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Vagally mediated heart rate variability ! International Headache Society 2015
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in headache patients—a systematic sagepub.co.uk/journalsPermissions.nav

DOI: 10.1177/0333102415583989
cep.sagepub.com
review and meta-analysis

Julian Koenig1, DeWayne P Williams1, Andrew H Kemp2,3 and

Julian F Thayer1

Abstract
Objective: Vagal nerve activity—indexed by heart rate variability (HRV)—has been linked to altered pain processing and
inflammation, both of which may underpin headache disorders and lead to cardiovascular disease (CVD). Here
we examined the evidence for differences in parasympathetic (vagal) activity indexed by time- and frequency-domain
measures of HRV in patients with headache disorders compared to healthy controls (HCs).
Methods: A systematic review and meta-analysis was conducted on studies investigating group differences in vagally
mediated HRV (vmHRV) including time- (root-mean-square of successive R-R-interval differences (RMSSD)) and fre-
quency- (high-frequency HRV) domain measures. Studies eligible for inclusion were identified by a systematic search of
the literature, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
Results: Seven studies reporting a total of 10 comparisons of patients with headache disorders (HF-HRV n ¼ 67, RMSSD
n ¼ 122) and HCs (HF-HRV n ¼ 64, RMSSD n ¼ 125) were eligible for inclusion. Random-effects meta-analysis revealed a
significant main effect on RMSSD (Z ¼ 2.03, p ¼ 0.04; Hedges’ g ¼ 0.63; 95% CI (1.24, –0.02); k ¼ 6) and similar
pooled effect size estimates for HF-HRV when breathing was controlled (g ¼ 0.30; 95% CI (0.69; 0.10)) but not
when breathing was not controlled (g ¼ 0.02; 95% CI (0.69; 0.74)). Controlling for breathing had no effect on RMSSD.
Conclusion: vmHRV is reduced in patients with headache disorders, findings associated with a medium effect size.
Suggestions for future research in this area are provided, emphasizing a need to investigate the impact of headache
disorders and commonly comorbid conditions—including mental disorders—as well as the investigation of the risk for
CVD in migraine in particular. We further emphasize the need for large-scale studies to investigate HRV as a mechanism
mediating the association of migraine and CVD.

Keywords
Primary headache disorders, migraine, tension-type headache, heart rate variability, parasympathetic activity,
meta-analysis
Date received: 3 November 2014; revised: 25 January 2015; accepted: 14 March 2015

