Clinical Neurophysiology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Editorial
Habituation or lack of habituation: What is really lacking in migraine? See Article, pages xxx–xxx
Migraine is very prevalent disease with consistent disability and socioeconomic burden (Lipton et al., 2007). Despite intensive research effort, particularly in last decades, allowing significant insight in many aspects of the disease, its precise pathophysiological bases remain still to be defined. One influential view suggests that dysfunctions in sensory information processing could play a critical role (de Tommaso et al., 2014). In this frame a relevant phenomenological marker is considered the inability of migraine patients to habituate to repeated sensory stimulation. Habituation, i.e. the ability to reduce, attenuate the nervous system response to repetitive irrelevant sensorial information, was first disclosed in its molecular mechanism by Kandel (1979), and is considered one of the fundamental implicit learning behavior that allows modulation and adaptation of nervous response to the relevance of the sensorial input. In humans habituation has been studied by means of evoked potential, indexed by the amplitude reduction of the evoked response to prolonged sensorial stimulation. The first evidence about lack of habituation in migraine is by Schoenen et al. (1995). In this study authors reported lack of amplitude reduction of visual evoked potential to the ongoing stimulation in patients with migraine. This evidence was then confirmed in further studies with visual stimuli and later on also in other sensory modalities (see Coppola et al., 2009, for a review). Indeed lack of habituation was found in migraineurs for acoustic, somatosensory (Ozkul and Uckardes, 2002) and in the last years even for nociceptive stimulation (Valeriani et al., 2003). For such consistency, the deficient ability to habituate to sensorial stimulation has been considered to represent a neurophysiological hallmark of migraine (Coppola et al., 2009; Brighina et al., 2009). However, a number of VEP studies did not confirm lack of habituation in migraine (see Omland et al., 2013). A matter for such discrepancy has been first considered the use of different stimulation parameters (Sand et al., 2008). Indeed, lack of habituation was demonstrated with small check sizes of 80 or 160 (in recent studies) and high repetition rate of 3.1 Hz while very different parameters were employed in some studies that did not confirm habituation impairment (Oelkers et al., 1999; Oelkers-Ax et al., 2005). The argument of different stimulation parameters however does not appear to work as well for other more recent reports, where, even using visual stimuli in the spatial and temporal frequencies range able to reveal the habituation defect, no evidence of lack of habituation was revealed in patients with migraine (Omland et al., 2013).
So, how to explain the inability to see habituation impairment in these reports? In a recent editorial provocatively entitled ‘‘We were blind so we can see. . .’’ Sand (2014) points to the relevance of a specific methodological factor: blindness, i.e. the unawareness of the examiner about the allocation of the subject under study. Indeed, in all these reports, differently from those showing habituation impairment in migraine, recording and analysis of visual responses were completely blinded. The examiner was in fact unaware about the diagnosis of the subject studied (migraineur or healthy control) in all the phases of the study. In his paper Sand (2014) stresses the general relevance of blinding as a tool to obtain an effective control for biases due to expectation even for neurophysiological studies. According to his view, the methodological issue of blinding represented the principal reason for the discrepancy concerning the finding about habituation to VEP in migraine. At this point a critical question naturally follows: if, independently from stimulation parameters used, blinding of the study no longer allows to see habituation impairment in migraine, how can we rule out that this neurophysiological abnormality would follow not to a specific disorder in processing sensory information but simply to an expectation bias? Moreover, given this criticism, how can we still mention habituation defect as a neurophysiological hallmark of migraine? This is indeed the position expressed in the paper by Omland et al. (2015) published in this issue of Clinical