Vision and Hyper-Responsiveness in Migraine

Round 1

Reviewer 1 Report

An interesting neuropsychological study, which needs some major revision.

To say that migraine is characterized by a state of cortical hyperexcitability, the authors cite articles from 12 to 20 years old. By now saying that the migraine brain is hyperexcited doesn't make much sense anymore in 2019. Recent scientific work has shown that the degree of excitability of the migraine's cortex changes continuously in the intercritical period and even more so in the critical period. Several exogenous factors (drugs, luminance) and endogenous factors (stress, hormones, sleep) can influence the level of excitability of the migraine brain. In addition, there are large differences in the level of excitability between migraineurs with and without auras [3]. Therefore, I suggest to be more neutral in the title and in the text: to use a term like hyperresponsive or disexcitable is certainly more neutral and implies a dynamism of the phenomenon. There is no table with all the clinical features of migraine: frequency of attacks, duration of attacks, intensity of migraine pain. To be added. Has the level of visual acuity of the subjects examined been tested? When needed, was visual correction also used?

Discussion:

I’m not convinced by the cortical excitability explanation of the visual phenomena observed in migraine with aura. More hypotheses must be explored such as that of the 1) abnormal thalamic processing activity [2,9], as previously described both with neuroimaging and neurophysiological studies [4,5,7,8,10], of the 2) abnormal functional connectivity [11], as observed again in neuroimaging and EEG studies [6,14], and of the 3) abnormal brainstem-to-thalamus connectivity [13], especially considering the supposed role of the brainstem as migraine generator [1,12,15]. A major discussion deserves the fact that most of the abnormalities were found in patients with migraine with aura, but not in those without aura.

 

References

[1]         Bahra A, Matharu MS, Buchel C, Frackowiak RS, Goadsby PJ. Brainstem activation specific to migraine headache. Lancet 2001;357:1016–1017.

[2]         Cheng H, Chino YM, Smith EL, Hamamoto J, Yoshida K. Transfer characteristics of lateral geniculate nucleus X neurons in the cat: effects of spatial frequency and contrast. J. Neurophysiol. 1995;74:2548–2557.

[3]         Coppola G, Bracaglia M, Di Lenola D, Di Lorenzo C, Serrao M, Parisi V, Di Renzo A, Martelli F, Fadda A, Schoenen J, Pierelli F. Visual evoked potentials in subgroups of migraine with aura patients. J. Headache Pain 2015;16.

[4]         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 thalamic microstructure of migraine without aura patients: A diffusion tensor magnetic resonance imaging study. 2014.

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

[6]         Faragó P, Tuka B, Tóth E, Szabó N, Király A, Csete G, Szok D, Tajti J, Párdutz Á, Vécsei L, Kincses ZT. Interictal brain activity differs in migraine with and without aura: resting state fMRI study. J. Headache Pain 2017;18:8.

[7]         Granziera C, Daducci A, Romascano D, Roche A, Helms G, Krueger G, Hadjikhani N. Structural abnormalities in the thalamus of migraineurs with aura: a multiparametric study at 3 T. Hum. Brain Mapp. 2014;35:1461–8.

[8]         Magon S, May A, Stankewitz A, Goadsby PJ, Tso AR, Ashina M, Amin FM, Seifert CL, Chakravarty MM, Müller J, Sprenger T. Morphological Abnormalities of Thalamic Subnuclei in Migraine: A Multicenter MRI Study at 3 Tesla. J. Neurosci. 2015;35:13800–13806.

[9]         Rathbun DL, Alitto HJ, Warland DK, Usrey WM. Stimulus Contrast and Retinogeniculate Signal Processing. Front. Neural Circuits 2016;10:8.

[10]      Rocca MA, Pagani E, Colombo B, Tortorella P, Falini A, Comi G, Filippi M. Selective diffusion changes of the visual pathways in patients with migraine: a 3-T tractography study. Cephalalgia 2008;28:1061–1068.

[11]      Sarabi MT, Aoki R, Tsumura K, Keerativittayayut R, Jimura K, Nakahara K. Visual perceptual training reconfigures post-task resting-state functional connectivity with a feature-representation region. PLoS One 2018;13:e0196866.

[12]      Stankewitz A, Aderjan D, Eippert F, May A. Trigeminal nociceptive transmission in migraineurs predicts migraine attacks. J. Neurosci. 2011;31:1937–1943.

[13]      Strumpf H, Noesselt T, Schoenfeld MA, Voges J, Panther P, Kaufmann J, Heinze H-J, Hopf J-M. Deep Brain Stimulation of the Pedunculopontine Tegmental Nucleus (PPN) Influences Visual Contrast Sensitivity in Human Observers. PLoS One 2016;11:e0155206.

[14]      de Tommaso M, Stramaglia S, Marinazzo D, Trotta G, Pellicoro M. Functional and effective connectivity in EEG alpha and beta bands during intermittent flash stimulation in migraine with and without aura. Cephalalgia 2013;33:938–47.

[15]      Weiller C, May A, Limmroth V, Jüptner M, Kaube H, Schayck R V, Coenen HH, Diener HC. Brain stem activation in spontaneous human migraine attacks. Nat. Med. 1995;1:658–660.

