Effects of Pattern-Reversal Visual Stimulation on Brain Activity in Migraineurs and General Population

Abstract

Background

A better understanding of migraine pathophysiology through standardized methods could facilitate the development of more effective therapeutic approaches for migraine sufferers. However, neurophysiological studies with migraine sufferers present larger variability, as most contain only a single measurement.

Objective

This observational study aimed to compare the cortical and visual excitability of migraine sufferers, individuals with other types of headaches, and healthy participants in response to pattern-reversal visual stimulation.

Methods

Fifty-nine individuals were classified by a neurologist into the following groups: (i) migraineurs (n = 25); (ii) other types of headaches (n = 23); (iii) healthy (n = 11). Habituation during pattern-reversal visual stimulation was assessed by visual evoked potentials. Visual and motor cortex excitability were evaluated before and after pattern-reversal visual stimulation.

Results

We found no intergroup differences in motor and visual excitability measures after pattern-reversal visual stimulation. Compared to the healthy group, migraineurs and individuals with other types of headaches displayed a reduction in phosphene threshold after pattern-reversal visual stimulation. Additionally, an increase in visual cortical excitability in these groups was also observed. Lastly, the habituation in individuals with migraines and other types of headaches was lower compared to healthy individuals. Therefore, the lack of habituation may not be exclusively associated with the pathophysiological mechanisms of migraine.

Conclusion

Individuals who experience headaches, including migraineurs, have an increased visual cortical excitability in response to visual stimuli. This finding is promising for guiding future neurophysiological research to identify cortical biomarkers in migraineurs and in other types of headaches.

Keywords

transcranial magnetic stimulation noninvasive brain stimulation migraine disorders headache

Introduction

The pathophysiology of migraine has been investigated in numerous studies, however, the underlying mechanisms are not fully elucidated (Brigo et al., 2013; Dodick et al., 2018). In fact, research has shown that sensory information processing in the nervous system of migraineurs is abnormal in all sensory modalities (excluding the olfactory) (Coppola & Magis, 2021). This dysfunction can be related to maladaptive neuroplasticity, including motor cortex disinhibition, due to a disruption in GABA-mediated intracortical inhibition (Parker et al., 2016).

Habituation, which is referred to as a progressive decrease of cortical response amplitude to repetitive stimuli, can be evaluated through different measures such as auditory, somatosensorial, and visual evoked potentials (VEPs) (Ambrosini et al., 2016; Coppola et al., 2015; Zhu et al., 2019). The lack of habituation has been considered a possible biological marker of migraine (Brighina et al., 2009; Coppola et al., 2009). Among the methods of evoking visual potentials, a commonly used one is the pattern-reversal visual stimulation, which has the advantage of greater precision in individual responses consequently providing more accurate and dynamic data (Moreira Filho & Dantas, 1994).

In migraineurs during the interictal phase, there is an increased infra-slow oscillatory power in the visual regions and furthermore, these visual regions displayed significantly increased coupling with auditory, gustatory, somatosensory, multisensory, and motor cortical regions, suggesting altered global processing of sensory information. These changes could explain the altered visual, auditory, gustatory, and somatosensory processing observed in migraineurs (Meylakh & Henderson, 2022). Indeed, the light deprivation could reverberate in altered motor cortex activity in individuals with migraine, when compared with healthy individuals (Conforto et al., 2012).

Previous studies have suggested that the motor and visual cortices are involved in individuals with migraine and may have central nervous system alterations such as an increase in visual cortex excitability (Aurora et al., 1998; Brigo et al., 2013; Gunaydin et al., 2006), enhanced motor cortical excitability, dysfunctions of inhibitory circuits in the visual cortex (Chadaide et al., 2007), and impaired/lack of habituation in response to repeated stimuli (Coppola et al., 2009; Kalita et al., 2014). Therefore, the investigation of both visual and motor cortex dysfunctions in migraineurs by electrophysiological methods could guide the elaboration of more effective therapeutic protocols (Brighina et al., 2010; Khedr et al., 2006; Maertens de Noordhout et al., 1992; Rocha et al., 2015; Viganò et al., 2013).