Neurophysiology. Here authors study habituation to VEP in normal subjects and in patients with migraine using visual stimuli of 160 size to complete the series of check sizes explored in previous studies (80 , 310 , 620 , 650 ). Here again, performing complete blinded recording and analysis of visual response, authors were not able to find differences in habituation to VEP between migraineurs and healthy subjects. They discuss such results interpreting them as further confirmation of previous findings obtained exploring a very large range of stimulation parameters, stressing again the matter of blinding. Independently from the stimuli used indeed, when applying blinding, the constant finding is the inability to reveal any impairment of habituation in migraine. The accumulated evidence in the authors opinion is huge enough to justify the criticism clearly expressed in the title of their paper: ‘‘Visual evoked potentials in migraine: Is the ‘‘neurophysiological hallmark’’ concept still valid?’’ Does this really represent the ‘‘end of the road’’ for the concept of habituation impairment in migraine? Lack of habituation
http://dx.doi.org/10.1016/j.clinph.2015.05.028 1388-2457/Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
2
Editorial / Clinical Neurophysiology xxx (2015) xxx–xxx
has been considered a basic finding, a milestone as concerns the general hypothesis of dysfunctioning of sensory information process in migraine. Habituation indeed is impaired during the interictal phase while it is restored during the migraine attack where normalization of cortical excitability and responsivity in the migraine brain has been hypothesized to occur (Coppola et al., 2009). Should we now consider instead the chance that lack of habituation would simply be the result of a methodological bias? From the evidence reported and reviewed by Omland et al. (2015) and Sand (2014) it would seem so or at least that a serious criticism should be raised about. However, important caveats exist and deserve mention. First of all, as stated also by Omland et al. (2015), the criticism about habituation impairment should be confined to visual sensory modality because the contrary evidence is till now limited to VEP studies. Moreover, a multiplicity of factors, other than blinding, can affect recording of evoked potentials and consequently the ability to explore habituation and its impairment in migraine. Among these, variables pertaining to the disease state (patient-related) like disease severity and duration, attack frequency, migraine cycle (examination performed during attack or interictally) and others concerning methods for recording and analysis (procedure-related) of the evoked responses like stimulation parameters, attention and concentration during the examination etc., can all play a relevant, even critical, role. So, even only theoretically, the opposite symmetrical condition should also be considered i.e. that, instead of blinding, differences in some of the other mentioned factors between ‘‘pro’’ and ‘‘cons’’ studies, could have hampered the emergence of a true habituation defect in migraine. Omland et al. (2015) in their paper accurately present and discuss these patient- and procedure-related variables. As mentioned above, no role seems to be played by procedure-related factors concerning stimulation parameters (check size and stimulation frequency) because a wide range of such parameters (including those used in studies reporting habituation impairment in migraine) have been employed by the Omland and Sand group. The same is true for patient-related variables like disease severity, attack frequency and phase of migraine cycle, because also under this respect no relevant differences emerge with studies confirming habituation impairment. Aside from blinding, Omland et al. (2015) mention also the potential effect of methodological differences concerning the subject recruitment and the instruction given to the subjects during examination to maintain their attention to the screen. In our opinion, this last point could be relevant because, due to the subtle visual attentional dysfunction described in migraine (Mickleborough et al., 2011), instruction given during task could exert different effect on habituation processing in migraine patients with respect to healthy controls. Last but not least, it is also to be considered the case of potential biases not adequately controlled by blinding. Omland et al. (2015) and Sand (2014) state that unconscious