Introduction of successive R-R-interval differences, RMSSD) pro-

Autonomic nervous system (ANS) dysfunction has vide a readily available, surrogate measure of vagal
been linked to common headache disorders including activity. While most studies have emphasized a role
migraine (1–3) and tension-type headache (TTH, 4,5).
The association between ANS dysfunction and 1
Department of Psychology, The Ohio State University, USA
migraine, in particular, is well documented within 2
University Hospital and Faculty of Medicine, University of São Paulo,
the literature. Heart rate variability (HRV) is Brazil
3
the beat-to-beat variation in the heart rate. School of Psychology & Discipline of Psychiatry, University of Sydney,
Parasympathetic modulation of the heart rate is Australia
fast (timescale in the order of milliseconds) while
Corresponding author:
sympathetic effects are much slower (6,7). Therefore, Julian Koenig, The Ohio State University, 175 Psychology Building,
high-frequency (HF) HRV and time-domain measures 1835 Neil Avenue, Columbus, OH 43210. USA.
reflecting these fast changes (i.e. the root-mean-square Email: koenig.393@osu.edu
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for sympathetic hyperactivity in headache disorders, and promising findings on vagus nerve stimulation in
examining a potential role for vagal parasympathetic people with chronic pain (29,30)—including migraine
activity may provide additional insights into the mech- (31) and cluster headaches (32)—is slowly gaining rec-
anism underlying headache disorders. ognition. Vagal activity in headache patients might be
Importantly, there is evidence that migraine with more than a simple marker of ANS dysfunction; it may
aura (MwA) is associated with increased risk of major actually be a major contributor to the condition itself.
cardiovascular disease (CVD), myocardial infarction, Recently, we were able to show (21), a negative correl-
ischemic stroke, and death due to ischemic CVD (8). ation of vmHRV and pain in multivariate adjusted ana-
Other studies found that both MwA and migraine with- lysis. Most interestingly—and deserving special
out aura (MwoA) are associated with CVD and risk notice—while individuals with chronic pain reported
factors for CVD (9,10). A recent systematic review lower vagal activity, the correlation of pain severity
found that migraine is associated with a twofold- and vmHRV was present only in respondents without
increased risk of ischemic stroke, which is apparent chronic pain, suggesting that the descending inhibitory
only among people who have MwA (11). Therefore, pathway via the vagus nerve is disturbed in patients
understanding the role of HRV in headache disorders with chronic pain (21).
might promote a deeper understanding of the increased Chronic reductions in HRV are also associated with
risk for CVD in headache patients. a variety of comorbidities that are themselves asso-
Vagal impairment—as indexed by HRV—may fur- ciated with headache disorders. While decreased HRV
ther lead to heightened inflammatory processes, which increases risk for morbidity, especially CVD, and is an
have also been associated with migraine (12). In par- independent risk factor for mortality (33,34), headache
ticular, impaired vagal efferent activity may lead to disorders are also associated with comorbid conditions
excessive inflammation via failure to inhibit release of such as depression and anxiety (35,36), which are also
pro-inflammatory cytokines, reflecting a poorly func- associated with reductions in HRV (37,38). The lifetime
tioning anti-inflammatory reflex (13–18). These inflam- prevalence of major depression is approximately three
matory processes may cause prolonged, ongoing times higher in patients with migraine and in individ-
excitation of primary nociceptive neurons leading uals with severe headache disorders (39). Depression
to chronic painful conditions. Recently, we were able without CVD is associated with reduced HRV
to show that vagally mediated HRV (vmHRV) pre- (37,40). While the underlying mechanisms in the asso-
dicts increased levels of inflammation four years later ciation of migraine and psychiatric comorbidity remain
(19), providing evidence for the anti-inflammatory unclear (41), vmHRV may provide a valuable tool to
reflex in humans. Vagal-nociceptive networks are further investigate the association of migraine, CVD,
also involved in pain processing (20), and decreased and comorbid depression. The present systematic
vagal activity leads to greater somatic and visceral review and meta-analysis reviews the current evidence
input via the spinothalamic track. Such loss of sen- on differences in vmHRV addressing if vmHRV is
sory integration due to decreased vagal activity may reduced in headache patients in comparison to healthy
result in greater affective processing of nociceptive controls (HCs).
information that results in overstraining adaptive cap-
abilities (21).
Lower vmHRV is reported in a variety of chronic Methods
painful conditions, such as chronic neck pain (22),
chronic pelvic pain (23), complex regional pain (24),
Systematic literature search
fibromyalgia (25,26) and irritable bowel syndrome A systematic search of the literature, according to the
(27). In light of this work, the vagus nerve is widely Preferred Reporting Items for Systematic Reviews and
perceived as a promising target for therapeutic inter- Meta-Analyses (PRISMA) statement (42), was
ventions in the treatment of chronic pain. An important employed. PubMed, PsycNET/PsycINFO, CINAHL
area involved in descending inhibitory modulation of Plus, and Web of Science (WOS) databases were
pain is the periaqueductal gray (PAG). It has been searched using the search terms ‘‘heart rate variability’’
shown that stimulation of the ventral PAG increases and ‘‘headache’’ OR ‘‘migraine’’ (see Appendix A for
HRV and decreases pain in humans with chronic pain search strategy by database). The number of initial hits
(28). Given that this pathway is distinct from dorsal was recorded and additionally a hand search (i.e.
PAG stimulation, it has been suggested that analgesia Google, Google Scholar and other sources) was per-
with deep brain stimulation in chronic pain is asso- formed. Reference lists of included studies were also
ciated with increased vagal parasympathetic activity checked for additional studies eligible for inclusion.
(28). Considering these anatomical connections, the After removing duplicates, abstracts of all articles
prominent role of the vagus nerve in pain processing, were screened based on predefined inclusion criteria.
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Koenig et al. 3

