plasticity, that is, regulatory mecha-s that act on thresholds for LTP or LTD to maintain neural

vity within a useful range. Indeed, in agreement with workiebner et al. [10], in which preconditioning with cathodal tDCSich reduces excitability) facilitated the effects of 1 Hz rTMS,elli et al. interpreted that the facilitation related to PAS 10caused by cortical hypoactivation. They reasoned that, accord-

1 mechanism in response to inhibitory paradigms (PAS 10 1 HzrTMS) that works perfectly well, and the other engaged by PAS25 that is instead defective. This generates a clear contradiction.In our opinion, a different explanation could be advanced thatwould reconcile the results found for both PAS 10 and 25. If wesuppose that a condition of dysfunctioning inhibition is presentin migraine (in agreement with consistent evidence [4]), this couldexplain the potentiation observed with PAS 10. Such an explana-tion is consistent with the paradoxical facilitation phenomenonobserved in models of functional deafferentation of sensorimotorand visual cortices [6,8,11] In this hypothetical scenario, in whichreduced inhibition could be the cause, or even the effect ofincreased responsivity of glutamatergic synapses, the applicationof further facilitatory (potentiating) stimulation (such as that ofPAS 25) could activate protective mechanisms of inhibitoryhomeostatic plasticity. Indeed, in a recent study in migraineursusing a paradigm of low-intensity, high-frequency rTMS, weobserved greater facilitatory responses, as compared to those inhealthy subjects, which changed to inhibitory responses whenstimulation intensity was increased [3]. So reduced inhibitionand increased cortical excitability could increase responsivity atthe level of glutamatergic synapses, thus favouring LTP-likeresponse to slight stimulation (eg, 1 Hz rTMS, PAS 10). At the sametime, a condition of cortical hyperexcitability would lower thethreshold for homeostatic inhibitory responses that in turn couldexplain the inhibition observed in regard to higher magnitudestimulation (HF-rTMS, PAS 25).

References

[1] Brighina F, Piazza A, Daniele O, Fierro B. Modulation of visual corticalexcitability in migraine with aura: effects of 1 Hz repetitive transcranialmagnetic stimulation. Exp Brain Res 2002;145:177–81.

[2] Brighina F, Giglia G, Scalia S, Francolini M, Palermo A, Fierro B. Facilitatoryeffects of 1 Hz rTMS in motor cortex of patients affected by migraine withaura. Exp Brain Res 2005;161:34–8.

[3] Brighina F, Cosentino G, Vigneri S, Talamanca S, Palermo A, Giglia G, Fierro B.

PAIN�

155 (2014) 643–647

w w w . e l s e v i e r . c o m / l o c a t e / p a i n

to homeostatic plasticity, PAS 10 reduces the threshold to LTP,ucing facilitation. This interpretation could work well for inhib-y PAS, but it seems not to fit as well with the effects observedPAS 25. Indeed, in a condition of cortical hypo activity (such ast induced by cathodal preconditioning in the experiments byg et al., [7]), one could expect a facilitatory response not onlyn inhibitory paradigm such as PAS10, but also to a facilitatory

adigm such as PAS 25. However, this was not the case in thelts by Pierelli et al. [9], in which no significant potentiationinduced by PAS 25 in patients with migraine. The authors

lain this lack of potentiation to PAS 25 as caused by a malfunc-ing of LTP mechanisms, in line with the hypothesis of corticaloactivation. However, if this was so, then we would have totulate 2 different LTP mechanisms operating in migraineurs:

Abnormal facilitatory mechanisms in motor cortex of migraine with aura. Eur JPain 2011;15:928–35.

[4] Brighina F, Palermo A, Fierro B. Cortical inhibition and habituation to evokedpotentials: relevance for pathophysiology of migraine. J Headache Pain2009;10:77–84.

[5] Fierro B, Ricci R, Piazza A, Scalia S, Giglia G, Vitello G, Brighina F. 1 Hz rTMSenhances extrastriate cortex activity in migraine: evidence of a reducedinhibition? Neurology 2003;25:1446–8.

