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Abstract

Background

Migraine is a complex multifactorial disease that arises from the interaction between a genetic predisposition and an enabling environment. Habituation is considered as a fundamental adaptive behaviour of the nervous system that is often impaired in migraine populations. Given that migraineurs are hypersensitive to light, and that light deprivation is able to induce functional changes in the visual cortex recognizable through visual evoked potentials habituation testing, we hypothesized that regional sunlight irradiance levels could influence the results of visual evoked potentials habituation studies performed in different locations worldwide.

Methods

We searched the literature for visual evoked potentials habituation studies comparing healthy volunteers and episodic migraine patients and correlated their results with levels of local solar radiation.

Results

After reviewing the literature, 26 studies involving 1291 participants matched our inclusion criteria. Deficient visual evoked potentials habituation in episodic migraine patients was reported in 19 studies. Mean yearly sunlight irradiance was significantly higher in locations of studies reporting deficient habituation. Correlation analyses suggested that visual evoked potentials habituation decreases with increasing sunlight irradiance in migraine without aura patients.

Conclusion

Results from this hypothesis generating analysis suggest that variations in sunlight irradiance may induce adaptive modifications in visual processing systems that could be reflected in visual evoked potentials habituation, and thus partially account for the difference in results between studies performed in geographically distant centers. Other causal factors such as genetic differences could also play a role, and therefore well-designed prospective trials are warranted.

Keywords

Migraine visual evoked potentials habituation sunlight irradiance

Background

Migraine is considered as a complex multifactorial disease that arises from the interaction between a genetic predisposition and an enabling environment (1,2). Still, the extent to which such interaction can influence the clinical phenotype of migraineurs remains ill-defined (3).

Cumulative research focused on the analysis of sensory processing in migraine has contributed to a better understanding of its underlying neurobiological mechanisms (4). Nonetheless, weak reproducibility between studies occasionally constitutes a matter of debate (5,6). Beside methodological dissimilarities, different genetic backgrounds and contrasting environmental conditions could probably explain, at least in part, the distinct electrophysiological profiles found between migraine populations worldwide (7,8).

Habituation is a response decrement that results from repeated stimulation and does not involve sensory adaptation or fatigue (9). It is considered as a fundamental adaptive behaviour of the nervous system that is often impaired in migraine populations (4). Indeed, a deficit in visual evoked potentials (VEP) habituation is among the most common neurophysiological findings in interictal migraineurs thus far (6). Yet, while addressing this phenomenon, not all VEP studies have reported the same findings (5,6). The discrepancies between studies are probably not explained on the sole basis of methodological differences (8,10).

Given that migraine patients are often hypersensitive to light (11,12) and that light deprivation is able to induce functional changes in the visual cortex recognizable through VEP habituation testing (13), we hypothesized that regional sunlight irradiance levels could influence visual processing and contribute to the variability of VEP habituation results between studies performed in different locations worldwide. To test this hypothesis, we reviewed previously published original studies in which VEP habituation had been compared between episodic migraine patients and healthy volunteers and correlated their results with in-situ sunlight irradiance levels.

Methods

Search strategy: We searched the Pubmed database using the terms: “visual evoked potentials”, “migraine disorders”, and “habituation”. The literature search ended in December 2016. Only original VEP studies comparing healthy volunteers (HV) and episodic migraine patients (EM, ICHD-3 beta codes 1.1 and 1.2 (14)), in adult populations, published in English, available in full text version were considered. Based on previous studies (15), only data from subjects not taking any migraine prophylactic treatment recorded in the interictal period were extracted for analysis.