However, inconsistent results for both motor and visual excitability measurements have been reported (Antal et al., 2006; Conforto et al., 2012), especially when assessed only at a single time-point. Migraine is characterized as a disorder of brain sensory processing that is influenced by genetic and environmental factors (Goadsby et al., 2017). The underlying mechanisms of its pathophysiology could be hidden by confounding factors, such as the type of migraine (chronic or episodic), presence of aura, ictal or interictal situation (Cortese et al., 2017), and others (Gomez-Pilar et al., 2020); (Bjørk et al., 2011; Mykland et al., 2018). For all of these aspects, it can be assumed that single-time point measurements may not reliably reflect individuals’ neuronal activity (Ambrosini et al., 2017). Instead, it may be more informative to compare the neuronal activity at rest versus during a task, or being presented stimuli, in order to better understand the maladaptive brain function in migraine patients (Hyder & Rothman, 2011).

Thus, the present study aimed to evaluate the motor and visual cortical excitability of migraineurs prior to, and following, pattern-reversal visual stimulation in comparison to healthy individuals and those with other types of headaches (OHG). It was hypothesized that the cortical excitability of the motor and visual cortex after pattern-reversal visual stimulation in migraineurs would be different from those of healthy individuals and with OHG.

Methods

This observational study was approved by the local Ethics and Research Committee and registered at www.clinicalTrials.gov. All participants gave written consent prior to participation and the experiment was conducted according to the Declaration of Helsinki.

Participants

Subjects were recruited from the general population via advertisement. Those between 18–53 years old, who presented at least one episode of headache in the last 12 months were included in the study. Exclusion criteria included: individuals with any contraindication to the application of transcranial magnetic stimulation (TMS) (S. Rossi et al., 2021), the presence of musculoskeletal, neurological and/or psychiatric disorders, and intake of any antidepressant or anxiolytic medication.

Screening and Diagnostic Assessment

Volunteers were screened through a semi-structured questionnaire administered through Typeform (www.typeform.com) before the neurological assessment. This contained questions regarding demographic (age and sex), behavioral (stress and depression level), and headache information (presence of aura, impact on daily life activities and disability related to headache). Additionally, participants were also asked about their handedness (Edinburgh Lateral Dominance Inventory (Oldfield, 1971)), their anxiety and depression (Beck Anxiety Inventory (Beck et al., 1988)); the impact of headaches on daily activities (Headache Impact Test (HIT-6) (Yang et al., 2011)) and whether they had any disabilities related to headache (Migraine Disability Scale (MIDAS) (Fragoso, 2002)). Those who met the criteria were asked to complete a headache diary for two months leading up to the experiment.

After the pre-screening, a board-certified neurologist diagnosed the subjects as: healthy (HG), migraineurs (MG) or with other headache types (OHG), such as tension-type and menstrual migraineur, in accordance with the criteria of the ICHD-III. To avoid memory bias and assist with the neurological assessment, each volunteer completed a headache diary for at least two months prior to meeting with the neurologist. To maintain blinding, the principal experimenter responsible for the data collection did not have access to the diagnoses until the end of the entire experiment.

Electrophysiological Assessments

All assessments were performed in the interictal period, at least 72 h before and/or after a headache attack. We asked about the occurrence of headache attacks by cell phone before scheduling the assessment. To avoid confounding bias, all women were evaluated up to seven days after the first day of menstruation, as the menstrual cycle can alter cortical excitability (Vasil’eva, 2005).

The phosphene threshold (PT) was obtained by single-pulse TMS, using a circular coil (10 cm in diameter; peak magnetic field 2.2 Tesla) connected to a transcranial magnetic stimulator (Neuro-MS Neurosoft, Russia). The coil was positioned over the occipital region with the handle pointing upwards. Single biphasic pulses were applied and participants were instructed to report the presence or absence of phosphenes (i.e., scintillating phenomena in the visual field) (Aurora et al., 1998). After determining the ideal position for phosphene induction (2, 3 or 4 cm above the inion), the stimulation was initially applied at 60% of the maximum stimulator output with a repeated frequency of 0.25 Hz. If the subject consistently reported a phosphene five or more times out of ten, the intensity was dropped in 5% increments and stimulation was administered 10 times again. The intensity of the stimulation was gradually lowered by 1–2% until the participant could no longer consistently perceive phosphenes, and was deemed as the PT (Stewart et al., 2001). In general, when PT is higher it means that the visual cortex is less excitable. In order to avoid changes in cortical excitability due to prolonged sensory deprivation (Boroojerdi et al., 2001), participants for which PT intensity could not be determined within 15 min were excluded from the study (Rocha et al., 2015). A total of 11 volunteers were excluded from this analysis.