Studies were included if they reported (i) an empirical estimates and confidence intervals (CI) on the
investigation in (ii) humans and (iii) recorded HRV in selected indices of HRV. Studies that reported mul-
(iv) headache patients compared to HCs. All titles tiple groups of headache patients were included as
meeting the inclusion criteria were retrieved and long as they reported findings against HCs, while stu-
reviewed in full text. Empirical investigations were dies that compared different groups of headache
defined as studies involving active data collection in patients only were excluded. When multiple groups of
humans. Reviews, meta-analysis, comments, or single- headache patients (e.g. MwoA and MwA) were
case reports were excluded. Animal studies and studies reported, each group was compared to the same
using a computational modeling approach (i.e. virtual group of HCs.
data) were also excluded. The number of studies meet-
ing the prespecified inclusion criteria, number of studies
Meta-analysis
excluded, and reasons for exclusion were recorded
(Figure 1). Descriptive statistics (means and standard deviations
(SD)) of time- (RMSSD) and frequency- (HF-HRV)
domain measures of vmHRV from HRV recordings
Data extraction were extracted for each group. In case descriptive stat-
Guidelines from the Task Force of the European istics were reported other than as mean and SD, data
Society of Cardiology and the North American were imputed if possible (44,45). Where longitudinal or
Society of Pacing and Electrophysiology (43) were pre-post data were reported, only baseline HRV was
used to define the HRV measurements included for included to minimize confounding effects by experi-
analysis. Only components reflecting primarily vagal mental manipulation and conflation of effect size esti-
cardiac modulation were included. These included the mates. True effect estimates were computed as adjusted
root-mean-square of successive R-R-interval differ- standardized mean differences (Hedge’s g).
ences (RMSSD) or any spectral measure in the We undertook meta-analyses using both fixed-
high-frequency (HF) range of 0.15–0.4 Hz (natural log effect and random-effects models. When results
transformed (lnHF), normalized (HFnu) or expressed of both analyses are consistent (with CI of fixed-
as absolute power in ms2 (HFP)). Authors who effect analyses being included within that of the
reported HRV but who did not report RMSSD or random-effects analysis), the results from random-
HF-HRV, or did not provide sufficient quantitative effects models are reported, as it better conveys the
data (e.g. only a graphical display), were contacted to variability of data. However, when fixed-effect and
request the necessary information to derive effect size random-effect models give different results, results of

PubMed PsycNET/PsycINFO CINAHL Plus WOS Hand search

n = 63 n=0 n = 17 n=6

n = 99 total
n = 77 after removing duplicates

n = 18 possibly eligible Screening of abstracts for eligibility

for inclusion based on abstract
Excluded (n = 59)
Non-empirical studies (n = 5)
Screening of full texts (n = 18) Data requests (n = 10) Case studies (n = 3)
Excluded (n = 10) No headache patients (n = 34)
Insufficient reporting (n = 10) No healthy control group (n = 15)
No response (n = 5)
No valid address (n = 5) No HRV (n = 2)
Full text not available (n = 1)

n = 0 included n = 7 included in meta-analysis

n = 7 included
missing data received

HF RMSSD
k=4 k=6

Figure 1. Systematic literature search flowchart.

