DR HENNER HANSSEN (Orcid ID : 0000-0001-5501-4205)

Accepted Article
Article type : Original Article

Effects of different endurance exercise modalities on migraine days and

cerebrovascular health in episodic migraineurs: A randomized controlled
trial

Short title: Exercise and microvascular health in migraine

Henner Hanssen1, Alice Minghetti1, Stefano Magon2,3, Anja Rossmeissl1, Maria Rasenack2,
Athina Papadopoulou2,3, Christopher Klenk1, Oliver Faude1, Lukas Zahner1, Till Sprenger2,4,
Lars Donath1

1
Department of Sport, Exercise and Health, University of Basel, Birsstrasse 320B, 4052 Basel,
Switzerland
2
Department of Neurology, University Hospital Basel, Switzerland; Medical Image Analysis Center,
University Hospital Basel, Switzerland
3
Medical Image Analysis Center, University Hospital Basel, Switzerland
4
Department of Neurology, DKD HELIOS Klinik Wiesbaden, Wiesbaden, Germany

Corresponding author

Prof. Dr. med. Henner Hanssen

Department of Sport, Exercise and Health
Birsstrasse 320B
4052 Basel, Switzerland
E-Mail: henner.hanssen@unibas.ch

Tel: +41 61 207 47 46; Fax: +41 61 207 47 45

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/sms.13023
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 Keywords: Migraine, Exercise Training, Retinal Vessel Diameters, Cerebral Circulation
Accepted Article
Abstract (241/250 words)

Background: Aerobic exercise training is a promising complementary treatment option in

migraine and can reduce migraine days and improve retinal microvascular function. Our aim

was to elucidate whether different aerobic exercise programs at high vs. moderate intensities

distinctly affect migraine days as primary outcome and retinal vessel parameters as a

secondary.

Methods: In this randomized controlled trial, migraine days were recorded by a validated

migraine diary in 45 migraineurs of which 36 (female: 28; age: 36 (SD:10)/ BMI: 23.1 (5.3)

completed the training period (dropout: 20%). Participants were assigned (Strata: age, gender,

fitness and migraine symptomatology) to either high intensity interval training (HIT),

moderate continuous training (MCT) or a control group (CON). Intervention groups trained

twice a week over a 12-week intervention period. Static retinal vessel analysis, central retinal

arteriolar (CRAE) and venular (CRVE) diameters as well as the arteriolar-to-venular diameter

ratio (AVR) were obtained for cerebrovascular health assessment. Incremental treadmill

testing yielded maximal and submaximal fitness parameters.

Results: Overall, moderate migraine day reductions were observed (ɳp²=0.12): HIT revealed

89% likely beneficial effects (SMD=1.05) compared to MCT (SMD=0.50) and CON

(SMD=0.59). Very large intervention effects on AVR improvement (ɳp²=0.27), slightly

favoring HIT (SMD=-0.43) over CON (SMD=0) were observed.

Conclusions: HIT seems more effective for migraine day reduction and improvement of

cerebrovascular health compared to MCT. Intermittent exercise programs of higher intensities

may need to be considered as an additional treatment option in migraine patients.

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 Introduction
Accepted Article
Fifteen per cent of the European population suffers from migraine (1). Migraine has a peak

prevalence ranging between 22 to 55 years of age (2) and is considered one of the most

disabling chronic neurological disorders (1). Patients with migraine show diminished life

activities and social participation(3). Depending on chronic (>15 days/month) or episodic

(<15 days/month migraine) migraine courses, the direct annual costs per patient can amount

up to 3800 Euros (4) and lead to notable headache-related absenteeism from workplace (5).

In a recent large scale prospective cohort study with more than 20 years of follow-up,

including more than 17000 women with a physician’s diagnosis of migraine, a consistent link

between migraine and cardiovascular disease events and cardiovascular mortality was made

(6). Recent evidence revealed associations between migraine and adverse peripheral vascular

risk profiles (7). Patients suffering from migraine have been associated with endothelial

dysfunction (8), impaired cerebral and peripheral vascular function as well as an increased

risk for hypercoagulability and inflammation (9). Retinal vessel diameters are valid

microvascular biomarkers for cardiovascular risk. Narrower retinal arteriolar and wider

venular diameters as well as a reduced arteriolar-to-venular ratio (AVR) have been shown to

be associated with increased risk of hypertension, stroke and cardiovascular mortality (10,

11).

