|Year : 2016 | Volume
| Issue : 3 | Page : 107-115
Migraine prevention by noninvasive electrical fastigial nucleus stimulation: a multi-center, randomized, double-blind, sham-controlled trial
Juan Yang1, Shu Ou2, Jie Zhang3, Wei-wei Dong4, Jian Wang M.D. 1, Jin-he Lou5
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
|Date of Web Publication||29-Jul-2016|
Department of Neurology, Chengdu Second People's Hospital, Chengdu, Sichuan Province
Source of Support: This study was supported by a grant from Scientific and Research Project of Health and Family Planning Committee of Sichuan Province of China (No. 150008); a grant from Science and Technology Department of Sichuan Province of China (No. 2016JY0248); and a grant from Medical Science Research Project of Sichuan Province of China (No. S15009)., Conflict of Interest: None
Background: Migraine is a global disease with a high morbidity rate, and while there is medication for migraine prevention, it has many side effects. Thus there is a need to find a non-drug therapy to prevent migraine in patients with frequent attacks of migraine, severe pain, and poor drug control. Cortical spreading depression (CSD) is an important pathological mechanism behind migraine. Electrical fastigial nucleus stimulation (FNS) can reportedly inhibit the occurrence and propagation of CSD, and therefore can be used to prevent migraine.
Methods/Design: This is a prospective, multi-center, randomized, double-blind, sham-controlled trial. It will be performed at Chengdu Second People's Hospital, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Fourth People's Hospital, the First Affiliated Hospital of Chongqing Medical University, and Chongqing People's Hospital, China. The approach is to randomly allocate 80 eligible migraine patients to undergo 3 months of either noninvasive electrical FNS (pulse width 90 μs, frequency 1.8 kHz, and output current 10 mA) or ineffective sham-stimulation (using the same stimulation equipment; pulse width 90 μs, frequency 10 kHz, and output current 0.18 mA). The primary outcomes are: change in monthly migraine days between the run-in month and 3 rd month of treatment, and percentage of patients having at least a 50% reduction of monthly migraine days in the 3 rd month of treatment. The secondary outcomes are: change between average monthly migraine days across 3 months of treatment and monthly migraine days in the 3 rd month of treatment, Visual Analogue Scale score in the 3 rd month of treatment, change in monthly anti-migraine drug use between the run-in month and 3 rd month of treatment, migraine disability assessment questionnaire score, accompanying symptoms, and adverse reactions.
Discussion: In previous studies on electrical FNS for the treatment of various brain injuries, sample sizes have been small with inclusion of only a small number of institutions and non-rigorous trial protocols. Accordingly, the data obtained were not very reliable. In this study, we will validate the efficacy of electrical FNS in migraine prevention using a multi-center, randomized, double-blinded, controlled trial. Our findings will provide evidence for clinical application of this method.
Trial registration: The trial protocol was registered at Chinese Clinical Trial Registry (www.chictr.org.cn) (registration number: ChiCTR-ICR-15006273) on 5 April 2015.
Ethics: This trial was approved by the Ethics Committee of Chengdu Second People's Hospital, China on 9 April 2015 (approval number: 2015010), and will be performed in accordance with the guidelines of the Declaration of Helsinki, formulated by the World Medical Association.
Informed consent: Written informed consent will be obtained from participants or their guardians.
Keywords: clinical trial; migraine; electrical stimulation; fastigial nucleus; prevention; multi-center, randomized sham-controlled trial
|How to cite this article:|
Yang J, Ou S, Zhang J, Dong Ww, Wang J, Lou Jh. Migraine prevention by noninvasive electrical fastigial nucleus stimulation: a multi-center, randomized, double-blind, sham-controlled trial. Asia Pac J Clin Trials Nerv Syst Dis 2016;1:107-15
|How to cite this URL:|
Yang J, Ou S, Zhang J, Dong Ww, Wang J, Lou Jh. Migraine prevention by noninvasive electrical fastigial nucleus stimulation: a multi-center, randomized, double-blind, sham-controlled trial. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2016 [cited 2018 Dec 19];1:107-15. Available from: http://www.actnjournal.com/text.asp?2016/1/3/107/187076
| 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 Classification 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 Classification 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 confirmed 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 inflammatory reactions by reducing the release of inflammatory 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 deficits (Golanov and Zhou, 2003). Accordingly, we have used FNS to treat various brain injuries ([Table 1]).
|Table 1: Previous studies addressing the treatment of acute massive cerebral infarction using nimodipine|
Click here to view
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, specifically, 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 confirmed 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 inflammatory 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 inflammation 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 efficacy of electrical cerebellar FNS for the prevention of migraine using a multi-center, randomized, double-blinded placebo-controlled trial.
| Methods/Design|| |
A multi-center, randomized, double-blind, sham-controlled trial.