k: number of included comparisons on respective measure of vagally mediated heart rate variability (vmHRV).
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fixed-effects analyses are reported, as they provide a circadian rhythm (48-hour recordings of HRV) in 27
more reliable estimate of the true effect (46). Possible patients with migraine and 24 HCs. The authors
sources of heterogeneity or inconsistency among trials report only values derived from the Midline
in the magnitude or direction of effects were investi- Estimating Statistic of Rhythms (MESOR) variable, a
gated. Heterogeneity was assessed using the standard measure derived from cosinor analysis of long-term
I2 index, chi-square, and Tau2 tests (47). Bias was recordings. There were no significant differences
examined using a funnel plot of effect size against between headache patients and HCs. We included
standard error for asymmetry. Meta-analytic computa- mean and SD of RMSSD from MESOR analysis for
tions were performed using RevMan (version 5.3.4, meta-analysis. The study by Vollono et al. (52) reported
Copenhagen: The Nordic Cochrane Centre, The HRV data in different sleep stages and wakefulness and
Cochrane Collaboration, 2014). Risk of bias was also found a significant reduction of RMSSD, HF total
assessed in regards to reporting of comorbid condi- power, and NN50 in patients with migraine compared
tions, medication intake at the time of testing, other to HCs during waking rest. The authors compare head-
restrictions prior to the recording of HRV (i.e., smok- ache patients to a larger sample of HCs and age- and
ing, alcohol), and sample homogeneity including age, sex-matched HCs, of whom the latter comparison was
gender, headache diagnosis, headache history and fre- used for meta-analysis. Sanya and colleagues (53)
quency reported. Furthermore, meta-regression on assessed the autonomic regulation of the heart and per-
potential covariates was conducted if sufficient data ipheral blood vessels in migraine patients (n ¼ 30) and
were available. These covariates include headache diag- HCs (n ¼ 30) during baroreflex stimulation by oscilla-
nosis, headache history (duration of disorder), symp- tory neck suction. Analysis of five-minute baseline rec-
tom/attack frequency, age differences, gender ording (paced breathing) revealed no significant
differences, differences in the length of HRV recording difference in measures of HF-HRV between patients
and control for respiration. and HCs. Thomsen and colleagues (54) compared car-
diovascular response in 50 participants (n ¼ 27 MwoA
and n ¼ 23 MwA) and HCs (n ¼ 30), undergoing a
Results head-up tilt test, a cold-pressor test, and a Valsalva
maneuver. Data reported from the normal breathing
Selection of studies
baseline recording (150 consecutive heart beats, outside
The systematic search of the literature revealed a total a migraine attack) expressed as mean successive differ-
of 77 abstracts (after removing duplicates) that were ence of the numeric values of the R-R intervals (MSD
screened for eligibility of inclusion within the present index) were extracted and subjected to meta-analysis.
meta-analysis. A total of 18 studies were considered The authors reported no significant difference between
eligible for inclusion and retrieved in full-text (if pos- headache patients and HCs within this condition.
sible). Of the 77 abstracts evaluated, seven studies Gass and Glaros (48) investigated whether HRV
(48–54) yielding a total of 10 comparisons (HF-HRV measures taken at rest from patients with headache dis-
k ¼ 4, n ¼ 67 headache patients and n ¼ 64 HCs; orders (n ¼ 21; TTH, migraine, and mixed) differed sig-
RMSSD: k ¼ 6, n ¼ 122 headache patients and n ¼ 125 nificantly from those without headaches (n ¼ 19). They
HCs) were included in the meta-analysis. The system- reported that headache patients had less variability in
atic literature search and reasons for exclusion of stu- all HRV time domain measures, increased sympathetic
dies are illustrated in Figure 1. nervous system (SNS) activity and decreased parasym-
pathetic nervous system (PNS) activity compared to
HCs. However, significant differences between groups
Included studies by clinical etiology were reported only for pNN50 and NN50 indices of
Sample characteristics of included studies are summar- HRV—both measures of vmHRV. RMMSD and
ized in Table 1. The majority of studies investigated HF-HRV derived from five-minute recordings of
patients with migraine. Nilsen and colleagues (49) HRV were subjected to the meta-analysis.
investigated differences in HRV and spontaneous bar- Furthermore, one study by Tubani and colleagues
oreflex sensitivity in female migraine patients (n ¼ 16) (50) investigated differences in 24-hour recordings of
compared to HCs (n ¼ 14). They recorded HRV for 24 HRV in patients with cluster headache (n ¼ 8) com-
hours and 10 minutes of paced breathing. To avoid pared to HCs (n ¼ 8). Results revealed significant
effect size inflation by including multiple measures differences in low-frequency HRV (LF-HRV) but not
from the same participants, only HRV indices derived HF-HRV. Reported HF-HRV values for the entire
from the 24-hour measurement period was used. Long- length of the recording (24-hour) were subjected to
term recordings were also obtained by Tabata and col- meta-analysis. Details on extracted HRV values and
leagues (51), who investigated differences in the conditions are provided in Table 2.
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Koenig et al.