Author Response

Thank you for the time and trouble you have taken with our manuscript.

We accept that a more neutral title is preferable, and have made the necessary alterations to refer to “hyper-responsiveness or hyperexcitability”.

Here we do not attempt to explain the physiology of migraine, complex as it undoubtedly is, but a particular abnormality of visual processing, measured psychophysically, with which migraine is clearly associated. There are many references to cortical hyperexcitability in migraine, and one of the more recent is below. We think the strongest evidence is surely to be found in the work of Huang and others who have shown hyperBOLD responses to visual patterns in the visual cortex of individuals with migraine, normalised with precision tinted lenses. One parsimonious explanation for the hyperBOLD response is that of hyperexcitability, and it fits with much of the literature, including recent studies, below.

The fluctuations in any responsiveness or excitability, whether exogenous or endogenous are to be expected, but their presence should surely increase the noise in discriminating individuals with migraine from healthy individuals. All of the individuals in our study were examined interictally and yet clear differences with normal behaviour emerge.

Tables with the clinical features of migraine have been added as Supplementary Materials because most of the important features are in fact included in the current text. 

The visual acuity of participants was not measured, and participants were examined with any habitual refractive correction, now noted.

Reference

Brighina, F., Bolognini, N., Cosentino, G., Maccora, S., Paladino, P., Baschi, R., Vallar, G., Fierro, B. Visual cortex hyperexcitability in migraine in response to sound-induced flash illusions.

Neurology May 2015, 84 (20) 2057-2061; DOI: 10.1212/WNL.0000000000001584

 

Reviewer 2 Report

Dear authors,

The manuscripts reports that the individuals with migraine have superior contrast sensitivity to controls. It also shows that this sensitivity is higher in visual field with aura. Such superiority is reduced with lens of preferable color. These results read interesting to know pathophysiology of migraine. However, the authors are requested to discuss their results from neurological points of view. Details are listed below:

1: Why does preferable color reduce excitability of V2 neurons ? Neurophysiological evidences should be shown in discussion.

2: How does hyperexcitation of V2 neurons improve contrast sensitivity ? Neurophysiological mechanisms should be described in discussion.

3: Migraine is hypothesized to be caused by cortical spreading depression and/ or cerebral vasomotor abnormality. The authors should discuss their results from such pathophysiological points of view.

4: Intrinsically photosensitive retinal ganglion cells (ipRGCs) are reported to be involved in migraine headache by light (for example, Noseda et al., Nat Neurosci. 2010 13(2):239-245). ipRGCs are also revealed to contribute to contrast sensitivity functions (for example, Zele et al., Vision Res. 2019;160:72-81). The authors should discuss the role of ipRGCs in abnormally high sensitivity and reduction of sensitivity with a tinted lens.

Author Response

Thank you for the time and trouble you have taken.

Point 1. If there exists a hyperexctability of the cortex in migraine then it is unlikely to be uniform but patchy (as it is, for example, in pattern-sensitive epilepsy, when patients can be sensitive to a limited range of pattern orientations). In visual area V2  neurons with similar responses to colour are clustered. It follows that, if this is the case, changing the colour of light may change the distribution of firing in V2. One possible hypothesis is that the colours that are comfortable reduce the firing in excitable patches of cortex. The draft has been amended to reflect the above.

 

Point 2. It is contrast discrimination (sensitivity to the relative contrast of two supra-threshold patterns), not contrast sensitivity (the limit of sensitivity to low-contrast patterns) that is of issue.  If neurons are hyper-excitable one might expect a spread of excitation that involves neurons that would not normally be excited by a stimulus. Such a spread is consistent with (1) lower thresholds for phosphenes in response to transcranial magnetic stimulation, as shown by Aurora et al  (2) greater interference between senses, as in sound-induced visual illusions, as shown by Brighina et al. We have amended the draft to clarify this.

 

Point 3. The causes of migraine are complex and poorly understood. We are concerned here with the visual differences with which migraine is associated. These may or may not be associated with the triggering of attacks. Cortical excitability in migraine, as proposed by others, provides one possible explanation for the visual differences. Cortical spreading depression is known to be triggered visually in cortex rendered excitable by the pro convulsant drug Metrazol. 

 

Point 4. The role of ipRGCs has received considerable discussion in the literature of late, to the extent of being offered as an explanation of photophobia. Here the photophobia was induced by patterns, not by bright light, and the ipRGC are not likely to be directly sensitive to images of this kind although there may be an indirect influence on other retinal pathways. Nevertheless melatonin responsively in the short wavelengths is not mirrored in the choices of colours our participants made. We have added a section discussing this.

Round 2

Reviewer 1 Report

The authors responded sufficiently to the comments I had on this paper.

But I would like to point out that, as far as Huang's article is concerned, an increase in the BOLD signal at fMRI does not mean an increase in cortical excitability at all. In fact, an increase in BOLD means an increase in the consumption of deoxyhemoglobin, therefore an increase in metabolism that can be due to any process that consumes energy: inhibitory interneurons, pyramidal cells, glial cells, etc..

 

Reviewer 2 Report

The authors succeeded in answering my questions and revising their manuscript appropriately. Therefore, I think the present form of manuscript is accepted for publication.