Juan Yang, Shu Ou, Jie Zhang, Wei-wei Dong, Jian Wang,, Jin-he Lou

1 Department of Neurology, Chengdu Second People’s Hospital, Chengdu, Sichuan Province, China

2 Department of Neurology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

3 Department of Neurology, Chongqing Fourth People’s Hospital, Chongqing, China

4 Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China

5 Department of Neurology, Chongqing People’s Hospital, Chongqing, China

BACKGROUND

Migraine is a primary pain characterized by recurrent episodes of moderate to severe headache. The pain generally affects one side of the head, is pulsating, lasts for 4-72 hours, is often accompanied by nausea, vomiting, and sensitivity to light, sound or smell, and is worsened after physical activity (Headache Classi fication Subcommittee of the International Headache Society, 2004). Global prevalence of migraine is appropriately 15%, with approximately 100 million people worldwide affected (Vos et al., 2012) and a higher prevalence in females than males (19% vs. 11%)(Vos et al., 2012). Moreover, migraine prevalence in Asian populations is lower than in European and American, but is still over 10% (Wang, 2003). Anti-epileptic drugs, antidepressants, calcium antagonists, and β-receptor blockers reduce the frequency and intensity of migraines (Gilmore and Michael, 2011; Jackson et al., 2012; Loder et al., 2012;Silberstein et al., 2012; Shamliyan et al., 2013). However,their use is limited because of strict medication times and high costs (Lipton et al., 2001), as well as potential adverse reactions including myocardial ischemia, disturbed sleep,sexual dysfunction, dry mouth, obesity, tremor, hair loss,and fetal birth defects (Silberstein et al., 2004; Bartleson and Cutrer, 2010; Gilmore and Michael, 2011). In addition,ergotamine overdose may increase migraine frequency and intensity (Headache Classi fication Subcommittee of the International Headache Society, 2004; Tepper and Tepper,2010). Thus, migraine patients have to weigh the adverse reactions of several drugs against repeated headache episodes. For migraine patients with frequent attacks, intense pain, and poor drug control, non-drug measures may help prevent migraine.

Cerebellar bioelectrical stimulation is a non-invasive physical therapy. The neuroprotective effects of electrical fastigial nucleus stimulation (FNS) were first con firmed by Reil et al. (1998) from Cornell University. FNS pretreatment can prevent subsequent cerebral ischemic injury, with the underlying mechanism reported to be related to FNS inhibition of peri-infarction depolarizing waves (PIDs) (Golanov and Zhou, 2003). FNS has also been shown to improve cerebrovascular microcirculation and regional cerebral blood flow (Nakai et al., 1983; Reis et al., 1991; Yamamoto et al., 1993; Zhang and Iadecola, 1993; Chronicle and Mulleners, 1996), inhibit in flammatory reactions by reducing the release of in flammatory factors (Galea et al., 1998a, b),alleviate cerebral edema and nerve injury, reduce neuronal necrosis and apoptosis in the ischemic region (Golanov et al., 1998; Glickstein et al., 1999), reduce infarct volume(Yamamoto et al., 1993; Golanov et al., 1996; Reis et al.,1998), stabilize brain excitability (Chronicle and Mulleners, 1996), and exhibit neuroprotective effects and promote the recovery of neurological de ficits (Golanov and Zhou,2003). Accordingly, we have used FNS to treat various brain injuries (Table 1).

The pathological mechanism underlying migraine remains poorly understood, but most authors assume that cortical spreading depression (CSD) and trigeminal nerve vasculitis co-mediate the occurrence of migraine. CSD refers to the phenomenon of neuronal activation followed by inhibition,speci fically, neurons propagate on the cortical surface at 2-5 mm/min for 15-30 minutes, leading to destruction of cellular ionic gradients and resulting in inhibition of neuronal activity. An imaging study con firmed the changes in cerebral blood flow and cerebral activity in patients with migraine(with or without aura), which suggest the presence of CSD(Sprenger and Borsook, 2012). CSD activates the trigeminal vascular system, increases sensitivity, and consequently initiates a series of nerve, vascular and in flammatory events that finally induce migraine (Gasparini et al., 2013; Karatas et al., 2013; Cui et al., 2014). As a pathogenic factor,CSD likely plays a key role in the occurrence of migraine.Therefore, FNS for CSD and in flammation inhibition can theoretically prevent migraine. Previous observational studies have demonstrated that non-invasive FNS prevents migraines with good safety (Huo and Yu, 2001; Lin et al.,2002; Wang et al., 2007). However, in these studies, the sample sizes are small, only a few institutions are included,and the trial protocol is not rigorous enough. Consequently,the data obtained are not reliable.

In this study, we will validate the ef ficacy of electrical cerebellar FNS for the prevention of migraine using a multicenter, randomized, double-blinded placebo-controlled trial.