Table 1. Sample characteristics of included studies.

N (female),
Authors Year Comparison Criteria Duration Frequency HCs HAP/HC Age mean (SD) HAP/HC
a
Gass and Glaros 2013 Mixed vs. HCs IHS criteria > 6 mths n.r. Sex and age matched 21 (19)/19 (17) 32.86 (11.74)/30.37 (11.2)
(ICHD-II)
[6.5.2015–10:10am]

Nilsen et al.b 2009 MwoA vs. HCs IHS criteria >1 yr 2.3 (1.1) Sex and age-matched 16 (16)/14 (14) 23.4 (3.2)/22.8 (1.5)
(ICHD-1) last mth controls
Sanya et al. 2005 MwoA/MwA vs. HCs IHS criteria 7.6 (4.5) yrs n.r. Sex- and age-matched 30 (25)/30 (22) 34 (2)/34 (2)
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Tabata et al. 2000 MwoA/MwA vs. HCs IHS criteria 10.5 (10.4) yrs 5.9 (5.7) Healthy volunteers 27 (n.r.)c/24 (n.r.)d 30.2 (12.7)/31.1 (12.1)
p mth
(CEP)

Thomsen et al. 1995 (a) MwoA vs. HCs IHS criteria 20 (1–38) yrs 24 (0.1–72) Sex- and age-matched 27 (n.r.)e/30 (n.r.)f n.r. (n.r.)g/42.0 (n.r.)h
p yr controls (5 yrs)
Thomsen et al. 1995 (b) MwA vs. HCs IHS criteria 23 (3–49) yrs 32 (2–75) Sex- and age-matched 23 (n.r.)i/30 (n.r.)j n.r. (n.r.)k/42.0 (n.r.)l
p yr controls (5 yrs)
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Tubani et al. 2003 CH vs. HCs IHS criteria n.r. n.r. Cross-matched for 8 (0)/7 (0) n.r. (n.r.)m/n.r. (n.r.)
sex and age
Vollono et al. 2013 MwoAn vs. HCs IHS criteria n.r.o 8.5 (1.4) Sex and age matched 8 (6)/8 (6) 48.1 (9.3)/46.7 (10.7)
(ICHD-II) p mth
HCs: healthy controls; HAP: headache patients; MwoA: migraine without aura; MwA: migraine with aura; CH: cluster headaches; IHS: International Headache Society; ICHD: International Classification of
Headache Disorders; mth: month; yr: year; n.r.: not reported; TTH: tension-type headache.
a
Eight TTH, seven migraine, six migraine and TTH.
b
Two comparisons reported for this study one on long-term HRV recordings and one on short-term.
c
Ratio reported, men to women: 5:19.
d
Ratio reported, men to women: 6:21.
e
Ratio reported for the entire sample, men to women: 7:43.
f
Ratio reported for the entire sample, men to women: 5:25.
g
Mean age and range reported for the entire sample of headache patients, mean 42.4 (range 19–66).
h
Range reported: 20–66.
i
Ratio reported for the entire sample, men to women: 7:43.
j
Ratio reported for the entire sample, men to women: 5:25.
k
Mean age and range reported for the entire sample of headache patients, mean 42.4 (range 19–66) used for meta-regression.
l
Range reported: 20–66.
m
Age range of headache patients: 26 to 42 years, age of 34 used for meta-regression.
n
Comorbid sleep-related headache.
o
Duration reported for every participant but no sample mean.
5
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Table 2. Details on HRV recording and data extracted from included studies.

