Cerebrovascular Response in Migraineurs During Prophylactic Treatment with Acupuncture: A Randomized Controlled Trial

Abstract

Objectives:

The study objective was to evaluate the effect of acupuncture on cerebrovascular response in migraineurs by transcranial Doppler ultrasound.

Design:

This study was a randomized, quasi double-blinded, placebo-controlled study.

Subjects:

Thirty-five (35) migraineurs were diagnosed according to the International Headache Society criteria. The stimulus paradigm was performed in 18 verum and 17 placebo acupuncture patients.

Interventions:

Participants were treated with acupuncture according to Traditional Chinese Medicine recommendations. All patients received one session of acupuncture each week for 8 weeks.

Outcome measures:

To evaluate the clinical effect of acupuncture treatment, headache frequency and intensity was monitored by a headache diary. Cerebral blood flow velocity data were analyzed with a validated technique based on automated stimulus-related averaging. Vasotonus was determined by systolic and mean flow velocities and pulsality index in right and left middle cerebral arteries during rest. Cerebrovascular response was evaluated by detecting the cerebrovascular Valsalva ratio by maximum end-diastolic flow velocity acceleration during the straining phase of a Valsalva maneuver. Additionally, the centroperipheral Valsalva ratio was determined by the quotient of the cerebrovascular ratio to the corresponding blood pressure acceleration.

Results:

Pre-/post-acupuncture treatment comparisons between verum- and placebo- acupuncture groups demonstrated a significant decrease of days with migraine headache in the verum group (-52.5%; p<0.001), whereas placebo-acupuncture patients profited to a smaller extent and the duration of headache attack (hours/month) did not decrease significantly. Pretreatment recordings showed increased vasotonus and exaggerated cerebrovascular response in migraineurs. Pre-/post-treatment comparisons demonstrated no significant differences in vasotonus between groups, while cerebrovascular response patterns to Valsalva stimulus were significantly (p<0.001) diminished in verum-acupuncture patients, but not in the placebo group.

Conclusions:

The findings indicate that prophylactic treatment of migraineurs by standardized acupuncture might positively influence the dysfunction of the cerebrovascular response to autonomic stimuli, but not the cerebral vasotonus during rest.

Introduction

R ecently, a Cochrane review has recommended acupuncture as a treatment option for migraine patients willing to undergo complementary treatment. There is evidence that acupuncture is at least as effective as, or possibly more effective than, prophylactic drug treatment and has fewer adverse effects.^1,2 Additionally, acupuncture is a cost-effective treatment option among patients with primary headache according to international cost-effectiveness threshold values.³ However, its mode of action remains unknown. In regard to this, the authors were interested in investigating whether repetitive sessions of acupuncture would modulate cerebrovascular response measured by functional transcranial Doppler sonography (f-TCD). Additionally, the clinical effect of prophylactic migraine treatment with acupuncture was investigated.

Migraine is considered to be a neurovascular headache disorder.⁴ Several studies performed by means of TCD have demonstrated hemodynamic abnormalities in migraineurs during the interictal period and the migraine attack. Increased baseline flow velocities were recorded in the basal cerebral arteries in migraine patients with (and without) aura.^5

–9 Especially, studies with f-TCD demonstrated altered interictal cerebrovascular reactivity to several stimuli, such as CO₂,^10,12

–15 visual stimulation,^16

–20 Valsalva maneuver,^21,22 or others.^23
–25 These methods are suggested to reflect interictal vasomotor changes of pathophysiologic interest and could be used as a monitoring tool under prophylactic migraine treatment. However, there have been sparse data on this. Fiermonte et al.²⁶ reported that an increased reactivity index to hypocapnia disappeared during flunarizine prophylactic migraine treatment. In contrast, the cerebrovascular CO₂ reactivity remained unchanged under treatment with metoprolol,²⁷ whereas acupuncture might positively influence the cerebrovascular response during visual stimulation with flickering light.²⁸

Materials and Methods

Population

A total of 35 patients (31 female, 4 male) were studied after giving informed consent. The local ethics committee approved the study protocol. Inclusion criteria were (1) diagnosis of migraine with/without aura according to the criteria of the International Headache Society²⁹ proven separately by 2 senior neurologists, (2) duration of migraine disease at least 2 years, and (3) monthly frequency of two to six attacks. Exclusion criteria were (1) medication overuse headache or another secondary headache; (2) comorbidity from migraine and tension-type headache; (3) migraine preventive treatment during the previous 3 months; (4) pregnancy; (5) arterial hypertension; (6) other neurological, metabolic, and pulmonary or psychiatric diseases; and (7) drug or alcohol abuse or contraindications against acupuncture therapy.