Data collection: In a classical VEP acquisition, subjects sit in a dark and quiet room in front of a screen. Recording electrodes are positioned on the scalp, with an active electrode placed over the occipital cortex (Oz, 10–20 EEG system) usually referenced to a frontal (Fz) electrode. The most common visual stimulation paradigm employed to evaluate habituation consists of a reversing black and white checkerboard (pattern-reversal VEP). When several stimulation parameters had been tested upon the same cohort of patients, only results obtained with the highest spatial contrast were included, since this is deemed to be the best condition to evaluate VEP habituation (16). For intervention studies, only baseline electrophysiological values were considered and subsequent measures were discarded. Except in one study (17), a total of 200 to 600 consecutive responses were collected during uninterrupted stimulation. Recordings were partitioned in blocks ranging between 50 and 100 epochs. From each publication, we extracted VEP initial (first block) N70-P100 amplitude, the last to first block N70–P100 proportional amplitude change, and the report of deficient VEP habituation in EM patients in contrast with HV. In the only study exceeding 600 trials, data from the sixth block were included in the last to first proportional amplitude change calculation. Habituation was considered deficient when studies reported a statistically significant difference in the habituation slope, repeated measures ANOVA, or the last to first block amplitude change between HV and EM in the interictal period.

Mean yearly sunlight irradiance values, based on a 1990–2004 registry, were obtained from the Solar radiation data webpage (http://www.soda-is.com, © 2014–2016 MINES ParisTech). When the location of the laboratory where VEP were recorded was not specifically provided, the city where the Institution’s Ethics Committee approving the study protocol is based was used instead. We compared mean yearly sunlight irradiance between locations of studies showing normal or deficient habituation in EM. Additionally, sunlight irradiance was correlated to the initial N70–P100 amplitude (first block), as well as to the proportional difference between last and first blocks’ amplitudes. Last to first block VEP proportional change was preferred over the habituation slope, because of its straightforward calculation method in contrast with the latter (i.e. to obtain the habituation slope, different methods were employed across studies). For correlation analyses and sub-group comparisons in Table 1, studies were weighted by their sample sizes. All correlations were corrected for possible confounding variables related to experimental conditions such as mean age of the participants, spatial and temporal frequencies of the stimulation protocol (since these parameters might have an influence on habituation) (16,18), and total number of averaged responses. Results from migraine without aura patients and migraine not otherwise specified were pooled for analysis.

Table 1.

Comparison between sub-groups’ characteristics. Studies’ results means are weighted by sample size. Asterisks (*) identify cells where values differ significantly with the mean of healthy volunteers. (SD: standard deviation.)

	Healthy volunteers		Migraine with aura patients		Migraine without aura patients		p value
	Mean	S.D	Mean	S.D	Mean	S.D
Age	30.41	±4.86	33.71	±3.11	31.15	±3.83	0.16
Female (%)	69.81	±13.55	73.77	±17.61	75.35	±11.22	0.45
First block N1-P1 amplitude (µV)	9.67	±0.68	7.38	±1.25	8.96	±0.72	0.28
Difference in N1-P1 amplitude between the last and the first blocks	−9.83	±2.34	6.45*	±4.05	4.99*	±2.4	<0.001

Significant p values are highlighted in bold.

Statistics: Student’s t-test or one-way ANOVA with post-hoc multiple comparisons Dunnet tests were used in case of normal data distribution (assessed by Shapiro-Wilk test) whereas Mann-Whitney U-Test, Kuskal-Wallis test, and Spearman’s rank correlation were used for not normally distributed data. Proportions in Table 2 were compared using Chi-square tests. Two-sided p values < 0.05 were considered statistically significant. The IBM Statistical Package for the Social Sciences (SPSS) for Windows (Version 20.0, IBM Corp, Armonk, NY) and Microsoft Excel (2016) were used for statistical analyses and graph design. Non-parametric partial correlations were performed with a SPSS script available at (MRC CBSU Wiki: http://imaging.mrc-cbu.cam.ac.uk/statswiki/FAQ/partsp).

Table 2.

Experimental characteristics and solar irradiance of studies showing deficient or preserved habituation in migraine. *For the only study exceeding 600 epochs, data from the sixth block were considered as last.