Table 1: Previous studies addressing the treatment of acute massive cerebral infarction using nimodipine

Table 1: Continued

METHODS/DESIGN

Study design

A multi-center, randomized, double-blind, sham-controlled trial.

Study setting

The trial will be performed at Chengdu Second People’s Hospital, the Second Af filiated Hospital of Chongqing Medical University, Chongqing Fourth People’s Hospital, the First Af filiated Hospital of Chongqing Medical University, and Chongqing People’s Hospital, China.

Study procedure

The study is designed to validate the ef ficacy and safety of non-invasive FNS on prevention of migraine. Patients with migraine were screened against our inclusion and exclusion criteria (see below). Eighty eligible patients were randomly allocated to FNS and sham-stimulation groups. The flow chart of the trial protocol is shown in Figure 1.

Study participants

Inclusion criteria

Patients satisfying all the following criteria were considered for admission to the trial:

· Diagnosed with migraine according to The International Classi fication of Headache Disorders: 2ndedition (Headache Classi fication Subcommittee of the International Headache Society, 2004)

Figure 1: Flow chart of the study protocol.

· Age 18-65 years

· First onset age ≤ 50 years old

· Course of disease ≥ 1 year

· In the remission stage, with a migraine attack frequency≥ twice per month

· Voluntarily participating in the trial with provision of informed consent regarding the trial procedure

Exclusion criteria

Patients presenting with any of the following criteria were excluded from the trial:

· Have taken anti-migraine drugs such as β receptor blockers, calcium antagonists, anti-epileptic drugs, antidepressants, or serotonin receptor antagonists in the previous 3 months

· Have used at least three types of preventive drugs such as β receptor blockers, calcium antagonists, anti-epileptic drugs, antidepressants, or serotonin receptor antagonists

· Headaches related to drug abuse (use of painkillers because of headaches lasting more than 10 days)

· Alcohol and/or other drug abuse

· Taking hormone therapy

· Severe mental disorder

· Complicated by severe primary cardiovascular, hepatic,renal, or hematopoietic system diseases

· Pregnant or lactating

Withdrawal criteria

Patients will be withdrawn from the trial because of any of the following conditions:

· Patients do not meet the inclusion criteria but conform to the exclusion criteria and are recruited because of errors

· Patients do not receive treatment according to the therapeutic regimen or cannot provide complete information

· Patients cannot participate in the trial because of severe adverse events

· Patients need to take emergency measures because of complications or a worsened pathological condition

· Poor patient compliance, and consequently receive treatment for ＜ 80% of required days or take other treatments

Sample size

From the perspective of safety issues, according to our preliminary experiments, the effective rate in the shamstimulation group was 15%, while in the FNS group was 55%. To test for signi ficant differences between shamstimulation and FNS groups, the signi ficance level was α= 5% (two-sided), with the power being β = 90%.According to the formula ,

uαand uβare u values corresponding to α and β, while p1and p2are the calculated frequency values for two samples,with p being the merged value of two sample frequencies.Accordingly, n = 28 was calculated. Taking into account a ‘lost to follow-up’ rate of 20%, n = 34 was calculated as the lowest sample size for each group. Therefore, n = 40 was used as the sample size for each group.

Recruitment

Migraine patients were recruited from five hospitals to participate in the trial through various public invitation methods including advertisements, posters, and lea flets. The invitation posters or lea flets were posted in the waiting room,rest room, and entrance of hospital buildings. Participants interested in participating in the trial contacted the person in charge by telephone or e-mail. After providing written and 3rdmonth of treatment; and 50% response rate, i.e.,percentage of patients having at least a 50% reduction of monthly migraine days in the 3rdmonth of treatment.informed consent, all potential participants were screened according to our inclusion and exclusion criteria.

Figure 2: Position of the stimulation electrode placed on the mastoid area behind the ear

Randomization

Eligible patients will be observed for 1 month for baseline collection prior to grouping. Patients suffering from two or more migraine attacks per month will be allocated to the FNS or sham-stimulation groups on a 1:1 ratio.

Blinding

Treatment allocation will not be disclosed until the end of the trial and will be performed according to the principle of block randomization. Noninvasive FNS equipment and sham-stimulation equipment look the same, and have the same manual and parameters. Therefore, FNS and shamstimulation equipment cannot be distinguished.

Interventions

FNS group

After cleaning the skin, the stimulating electrode (Chongqing Haikun Medical Appliance Co., Ltd., Chongqing, China)will be positioned in the mastoid bone behind the ear. The size of the electrode is 42 mm × 24 mm with a conductive area of Φ19 mm (Figure 2). The stimulation parameters include: pulse width 90 μs, frequency 1.8 kHz, and output current 10 mA. Participants will receive FNS once a day for 45 minutes, for 3 successive days.