Mean HF (SD) RMSSD mean (SD)

[6.5.2015–10:10am]

Authors Year Comparison Condition extracted vmHRV finding HAP HCs HAP HCs

Gass and Glaros 2013 Mixed vs. HCs Five min, resting Ø 49.50 (19.44) 59.74 (18.77) 46.20 (38.14) 63.79 (33.19)
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(breathing recorded)
Nilsen et al. 2009 MwoA vs. HCs 24 hours Ø n.r. (n.r.) n.r. (n.r.) 85.2 (42.8) 68.9 (23.8)
(CEP)

Sanya et al. 2005 MwoA/MwA vs. HCs Five min baseline Ø 6.21 (0.26)i 6.45 (0.31)i n.r. (n.r.) n.r. (n.r.)
(paced breathing)
Tabata et al. 2000 MwoA/MwA vs. HCs 48-hour recordings, averaged Ø n.r. (n.r.) n.r. (n.r.) 41.6 (0.2)a 43.6 (0.2)a
to 24 hours (MESOR)
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Thomsen et al. 1995 (a) MwoA vs. HCs 150 consecutive heart beats, Ø n.r. (n.r.) n.r. (n.r.) 3.6 (0.3)b 4.9 (0.7)b
rest supine (normal breathing)
Thomsen et al. 1995 (b) MwA vs. HCs 150 consecutive heart beats, Ø n.r. (n.r.) n.r. (n.r.) 3.6 (0.5)b 4.9 (0.7)b
rest supine (normal breathing)
Tubani et al. 2003 CH vs. HCs 24 hours Ø 9.043 (3.796) 7.654 (3.002) n.r. (n.r.) n.r. (n.r.)
Vollono et al. 2013 MwoAc vs. HCs Five min, quiet wakefulness HAP #RMSSD 33.7 (n.r.)e 40.7 (n.r.)d,e 24.6 (n.r.) 35.4 (n.r.)
and HFd
HCs: healthy controls; HAP: headache patients; HF: high-frequency; RMSSD: root-mean-square of successive R-R-interval differences; MwoA: migraine without aura; MwA: migraine with aura; CH: cluster
headaches; n.r.: not reported; n.a.: not applicable; h: hour; min: minute; vmHRV: vagally mediated heart rate variability; Ø: no significant differences comparing HAP and HCs.
a
SD imputed from standard error.
b
Reported as MSD in percentage of mean R-R. SD imputed from standard error.
c
Comorbid sleep-related headache.
d
Significant lower total HF power in headache patients compared to matched controls reported. Normalized units used for analysis (no significant effect).
e
SD imputed from p values of Mann-Whitney U test.
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Koenig et al. 7
Meta-analysis main effect (Figure 4(a)) revealed considerable asymmetry for
First, we aimed to identify an overall effect of headache RMSSD, indicating publication bias. Substantial het-
disorder on vmHRV, followed by subsequent analysis erogeneity was assumed if I2 was greater than 50%,
that aimed to investigate differences between clinical indicating that 50% of the variability in the outcome
etiologies (diagnosis). Random-effect meta-analysis, cannot be explained by sampling variation.
on RMSSD, revealed that headache patients (n ¼ 122) As we assumed that the significant effect on RMSSD
displayed significantly lower vmHRV compared to HCs might relate to the considerable asymmetry of included
(n ¼ 125) (Z ¼ 2.03, p ¼ 0.04) (g ¼ 0.63; 95% CI studies, in particular the unlikely large effect reported
(1.24, 0.02); k ¼ 6) indicating lower vagal activity by Tabata et al. (51), and given that this effect estimate
in headache patients. CIs of fixed-effect models was derived from a different analytical approach
(Z ¼ 4.35, p < 0.00001; Hedges’ g ¼ 0.58; 95% CI (MESOR analysis) we excluded the study in a second-
(minus0.85, 0.32); k ¼ 6) were included in those of ary analysis (leave-one-out meta-analysis). When
random-effect models, thus random-effects are illu- excluding the study (see outlier in Figure 4), the signifi-
strated in Figure 2 (negative effect estimates reflect cant main effect on RMSSD remained in fixed-effect
lower RMSSD in headache patients). meta-analysis (Z ¼ 2.33, p ¼ 0.02; Hedges’ g ¼ 0.34;
Random-effect meta-analyses on HF-HRV revealed 95% CI (0.63, 0.05); k ¼ 5) (CIs of fixed-effect not
no significant difference (Z ¼ 1.26, p ¼ 0.21) between included in those of random-effect models). Thus, we
headache patients (n ¼ 67) and HCs (n ¼ 64) (Hedges’ conclude that the main effect reported for RMSSD is
g ¼ 0.22; 95% CI (0.57, 0.12); k ¼ 4). As the CI of likely driven by study heterogeneity, but remains sig-
the fixed-effects model (Z ¼ 1.26, p ¼ 0.21; Hedges’ nificant when controlling for such bias.
g ¼ 0.22; 95% CI (0.57, 0.12); k ¼ 4) was included
in that of the random-effects model, results of random-
effects are illustrated (Figure 3; negative effect estimates
Risk of bias and meta-regression
reflect lower HF in headache patients). Risk of bias assessment (Table 3), revealed large risk of
Significant heterogeneity was observed for RMSSD bias regarding the reporting of comorbid conditions
(see test results in Figure 2), and visual examination of (i.e. depression, anxiety), medication intake, and other
funnel plots for HF (Figure 4(b)) and RMSSD restrictions prior to the examination (i.e. smoking,