The clinical effect was monitored by a headache diary according to the guidelines of the German Migraine and Headache Society. The patients were asked to document their frequency of attacks and headache intensity and duration in the diary on a daily basis. The diary was kept 6 weeks before the first acupuncture session (pre-acupuncture phase), during the 8 weeks of acupuncture treatment (acupuncture phase), and 12 weeks after the end of acupuncture sessions (postacupuncture phase). For evaluation, data of the pre-acupuncture phase were used and compared with those of the acupuncture phase (at the end of the 8-week treatment) and the postacupuncture phase (12 weeks after ending of the acupuncture phase).

Functional transcranial Doppler measurements

At first, all patients underwent continuous wave-extracranial Doppler sonography to exclude a carotid stenosis. The transcranial Doppler examinations were performed in the headache-free interval at least 24 hours after the last migraine attack and within 10 days before the first and 10 days after the last acupuncture sessions. Doppler signals were obtained according to the technique described by Aaslid.³⁰ Two (2) commercially available dual TCD ultrasonographic devices were used, which were especially prepared for dual-channel recordings (TC 2–64, EME, Überlingen, Germany). The middle cerebral artery was bilaterally insonated with fixed 2-MHz pulsed Doppler probes at a depth of 45–55 mm. Simultaneously, arterial blood pressure was recorded continuously and noninvasively using the Finapres system, Ohmeda, USA.³¹ Additionally, end-tidal pCO₂ concentrations were performed (Capnolog, Dräger, Germany). During the examination, subjects were sitting comfortably in a quiet room. All curves were monitored simultaneously using an analog-digital transducer and data were stored using a personal computer with a specialized software (Datenlogger Company, Rhothron, Germany). For each measurement, data were sent to an SPSS-readable file. Figure 1 shows an example curve.

FIG. 1.

Printout of a transcranial Doppler record within an epoch of 26 seconds. The upper trace represents the end-diastolic flow velocity (cm/s). Cerebral Valsalva ratio (CVR) is calculated by changes of flow velocity per time using the end-diastolic maximum blood flow acceleration (dV/dT). The lower trace is a recording of the corresponding blood pressure (mm Hg). Centroperipheral Valsalva ratio is calculated by the quotient of CVR (dV/dT) and the concomitant changes of blood pressure per time (dP/dT). Blood pressure restoration happens later than cerebral blood flow acceleration, indicating autonomic cerebrovascular reactivity during straining in Valsalva maneuver (phase IIb).

After stable baseline readings of cerebral blood flow velocities and arterial pressure had been obtained for at least 10 minutes, a standardized Valsalva maneuver (VM) was performed as described by Ewing.³² Briefly, the subjects blew into a mouthpiece connected to a modified sphygmomanometer and maintained a pressure of 40 mm Hg for a duration of 10 seconds. Exact details of the methodology are given elsewhere.^21,22

Randomization and acupuncture treatment

The study was randomized, quasi double-blinded, and placebo controlled.³³ To test whether acupuncture is able to reduce the primary clinically endpoints (days with migraine/month and duration of migraine attacks in hours/month) and to modulate vasotonus and cerebrovascular response for needling of classic acupuncture points according to Traditional Chinese Medicine recommendations, patients were randomly allocated to 2 groups receiving either verum acupuncture (VA; n=18) or a placebo acupuncture (PA; n=17) treatment. Groups were parallelized according to age, sex, duration of migraine disorder, and headache frequency. Patients were blinded for the treatment. None of the patients have received acupuncture treatment prior to the study. Demographic and clinical data of the patients are shown in Table 1.

Table 1.