The Atherosclerosis Risk in Communities Study (ARIC) suggests that subjects with migraine

are more likely to present a retinopathy indicating a potential role for the development of

neurovascular dysfunction in the pathogenesis of vascular headaches (12). Furthermore, the

Blue Mountain Eye Study associated migraineurs with narrower retinal arteriolar diameters

compared to healthy controls (13). Physical activity and fitness have been proven to affect

retinal vessel diameters (14, 15). A study examining the effects of a 10 week moderate-to-

high intensity exercise training in lean and obese adults observed a direct association between

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 physical fitness and higher retinal AVR (16). The exercise intervention improved AVR in
Accepted Article lean and obese subjects by arterial dilatation and venous constriction. It is known that both

higher levels of physical activity and cardiorespiratory fitness reduce all-cause mortality and

cardiovascular disease (CVD) mortality and, consequently, moderate endurance exercise is

oftentimes recommended in primary and secondary prevention of CVD (17).

Few studies have investigated the influence of exercise on migraine days and the results seem

controversial (18). Nonetheless, physical activity is being promoted as a method of migraine

management either combined or as an alternative for pharmacological treatment.

Pharmacological first line options have the potential to reduce attack frequency by 50% in

half of the patients but since it can entail side effects and the efficacy remains limited,

alternative non-pharmacological options should be considered and are often preferred by

patients. The question remains, however, whether and to what extent aerobic exercise results

in pain reduction and which exercise modality is most efficient in reducing migraine days and

cardiovascular risk.

To the best of our knowledge, no randomized controlled trial has investigated the effects of

different aerobic exercise modalities on migraine days. The present study aimed to investigate

the effects of high intensity interval training (HIT) compared to moderate continuous training

(MCT) on migraine frequency in patients with episodic migraine (primary outcome). In

addition to this, we intended to investigate the impact of different exercise modalities on

retinal vessel adaptations as a microvascular biomarker for cerebrovascular health (secondary

outcome). The knowledge of retinal vessel diameter changes in response to exercise may help

to better understand the underlying adaptations of the cerebral microcirculation.

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 Methods
Accepted Article
Study design and participants

The present study was designed as a three-armed randomized controlled clinical trial (RCT).

In order to determine a clinical baseline for disease severity, patients underwent a four-week

run-in period prior to the start of the intervention period. After the run-in and pre-testing

period, 45 patients were randomly assigned (minimization method, (19) strata: age, gender,

BMI, physical activity, migraine days, physical fitness using the VO2max) in a 1:1:1 fashion to

one of three groups: high intensity interval training group (HIT), moderate continuous aerobic

training group (MCT) or control group (CON). Baseline parameters are depicted in Table 1.

Random allocation was conducted by the principal investigator and participants were enrolled

and assigned to the interventions groups by research assistants. The intervention groups MCT

and HIT trained for 12 weeks twice a week. CON were requested to maintain their habitual

daily physical activity profile. In addition, they received standard physical activity

recommendations. During the 12 weeks, two patients in the HIT group, four in the MCT and

three in the control group dropped out due to non-intervention-related injury, lack of

motivation or personal reasons (Figure 1). Before and after twelve weeks of training,

cardiopulmonary exercise testing and retinal vessel analysis were conducted. Post intervention

assessment was performed in an identical manner as the pre-measurement procedure. After

assignment to an intervention, the assessors were blinded for the intervention. Anonymous

study codes were used and raw data did not give information about group allocation. During

the course of the entire study, patients were asked to keep a migraine and physical activity

diary documenting the frequency and side effects of the attacks as well as their physical

activity profiles. The study was registered in the German clinical trial register (DRKS-ID:

DRKS00008015; https://www.drks.de/) and has been approved by the regional ethics

committee (Ethical approval number: 194/13). We assumed medium to large aerobic exercise-

induced effect sizes for the main primary outcome migraine frequency. Thus, a sample size of
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 38 patients has been estimated. Thereby, a significant effect (p<0.05) can be detected with a
Accepted Article statistical power of 90%. Considering a reasonable dropout rate of 15-20%, at least 45

patients had to be recruited. All subjects signed an informed written consent after receiving all

relevant study information. The first patient was included in May 2014 and the trail ended in

April 2017. Recruitment occurred 4-6 weeks prior to the intervention since a migraine diary

had to be kept for four weeks pre-intervention. All patients were screened within 10 days after

the intervention. All examinations were performed at the University of Basel, Switzerland.