	Deficient habituation in migraine
	No		Yes		p value
Studies (n = 26)	7		19		0.031
Sunlight irradiance (W/m²) (mean, SD)	86.00	11.49	131.16	43.42	0.010
Total number of subjects	319		972		<0.001
Sample size (mean, SD)	45.6	24.5	51.2	24.8	0.61
Temporal frequency (Hz) (mean, SD)	2.60	0.83	2.97	0.34	0.29
Spatial frequency (degrees) (mean, SD)	27.9′	25.21	26.1′	24.11	0.86
Total number of epochs (mean, SD)*	442.9	196.7	481.6	166.01	0.62
Epochs per block (mean, SD)	78.6	26.7	86.0	21.8	0.47

Significant p values are highlighted in bold.

Results

Our search strategy returned 69 articles of which 26, involving 1291 participants, met our inclusion criteria. The characteristics of studies included are summarized in Tables 3 and 2. Nineteen studies (73%) reported a significant impairment of VEP habituation in EM. The sample sizes, number of epochs in total or in each block, spatial and temporal frequencies of stimulation, and mean age of participants did not differ between studies showing either preserved or impaired habituation (Table 2). Overall, mean yearly sunlight irradiance was significantly higher in sites of studies reporting deficient habituation (deficit: 131.16 ± 43.4 W/m² vs. no deficit: 86.00 ± 11.5 W/m², n = 393; Mann Whitney test p = 0.010) (Figure 1).

Table 3.

Studies included in this review with their characteristics and yearly mean sunlight irradiance levels. *Data from the 6th block (600 epochs) was considered for proportional changes analysis.