Comparison of Demographic and Clinical Data Between Verum- and Placebo-Acupuncture Group

Variable	Acupuncture verum	Placebo	p
N	18	17
Sex
F	16	15	χ²: n.s.
M	2	2
Age (y)	37.2 (9.6)^a	39.3 (11.7)^a	n.s.
Duration of disease (y)	16.8 (11.2)^a	18.5 (10.9)^a	n.s.
Migraine frequency (attacks/month)	3.3 (3.3)^a	2.8 (2.0)^a	n.s.

n.s., not significant; y, years.

Numbers in parentheses are standard deviations.

Treatment was performed by a licensed acupuncturist according to the standard literature for acupuncture treatment of headache³⁴ and with a long experience in Traditional Chinese Medicine and a history of practicing acupuncture methodology in China. All patients received one acupuncture session each week over a period of 8 weeks.

Acupuncture was performed by inserting fine stainless-steel needles (35 mm×0.30 mm, sterilized and single use, Product of Seirin Ltd., Europe). Patients were lying down during the acupuncture procedure.

VA was performed in a standardized sequence during the same period of time, needling the same points bilaterally into described areas of the skin (basic acupuncture points) with normal needle depth (6–10 needles). Acupuncture was based on an expert consensus process for acupuncture treatment (German Association of Medical Practitioners for Acupuncture) using a state-of-the art acupuncture protocol. For detailed information about the anatomic localization of the acupuncture points,³⁵ see Table 2. After insertion of the needles, they were manually rotated to achieve a needle sensation (de qi sensation). All needles were then kept in their locations for 30 minutes.

Table 2.

Anatomical Location of Acupuncture Points (35)

Channel points	Location
Hegu (L.I. 4)	On the middle of the 2nd metacarpal bone, on the radial aspect
Zusanli (S.T.36)	About 4 cm below lateral patellar side, 0.5 cm from the anterior crest of the tibia
Waiguan (3B. 5)	Dorsal side of forearm, about 4 cm proximal to dorsal crease of wrist between radius and ulna
Zulinqi (G.B. 41)	Lateral side of instep of foot, posterior to fourth metatarso-phalangeal joint, in depression lateral to tendon of extensor muscle of little toe
Houxi (S.I. 3)	At the end of the transverse crease proximal to the 5th metacarpo-phalangeal joint when hand is half clenched
Shenmai (U.B. 62)	Directly below the tip of the external malleolus, and about 0.5 cm lateral to its lower border
Local and energetic points
Baihui (DU20)	Vertex, 8–10 cm above midpoint of anterior hairline, at midpoint of line connecting apices of both ears
Fengchi (G.B. 20)	Neck, below occipital bone, in depression between upper ends of sternocleidomastoid and trapezius muscle
Taiyang (ExNH5)	Face, in depression 2 cm posterior to midpoint of l line joining tip of eyebrow and outer canthus
Sizhukong (3B. 23)	Face, in depression at lateral end of eyebrow
Taichong (Li. 3)	Instep of foot, in depression of posterior end of first interosseus metatarsal space
Taixi (K. 3)	Midway between the tip of medial malleolus and tendo calcaneus

PA was performed in the same way in every session, but areas of the skin that were outside a classically described acupuncture point (minimum 1–2 cm beside) were chosen. Additionally, acupuncture needles were inserted superficially into the subcutaneous layer. The number of needles did not differ between groups. After insertion, the needles remained in their location for a period of 30 minutes without further stimulation. The same combination of acupuncture points and mode of stimulation was used in all patients and sessions. Permanent needle application was not performed for treatment.