expectation toward one of the subjects group under study can bias the results and can be avoided by a blinded design. However, in the instance, even if unlikely, of a tendency during VEP analysis, to discard higher amplitude responses the efficacy of blinding could be lost. In such a case indeed, even if equally applied (in patients and controls) a reduction in the number of higher potentials would follow favoring the final result of habituation, while hampering the emergence of potential habituation defect. In conclusion, data against the concept of lack of habituation, till now considered a neurophysiological hallmark in migraine, have been recently provided in blinded VEP studies. However, the precise role of blinding or other factors in determining such result remains unclear. Further high-powered studies with blinded design (Sand, 2014), controlling potential sources of bias and other parameters that can affect VEP habituation are needed to adequately
explore this issue. Moreover, to effectively approach the role of less controllable confounding factor (see above) it could be useful that authors with different views about habituation in migraine will perform similar comparable studies with blind design. Finally, to definitely evaluate the role of sensorial habituation in migraine pathogenesis similar well designed and controlled studies should be extended also to other sensory modalities. Habituation indeed is a general physiological phenomenon and is not specific for visual input. On the other hand impairment of habituation, would not be specific of migraine because a defective ability to habituate to sensory stimulation has been described also in other pathological brain conditions and hypothesized to depend upon dysfunction of cortical activation, principally to defective cortical inhibition (Brighina et al., 2009). An example of such combined dysfunctions could be Parkinson’s disease (PD) where habituation and inhibitory cortical circuits are impaired and can both be restored by effective L-DOPA treatment that has been shown to reset cortical inhibition in this disease. Conflict of interest Authors have no interest to disclose. References Brighina F, Palermo A, Fierro B. Cortical inhibition and habituation to evoked potentials: relevance for pathophysiology of migraine. J Headache Pain 2009;10:77–84. Coppola G, Pierelli F, Schoenen J. Habituation and migraine. Neurobiol Learn Mem 2009;92:249–59. de Tommaso M, Ambrosini A, Brighina F, Coppola G, Perrotta A, Pierelli F, et al. Altered processing of sensory stimuli in patients with migraine. Nat Rev Neurol 2014;10:144–55. Kandel ER. Cellular insights into behavior and learning. Harvey Lect 1979;73:19–92. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF, et al. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology 2007;68:343–9. Mickleborough MJ, Truong G, Handy TC. Top-down control of visual cortex in migraine populations. Neuropsychologia 2011;49:1006–15. Oelkers R, Grosser K, Lang E, Geisslinger G, Kobal G, Brune K, et al. Visual evoked potentials in migraine patients: alterations depend on pattern spatial frequency. Brain 1999;122:1147–55. Oelkers-Ax R, Parzer P, Resch F, Weisbrod M. Maturation of early visual processing investigated by a pattern-reversal habituation paradigm is altered in migraine. Cephalalgia 2005;25:280–9. Omland PM, Nilsen KB, Uglem M, Gravdahl G, Linde M, Hagen K, et al. Visual evoked potentials in interictal migraine: no confirmation of abnormal habituation. Headache 2013;53:1071–86. Omland PM, Uglem M, Hagen K, Linde M, Tronvik E, Sand T. Visual evoked potentials in migraine: is the ‘‘neurophysiological hallmark’’ concept still valid? Clin Neurophysiol 2015 [in this issue]. Ozkul Y, Uckardes A. Median nerve somatosensory evoked potentials in migraine. Eur J Neurol 2002;9:227–32. Sand T. We were blind, so now we can see: the EP/ERP story in migraine. Clin Neurophysiol 2014;125:433–4. Sand T, Zhitniy N, White LR, Stovner LJ. Visual evoked potential latency, amplitude and habituation in migraine: a longitudinal study. Clin Neurophysiol 2008;119:1020–7. Schoenen J, Wang W, Albert A, Delwaide PJ. Potentiation instead of habituation characterizes visual evoked potentials in migraine patients between attacks. Eur J Neurol 1995;2:115–22. Valeriani M, de Tommaso M, Restuccia D, Le Pera D, Guido M, Iannetti GD, et al. Reduced habituation to experimental pain in migraine patients: a CO2 laser evoked potential study. Pain 2003;105:57–64.