Patients were recruited from the outpatient division of the Department of Neurology at the

University Hospital Basel and via advertisements. Following the initial clinical screening,

confirmation of the diagnosis was given by a neurologist. The neurological examinations were

normal in all patients. This study was funded by the Research Fund of the University of Basel.

Inclusion and exclusion criteria

Inclusion criteria comprising the diagnosis of episodic migraine without aura was confirmed

by an experienced neurologist according to the International Classification of Headache

Disorders, third edition (ICHD-IIIb) (20). Exclusion criteria were (a) current medical

preventive therapy (patients were included if preventive medication was stopped at least 8

weeks prior to study participation), (b) other internal or neurological diseases and (c) regular

exercise experience within the last 6 months. The ability to participate in an intense exercise

program was confirmed using the physical activity readiness questionnaire (PAR-Q) and the

exercise test. Patients with cardiovascular disease or acute or chronic inflammatory disease

were not included in the study.

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 Testing Procedures
Accepted Article Primary outcome: Recording migraine frequency

Prior to training (4-week run-in period) and during the exercise intervention a standardized

paper and pencil migraine diary was kept by all patients (21). The use of acute medication

was also noted. Recorded headaches which lasted longer than four hours and fulfilled the

following criteria were considered migraine attacks: light headache with at least two

accompanying symptoms, moderate pain with at least one other symptom, or severe

headaches with or without accompanying symptoms. The side effects were nausea, vomiting,

phonophobia, photophobia or partial visual impairment. Migraine frequency was reported as

migraine days per month.

Secondary outcome: Static vessel analysis

Retinal vessel diameters were analyzed using the Retinal Vessel Analyzer (SVA-T, Imedos

Systems UG, Jena, Germany). The system enables non-invasive retinal vessel diameter

assessment using a special automated analysis software (Vesselmap 2, Visualis, Imedos

Systems UG) without inducing mydriasis. The central retinal arteriolar (CRAE) and venular

(CRVE) equivalents were calculated and used to define the arteriolar-to-venular diameter

ratio (AVR) as previously described (16, 22). Two images of each eye were captured and the

average of all images was used to calculate the three retinal parameters. Vessel diameters are

presented in micrometres (μm). In the model of Gullstrand’s normal eye, 1 measuring unit

relates to 1 μm. All assessments were performed by a single experienced examiner. Patients

were required to refrain from eating 3 hours prior to vascular testing and from physical

exercise, drinking alcohol or caffeine 12 hours prior to measurements.

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 Maximal exercise testing
Accepted Article Exercise testing was conducted on a treadmill (HP Cosmos Pulsar, H/P/COSMOS Sports &

Medical, Germany) to determine the individual anaerobic lactate-threshold (LT), maximal

heart rate (HRmax) and VO2max. To obtain these data within one test, incremental protocols

were combined with a ramp-like protocol (23). Therefore, patients started at 5 km/h, step

duration lasted 3 minutes with an increment of 1 km/h for each step. Capillary blood samples

for lactate measurements were taken from the earlobe before initiating the exercise test

followed by withdrawals within the 30s breaks between each step and one final one after the

subjects complete the test in exhaustive state. After 5 steps (9 km/h), a ramp-wise increase of

1.0 km/h per minute without lactate withdrawal was applied to assess VO2max(24). Patients

were required to exercise until subjective perceived exertion was reported. They were verbally

encouraged in a standardized manner to ensure objective exhaustion criteria (25). During

exercise testing, breath-by-breath spirometric gas-exchange data (Metamax 3b, Cortex,

Leipzig, Germany), heart rate (HR) (Polar Electro Oy, Kempele, Finland) and ratings of

perceived exertion (RPE) (26) were collected. The maximum of the three highest consecutive

oxygen uptake and heart rate values were regarded as VO2max and HRmax while the individual

anaerobic LT was determined according to Hagberg & Coyle (27), whereby 1,5mmol/l of the

lactate concentration is aggregated to the identified baseline lactate concentration. For the

analyses, the running speed at the LT in kilometer per hour (km/h) was used.