The trial will be performed at Chengdu Second People's Hospital, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Fourth People's Hospital, the First Affiliated Hospital of Chongqing Medical University, and Chongqing People's Hospital, China.
The study is designed to validate the efficacy 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].
Patients satisfying all the following criteria were considered for admission to the trial:
- Diagnosed with migraine according to The International Classification of Headache Disorders: 2 nd edition (Headache Classification Subcommittee of the International Headache Society, 2004)
- 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
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
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
From the perspective of safety issues, according to our preliminary experiments, the effective rate in the sham-stimulation group was 15%, while in the FNS group was 55%. To test for significant differences between sham-stimulation and FNS groups, the significance level was α = 5% (two-sided), with the power being β = 90%.
According to the formula ,
u α and u β are u values corresponding to α and β, while p 1 and p 2 are 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.
Migraine patients were recruited from five hospitals to participate in the trial through various public invitation methods including advertisements, posters, and leaflets. The invitation posters or leaflets 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 informed consent, all potential participants were screened according to our inclusion and exclusion criteria.
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.
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 sham-stimulation equipment cannot be distinguished.
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.
|Figure 2: Position of the stimulation electrode placed on the mastoid area behind the ear|
Click here to view
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.
Primary outcome measures
Change in monthly migraine days between the run-in month and 3 rd month of treatment; and 50% response rate, i.e., percentage of patients having at least a 50% reduction of monthly migraine days in the 3 rd month of treatment.
Secondary outcome measures
(1) Change in average monthly migraine days across 3 months of treatment.
(2) Monthly migraine days in the 3 rd month 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 3 rd month 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 3 rd month of treatment.
(5) Migraine disability assessment (MIDAS) questionnaire score. The questionnaire is designed to examine headache-caused 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].
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 scientific, rigorous, real, and complete research process. Anonymized trial data will be published at http://www.figshare.com.
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 3 rd month 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 significant.
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.
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 confidentiality 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 significance of the results. Thus, our results will clarify the efficacy of daily FNS treatment in the prevention of migraine, and objectively provide effective theoretical evidence for the clinical application of FNS.
Data summary and statistical analysis are undergoing at the time of submission.
| References|| |
Bartleson JD, Cutrer FM (2010) Migraine update. Diagnosis and treatment. Minn Med 93:36-41.
Chronicle E, Mulleners W (1996) Visual system dysfunction in migraine: a review of clinical and psychophysical findings. Cephalalgia 16:525-535.
Collins SL, Moore RA, McQuay HJ (1997) The visual analogue pain intensity scale: what is moderate pain in millimetres? Pain 72:95-97.
Cui Y, Kataoka Y, Watanabe Y (2014) Role of cortical spreading depression in the pathophysiology of migraine. Neurosci Bull 30:812-822.
Deng ZK, Dong WW (2003a) The effect of fastigial nucleus electrical stimulation on the therapeutic window of opportunity for in tervention of focal cerebral ischemia. Zhonghua Yixue Zazhi 83:1173-1175.
Deng ZK, Dong WW (2003b) The effect of fastigial nucleus electrical stimulation on the activity of calpain during permanent focal cerebral lschemia. Zhongguo Linchuang Shenjing Kexue 11:250-253.
Galea E, Glickstein SB, Feinstein DL, Golanov EV, Reis D (1998a) Stimulation of cerebellar fastigial nucleus inhibits interleukin-1beta-induced cerebrovascular inflammation. Am J Physiol 275: H2053-2063.
Galea E, Golanov EV, Feinstein DL, Kobylarz KA, Glickstein SB, Reis DJ (1998b) Cerebellar stimulation reduces inducible nitric oxide synthase expression and protects brain from ischemia. Am J Physiol 274:H2035-2045.
Gasparini CF, Sutherland HG, Griffiths LR (2013) Studies on the pathophysiology and genetic basis of migraine. Curr Genomics 14:300-315.
Gilmore B, Michael M (2011) Treatment of acute migraine headache. Am Fam Physician 83:271-280.
Glickstein SB, Golanov EV, Reis DJ (1999) Intrinsic neurons of fastigial nucleus mediate neurogenic neuroprotection against excitotoxic and ischemic neuronal injury in rat. J Neurosci 19:4142-4154.
Golanov EV, Zhou P (2003) Neurogenic neuroprotection. Cell Mol Neurobiol 23:651-663.