⇑
Filippo Brighina Giuseppe Cosentino Brigida Fierro Department of Experimental Biomedicine and Clinical Neuroscience (BioNeC), University of Palermo, Sezione di Neurologia, Via del Vespro, 143, 90129 Palermo, Italy ⇑ Tel.: +39 0916556677, +39 3392118412. E-mail address: fi[email protected] (F. Brighina)
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Editorial
Habituation or lack of habituation: What is really lacking in migraine? See Article, pages xxx–xxx
Migraine is very prevalent disease with consistent disability and socioeconomic burden (Lipton et al., 2007). Despite intensive research effort, particularly in last decades, allowing significant insight in many aspects of the disease, its precise pathophysiological bases remain still to be defined. One influential view suggests that dysfunctions in sensory information processing could play a critical role (de Tommaso et al., 2014). In this frame a relevant phenomenological marker is considered the inability of migraine patients to habituate to repeated sensory stimulation. Habituation, i.e. the ability to reduce, attenuate the nervous system response to repetitive irrelevant sensorial information, was first disclosed in its molecular mechanism by Kandel (1979), and is considered one of the fundamental implicit learning behavior that allows modulation and adaptation of nervous response to the relevance of the sensorial input. In humans habituation has been studied by means of evoked potential, indexed by the amplitude reduction of the evoked response to prolonged sensorial stimulation. The first evidence about lack of habituation in migraine is by Schoenen et al. (1995). In this study authors reported lack of amplitude reduction of visual evoked potential to the ongoing stimulation in patients with migraine. This evidence was then confirmed in further studies with visual stimuli and later on also in other sensory modalities (see Coppola et al., 2009, for a review). Indeed lack of habituation was found in migraineurs for acoustic, somatosensory (Ozkul and Uckardes, 2002) and in the last years even for nociceptive stimulation (Valeriani et al., 2003). For such consistency, the deficient ability to habituate to sensorial stimulation has been considered to represent a neurophysiological hallmark of migraine (Coppola et al., 2009; Brighina et al., 2009). However, a number of VEP studies did not confirm lack of habituation in migraine (see Omland et al., 2013). A matter for such discrepancy has been first considered the use of different stimulation parameters (Sand et al., 2008). Indeed, lack of habituation was demonstrated with small check sizes of 80 or 160 (in recent studies) and high repetition rate of 3.1 Hz while very different parameters were employed in some studies that did not confirm habituation impairment (Oelkers et al., 1999; Oelkers-Ax et al., 2005). The argument of different stimulation parameters however does not appear to work as well for other more recent reports, where, even using visual stimuli in the spatial and temporal frequencies range able to reveal the habituation defect, no evidence of lack of habituation was revealed in patients with migraine (Omland et al., 2013).
So, how to explain the inability to see habituation impairment in these reports? In a recent editorial provocatively entitled ‘‘We were blind so we can see. . .’’ Sand (2014) points to the relevance of a specific methodological factor: blindness, i.e. the unawareness of the examiner about the allocation of the subject under study. Indeed, in all these reports, differently from those showing habituation impairment in migraine, recording and analysis of visual responses were completely blinded. The examiner was in fact unaware about the diagnosis of the subject studied (migraineur or healthy control) in all the phases of the study. In his paper Sand (2014) stresses the general relevance of blinding as a tool to obtain an effective control for biases due to expectation even for neurophysiological studies. According to his view, the methodological issue of blinding represented the principal reason for the discrepancy concerning the finding about habituation to VEP in migraine. At this point a critical question naturally follows: if, independently from stimulation parameters used, blinding of the study no longer allows to see habituation impairment in migraine, how can we rule out that this neurophysiological abnormality would follow not to a specific disorder in processing sensory information but simply to an expectation bias? Moreover, given this criticism, how can we still mention habituation defect as a neurophysiological hallmark of migraine? This is indeed the position