Exercise intervention

Both HIT and MCT were conducted individually under supervision of a sports scientists at the

Department of Sports, Exercise and Health (DSBG) of the University of Basel, Switzerland,

and consisted of an individual running program on a treadmill. A general warm-up of 400m

easy running followed by two skipping exercises and a cool-down period of 400m and

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 stretching exercises were included. MCT was performed by maintaining the calculated target
Accepted Article heart rate of 70% (± 5 beats per minutes, bpm) of HRmax for 45 minutes (28). Exercising 45

minutes at this specific intensity results in similar energy expenditure (EE) as the chosen HIT

program (28). During HIT, the target intensity of 90 to 95% HRmax (± 5 bpm) was generally

reached after 1 minute. Each interval lasted 4 minutes, followed by an active rest period of 3

minutes at 70% of HRmax. The 4-minute intervals were repeated four times (28). HR-monitors

collected heart rate data of each training session. The total training distance was recorded for

each session. In total, 24 training sessions were conducted. It was required to complete at least

20 training sessions (~80% attendance, “per protocol” analysis) during the 12-week training

period. No adverse and serious adverse events were reported.

Statistics

Migraine Attack frequency, maximal and submaximal fitness parameters as well as retinal

vessel diameters are given as means with standard deviations (SD). Normal distribution and

homogeneity of variances were tested prior to the analyses using the Kolmogorov-Smirnov

test and the Levene test, respectively. In order to adjust for between-group baseline

differences in the respective outcome measures (e.g., migraine days per month, physical

fitness and retinal vessel diameters), independent repeated analyses of variances (rANOVA),

including pre-values and age as covariates (29), were conducted. For this purpose, we

computed a 3 (Group: HIT, MCT, CON) x 2 (Time: pre, post) model independently for all

variables. To estimate practical relevance of the rANOVA interaction effect, effect sizes

(partial eta squared, ηp²) were additionally calculated. According to Cohen (30), an ηp² ≥ 0.01

indicates a small, ≥0.06 a medium and ≥0.14 a large effect. In case of group × time

interactions with p < 0.1, Tukey HSD post-hoc tests for uneven group sample sizes were

computed for pairwise comparison. Thereby, standardized mean differences (Cohen’s d,

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 trivial: (SMD) <0.2, small: 0.2≤SMD<0.5, moderate: 0.5≤SMD<0.8, large SMD≥0.8 (31))
Accepted Article were calculated for each pairwise comparison. Additionally, the absolute and percentage

differences as well as the standardized mean differences (Cohen’s d) in the change scores

between HIT, MCT and CON from pre- to post-testing were also calculated together with

90% confidence intervals according to the magnitude-based inference approach (32). These

calculations were adjusted for pre-test values as well. A practically worthwhile change was

assumed when the difference score was at least 0.2 of the between-subject standard deviation

(33). The probability for an effect being practically worthwhile was calculated according to

the magnitude-based inference approach using the following scale: 25–75%, possibly; 75–

95%, likely; 95–99.5%, very likely; >99.5%, most likely (32). The default probabilities for

declaring an effect practically beneficial were <0.5% (most unlikely) for harm and >25%

(possibly) for benefit (33). All calculations were conducted using a published spreadsheet in

Microsoft® excel (34).

Results

Migraine days

The analysis was performed in the number of participants shown in figure 1 and was by

original assigned groups. We found moderate interaction effects on migraine day reduction

(ɳp²=0.12) with more pronounced reductions in favor of HIT (pre: 3.8 (SD: 3.0), post: 1.4

(1.2), SMD=1.05) compared to MCT (pre: 4.5 (2.1), post: 3.2 (3.0), SMD=0.50) and CON

(pre: 3.2 (2.4), post: 2.0 (1.6)) (Table 2). However, CON also showed moderate effect sizes

(SMD: 0.50) for migraine day reduction after the 12-week intervention. Corroboratively, the

magnitude-based interference analysis suggested a 89% likely beneficial reduction of

migraine days for HIT compared to MCT (Table 3). Compared to CON, HIT also revealed a

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 large intervention effect (71% possibly beneficial), whereas MCT merely showed a 21%
Accepted Article unlikely beneficial effect (Table 3).