Analysis

The staff performing TCD examinations was blinded according the treatment protocol. Vasotonus was measured using the blood-flow velocity parameters systolic (SFV) and mean flow velocity (MFV) both in cm/s and the pulsality index (PI) defined as (systolic – diastolic flow velocity)/MFV. All of these parameters were calculated automatically by the Doppler device. Analysis of the cerebrovascular response was performed off-line with an analysis software, TRANSDOP, which was especially programmed for f-TCD Valsalva reactivity measurements. For the analysis, the following procedure was performed: At the steepest part of the rise of end-diastolic flow velocity and pressure during straining, end-diastolic flow acceleration (dv/dt) and pressure rise per second (dp/dt) were determined in cm/s² and mm Hg/s, respectively. Cerebrovascular Valsalva ratio (CVR) was calculated from the longest R-R interval shortly after the maneuver to the shortest R-R interval during straining. Finally, the centroperipheral Valsalva ratio (CPVR) was derived from the velocity and arterial blood flow data for Valsalva phase IIb and defined as the quotient of CVR to the corresponding peripheral blood pressure acceleration (dv/dt/dp/dt) in cm/mm Hg×s. This is deemed valid because cerebral perfusion pressure varies with arterial blood pressure, and intracranial pressure is practically constant during phase II of VM and cerebral blood flow velocity varies with cerebral blood flow.^36,37 pCO₂ retention was determined by computing the difference between values before and after the experiment. Demographic parameters between groups were analyzed using the χ² test. Comparisons of Doppler parameters were performed using Student's t-test. Differences of clinical parameters were analyzed using Mann Whitney U test and Wilcoxon test. For all tests, the level of significance was set at p<0.05.

Results

From 35 included patients, 18 received VA and 17 were treated with PA. Complete data were recorded for 13 VA and 14 PA patients and were included in the final analysis. Dropouts were caused by artifacts in TCD measurements, which made curves unable to be analyzed, or because patients did not accept TCD measurement in the postacupuncture phase.

Clinical response to VA and PA

Across all patients, there was a significant improvement in headache frequency and intensity. Days with migraine headache decreased in VA from 7.86±3.32 in the pre-acupuncture phase to 4.13±2.55; minus 47.5% during the acupuncture phase. The result in the postacupuncture phase was 3.76±3.03; minus 52.2%. Pre-/post measurements differed significantly; p<0.001. Corresponding results in PA group were the following: pre-acupuncture phase 6.05±2.88; acupuncture phase 4.82±1.98; minus 20.4% and postacupuncture phase 4.34±2.63; minus 28.2%. Pre-/post measurements differed and reached significance (p=0.028). The duration of headache attacks (h/month) was in VA /PA for pre-acupuncture phase 89.2±42.2/68.5±39.5 and in the acupuncture phase 49.3±33.0; minus 46.8%/52.9±33.9; minus 22.9%. Results in the postacupuncture phase were 43.9±34.3 (minus 50.8%)/51.8±36.4 h/month (minus 24.5%). Table 3 presents statistical calculations, and Figure 2 illustrates the changes.

FIG. 2.

Change (percentage) in duration of headache attacks (hours/month) of verum (black line) and placebo (dotted line) acupuncture. Pre, pre-acupuncture; post 1, at the end of the 8-week acupuncture phase; post 2, 12 weeks after ending of the acupuncture phase. Pre was set to 100%. Verum acupuncture (verum): pre versus post 2: t=3.53, p<0.01; placebo acupuncture (placebo): t=1.28, p>0.05, verum versus placebo (pre: t=2.04, p>0.05).

Table 3.

Duration of Headache Attacks (Hours/Month) of Verum and Sham Acupuncture at Pre, Post 1 (at the End of the 8-Week Acupuncture Phase), and Post 2 (12 Weeks After Ending of the Acupuncture Phase)

	Pre	Post 1	Post 2	Pre vs. post 2
Verum	89.2 (42.2)	49.3 (33.0)	43.9 (34.3)	t=3.53, p<0.01
Sham	68.5 (39.5)	52.9 (33.9)	51.8 (36.4)	t=1.28, p>0.05

Statistical calculations are referenced to the precondition. In the precondition, verum vs. sham acupuncture did not differ significantly (t=2.04, p>0.05).

f-TCD measurements

Vasotonus was recorded using the parameters SFV/ MFV and PI and are shown in Table 4 for VA and PA separated for right/left middle cerebral artery sides. There were no significant differences between recordings for VA and PA patients in pre-/post measurements in all parameters.

Table 4.