To measure the resting motor threshold (RMT), a figure-of-8-coil (diameter 100 mm, peak magnetic field 2.2 Tesla) connected to a transcranial magnetic stimulator (Neuro-MS -Neurosoft,Russia) was initially positioned at 45° over the motor cortex (C3, according to the International 10–20 system). Surface electromyography was recorded from the first dorsal interosseous muscle (FDI) by Ag-AgCl electrodes in a belly-tendon montage. The hotspot (optimal stimulation position) was defined as the site where TMS pulses applied consistently resulted in the largest peak-to-peak MEP amplitudes of the right FDI (Pellicciari et al., 2013). After determining the hotspot, RMT was acquired using the Motor Threshold Assessment Tool software, version 2.0 (http://www.clinicalresearcher.org/software) (Groppa et al., 2012). Higher values of RMT reflect lower excitability of the motor cortex. For MEPs, the intensity of the magnetic stimulator was adjusted to 120% of the RMT, and electromyographic responses resulting from the application of 10 monophasic stimuli of single-pulse TMS were recorded at a frequency of 0.25 Hz while the participant was fully relaxed (Filipović et al., 2010). Higher values of MEP reflect higher motor cortex excitability.

The reversal-pattern visual stimulation consisted of a black and white checkerboard (3.1 reversal per second, 600 sweeps lasting ∼300 ms) (Viganò et al., 2013). The participants’ left eye was blindfolded while the right eye focused on a red point centered on the screen. The visual stimulus was a checkerboard pattern of black and white squares (1.0 cycle per degree, 80% contrast, mean luminance 250 cd/m2, color temperature 9500 K). To assess habituation, VEPs were recorded using AgCl electrodes positioned over Oz and referenced to Fz, according to the International 10–20 system (Klem et al., 1999). The ground electrode was placed on the right collarbone and impedance was maintained below 10 KΩ. The impedance was checked prior to beginning and was monitored throughout the data collection (Neuron-Spectrum.NETomega). Reference electrodes, A1 and A2, were placed on the mastoid process bilaterally and the ground electrode was positioned on the right clavicle. The data were processed and analyzed through Neuron-Spectrum.NETomega. A high pass filter at 0.5 Hz, a low pass filter at 100 Hz and a notch filter at 60 Hz was used to remove the low frequency component of the signal.

Experimental Procedures

Following the screening and diagnostic assessment, participants were invited to participate in the study. First, motor cortex excitability measures (RMT and MEP) of the left hemisphere were recorded while the participant sat in a comfortable, upright chair (lower and upper limb support) with their hand muscles relaxed. Next, to determine PT, participants were moved to a massage chair in the same room while they were blindfolded with their eyes closed. Once baseline measurements (MEPs, RMT, PT) were collected, subjects were placed in a different quiet and dark room to record visual cortex habituation.

They sat in a comfortable chair 90 cm from the computer screen which was measured in reference to the distance from their right eye. The participants’ wore an eye-patch on the left eye while the right eye was fixated on a red dot centered on the screen. Once habituation was assessed, post-stimulation measurements were recorded (MEPs, RMT, PT). In order to avoid performance bias, the same evaluator performed all pattern-reversal visual stimulation measurements, while a different evaluator performed both pre- and post-stimulation assessments. Figure 1 shows the experimental procedure.

Figure 1.

Study design. The volunteer underwent an evaluation of brain electrical activity in response to pattern-reversal visual stimuli. Subsequently, they were subjected to a diagnostic evaluation and allocated to the migraine, other r headache, or healthy group.

Data Processing and Analysis

Initially, a descriptive analysis was carried out to characterize the sample. Data distribution was verified through the Kolmogorov-Smirnov test. PT, RMT, and MEP values before and after pattern-reversal visual stimulation were compared between the three groups (i) MG; (ii) OHG and (iii) HG using Kruskal-Wallis and ANOVA one-way tests. First, individual peak-to-peak MEP amplitudes were visually inspected to exclude trials with muscular activation prior to the TMS pulse. Subsequently, the remaining MEP amplitudes (mV) were averaged and used for further analysis. Post-stimulation data were normalized to pre-stimulation and also used for the main analysis.