Retinal vessel diameters

AVR showed a very large group × time interaction effect (ɳp²=0.27) in favor of HIT (HIT:

pre: 0.87 (0.07), post: 0.90 (0.07), SMD=-0.43) compared to MCT (pre: 0.85 (0.06), post:

0.87 (0.07), SMD=-0.31) and CON (pre: 0.87 (0.06), post: 0.87 (0.05), SMD<0.01). The

notable increase of AVR in the HIT group resulted from a dilatation of retinal arterioles

(CRAE pre: 181.8 (18.2), post: 187.2 (20.2), SMD=-0.33; CRVE pre: 210.2 (21.0), post:

208.7 (20.5), SMD=0.39), while the improvement of AVR in MCT was due to venular

constriction (CRAE pre: 197.7 (14.4), post: 198.1 (14.6), SMD=-0.03; CRVE pre: 232.9 (8.4),

post: 229.6 (8.3), SMD=0.40) (Table 2). Magnitude-based interference analysis for AVR

revealed that HIT vs. CON was 96% very likely beneficial, whereas MCT vs. CON was only

63% possibly beneficial to the participants (Table 3). HIT was possibly more beneficial than

MCT (67% probability) with respect to the arterioles (CRAE, Table 3).

Maximal and submaximal physical fitness

2
We observed moderate to large group × time interaction effects (0.12< η p<0.20) for maximal

(VO2max) and submaximal (workload at the LT) physical fitness variables. Pairwise

standardized mean differences revealed moderate effects for HIT (-0.65<SMD<-0.71)

compared to small effects for MCT (-0.26<SMD<0.11) (Table 2). In the magnitude-based

interference analysis, HIT was 99% very likely beneficial for improvement of the submaximal

lactate threshold (LT) compared to MCT while MCT vs. CON depicted 78% possibly

beneficial effects. VO2max values revealed likely beneficial effects in favor of HIT compared

to both CON (91%) and MCT (78%) (Table 3).

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 Discussion
Accepted Article The main goal of the present study was to investigate whether different aerobic exercise

modalities lead to differential effects on migraine days in patients with episodic migraine. In

addition, we aimed at investigating the effects of exercise training on cerebrovascular risk

reduction in these patients. Neither HIT nor MCT revealed any unintended side-effects and

was well tolerated by all migraine patients.

We found that both HIT and MCT can serve as an exercise training therapy for patients

suffering from migraine as they both revealed beneficial effects on migraine days, retinal

vessel diameters and aerobic fitness with more pronounced effects in favor of HIT. Our

results demonstrate that HIT is an efficient treatment strategy in migraineurs as it

considerably reduced migraine days per month. With respect to migraine days, our results are

in line with previous findings of a 10-week moderate continuous exercise intervention (35),

demonstrating positive effects of regular endurance exercise training on migraine day

frequency. Most importantly however, our data suggests that the exercise effects on migraine

days is linked to the applied exercise modality and intensity of the prescribed exercise. Higher

intensities applied in intervals seem to have more favorable effects not only in reducing

migraine days but also on cerebrovascular health in migraineurs.

As mentioned before, migraine is associated with an adverse vascular risk profile (36, 37).

Whether cerebral and meningeal vessel changes are involved in migraine pathophysiology is

strongly debated (38) and some studies suggest that small cerebral vessel changes may

potentially trigger cortical spreading depressions, which in turn is thought to underlie

migraine aura (39, 40). No previous study has described the link between migraine frequency,

physical fitness levels and retinal vessel diameters in migraineurs. The results of our study

reveal that migraine pain and retinal vessel health are linked to exercise and fitness levels and

that the improvements of both parameters depend on exercise modality and intensity. In the

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 HIT group, the considerable increase in AVR was caused mostly by dilatation of arteriolar
Accepted Article diameters. In MCT on the other hand, the slight increase in AVR was mediated by venular

constriction. It may be postulated that higher exercise intensities applied in intervals primarily

affect retinal arteriolar dilatation, whereas continuous moderate intensities may primarily

induce venular constriction in migraineurs. The findings of an exercise-induced retinal

arteriolar dilatation and an increased AVR as well as the concomitant reduction of migraine

days suggest a potential link between cerebral blood flow and migraine days. Since migraine

days improved significantly in HIT, but not in MCT, it may be speculated that a repetitive

higher exercise- intensity threshold needs to be reached to improve migraine

symptomatology. Our data, however, is mainly suggestive and cannot prove such a causal

relationship. Future larger intervention trials will have to investigate this association.

Improvements of migraine symptoms are likely to also be linked to the individual’s quality of

life and social participation attributed in large part to exercise training. As expected, retinal

vessel diameters underwent no changes in CON. However, migraine days decreased in CON

to the same extent as in MCT. This finding could be associated with an all-around

sensitization due to an increase of physical activity based on the initial physical activity

recommendations provided for CON as well as social factors due to participating in the study.