Mean Transcranial Doppler Sonography-Parameters SFV, MFV, and PI of Middle Cerebral Artery (Right vs. Left) Before (Pre) and After (Post) Acupuncture Treatment for Verum and Placebo Groups

	n	Pre	p (pre) VA vs. PA	Post	p (post) VA vs. PA	p pre vs. post
a) SFV		cm/s		cm/s
Verum right	13	93.45 (25.3)		86.19 (26.7)		0.156
			0.281		0.156
Placebo right	14	84.20 (24.6)		80.04 (11.7)		0.448
Verum left	13	96.00 (23.0)		86.50 (18.8)		0.079
			0.181		0.122
Placebo left	14	86.52 (17.6)		77.62 (13.6)		0.146
b) MFV		cm/s		cm/s
Verum right	13	63.10 (16.6)		60.77 (18.0)		0.414
			0.423		0.652
Placebo right	14	58.64 (15.8)		58.48 (10.6)		0.963
Verum left	13	66.54 (16.3)		61.12 (11.5)		0.070
			0.158		0.205
Placebo left	14	60.10 (9.2)		56.41 (9.9)		0.317
c) PI
Verum right	13	0.78 (0.13)		0.77 (0.15)		0.809
			0.074		0.675
Placebo right	14	0.70 (0.13)		0.75 (0.13)		0.308
Verum left	13	0.74 (0.10)		0.74 (0.12)		0.924
			0.056		0.198
Placebo left	14	0.67 (0.10)		0.69 (0.10)		0.472

Figures in parentheses represent standard deviation.

SFV, systolic flow velocity; MFV, mean flow velocity; PI, pulsality index; p, error-probability; VA, verum acupuncture; PA, placebo acupuncture.

Cerebrovascular response was measured during a VM and was defined as maximum end-diastolic flow velocity acceleration during the straining phase in (cm/s²) (CVR). Finally, the centroperipheral Valsalva ratio (CPVR) was calculated in (cm/mm Hg×s).

VA: In the pre-acupuncture phase, CVR results for right/left middle cerebral artery measurements were 7.61±3.11/7.62±3.93 cm/s². CVR decreased in the postacupuncture phase and were 5.23±2.51/7.62±3.93 cm/s². There was a significant difference in pre/post acupuncture comparison (p<0.001). Corresponding CPVR for right/left measurements were 1.85±1.14 / 1.70±0.79 cm/mm Hg×s in the pre-acupuncture phase and 1.06±0.40/1.06±0.34 cm/mm Hg×s in the postacupuncture phase (p<0.004).

PA: CVR results in the pre-acupuncture phase were 10.08±7.83/10.13±7.67 cm/s² for right/left measurements. There was no significant difference compared to VA (p=0.299/0.300). Higher mean values in PA were caused by 2 patients with extreme variables (25.8/23.0 cm/s² and 27.8/27.0 cm/s²); mean values without these would be 7.29/7.65 cm/s². CVR was 6.9±3.6/6.64±2.85 cm/mm Hg×s in the postacupuncture phase and reached in pre/post acupuncture comparison no significance (p=0.094/0.064). Corresponding CPVR for right/left measurements were 1.3±0.51/1.28±0.51 cm/mm Hg×s in the pre-acupuncture phase. There was no significant difference compared to VA (p=0.117/0.113). Results for postacupuncture CPVR decreased just the same and were 1.06±0.34/1.05±0.27 cm/mm Hg×s. There was a tendency, but not a significant difference in pre-/post comparison (p=0.051/0.057).

No changes of end-tidal pCO₂ measurements were observed during the VM. Courses of right/left CVR and CPVR of individuals are shown in Table 4.

Discussion

The current findings indicate that prophylactic treatment with acupuncture might have an influence on the altered cerebrovascular reactivity in migraineurs during the interictal period measured by means of f-TCD during the VM, but not on vasotonus during rest.

However, in this randomized, double-blind study, there was a strong significant clinical benefit for VA patients according to the primary endpoint, headache days/month. PA patients have had a clinical improvement also, but VA compared with PA demonstrated a stronger and significant decrease of headache frequency. These findings are in accordance with the observations of others. Linde et al.³⁸ reported from an explorative analysis that VA was better than PA. Additionally, results of the German Acupuncture study on migraineurs demonstrated the efficacy of VA and PA and indicating that needling at nonacupuncture points could exert biologic effects.³⁹ Recently, a Cochrane review showed that there is no evidence for an effect of “true” acupuncture over placebo interventions, but available studies suggest that acupuncture is at least as effective as prophylactic migraine drug treatment.²⁶ Nevertheless, its mode of action remains unknown. In particular, there are sparse data dealing with the neurovascular effects of acupuncture treatment.