Sham-stimulation group

The sham-stimulation parameters include: pulse width 90 μs, frequency 10 Hz, and output current 0.18 mA. Participants will receive FNS once a day for 45 minutes, for 3 successive days.

Outcome measures

Primary outcome measures

Change in monthly migraine days between the run-in month

Secondary outcome measures

(1) Change in average monthly migraine days across 3 months of treatment.

(2) Monthly migraine days in the 3rdmonth of treatment.

(3) Severity of migraine as determined by the visual analogue scale (VAS) score, with score 0 indicating no pain and score 10 representing most pain (Collins et al., 1997),in the 3rdmonth of treatment; accompanying symptoms include migraine aura, nausea/vomiting, extreme sensitivity to light, sounds, or smells, and use of analgesics.

(4) Change in monthly anti-migraine drug use between the run-in month and 3rdmonth of treatment.

(5) Migraine disability assessment (MIDAS) questionnaire score. The questionnaire is designed to examine headachecaused disability in working and daily life. The questionnaire score is calculated by the sum of days in the last 3 months in which the patient missed work or school; did not perform household work; missed family, social, or leisure activities; or experienced a reduction in work or school productivity by half or more because of headache (Stewart et al., 1999).

(6) Adverse reactions including local skin irritation, pain,or other discomfort.

Patient’s baseline characteristics are shown in Table 2 and the schedule for outcome assessments is shown in Table 3.

Table 2: Patient’s baseline data

Table 3: Schedule of outcome assessments

Data collection, management, analysis, and open access

Two persons will not participate in recruitment of participants, and will be responsible for collecting patients’migraine diaries (containing number of FNS applications and duration of a single stimulation, and which will be completed by the patients themselves), and creating a database. During treatment, patients will be followed up once per month. After blinded auditing and collation,the created database will be locked by the researcher in charge and will not be altered. All information relating to this trial will be stored by Chengdu Second People’s Hospital. The electronic database will be fully disclosed to a professional statistician for statistical analysis, and the results reported to the researcher in charge. An independent data-monitoring committee will monitor data collection and management to ensure a scienti fic, rigorous, real, and complete research process. Anonymized trial data will be published at http://www. figshare.com.

Statistical analysis

All data will be statistically analyzed using SPSS 11.5 software. Accompanying symptoms and adverse reactions will be expressed as percentages and tested using the chi-square test. The remaining results will be expressed as the mean ±SD. The Mann-Whiney U test will be used for comparisons of primary and secondary outcome measures between FNS and sham-stimulation groups. The non-parametric Sign test will be used for comparisons of monthly changes in indices between the 3rdmonth of treatment and run-in month, as well as between average outcomes across 3 months and the run-in month. A level of P ＜ 0.05 will be considered statistically signi ficant.

Auditing

Trial progression will be reported to the ethics committee of Chengdu Second People’s Hospital, China every 6-12 months, and the trial status updated in the registration database.

Confidentiality

All information relating to this trial will be stored in a secure, locked place for future viewing, and not disclosed to any non-authorized person. Researchers participating in this trial will adhere to the con fidentiality and privacy agreements.

DISCUSSION

In this trial, to reduce the body surface sensation of current stimulation, intermediate frequency peak currents will be superimposed, with the largest current peak being 10 mA, and leading to a current change of 1-1.2 mA. This low-frequency signal will be modulated within 13-45 Hz.Within this frequency range, current change and modulated signal do not cause an obvious body surface sensation of current stimulation, and only a slight squeezing sensation is felt. The intermediate frequency signal is an exponential decay signal, with ‘a’ (0 ＜ a ＜ 1) as the base. Nonpolar differential exponential waveform is composed of positive and negative pulse waves with equal charge. Negative exponential pulses play a role in nerve fiber depolarization,while positive pulses have a charge-balancing role, resulting in an ingested static charge of 0 and leading to the lowest production of electrical stimulation-caused adverse electrochemical reactions. To reduce single pulse energy, under the condition of a constant pulse width of 90 μs, reduced base value accelerates decay and alleviates the squeezing sensation. When subjected to sham-stimulation, a patient’s body surface sensation will be periodically point-touch sensitive. Therefore, patients and physicians cannot distinguish between FNS and sham-stimulation, which ensures double-blinded clinical signi ficance of the results. Thus, our results will clarify the ef ficacy of daily FNS treatment in the prevention of migraine, and objectively provide effective theoretical evidence for the clinical application of FNS.

Trial status

Data summary and statistical analysis are undergoing at the time of submission.

Conflicts of interest

None declared.

Author contributions

JW conceive and design the trial protocol. SO, JZ, WWD and JHL are the head of each trial center. JY write the manuscript. All authors approve the final version of this manuscript for publication.

Plagiarism check

This paper was screened twice using CrossCheck to verify originality before publication.

Peer review

This paper was double-blinded and stringently reviewed by international expert reviewers.

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