[6] Fierro B, Brighina F, Vitello G, Piazza A, Scalia S, Giglia G, Daniele O, Pascual-Leone A. Modulatory effects of low- and high-frequency repetitive transcranialmagnetic stimulation on visual cortex of healthy subjects undergoing lightdeprivation. J Physiol 2005;565:659–65.

[7] Lang N, Siebner HR, Ernst D, Nitsche MA, Paulus W, Lemon RN, Rothwell JC.Preconditioning with transcranial direct current stimulation sensitizes themotor cortex to rapid-rate transcranial magnetic stimulation and controls thedirection of after-effects. Biol Psychiatry 2004;56:634–9.

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644 Correspondence / PAIN�

155 (2014) 643–647

vy LM, Ziemann U, Chen R, Cohen LG. Rapid modulation of GABA insorimotor cortex induced by acute deafferentation. Ann Neurol

02;52:755–61.relli F, Iacovelli E, Bracaglia M, Serrao M, Coppola G. Abnormal sensorimotorsticity in migraine without aura patients. PAIN� 2013;154:1738–42.bner HR, Lang N, Rizzo V, Nitsche MA, Paulus W, Lemon RN, Rothwell JC.

econditioning of low-frequency repetitive transcranial magnetic stimulationth transcranial direct current stimulation: evidence for homeostaticsticity in the human motor cortex. J Neurosci 2004;24:3379–85.mann U, Corwell B, Cohen LG. Modulation of plasticity in human motor

rtex after forearm ischemic nerve block. J Neurosci 1998;18:1115–23.

Filippo Brighina⇑Giuseppe Cosentino

Simone VigneriBrigida Fierro

Dipartimento di BiomedicinaSperimentale e Neuroscienze Cliniche (BioNec),

University of Palermo, Via G. La Loggia1, 90129 Palermo, Italy

⇑ Corresponding author. Tel.: +39 0916555108;fax: +39 0916555127.

E-mail address: filippo.brighina@unipa.it (F. Brighina)

59/$36.00 � 2013 International Association for the Study of Pain. Published byB.V. All rights reserved.

x.doi.org/10.1016/j.pain.2013.11.012

nse to letter to the Editor

their letter, Brighina and colleagues criticize the interpreta-f our key finding: a lack of paired associative stimulationinduced long-term depression (PAS10) and potentiation5) effects in interictal migraine without aura patients. In aup of subjects, PAS-induced plastic changes were inversely

d to the level of thalamocortical activation; as such, we rea-that malfunctioning in PAS-induced effects in migrainereflect low cortical preactivation, preventing short-term

nger-term changes in cortical synaptic effectiveness [15].ghina and colleagues provided a different explanation, pro-

that the changes in cortical excitability we observed in mi-in response to modulation using PAS10 and PAS25 are annomenon of primary cortical GABAergic dysfunction. This

retation is self-contradictory and is not supported by themental data. First, the hypothesis that impaired inhibitionexplain the results after PAS10 while functional inhibitionvely prevented PAS25 potentiation is conflicting. Second,uthors subsequently compared the facilitatory effect of

with that observed in experiments of deafferentation-in-cortical plasticity without explaining from what region thecould be deafferented. This effect definitely did not origi-

y the absence of peripheral impulses after forearm ischemic

or enhance the efficacy of weakly and/or strongly activated excit-atory glutamatergic synapses through AMPA receptor traffickingrather than by enhancing or diminishing the effectiveness ofGABA-mediated inhibition [9,11]. Following this line of thought,we attributed significant PAS10-related increases in motor-evokedpotential (MEP) amplitudes and nonsignificant PAS25-relatedenhancement of baseline MEP amplitude to an overall malfunctionin migraine cortical long-term mechanisms, which likelyunderlines a dysfunction in synchronous regulation of excitatorysynapses within the sensorimotor cortex [19].

Furthermore, contrary to the authors’ statements, we believethat our results are more consistent with the homeostatic meta-plasticity theory than the results shown in the cited work of Langet al. [12]. In fact, we observed a conceivable homeostatic increasein MEP amplitude (+18.8%) induced by PAS25 ‘‘immediately after’’a cortical enhancing excitability procedure at a time point whenamplitudes had not yet changed in Lang et al. In the latter study,homeostatic compensatory increase in MEP amplitude in responseto enhancing rTMS was only apparent ‘‘20 minutes’’ after the endof the conditioning session.