Author, year	City, country	Mean sunlight irradiance (W/m2)	Temporal/spatial stimulating frequency (Hz/minutes of arc)	Number of epochs (per block/total)	Healthy volunteers (n)	Mean age ± standard deviation or range	Female (%)	Migraine without aura (n)	Mean age ± standard deviation or range	Female (%)	Migraine with aura (n)	Mean age ± standard deviation or range	Female (%)	Migraine not otherwise specified (n)	Mean age ± standard deviation or range	Female (%)	Total number of participants (n)	Statistical analysis	Blinding to diagnosis	Definition of interictal	Deficient habituation in migraine
Schoenen et al. (19), 1995	Liège, Belgium	94	3.1/8′	50/250	16	33 ± n/a	75	27			9				32 ± n/a	77.8	52	Response curves comparison (Zerbe’s non parametric method)	No	+ 168	Yes
Áfra et al. (17),* 1998	Liège, Belgium	94	3.1/8′	100/1500*	25	30 ± n/a	68	25			15				36 ± n/a	77.5	65	Response proportion curves comparison (Zerbe’s non parametric method)	No	+ 120	Yes
Oelkers et al. (18), 1999	Erlangen, Germany	92	1/7.5′	50/250	28	27.1 ± 4.1	64.3	13			13				29.1 ± 5.9	96.1	54	MANOVA of proportional responses	No	± 72	No
Wang et al. (20), 1999	Hefei, China	198	3/8′	50/250	26	32 ± 12.3	57.9	22	35.3 ± 9.6	81.8							48	Least square of amplitude changes	No	+ 168	Yes
Áfra et al. (21), 2000	Liège, Belgium	94	3.1/68′	50/250	23	27 ± 7	78.3	37			22				36 ± 11	78	82	MANOVA of proportional changes	No	± 72	Yes
Áfra et al. (22), 2000	Liège, Belgium	94	3.1/68′	50/250	10	28 ± 6	80				12	34 ± 16	50				22	Response curves comparison (Zerbe’s non parametric method)	No	± 72	No
Sand et al. (23), 2000	Trondheim, Norway	74	2/8′	100/200	22	39.5 ± 8.7	81.8	8			5				39.3 ± 10	76.9	35	Repeated measures ANOVA of amplitude	Yes	± 72	Yes
Ozkul et al. (24), 2002	Sanliurfa, Turkey	182	3.1/68′	50/250	40	33 ± 8	72.5	44	36 ± 10	81.8	35	34 ± 9	83				119	ANOVA of proportional differences	No	± 72	Yes
Fumal et al. (25), 2005	Liège, Belgium	94	3.1/8′	100/600	8	23.2 ± 1,9	37.5	6			2				23.3 ± 1	62.5	16	t-test of percentage change	No	± 72	Yes
Di Clemente et al. (26), 2005	Liège, Belgium	94	3.1/68′	100/600	15	23.9 ± 3,4	66.7	15	28 ± 10.8	66.7							30	t-test of percentage change and slope	No	± 48	Yes
Coppola et al. (27), 2007	Liège, Belgium	94	3.1/15′	100/600	15	27.7 ± 8	60	15	31 ± 10	66.7	15	30 ± 10	73.3				45	MANOVA of amplitude change	No	± 72	Yes
Sand et al. (28), 2009	Trondheim, Norway	74	1.9/31′	50/200	31	40 ± 11.4	90.3	33	37.4 ± 12.6	90.9	8	37.4 ± 15.5	100				72	ANOVA of three visits’ values averaged	Yes	± 72	No
Coppola et al. (29), 2010	Rome, Italy	166	3.1/15′	100/600	18	27.1 ± 7.7	66.7	18	30.5 ± 9.5	61.1							36	Linear regression slope of amplitude and last to first block proportion differences	No	± 72	Yes
Coppola et al. (30), 2010	Rome, Italy	166	3.1/15′	100/600	19	26.2 ± 3.5	52.6	12	28.1 ± 5.8	66.7							31	Linear regression slope of amplitude and last to first block proportion differences	No	± 72	Yes
Coppola et al. (13), 2011	Liège, Belgium	94	3.1/15′	100/600	17	28.8 ± 11.4	82.4	17	28.9 ± 12.1	82.4							34	Linear regression slope of amplitude	No	± 72	Yes
Hansen et al. (31), 2011	Copenhagen, Denmark	100	3.1/8′	100/600	6	29 (28–31)	57.1				9	38 (20–63)	55.6				15	Linear regression slope of amplitude	Yes	“Headache free”	No
Omland et al. (32), 2013	Trondheim, Norway	74	3/8′	100/600	34	30.9 ± 10.4	85.3							27	27.6 ± 8.4	88.9	61	Least squares slope of amplitude changes	Yes	± 48	No
Coppola et al. (33), 2013	Rome, Italy	166	3.1/15′	100/600	21	28.1 ± 7.6	76.2	17	27.3 ± 6.5	81	19	30.8 ± 9.7	86.4				57	Repeated measures ANOVA of amplitude	Yes	± 72	Yes
Vigano et al. (34), 2013	Liège, Belgium	94	3.1/57′	100/600	11	25.8 ± 5.7	54.5	13	29.3 ± 5.1	84.6							24	Linear regression slope of amplitude	No	± 72	No
Bednár et al. (35), 2014	Hradec Králové, Czech Republic	88	2/13′	60/300	36	37 ± 12.7	75							19	37 ± 10.9	68,4	55	Linear regression slope of amplitude	Yes	± 72	Yes
Ambrosini et al. (36), 2015	Pozzilli, Italy	166	3.1/68′	100/600	15	30 ± 7.9	53.3	13	32.8 ± 10.2	53.85							28	Linear regression slope of amplitude	Yes	± 72	Yes
Rauschel et al. (37), 2015	Munich, Germany	102	3/51′	75/450	40	28 ± 8	87.5	38			3				30 ± 10	92.7	81	Linear regression slope of amplitude	No	± 48	Yes
Omland et al. (5) 2015	Trondheim, Norway	74	3/16′	100/600	30	37.8 ± 11,2	83.3	24			17				38.5 ± 9.6	87.8	71	Least squares slope of amplitude changes	Yes	± 48	No
Coppola et al. (38), 2015	Rome, Italy	166	3,1/15′	100/600	30	33,4 ± 13,4	60				47	31,8 ± 9,3	68,1				77	repeated measures ANOVA of amplitude	yes	± 72	yes
Lisicki et al. (39), 2016	Córdoba, Argentina	194	3.1	100/600	15	25.27 ± 3.43	60	30	26.87 ± 6.99		80						45	Least square of amplitude ratios	No	± 72	Yes
Di Lorenzo et al. (40), 2016	Rome, Italy	166	3.1/15′	100/600	18	38.8 ± 9.3	88.9	14			4				38.8 ± 9.3	88.9	36	Linear regression slope of amplitude	Yes	± 72	Yes

Figure 1.