Our results of maximal and submaximal fitness parameters support the evidence of HIT being

superior to MCT in improving fitness levels, while CON showed no improvement. Whether

migraine days are influenced by fitness levels still remains to be proven, although our results

suggest an association of fitness improvement with larger migraine day reduction following

HIT. There was no statistically significant association between improvement of physical

fitness and reduction of migraine days, which can be explained by the relatively small sample

size.

Previous studies show that retinal arterioles dilate in response to acute submaximal exercise in

young adults, indicating normal endothelial reactivity (41). In contrast, retinal arterioles

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 physiologically constrict in response to acute bouts of maximal exhaustive exercise and the
Accepted Article consequent increase in perfusion pressure. This auto-regulated myogenic vasoconstriction,

also known as Bayliss effect, induces an increase in vascular resistance ensuring maintenance

of normal blood flow in central arteries and veins during dynamic exercise. Nitric oxide-

(NO) mediated endothelial function and myogenic vasoconstriction of retinal vessels are

impaired in older adults and in chronic cardiovascular disease states (12). NO has been shown

to play a key mechanistic role in the exercise-induced dilatation of retinal arterioles following

regular moderate to high intensity endurance training (16). Regular exercise seems to improve

both auto-regulated vascular properties, the pressure-induced myogenic vasoconstriction as

well as NO-mediated endothelial function. The stimulus created by intermittent changes in

intensity during HIT evoked a larger vascular response than continuous exercise, thus forcing

the vasculature to improve vascular reactivity and blood flow regulation more efficiently. This

greater vascular shear stress and consequent physiological adaptations bests explains the

increase of CRAE following HIT. The adaptations are likely to represent exercise-induced

improvements of endothelial function in retinal arterioles resulting from changes in NO

response and bioavailability. The role of NO in migraine has been controversially debated. In

one study, impaired vascular reactivity has been attributed to a reduced response of vascular

smooth muscle cells to NO, whereas the endothelial response appears to remain intact (16).

Other research shows an increased nitrate-mediated response supporting the theory of an

overregulated NO sensitivity during the course of migraine pathophysiology (42). The net

effect of endurance exercise seems to be an improvement of vascular reactivity and blood

flow regulation, which, according to our results, may be linked to a reduction of migraine

days. Future research in larger longitudinal studies will have to further investigate the role of

the cerebrovascular bed in the reduction of migraine attacks following exercise training.

Whether improvement of retinal AVR has a causative link to migraine day reduction needs to

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 be elucidated further, however and most importantly, improvement of retinal vessel diameters
Accepted Article represents an exercise-induced cardiovascular risk reduction in migraine patients.

Retinal vessel diameters are valid microvascular biomarkers for cardiovascular risk. Smaller

arteriolar diameters are related to hypertension while wider venules are associated with

diabetes, obesity, dyslipidemia, systemic markers of inflammation as well as endothelial

dysfunction (38). The exercise-induced increase in AVR in our study due to retinal arteriolar

dilatation and venular constriction can, therefore, be associated with a cardiovascular risk

reduction in migraine patients. Higher exercise intensities may provide the potential to

counteract the progression of small vessel disease in migraineurs. Our results are of high

clinical relevance since it has recently been shown that there are about 2.6 million individuals

in the U.S. suffering from episodic migraine with one or more cardiovascular events or

conditions. Many of the routinely used acute migraine treatments such as triptans and ergot

alkaloids are addressed with precautions for use in patients with cardiovascular disease (43).

The aforementioned prospective cohort study by Kurth et al. (6) concluded that future

research should try to identify preventive strategies to reduce cardiovascular risk in patients

with migraine. HIT has previously been shown to be superior to MCT with respect to

cardiometabolic risk reduction in patients with cardiovascular disease (44). The improvement

of retinal microvascular health following HIT in our study indicates the potential to reduce

cardiovascular risk in migraineurs. Therefore, HIT may prove to be an effective therapy for

the reduction of migraine symptoms as well as cardiovascular risk. The efficacy of MCT

could not be proven to the extent of HIT. Changes in migraine day reduction in MCT were

comparable to CON, even though AVR and fitness levels improved considerably. Exercise

therapy has the potential to play a crucial role in future preventive strategies to combat

migraine-associated pain and cardiovascular disease.