For the VEP analysis, of the 600 recorded sweeps, the first 100 (B1) and last 100 (B6) responses were analyzed individually. First, a 1 Hz high-pass filter and a 50 Hz low pass filter were applied. Second, each wave was analyzed individually, and according to their latencies. N1 was defined as the most negative peak amplitude with a latency between 60–90 ms after the visual stimulus; P1 as the most positive peak amplitude with a latency between 80–130 ms after the visual stimulus, and N2 as the most negative peak amplitude with latency between 90–200 ms after the visual stimulus (Viganò et al., 2013). All other data points were discarded from the analysis. Third, the mean values of the differences between N1-P1 and P1-N2 in B1 and B6 were calculated and were normalized to the mean of B1. Finally, habituation was computed as the percentage change of N1-P1 between the B6 and B1, as described by Ambrosini et al. (2016).

Negative results were considered in the analyses as habituation, while positive ones were considered potentiation (Ambrosini et al., 2003; Coppola et al., 2007). A supplementary control analysis was performed dividing individuals who habituated from those who did not within each group. Thus, the three groups were divided into: migraineurs who habituated (MG-H); migraineurs who did not habituate (MG-NH); individuals with other types of headaches who habituated (OHG-H); individuals with other types of headaches who did not habituate (OHG-NH); healthy individuals who habituated (HG-H); and healthy individuals who did not habituate (HG-NH).

The VEP data were processed using Matlab R2014a with the Brainstorm toolbox (Tadel et al., 2011). A one-way ANOVA (with post-hoc LSD) or the Kruskal-Wallis test (with post-hoc Mann-Whitney test) were used to compare means among groups. The paired t-test and the Wilcoxon test were used for intragroup comparisons. Categorical data were analyzed using Fisher's exact test or chi-square. For the PT, MT, MEP and VEP statistical analyses, we opted to use non-parametric statistical tests for the analyses due to a non-normal distribution.

Sample size was calculated based on the PT measurement from a pilot study with fifteen volunteers, considering a significance level of 0.05 and a power of 80% (GPower software version 3.1.3 for Windows). The calculation suggested that a sample of 13 volunteers per group would be necessary for comparison. SPSS version 20.0 was used for all statistical analyses, with a significance level set to p ≤ 0.05.

Results

Of the 202 individuals that expressed interest in participating, 93 were screened. Of those, 26 were excluded prior to the diagnosis assessment and another three dropped out due to side-effects from the TMS stimulation (one suffered with a severe headache during PT assessment, one felt dizziness and vertigo during cortical excitability assessment, another experienced uncomfortable muscle contractions in the upper limbs and face). Moreover, four participants did not complete the headache diary and one completed the headache diary but did not come for the assessments. In total, 59 individuals were analyzed and grouped as follows: (i) migraine (n = 25); (ii) other headaches (n = 23); (iii) healthy (n = 11). Figure 2 shows the Flow diagram of the study. The data from two migraineurs (one for MEP and another one for VEP) were excluded due to a technical problem during data acquisition. The final analysis showed no group differences concerning sample characteristics, except for habitual sleep hours (Table 1).

Table 1.

Sample Characteristics.