Headache Patients Healthy Controls Std. Mean Difference Std. Mean Difference
Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random,95% CI IV, Random,95% CI
Nilsen et al. 2009 85.2 42.8 16 68.9 23.8 14 16.3% 0.45 [–0.28, 1.18]
Thomsen et al. 1995 (b) 3.6 2.398 23 4.9 3.834 30 18.3% –0.39 [–0.94, 0.16]
Thomsen et al. 1995 (a) 3.6 1.559 27 4.9 3.834 30 18.4% –0.43 [–0.96, 0.10]
Gass & Glaros 2013 46.2 38.14 21 63.79 33.19 19 17.4% –0.48 [–1.11, 0.15]
Volono et al. 2013 24.6 9.313 8 35.4 9.313 8 12.8% –1.10 [–2.17, –0.02]
Tabata et al. 2000 41.6 1.039 27 13.6 0.98 24 16.9% –1.95 [–2.62, –1.27]

Total (95% CI) 122 125 100.0% –0.63 [–1.24, –0.02]

Heterogeneity: Tau2 = 0.45; Chi2 = 25.15, df = 5 (P = 0.0001); I2 = 80%
–2 –1 0 1 2
Test for overall effect: Z = 2.03 (P = 0.04)
Lower RMSSD Greater RMSSD

Figure 2. Random-effect meta-analysis main effect Forrest plot for root-mean-square of successive R-R-interval differences
(RMSSD).

Headache Patients Healthy Controls Std. Mean Difference Std. Mean Difference
Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random,95% CI IV, Random,95% CI
Tubani et al. 2003 9.043 3.796 8 7.654 3.002 7 11.3% 0.38 [–0.65, 1.41]
Sanya et al. 2005 6.21 1.424 30 6.45 1.698 30 46.5% –0.15 [–0.66, 0.36]
Volono et al. 2013 33.7 21.685 8 40.7 21.685 8 12.3% –0.31 [–1.29, 0.68]
Gass & Glaros 2013 49.5 19.44 21 59.74 18.77 19 29.9% –0.52 [–1.16, 0.11]

Total (95% CI) 67 64 100.0% –0.22 [–0.57, 0.12]

Heterogeneity: Tau2 = 0.00; Chi2 = 2.30, df = 3 (P = 0.51); I2 = 0% –2 –1 0 1 2
Test for overall effect: Z = 1.26 (P = 0.21) Lower HF–HRV Greater HF–HRV