The study comprises some limitations that need to be addressed. The sample size of the pilot

study might be considered low. In our group analysis, we refrained from interpreting our data

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 on the basis of mere conventional p-values to estimate relevant between-group effects, as p-
Accepted Article values do not sufficiently allow for continuous estimation of relevant interventional effect

sizes (19). Indeed, these would have failed to reach significance due to the small sample size

of this pilot study. In addition, despite group allocation based on physical fitness and migraine

days per month, notable baseline differences in migraine days as well as retinal diameters

need to be addressed. These findings might be caused by the dropouts. We applied fitness and

the MIDAS (migraine disability assessment) questionnaire as strata for group allocation.

Moreover, we included baseline values and age as covariates. Thus, our results are adjusted

for potential baseline differences.

Perspectives

Aerobic exercise at high exercise intensities performed in intervals revealed notable beneficial

effects on migraine days, cerebrovascular health as well as submaximal and maximal fitness

levels. The exercise-induced changes in retinal arteriolar and venular diameters were more

pronounced in HIT than in MCT. These exercise adaptations have reached the level of clinical

relevance for AVR changes, considered to be in the range of 0.03 based on larger cohort data

(45). Moreover, the results support the hypothesis that aerobic exercise positively influences

migraine symptoms by reducing migraine days. Our results may lead to new complementary

exercise therapies in migraine. Exercise-based treatment strategies may in future be based on

individual preferences and responses to specific exercise modalities. Patients’ lifestyle and

physical activity levels may need to be considered a crucial factor in the treatment of

migraine. The findings provide initial evidence that individual exercise programs of higher

intensities should be considered an additional treatment option in migraineurs.

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 Acknowledgements
Accepted Article
We cordially thank all participants for their confidence and compliance in taking part in our

research. We wish to thank the Neurology Department of the University Hospital of Basel

(Alain Thoeni, Elena Gross) for their collaboration and flexibility. Furthermore, we would

like to thank the students who were involved in study coordination (Gavin Brupbacher), data

acquisition and conduction of measurements as well as coordination with the patients and

supervision of training sessions.

Conflict of interest statement

All authors do not have any conflict of interest concerning the present study including data

acquisition, manuscript writing and data presentation.

Author contributions

Study design: HH, TS, LD; data collection: AM, SM, AR, MR, AP, CK; statistical analysis:

AM, LD; manuscript preparation: HH, AM, TS, LD; manuscript revision: OF, LZ.

Funding sources

This study was funded by the Research Fund of the University of Basel.

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Figure Legend:
Figure 1: Flow chart of the randomized controlled trial

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 Table 1 Baseline data of the participants for both intervention groups (HIT and MCT) and the control group
(CON) other than mentioned in Table 2. Data are provided as means with standard deviations (SD).
Abbreviations: Gender is indicated as f, female; m, male; BMI, body mass index; BP, blood pressure;
Accepted Article FFKA_MET, Freiburger Physical Activity Questionnaire expressed in metabolic equivalents per week; MIDAS,
Migraine Disability Assessment Questionnaire expressed in MIDAS score.

HIT MCT CON

(n = 13) (n = 11) (n = 12)
Gender [m/f] 3/10 2/9 2/10
Age [years] 36.2 (10.7) 37.0 (8.7) 37.3 (11.9)
-2
BMI [kg·m ] 22.4 (3.0) 23.6 (8.7) 23.4 (2.8)
Systolic BP [mmHg] 118.1 (23.4) 110.5 (9.1) 113.7 (10.8)
Diastolic BP [mmHg] 78.7 (5.9) 77.5 (6.5) 78.3 (7.6)
FFKA_MET [MET/week] 36.5 (50.8) 39.7 (38.7) 35.1 (20.6)
MIDAS [score] 21.4 (13.4) 24.0 (21.8) 16.3 (8.9)

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 Table 2 Pre and post intervention parameters for HIT, MCT and CON. Data are provided as means with
standard deviations (SD). Abbreviations: CRAE, central retinal arteriolar equivalent; CRVE, central retinal
Accepted Article venular equivalent; AVR, arteriolar-to-venular ratio; VO2max, maximal oxygen uptake; LT, lactate threshold.