	MG (n = 25)	OHG (n = 23)	HG (n = 11)	p-value
Gender, n (%)
Female	20 (80)	17 (73.9)	6 (54.5)	0.283¹
Age (years), mean (SD)	23.8 (3.5)	25.5 (6.6)	24.4 (5.1)	0.452²
CP (cm), mean (SD)	56.3 (3.1)	55 (2.3)	56 (1.8)	0.180³
Sleep hours in the last 24hs, median (IQR)	6 (5.5–7.5)	7 (6–8)	6 (6–7)	0.689²
Habitual sleep hours, median (IQR)	7 (6–8)	6 (5–7)	7 (6–8)	0.009²
Dominance, n (%)
Right handed	21 (84)	19 (82.6)	8 (72.7)	0.712^a
Left handed	4 (16)	4 (17.4)	3 (27.3)
Depression level, n (%)
Minimal	23 (92)	18 (78.3)	11 (100)	0.400^a
Mild	1 (4)	3 (13)	-
Moderate	1 (4)	2 (8.7)	-
Anxiety level, n (%)
Minimal	19 (76)	16 (69.6)	10 (90.9)	0.317^a
Mild	5 (20)	4 (17.4)	1 (9.1)
Moderate	-	3 (13)	-
Severe	1 (4)	-	-
Pain intensity, median (IQR)	5 (4–7)	5 (4–8)	-	0.631^d
Frequency of crisis, mean (SD)	4.46 (3.5)	4.40 (2.7)	-	0.632^d
Aura, n (%)
Yes	9 (36)	4 (17.4)	-	0.200^e
Phosphenes perception, n (%)
No	5 (20)	3 (13.6)	3 (23.1)	0.754^a
HIT classification, n (%)
No or little impact	3 (12)	6 (26.1)	-	0.464^a
Some impact	3 (12)	4 (17.4)	-
Substantial impact	4 (16)	4 (17.4)	-
Severe impact	15 (60)	9 (39.1)	-
MIDAS classification, n (%)
Little or no disability	7 (28)	11 (47.8)	-	0.313^a
Mild disability	3 (12)	4 (17.4)	-
Moderate disability	7 (28)	5 (21.7)	-
Severe disability	8 (32)	3 (13)	-

Legend: SD: standard deviation; MG: migraine group; OHG: other type of headache group; HG: healthy group; IQR: interquartile reange; CP: total cephalic perimeter; HIT-6: Headache impact test; MIDAS: Migraine disability scale. a: chi-square test; b: Kruskal-Wallis test; c: ANOVA one-way test; d: Mann-Whitney test; e: Fisher's exact test.

Figure 2.

Flow diagram of the study.

Visual and Cortical Excitability Measurements

No within-group differences were observed in relation to the cortical and visual excitability measures before and after pattern-reversal visual stimulation (Table 2). Following pattern-reversal visual stimulation, the Wilcoxon test revealed a significant reduction in PT in MG (Z = -3.545, p < 0.001) and OHG (Z = 3.608, p < 0.001). However, the Kruskal-Wallis test showed no significant difference when PT values of MG were compared to OHG (p = 0.411) and to HG (p = 0.547), before and after pattern-reversal visual stimulation. For both RMT and MEP, no significant differences were found within and between groups (Table 2).

Table 2.

Visual and Motor Cortex Excitability Measures Before and After Pattern-Reversal Visual Stimulation, or Visual Evoked Potential.

PHOSPHENE THRESHOLD – median (IQR)
Group	Before	After	Intragroup analysis
MG	50.5 (45–64.5)	46.5 (41–58)	p < 0.001 ^a
OHG	57.0 (51–70)	47.0 (44–75)	p < 0.001 ^a
HG	58.0 (42–100)	55.0 (39–100)	p: 0.260^a
Intergroup analysis	p:0.411^b	p:0.547^b
MOTOR THRESHOLD – median (IQR)
Group	Before	After	Intragroup analysis
MG	56.5 (47.5–63)	55.00 (47–61)	p: 0.536^a
OHG	59.5 (46–70)	57.0 (46–64)	p: 0.096^a
HG	56.0 (52–63)	56.0 (52–58)	p: 0.151^a
Intergroup analysis	p:0.919²	p:0.818²
MOTOR EVOKED POTENTIAL – mean (SD)
Group	Before	After	Intragroup analysis
MG	0.628 (0.469)	0.708 (0.642)	p: 0.348^c
OHG	0.687 (0.509)	0.651 (0.570)	p: 0.631^c
HG	0.609 (0.320)	0.782 (0.470)	p: 0.151^c
Intergroup analysis	p:0.867^d	p:0.828^d

Legend: SD: standard deviation; MG: migraine group; OHG: other headache group; HG: healthy group; IQR: interquartile range. a – Wilcoxon test; b: Kruskal-Wallis test; c: paired t test; d: ANOVA-oneway test.

Habituation

It was observed that both MG (X² = 20.617; p < 0.001) and OHG (X² = 19.104; p < 0.001) presented a decrease in habituation, compared with HG. However, between MG and OHG no difference was found (X² = 0.012; p = 1.000) (Figure 3A). The risk of lack of habituation seemed to be 55% higher in those who present headache, irrespective of the type. The risk of non-habituation in migraines was 59%, whereas this dropped to 52% in individuals with other headaches. When we compared the behavioral and clinical characteristics of the individuals who habituated and those who did not in each group, no difference was noted.