Further studies in a large cohort of migraineurs are needed toconfirm our observation that PAS-induced plastic changes are in-versely related with somatosensory thalamocortical activation[15].

Nevertheless, it is noteworthy that overall, these sensorimotordata are consistent with results previously obtained regarding cor-tical evoked potentials in which lack of short- and long-term habit-uation/depression and low activity of the thalamocortical drivewere frequently observed between attacks [4] and for which theanatomical correlates are only recently beginning to be understood[6,18].

Conflict of interest statement

The authors report no conflict of interest.

References

[1] Bahra A, Matharu MS, Buchel C, Frackowiak RS, Goadsby PJ. Brainstemactivation specific to migraine headache. Lancet 2001;357:1016–7.

[2] Brighina F, Giglia G, Scalia S, Francolini M, Palermo A, Fierro B. Facilitatoryeffects of 1 Hz rTMS in motor cortex of patients affected by migraine withaura. Exp Brain Res 2005;161:34–8.

[3] Burstein R, Jakubowski M, Garcia-Nicas E, Kainz V, Bajwa Z, Hargreaves R,Becerra L, Borsook D. Thalamic sensitization transforms localized pain intowidespread allodynia. Ann Neurol 2010;68:81–91.

[4] Coppola G, Di Lorenzo C, Schoenen J, Pierelli F. Habituation and sensitization inprimary headaches. J Headache Pain 2013;14:65.

[5] Coppola G, Iacovelli E, Bracaglia M, Serrao M, Di Lorenzo C, Pierelli F.Electrophysiological correlates of episodic migraine chronification: evidencefor thalamic involvement. J Headache Pain 2013;14:76.

[6] Coppola G, Tinelli E, Lepre C, Iacovelli E, Di Lorenzo C, Di Lorenzo G, Serrao M,Pauri F, Fiermonte G, Bianco F, Pierelli F. Dynamic changes in thalamicmicrostructure of migraine without aura patients: a diffusion tensor magnetic

block, as described in Ziemann et al. [21], a study cited byna and colleagues. However, involvement of subcorticalures in both interictal and ictal migraine pathophysiologyen confirmed in several studies. In particular, biochemicalneurophysiological [5,7,8,16,17], and neuroimaging

,14,20] studies have shown that brain stem and thalamicare profoundly involved in expression of migraine clinical

europhysiological correlates.ghina and colleagues are fundamentally incorrect in basingnterpretation of our results on the assumption that repeti-ranscranial magnetic stimulation (rTMS) exclusively en-s (low-frequency rTMS) or reduces (high-frequency rTMS)l GABAergic inhibition [2]. In fact, long-term-like effects

rTMS protocols, such as PAS, appear to primarily diminish

resonance imaging study. Eur J Neurol; in press. http://dx.doi.org/10.1111/ene.12296.

[7] Coppola G, Vandenheede M, Di Clemente L, Ambrosini A, Fumal A, De PasquaV, Schoenen J. Somatosensory evoked high-frequency oscillations reflectingthalamo-cortical activity are decreased in migraine patients between attacks.Brain 2005;128:98–103.

[8] Evers S, Quibeldey F, Grotemeyer KH, Suhr B, Husstedt IW. Dynamic changes ofcognitive habituation and serotonin metabolism during the migraine interval.Cephalalgia 1999;19:485–91.

[9] Fitzgerald P, Fountain S, Daskalakis Z. A comprehensive review of the effects ofrTMS on motor cortical excitability and inhibition. Clin Neurophysiol2006;117:2584–96.

[10] Hamel E. Serotonin and migraine: biology and clinical implications.Cephalalgia 2007;27:1293–300.

[11] Heide G, Witte O, Ziemann U. Physiology of modulation of motor cortexexcitability by low-frequency suprathreshold repetitive transcranial magneticstimulation. Exp Brain Res 2006;171:26–34.