expressed in the paper by Omland et al. (2015) published in this issue of Clinical Neurophysiology. Here authors study habituation to VEP in normal subjects and in patients with migraine using visual stimuli of 160 size to complete the series of check sizes explored in previous studies (80 , 310 , 620 , 650 ). Here again, performing complete blinded recording and analysis of visual response, authors were not able to find differences in habituation to VEP between migraineurs and healthy subjects. They discuss such results interpreting them as further confirmation of previous findings obtained exploring a very large range of stimulation parameters, stressing again the matter of blinding. Independently from the stimuli used indeed, when applying blinding, the constant finding is the inability to reveal any impairment of habituation in migraine. The accumulated evidence in the authors opinion is huge enough to justify the criticism clearly expressed in the title of their paper: ‘‘Visual evoked potentials in migraine: Is the ‘‘neurophysiological hallmark’’ concept still valid?’’ Does this really represent the ‘‘end of the road’’ for the concept of habituation impairment in migraine? Lack of habituation
http://dx.doi.org/10.1016/j.clinph.2015.05.028 1388-2457/Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
2
Editorial / Clinical Neurophysiology xxx (2015) xxx–xxx
has been considered a basic finding, a milestone as concerns the general hypothesis of dysfunctioning of sensory information process in migraine. Habituation indeed is impaired during the interictal phase while it is restored during the migraine attack where normalization of cortical excitability and responsivity in the migraine brain has been hypothesized to occur (Coppola et al., 2009). Should we now consider instead the chance that lack of habituation would simply be the result of a methodological bias? From the evidence reported and reviewed by Omland et al. (2015) and Sand (2014) it would seem so or at least that a serious criticism should be raised about. However, important caveats exist and deserve mention. First of all, as stated also by Omland et al. (2015), the criticism about habituation impairment should be confined to visual sensory modality because the contrary evidence is till now limited to VEP studies. Moreover, a multiplicity of factors, other than blinding, can affect recording of evoked potentials and consequently the ability to explore habituation and its impairment in migraine. Among these, variables pertaining to the disease state (patient-related) like disease severity and duration, attack frequency, migraine cycle (examination performed during attack or interictally) and others concerning methods for recording and analysis (procedure-related) of the evoked responses like stimulation parameters, attention and concentration during the examination etc., can all play a relevant, even critical, role. So, even only theoretically, the opposite symmetrical condition should also be considered i.e. that, instead of blinding, differences in some of the other mentioned factors between ‘‘pro’’ and ‘‘cons’’ studies, could have hampered the emergence of a true habituation defect in migraine. Omland et al. (2015) in their paper accurately present and discuss these patient- and procedure-related variables. As mentioned above, no role seems to be played by procedure-related factors concerning stimulation parameters (check size and stimulation frequency) because a wide range of such parameters (including those used in studies reporting habituation impairment in migraine) have been employed by the Omland and Sand group. The same is true for patient-related variables like disease severity, attack frequency and phase of migraine cycle, because also under this respect no relevant differences emerge with studies confirming habituation impairment. Aside from blinding, Omland et al. (2015) mention also the potential effect of methodological differences concerning the subject recruitment and the instruction given to the subjects during examination to maintain their attention to the screen. In our opinion, this last point could be relevant because, due to the subtle visual attentional dysfunction described in migraine (Mickleborough et al., 2011), instruction given during task could exert different effect on habituation processing in migraine patients with respect to healthy controls. Last but not least, it is also to be considered the case of potential biases not adequately controlled by blinding. Omland et al. (2015) and Sand (2014) state that unconscious expectation toward one of the subjects group under study can bias the results and can be avoided by a