Cumulative number of participants in VEP habituation in migraine studies, grouped by location and main outcome (yellow: preserved habituation, red: deficient habituation), over a color-coded averaged solar radiation map (detail of the original by Michel Albuisson, Mireille Lefèvre, Lucien Wald. Edited; produced by Thierry Ranchin. Centre for Energy and Processes, Ecole des Mines de Paris/Armines/CNRS. 2006.)

A logistic regression was performed to determine the effects of local sunlight irradiance, participants’ age, and experimental conditions on the probability that studies would report a deficit of habituation in EM. The resulting logistic regression model was statistically significant, (χ²(6) = 13.224, p = 0.040), and correctly classified 84.6% of studies. When sunlight irradiance was removed, the model built upon the remaining variables turned not significant (χ²(5) = 4.170, p = 0.53).

Correlations between mean sunlight irradiance and last to first block proportional amplitude differed between EM subgroups: It was positive for migraine without aura (ρ = 0.534, p < 0.001) and negative for migraine with aura (ρ = −0.813, p < 0.001). Correlations remained significant after correcting for spatial and temporal frequencies of stimulation, total number of epochs and mean age of the participants. Interestingly, there was no significant correlation between mean sunlight irradiance and last to first block proportional amplitude difference in HV (ρ = .020, p = 0.74). Overall, there was also no correlation between VEP initial (first block) amplitude and mean sunlight irradiance in any of the groups after controlling for possible confounding parameters (Figure 2).

Figure 2.

Bubble plot of last to first block proportional amplitude modifications in relation with mean yearly solar irradiance in migraine without aura and migraine not otherwise specified cohorts (n = 282). The surface of each bubble is proportional to the number of patients. The dashed black line represents the linear regression.

Discussion

Based on the results of this retrospective analysis of VEP studies comparing interictal EM to HV populations, we hypothesize that sunlight irradiance could partly influence the habituation phenomenon and provide an additional explanation for discrepancies between studies, aside from genetics and methodological issues. Indeed, we found that mean yearly sunlight irradiance in situ was significantly higher in locations of studies that reported a deficit of habituation in migraineurs in the interictal period. Furthermore, correlation analyses suggest that VEP habituation decreases with increasing yearly sunlight irradiance in migraine without aura patients.

Even if this study is, by definition, rather hypothesis generating, we will briefly discuss the possible mechanisms by which sunlight could influence VEP habituation. Sunlight irradiance can modify brain physiology through variations in neurotransmitter concentrations (41), growth factor expression (42) and vitamin D availability (43). In particular, seasonal variations in daylight strongly influence the brain’s serotoninergic system, which may predispose to seasonal depression. Reduced global light radiation, as occurs during the winter, decreases serotonin production (41) and post-synaptic serotonin-1 A receptor binding (44), while increasing serotonin transporter binding (45). For a long time, serotonin has been thought to play a crucial role in migraine pathophysiology, and interictal episodic migraine has even been considered as a low serotonin disorder (46). It has been hypothesized that the interictal habituation deficit in migraine patients may be related to reduced serotonergic neurotransmission (47), which is partly supported by the finding that serotonin reuptake blockers increase VEP habituation in migraine patients (24) and that during the crisis, while brain serotonin synthesis increases (48), VEP habituation normalizes (15). Thus, one would expect that a more pronounced habituation would be reported in studies coming from areas with higher yearly sunlight irradiance. As this only seems to be the case for migraine with aura patients, where last to first block VEP proportional amplitude was inversely correlated to sunlight irradiance, our findings can probably not be explained by a light-dependent effect on serotoninergic pathways in the brain of episodic migraineurs. This is in line with the findings of Sand et al., who described VEP amplitude habituation correlating strongly with serotonin levels (in platelet-rich plasma) only in migraineurs with aura during the attack, but not in migraine without aura patients (49), as well as with Evers et al., who found no relation between habituation and serotonin levels (plasmatic) in a small cohort composed of 80% migraineurs without aura (50).