Pre Post SMD ANCOVA

mean (SD) mean (SD) p η2p

HIT 3.8 (3.0) 1.4 (1.2) 1.05 0.12 0.12

Migraine Days MCT 4.5 (2.1) 3.2 (3.0) 0.50

[days/month]
CON 3.2 (2.4) 2.0 (1.6) 0.59

HIT 181.8 (18.2) 187.2 (20.2) -0.33 0.11 0.13

CRAE MCT 197.7 (14.4) 198.1 (14.6) -0.03

[µm]
CON 190.2 (18.5) 190.4 (18.3) -0.01

HIT 210.2 (21.0) 208.7 (20.5) 0.07 0.39 0.06

CRVE MCT 232.9 (8.4) 229.6 (8.3) 0.40

[µm]
CON 218.9 (12.1) 219.1 (15.2) -0.01

HIT 0.87 (0.07) 0.90 (0.07) -0.43 0.07 0.27

AVR MCT 0.85 (0.06) 0.87 (0.07) -0.31

CON 0.87 (0.06) 0.87 (0.05) 0

HIT 36.8 (5.2) 41.3 (8.3) -0.65 0.14 0.12

VO2max MCT 36.8 (5.3) 38.3 (6.4) -0.26

[ml/min/kg]
CON 36.2 (6.3) 36.3 (5.7) -0.02

HIT 8.2 (0.8) 8.7 (0.6) -0.71 0.03 0.20

LT [km/h] MCT 8.4 (1.0) 8.3 (0.9) 0.11

CON 8.5 (1.1) 8.3 (1.2) 0.17

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 Table 3 Parallel Group Trials for HIT, MCT and CON. Parallel Group Trials Difference in means as well as
standardized mean differences (90% confidence intervals) are given for migraine days, fitness parameters and
retinal vessel parameters. The probability for an effect being practically beneficial was calculated according to
Accepted Article the magnitude-based inference method. Abbreviations: CRAE, central retinal arteriolar equivalent; CRVE,
central retinal venular equivalent; AVR, arteriolar-to-venular ratio; VO2max, maximal oxygen uptake; LT, lactate
threshold.

Maximal parameters Differences in Standardized mean Probability for a practically

means difference [90% CI] worthwhile effect
Migraine Days [per month]
HIT vs. CON -0.8 [-1.7; 0.0] -0.28 [-0.58; 0.02] 71%; possibly beneficial
MCT vs. CON 0.1 [-1.1; 1.4] 0.05 [-0.45; 0.54] 21%; unlikely beneficial
HIT vs. MCT -1.4 [-2.6; -0.2] -0.50 [-0.93; -0.07] 89%; likely beneficial
CRAE [µm]
HIT vs. CON 5.0 [0.7; 9.4] 0.26 [0.04; 0.47] 70%; possibly beneficial
MCT vs. CON 0.7 [-4.2; 5.5] 0.04 [-0.23; 0.31] 18%; unlikely beneficial
HIT vs. MCT 4.8 [0.0; 9.7] 0.25 [0.0; 0.50] 67%; possibly beneficial
CRVE [µm]
HIT vs. CON -1.2 [-5.1; 2.6] -0.07 [-.0.27; 0.14] 27%; possibly beneficial
MCT vs. CON -2.7 [-8.0; 2.6] -0.20 [-0.59; 0.19] 53%; possibly beneficial
HIT vs. MCT -1.8 [-7.9 4.3] -0.08 [-0.37; 0.20] 27%; possibly beneficial
AVR
HIT vs. CON 0.032 -0.014; 0.050] 0.50 [0.22 0.75] 96%; very likely beneficial
MCT vs. CON 0.016 [0.000; 0.033] 0.25 [0.00; 0.50] 63%; possibly beneficial
HIT vs. MCT 0.015 [-0.003; 0.032] 0.21 [-0.04; 0.46] 52%; possibly beneficial
VO2max [ml/min/kg]
HIT vs. CON 4.7 [0.2; 9.3] 0.79 [0.04; 1.54] 91%; likely beneficial
MCT vs. CON 1.5 [-1.2; 4.2] 0.24 [-0.20; 0.68] 59%; possibly beneficial
HIT vs. MCT 3.1 [-1.3; 7.4] 0.56 [-0.23; 1.35] 78%; likely beneficial
LT [km/h]
HIT vs. CON 1.1 [0.5; 1.6] 1.07 [0.52; 1.61] 99%; very likely beneficial
MCT vs. CON 0.5 [-0.2; 1.2] 0.46 [-0.14; 1.06] 78%; likely beneficial
HIT vs. MCT 0.5 [0.1; 0.9] 0.55 [-0.13; 0.97] 92%; likely beneficial

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Accepted Article

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