Golanov EV, Yamamoto S, Reis DJ (1996) Electrical stimulation of cerebellar fastigial nucleus fails to rematch blood flow and metabolism in focal ischemic infarctions. Neurosci Lett 210:181-184.
Golanov EV, Liu F, Reis DJ (1998) Stimulation of cerebellum protects hippocampal neurons from global ischemia. Neuroreport 9:819-824.
He LY, Luo Y, Wang J, Dong WW (2015) Effect of electrical stimulation to cerebellar fastigial nucleus on cerebral ischemia-reperfusion injury in Rats. Zhongguo Kangfu Lilun yu Shijian 21:1012-1015.
He LY, Zhang B, Luo Y, Dong WW, Wang YL (2014) Effects of electrical stimulation to cerebellar fastigial nucleus on expressions of NF-κB, PPARγ, IκBα and COX-2 mRNA under cerebral ischemia/reperfusion in rats. Zhongguo Kangfu Yixue Zazhi 29:107-112.
Headache Classification Subcommittee of the International Headache Society (2004) The International Classification of Headache Disorders: 2 nd
edition. Cephalalgia 24 Suppl 1:9-160.
Heurteaux C, Lauritzen I, Widmann C, Lazdunski M (1995) Essential role of adenosine, adenosine A1 receptors, and ATP-sensitive K +
channels in cerebral ischemic preconditioning. Proc Natl Acad Sci U S A 92:4666-4670.
Huang W, Xu MM, Chen X, Dong WW, Xie P (2009) Experimental study of effects of FNS on intercellular adhesion in acute cerebral ischemia in rats. Chongqing Yixue 38:1993-1998.
Huo S, Yu WH (2001) Curative effects of electrical cerebellar fastigial nucleus stimulation on migraine. Xiandai Kangfu 25:88.
Jackson JL, Kuriyama A, Hayashino Y (2012) Botulinum toxin A for prophylactic treatment of migraine and tension headaches in adults: a meta-analysis. JAMA 307:1736-1745.
Karatas H, Erdener SE, Gursoy-Ozdemir Y, Lule S, Eren-Koçak E, Sen ZD, Dalkara T (2013) Spreading depression triggers headache by activating neuronal Panx1 channels. Science 339:1092-1095.
Lin BR, Wang T, Hu WK (2002) Electro-stimulation on cerebellum fastigial nucleus for migraine in 40 cases. Shanghai Zhongyiyao Zazhi 36:26-27.
Lipton RB, Diamond S, Reed M, Diamond ML, Stewart WF (2001) Migraine diagnosis and treatment: results from the American Migraine Study II. Headache 41:638-645.
Liu JL, Dong WW, Li JP (2003) Effect of fadtigial nucleus electrical stimulation on Ku expression in rat with focal cerebral ischemia and reperfusion. Zhongguo Linchuang Shenjing Kexue 11:117-120.
Liu JL, Li JP, Dong WW (2004) Fastigial nucleus electrical stimulation protecting against ischemia-reperfusion induced oxidative DNA damage in rat brain. Zuzhong yu Shenjing Jibing 11:147-150.
Loder E, Burch R, Rizzoli P (2012) The 2012 AHS/AAN guidelines for prevention of episodic migraine: a summary and comparison with other recent clinical practice guidelines. Headache 52:930-945.
Nakai M, Iadecola C, Ruggiero DA, Tucker LW, Reis DJ (1983) Electrical stimulation of cerebellar fastigial nucleus increases cerebral cortical blood flow without change in local metabolism: Evidence for an intrinsic system in brain for primary vasodilation. Brain Res 260:35-49.
Reis DJ, Berger SB, Underwood MD, Khayata M (1991) Electrical stimulation of cerebellar fastigial nucleus reduces ischemic infarction elicited by middle cerebral artery occlusion in rat. J Cereb Blood Flow Metab 11:810-818.
Reis DJ, Kobylarz K, Yamamoto S, Golanov EV (1998) Brief electrical stimulation of cerebellar fastigial nucleus conditions long-lasting salvage from focal cerebral ischemia: conditioned central neurogenic neuroprotection. Brain Res 780:161-165.
Shamliyan TA, Choi JY, Ramakrishnan R, Miller JB, Wang SY, Taylor FR, Kane RL (2013) Preventive pharmacologic treatments for episodic migraine in adults. J Gen Intern Med 28:1225-1237.
Shi ZH, Dong WW (2003) Role of fastigial nuclei stimulation on angiogenesis in rats with local cerebral ischemia. Zhongfeng yu Shenjing Jibing Zazhi 20:250-252.