On the other hand, experimental evidence suggests that migraine patients are hypersensitive to light in both the image-forming (6) and the intrinsic photosensitive retinal ganglion pathways (11,51,52). The role of the latter is not limited to pain exacerbation and photophobia, as selective stimulation of this pathway has been shown to modify electroencephalographic activity (53) and task performance (54) in healthy volunteers, effects probably mediated by activation of the thalamus and the anterior insula. From an electrophysiological point of view, a plausible explanation for the habituation deficit in migraine patients is a decreased pre-activation level of the visual cortex that allows the brain response to increase in amplitude for a longer time before reaching the “ceiling” (i.e. the time point where habituation starts) during repetitive stimulation (55). This range of cortical activation depends on the interplay between excitatory and inhibitory mechanisms (33). Based on the results of this study, we propose that sunlight exposure could modify this balance in the long term through cortical metaplastic changes. Specifically, high sunlight irradiance might enhance cortical inhibition as a protective mechanism, leading to a decreased level of pre-activation and subsequently an impaired habituation. This notion is supported by the findings of Coppola et al., who found an increased degree of lateral inhibition in the visual cortex that progressively diminished with successive stimulation in migraine patients (33).

Our review has several shortcomings. Although 11 centers from nine different countries were represented, most VEP habituation studies were performed in three main European centers, located in Norway, Italy and Belgium. However, if these three countries were excluded from the analysis, the difference in mean sunlight irradiance between the five remaining study sites where deficient habituation has been reported (mean 152.8 W/m², n = 348) and the two remaining studies where preserved habituation was described (mean 96 W/m², n = 69) is even greater. Unfortunately, we found no study from Africa, North America, or Oceania matching the inclusion criteria. Another issue to consider is that the investigations might have been conducted rather seasonally but, since the period during which the recordings took place was not reported in most studies, this level of precision could not be achieved. A similar situation occurred with migraine frequency. Even if all migraine cohorts here compared consisted of episodic migraine patients (and thus had a headache frequency below 15 days/month with less than eight migraine attacks) (14), it is possible that correcting for the exact headache frequency could have increased the rigor of our assessments (56). Moreover, recordings from a small number of pre-ictal migraineurs may have been included, since they were not actively excluded in four studies. Finally, even if it has been shown to not affect the final outcome (8). a blinded assessment for migraine electrophysiological studies has been previously recommended (5). In sum, although we aimed to minimize the effect of methodological differences, our results would need to be corroborated through a prospective study of VEP using the same experimental protocol in various locations with different sunlight irradiance before categorical conclusions can be drawn.

In conclusion, this retrospective study suggests that variations in sunlight irradiance may induce adaptive modifications in visual processing that are reflected in VEP habituation studies, which could in part account for the different results found in geographically distant centers. Increased sunlight irradiance apparently reduces the habituation capability in migraine without aura patients. Other causal factors such as genetic differences could certainly play a role, and thus well-designed prospective trials are warranted.

Clinical implications

Solar irradiance could induce adaptive modifications in the visual system of migraine patients, influencing the outcome of VEP habituation studies.

Environmentally-induced adaptive modifications should be considered when contrasting the results from studies performed in geographically distant centers.

Footnotes

Acknowledgements

We wish to thank Michel Albuisson, Mireille Lefèvre and specially Lucien Wald for their permission for the use of the solar radiation map in .

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the European Union (Euroheadpain – FP7 grant 602633).

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Sunlight irradiance and habituation of visual evoked potentials in migraine: The environment makes its mark

Abstract

Background

Methods

Results

Conclusion

Keywords

Background

Methods

Results

Discussion

Clinical implications

Footnotes

Acknowledgements

Declaration of conflicting interests

Funding

References