Figure 3.

Responses to pattern-reversal visual stimulation across different participant groups. Legend: (A) Habituation occurrence in each group: (*) p < 0,01 for chi-square test; (B) Variation of phosphene threshold before and after pattern-reversal visual stimulation: (#) significant difference in comparison to the baseline (GM-H: Z = -2,521, p = 0,012; GM-NH: Z = -2,670, p = 0,008; GOC-H: Z = -2,320, p = 0,020; GOC-NH: Z = -2,805, p = 0,005 for Wilcoxon test); (C) Variation of motor evoked potential before and after pattern-reversal visual stimulation: there was no significant intergroup difference. (B and C) Data are presented as mean and standard deviation in each subgroup. The detailed data regarding the phosphene threshold before and after stimulation are presented in the Supplementary Table 1. H – habituated; HG – healthy group; MEP – motor evoked potential; MG – migraine group; mV – millivolt; NH – not habituated; OHG – other type of headache group; PT – phosphene threshold.

With respect to clinical characteristics and electrophysiological measurements, no difference was found between the subgroups. MEP and PT measurements in each subgroup are detailed in Figures 3B and 3C. However, the Wilcoxon test revealed a significant decrease in PT after pattern-reversal visual stimulation for MG-H (Z = -2.521, p = 0.012), MG-NH (Z = -2.670, p = 0.008), OHG-H (Z = -2.320, p = 0.020) and OHG-NH (Z = -2.805, p = 0.005); details are shown in Supplementary Table 1.

Discussion

This study investigated the pattern of cortical and visual activity of migraineurs prior to, and following, pattern-reversal visual stimulation in comparison with healthy individuals and those with other types of headaches. Migraineurs and individuals with other types of headaches showed a reduction in PT after pattern-reversal visual stimulation in comparison to the healthy group. We observed that even milder stimuli could potentially induce a change in visual cortex excitability in individuals with migraine or other types of headaches. However, since this is not only seen in migraineurs, it can be inferred that a change in visual excitability is not specific to the pathophysiological mechanisms of migraine.

With respect to motor cortex excitability, healthy individuals, migraineurs and those with other types of headaches did not have altered motor cortex excitability in response to pattern-reversal visual stimulation. Despite generating a change in visual cortex excitability, it is possible that the applied stimulation was not intense enough to provoke any changes at the motor cortex level. Similar results were reported in a study with fMRI in migraineurs. The visual stimuli presented in the experiment could modify visual cortex activation, but not motor cortex activity. It might be possible that the visual stimulation in the current study was not an ideal paradigm to achieve the anomalous activation in sensorimotor areas, as it was not specific enough to activate the motor cortex like a motor-related task could, as shown in other studies (Conforto et al., 2017).

While other studies have noticed hyperexcitability of the visual cortex in migraineurs as compared to non-migraineurs (Aurora et al., 1998; Battelli et al., 2002; Brigo et al., 2013; Gerwig et al., 2005; Gunaydin et al., 2006; Rocha et al., 2015), this was not seen in the present study. One possible explanation could be the manner in which we analyzed the data of individuals who did not report phosphenes. In such cases, the PT value was considered as 100% of the stimulation output, thus provoking an increase in the standard deviation, and a decrease in statistical inference, which could justify the lack of between-group differences (Bohotin et al., 2003).

It has been pointed out that there is an absence of studies aiming to confirm the lack of habituation in migraineurs (Omland et al., 2016). Therefore, we decided to perform a subgroup analysis considering the individuals that habituated and those that did not habituate within each group. Notably, when looking at visual cortex responses assessed by PT, we found an increase in visual excitability following pattern-reversal visual stimulation in MG-H, MG-NH, OHG-H, OHG-NH. It can then be inferred that the activation of the visual cortex, whether the stimulus was inhibitory or excitatory, generated a post-stimulation increase in the visual excitability of individuals with headaches. However, during pattern-reversal visual stimulation assessed via VEPs, the excitability of the visual cortex was altered more or less equally in both groups (i.e., those that habituated vs. those who did not). While it was previously reported that there was a lower habituation occurrence in migraineurs (Kalita et al., 2014; Lisicki et al., 2018; Magis et al., 2013), we observed this same phenomenon in both the MG and OHG. This finding suggests that lack of habituation may be associated with headaches in general, rather than a “biological marker” (Brighina et al., 2009; Coppola et al., 2009) solely linked to the pathophysiological mechanisms of migraine [(Brighina et al., 2015; Omland et al., 2016).