blinded design. However, in the instance, even if unlikely, of a tendency during VEP analysis, to discard higher amplitude responses the efficacy of blinding could be lost. In such a case indeed, even if equally applied (in patients and controls) a reduction in the number of higher potentials would follow favoring the final result of habituation, while hampering the emergence of potential habituation defect. In conclusion, data against the concept of lack of habituation, till now considered a neurophysiological hallmark in migraine, have been recently provided in blinded VEP studies. However, the precise role of blinding or other factors in determining such result remains unclear. Further high-powered studies with blinded design (Sand, 2014), controlling potential sources of bias and other parameters that can affect VEP habituation are needed to adequately
explore this issue. Moreover, to effectively approach the role of less controllable confounding factor (see above) it could be useful that authors with different views about habituation in migraine will perform similar comparable studies with blind design. Finally, to definitely evaluate the role of sensorial habituation in migraine pathogenesis similar well designed and controlled studies should be extended also to other sensory modalities. Habituation indeed is a general physiological phenomenon and is not specific for visual input. On the other hand impairment of habituation, would not be specific of migraine because a defective ability to habituate to sensory stimulation has been described also in other pathological brain conditions and hypothesized to depend upon dysfunction of cortical activation, principally to defective cortical inhibition (Brighina et al., 2009). An example of such combined dysfunctions could be Parkinson’s disease (PD) where habituation and inhibitory cortical circuits are impaired and can both be restored by effective L-DOPA treatment that has been shown to reset cortical inhibition in this disease. Conflict of interest Authors have no interest to disclose. References Brighina F, Palermo A, Fierro B. Cortical inhibition and habituation to evoked potentials: relevance for pathophysiology of migraine. J Headache Pain 2009;10:77–84. Coppola G, Pierelli F, Schoenen J. Habituation and migraine. Neurobiol Learn Mem 2009;92:249–59. de Tommaso M, Ambrosini A, Brighina F, Coppola G, Perrotta A, Pierelli F, et al. Altered processing of sensory stimuli in patients with migraine. Nat Rev Neurol 2014;10:144–55. Kandel ER. Cellular insights into behavior and learning. Harvey Lect 1979;73:19–92. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF, et al. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology 2007;68:343–9. Mickleborough MJ, Truong G, Handy TC. Top-down control of visual cortex in migraine populations. Neuropsychologia 2011;49:1006–15. Oelkers R, Grosser K, Lang E, Geisslinger G, Kobal G, Brune K, et al. Visual evoked potentials in migraine patients: alterations depend on pattern spatial frequency. Brain 1999;122:1147–55. Oelkers-Ax R, Parzer P, Resch F, Weisbrod M. Maturation of early visual processing investigated by a pattern-reversal habituation paradigm is altered in migraine. Cephalalgia 2005;25:280–9. Omland PM, Nilsen KB, Uglem M, Gravdahl G, Linde M, Hagen K, et al. Visual evoked potentials in interictal migraine: no confirmation of abnormal habituation. Headache 2013;53:1071–86. Omland PM, Uglem M, Hagen K, Linde M, Tronvik E, Sand T. Visual evoked potentials in migraine: is the ‘‘neurophysiological hallmark’’ concept still valid? Clin Neurophysiol 2015 [in this issue]. Ozkul Y, Uckardes A. Median nerve somatosensory evoked potentials in migraine. Eur J Neurol 2002;9:227–32. Sand T. We were blind, so now we can see: the EP/ERP story in migraine. Clin Neurophysiol 2014;125:433–4. Sand T, Zhitniy N, White LR, Stovner LJ. Visual evoked potential latency, amplitude and habituation in migraine: a longitudinal study. Clin Neurophysiol 2008;119:1020–7. Schoenen J, Wang W, Albert A, Delwaide PJ. Potentiation instead of habituation characterizes visual evoked potentials in migraine patients between attacks. Eur J Neurol 1995;2:115–22. Valeriani M, de Tommaso M, Restuccia D, Le Pera D, Guido M, Iannetti GD, et al. Reduced habituation to experimental pain in migraine patients: a CO2 laser evoked potential study. Pain 2003;105:57–64.
⇑
Filippo Brighina Giuseppe Cosentino Brigida Fierro Department of Experimental Biomedicine and Clinical Neuroscience (BioNeC), University of Palermo, Sezione di Neurologia, Via del Vespro, 143, 90129 Palermo, Italy ⇑ Tel.: +39 0916556677, +39 3392118412. E-mail address: fi[email protected] (F. Brighina)