In regard to this, cerebral autoregulation was evaluated during prophylactic migraine treatment with acupuncture. Cerebral autoregulation refers to the ability of the brain to maintain constant blood flow despite changes in cerebral perfusion pressure.

Evaluation of cerebral autoregulation can be performed under steady-state conditions, which means that a constant baseline arterial blood pressure exists (static method).⁴⁰ In the present investigation, this condition was evaluated by determining the vasotonus, which was obtained during rest. Moreover, cerebral autoregulation can be detected during the response to a rapid change in arterial blood pressure (dynamic method). VM can be used to study dynamic cerebral autoregulation,⁴¹ because VM is associated with marked changes in arterial blood pressure. Its characteristic changes in arterial blood pressure (phases I– IV) are well established.^42

–45 Therefore, the cerebrovascular response was evaluated during the late straining phase (phase IIb) of VM, which is mediated by vasodilatation of the cerebral arterioles.^37,46 Vasodilatation of cerebral resistance vessels could theoretically be caused by a change in pCO₂ due to breath holding. Respectively, the authors did not observe any changes in endtidal-pC0₂ concentrations during VM.

To evaluate the static and dynamic cerebral autoregulation, f-TCD was used. Data acquired by f-TCD are highly congruent with those gained by other functional techniques such as functional magnetic resonance imaging (MRI).⁴⁷ Finally, evidence exists that TCD measurements can reflect changes in cerebral blood flow. Recently, Sorond et al.⁴⁸ showed that changes in cerebral blood flow velocity in the middle cerebral artery were highly correlated with changes in cerebral blood flow using gadolinium-enhanced and arterial spin-labeling MRI-techniques. Thus, f-TCD can be assumed to accurately reflect relative changes in cerebral blood flow.

In this study, pre-/post-acupuncture f-TCD measurements of vasotonus were compared. Results demonstrated no significant differences between the studied parameters, but SFV and MFV were evaluated and PI was decreased compared to reports of normal individuals.⁴⁹ These findings are in accordance with earlier observations,^5

–9 while Thomsen et al.,²³ Silvestrini et al.,²⁵ and Totaro et al.⁵⁰ were not able to detect differences between migraineurs and healthy subjects. Evaluation of cerebrovascular response by calculating CVR during phase IIb of VM showed a highly significant decrease in the VA group after acupuncture, indicating a positive influence on abnormal cerebrovascular response. Results of the PA group reached no significance, but showed a similar tendency for CVR measurements. Additionally, the centroperipheral Valsalva ratio (CPVR) was calculated, which is a quotient of cerebrovascular to peripheral autoregulation during phase IIb of VM. The test showed an increased index in pre-acupuncture migraineurs. In those patients, the cerebrovascular reactivity during the VM was exaggerated compared to the peripheral response. After acupuncture, the autonomic dysfunction in VA patients was positively influenced and almost normalized. These findings are in accordance with those of Bäcker et al.,²⁸ who showed that f-TCD response pattern during flickering light visual stimulation was significantly diminished in those who benefited from acupuncture treatment.

Conclusions

The current findings indicate that prophylactic acupuncture treatment influences the sympathetic-mediated dynamic cerebral autoregulation of migraineurs. Acupuncture might positively influence the dysfunction of the cerebrovascular response to autonomic stimuli, but not the cerebral vasotonus during rest. These results are in accordance with observations of Bäcker et al.,¹¹ who reported a dysregulation of the sympathetic nerve activity in migraine and a beneficial influence on the autonomic nervous system in migraineurs by acupuncture.

Footnotes

Acknowledgments

We thank Oliver Winzer, physicist, Department of Medical Psychology and Medical Sociology, University of Kiel, for programming the analysis software TRANSDOP. We also thank Stefan Theveßen for medical assistance.

Disclosure Statement

No competing financial interests exist.

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