Silberstein SD, Neto W, Schmitt J, Jacobs D; MIGR-001 Study Group (2004) Topiramate in migraine prevention: Results of a large controlled trial. Arch Neurol 61:490-495.
Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E (2012) Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 78:1337-1345.
Sprenger T, Borsook D (2012) Migraine changes the brain: neuroimaging makes its mark. Curr Opin Neurol 25:252-262.
Stewart W, Lipton R, Kolodner K, Liberman J, Sawyer J (1999) Reliability of the migraine disability assessment score in a population-based sample of headache sufferers. Cephalalgia 19:107-114.
Takaba H, Nagao T, Yao H, Kitazono T, Ibayashi S, Fujishima M (1997) An ATP-sensitive potassium channel activator reduces infarct volume in focal cerebral ischemia in rats. Am J Physiol 273:R583-586.
Tan XL, Dong WW, Yang QD (2004) The prophylactic and curative effects of electrical stimulation of cerebellar fastigial nucleus on vascular dementia in rats. Zuzhong yu Shenjing Jibing 11:349-352.
Tang WJ, Dong WW, Xie P, Cheng PF, Bai SJ, Ren YF, Wang G, Chen XY, Cui C, Zhuang XX, Huang W (2016) Effect of pre-condition cerebella fastigial nucleus electrical stimulation within and beyond the time window of thrombolytic on ischemic stroke in rats. Disan Junyi Daxue Xuebao 38:27-31.
Tepper SJ, Tepper DE (2010) Breaking the cycle of medication overuse headache. Cleve Clin J Med 77:236-242.
Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, Shibuya K, Salomon JA, Abdalla S, Aboyans V, Abraham J, Ackerman I, Aggarwal R, Ahn SY, Ali MK, AlMazroa MA, Alvarado M, Anderson HR, Anderson LM, Andrews KG, et al. (2012) Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380:2163-2196.
Wang H, Han XR, Zhang N (2007) Curative efficacy of electrical cerebellular fastigial nucleus stimulation in the treatment of migraine. Zhongguo Shiyong Shenjing Jibing Zazhi 10:114.
Wang J, Dong WW, He W (2005) Effect of preconditioning electrostimulation of fastigial nucleus on neuronal mitochondrion of rat early after cerebral ischemia. Zhonghua Wuli Yixue yu Kangfu Zazhi 27:9-13.
Wang SJ (2003) Epidemiology of migraine and other types of headache in Asia. Curr Neurol Neurosci Rep 3:104-108.
Wang YM, Liu XD, Dong WW, Luo XD, Yang ZC (2003) Effects of electric stimulation of the cerebellar fastigial nucleus on the expression of insular cortex neuropeptide Y in rats with cerebral embolism. Disan Junyi Daxue Xuebao 19:1751-1754.
Yamamoto S, Golanov EV, Reis DJ (1993) Reductions in focal ischemic infarctions elicited from cerebellar fastigial nucleus do not result from elevations in cerebral blood flow. J Cereb Blood Flow Metab 13:1020-1024.
Yang J, Dong WW (2004) The effect of fastigial nucleus stimulation on cerebral blood flow of cerebral infarction patients. Xiandai Yiyao Weisheng 20:3-4.
Yang J, Dong WW, Zhong SH (2004) Clinical research of fastigial nucleus electrical stimulation in treatment of disorders of consciousness by brain damage. Chongqing Yike Daxue Xuebao 29:383-385.
Yu G, Dong WW, Luo Y, Peng GG (2002) Effect of fore-stimulation of cerebellar fastigial nucleus on cerebral PKC γ and PKC δ expression in cerebral ischemia-reperfusion rats. Zhenci Yanjiu 27:10-13.
Zeng JQ, Yu G, Dong WW (2002a) Expression of inflammatory factors in ischemic penumbra after experimental cerebral haemorrhage and the effects of fastigial nucleus stimulation (FNS). Chongqing Yixue 31:394-396.
Zeng JQ, Dong WW, Yu G (2002b) Expression of HSP70 and NF-êB in hippocampus CA1 of rat brain after focal cerebral ischemia/reperfusion and the effects of fastigial nucleus stimulation (FNS). Zhongguo Laonian Xue Zazhi 22:289-291.
Zhang F, Iadecola C (1993) Fastigial stimulation increases ischemic blood flow and reduces brain damage after focal ischemia. J Cereb Blood Flow Metab 13:1013-1019.
Conflicts of interest
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.
This paper was screened twice using CrossCheck to verify originality before publication.
This paper was double-blinded and stringently reviewed by international expert reviewers.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]