Our results are also in line with clinical studies using non-invasive brain stimulation (NIBS) applied over the visual cortex. In these studies, a significant increase in visual excitability assessed by PT was seen after both excitatory and inhibitory (Brighina et al., 2002; Chadaide et al., 2007; Rocha et al., 2015) non-invasive brain stimulation. It is likely that an inhibitory circuit deficit may be the root for this increase in excitability, even after inhibitory stimulation (Brighina et al., 2002; Chadaide et al., 2007). It has been suggested that the increased or lack of change in visual excitability after inhibitory stimuli is related to the deficiency of GABA-mediated circuits, which can be expressed as a reduction/lack of inhibition (Antal et al., 2006; Brighina et al., 2002; Kalita et al., 2014; Mulleners et al., 2001). Be that as it may, in individuals with other headaches, the effectiveness of the activation of inhibitory circuits after visual stimuli still requires further elucidation.

Nevertheless, several limitations should be considered. First, it is important to note the small sample size of the HG. It was difficult to find individuals for this group simply because this disease is under-diagnosed and under-treated, leading to an underestimation of its actual prevalence (Leonardi et al., 2005). Despite not having an official diagnosis, many participants were subsequently placed in one of the headache groups following the neurological assessment. Besides this, the majority of the studies do not specify the criteria used to classify healthy individuals, increasing selection bias. Second, we did not control for photophobia. Previous studies suggest that cortical hyperexcitability, lack of habituation, or both could be related to the presence of photophobia (Boulloche et al., 2010; Martín et al., 2011; Rossi & Recober, 2015). However, it remains unclear if the presence or absence of photophobia may be useful to predict the occurrence of habituation in individuals with various types of headaches.

It is also important to evaluate other possible predictive factors for the occurrence of habituation. Variables such as disease characteristics (time since diagnosis, type and frequency of migraine, etc.) and intake of abortive medications may be important aspects to be considered in future studies. Another gap in the literature worth exploring is whether the lack of habituation in healthy individuals is associated with a predisposition to developing headaches or whether it may be indicative of disease management. Moreover, observing responses of the visual and motor cortex through pattern-reversal visual stimulation of different intensities and approaches may guide new research to develop more targeted and effective treatment protocols for migraineurs.

Conclusion

To the best of our knowledge, this is the first study to assess motor and visual excitability of migraineurs prior to, and following, pattern-reversal visual stimulation in comparison to healthy individuals and those with other types of headaches. We have demonstrated that regardless of their diagnosis, individuals who experience headaches are more susceptible to having increased excitability of the visual cortex in response to visual stimuli. This result may guide future neurophysiological research to identify cortical biomarkers in migraineurs or in other types of headaches.

Supplemental Material

sj-pdf-1-rnn-10.1177_09226028241292033 - Supplemental material for Effects of Pattern-Reversal Visual Stimulation on Brain Activity in Migraineurs and General Population

Supplemental material, sj-pdf-1-rnn-10.1177_09226028241292033 for Effects of Pattern-Reversal Visual Stimulation on Brain Activity in Migraineurs and General Population by Lívia Shirahige, Fernanda Nogueira, Lorena Melo, Ruxandra Ungureanu, Sérgio Rocha, Rodrigo Brito, Thyciane Mendonça, Abelardo de Farias, Maria das Graças Rodrigues de Araújo, Daniele Piscitelli and Kátia Monte-Silva in Restorative Neurology and Neuroscience

Footnotes

Acknowledgements

The authors thank Abrahão Fontes Baptista, Andrea Lemos and Erika Rodrigues for the methodological review.

Funding

KMS is supported by CNPq (grant number 308291/2015-8) and LS is supported by FACEPE (grant number IBPG-1548-4.01/16).

Declaration of Conflicting Interests

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

Datasets/Data Availability Statement

The data supporting the findings of this study are available on request from the corresponding author [DP]. The data are not publicly available due to privacy or ethical restrictions.

Supplemental Material

Supplemental material for this article is available online.

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