Figure 3. Random-effect meta-analysis main effect Forrest plot for headache disorders-heart rate variability (HF-HRV).
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8 Cephalalgia 0(0)
(a) SE(SMD)
0 (g ¼ 0.18; 95% CI (0.63; 0.27)). No other covariate
0.2
0.4
0.6
0.8
1
–2 –1 0 1
(b) SE(SMD)
0 RMSSD (Hedges’ g ¼ 0.63) and similar effect-size
0.2
0.4
0.6
0.8
1
–2 –1 0 1
Figure 4. Funnel plot for (a) RMSSD and (b) HF-HRV.
RMSSD: root-mean-square of successive R-R-interval differences;
HF-HRV: headache disorders-heart rate variability; SMD:
standardized mean difference; SE: standard error.
alcohol) that have substantial effects on HRV.
Furthermore, reported samples from studies showed
large heterogeneity in age, gender, headache history
and symptom frequency.
We performed a series of meta-regressions and sub-
group analysis to identify potential covariates of the
observed main effect found. There were not enough
studies to address differences between studies recording
HRV during uncontrolled (free) breathing and paced
breathing using meta-regression on HF but RMSSD
(Table 2). In a sub-group analysis on HF, studies that
controlled or recorded breathing showed a significant
greater pooled effect estimate for HF (g ¼ 0.30; 95%
CI 0.69; 0.10)), compared to studies using uncon-
trolled conditions (g ¼ 0.02; 95% CI (0.69; 0.74)).
Controlled breathing was not a significant covariate
of RMSSD ( ¼ 0.822, SE ¼ 0.637; 95% CI (0.427;
0.637); p ¼ 0.197). Further subgroup analysis on eti-
ology indicated lower RMSSD in migraine patients
(g ¼ 0.93; 95% CI (1.69; –0.18)) compared to a
sample of patients with a variety of headache disorders,
including migraine and TTH (g ¼ 0.48; 95% CI
(0.48; 0.15)). Furthermore, patients with cluster head-
ache showed increased HF (g ¼ 0.48; 95% CI (0.65;
[1–14]
(CEP) [PREPRINTER stage]
1.41)) and patients with migraine decreased HF
yielded a significant influence on the effects reported.
Discussion
Research on differences in vagal activity in headache
patients may have important implications for better
understanding the elevated risk for CVD in these indi-
viduals. The present meta-analysis is the first to sum-
marize the current evidence on vagal activity as indexed
SMD
2
by vmHRV in headache patients. Meta-analysis
revealed a significant and sizeable main effect on
estimates for HF-HRV when breathing was controlled
(Hedges’ g ¼ 0.30). The effect for both selected indices
of vmHRV revealed similar findings, indicating
decreased vagal activity in headache patients.
While our initial analysis indicated significant differ-
ences between headache patients and HCs on RMSSD
only, subgroup analysis showed an effect of respiratory
control on the reported effects for HF-HRV, but not
SMD RMSSD. Our findings demonstrate that studies con-
2 trolling for respiration reported larger effect sizes than
those that did not control for respiration. Thus, the
results for RMSSD and HF-HRV are consistent when
respiration is controlled. The fact that respiration had a
greater effect on HF-HRV than on RMSSD is not sur-
prising. Our group (55) as well others have shown that
RMSSD is less affected by respiration than other indi-
ces of HRV including spectrally derived HF-HRV (56).
HRV indices derived from frequency domain analysis
provide information of different quality and detail com-
pared to time-domain analysis (57). While RMSSD and
HF are highly correlated (58), it has been suggested that
time-domain parameters can be estimated with less bias
and considerably smaller variability as compared with
frequency-domain parameters (59).
While we selected the two most prominent and fre-
quently used parameters of vmHRV (RMSSD and HF)
for the present analysis, other indices reflecting vagal
activity such as the NN50 or pNN50 component are
of interest. Three studies by Gass and Glaros (48),
Tabata et al. (51) and Vollono et al. (52) reported
these and found significantly lower NN50 and pNN50
in headache patients compared to HCs in line with
our findings of lower vagal activity indexed by
RMSSD and HF.
Of the four studies reporting RMSSD, only two stu-
dies initially reported significant differences between
headache patients and HCs (49,52), while three found
no significant differences in the selected indices of vagal
activity (48,51,54). One study that reported significant
differences found RMSSD to be greater in headache
patients (49), and one found RMSSD to be lower in
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Koenig et al. 9

Table 3. Risk of bias assessment of included studies.

Patient sample homogeneity

Authors Year Medication Comorbidity Restrictions Age Gender Diagnosis Frequency HA History
Gass & Glaros 2013
? 1 - ? 2 - 3 - 4 - 5 - - 6

Nilsen et al. 2009

? 7 + ? 8 + - 9 + + ? 10

Sanya et al. 2005

- - ? 11 + - 12 ? 13 - + 14

Tabata et al. 2000

+ 15 - - - 16 - 17 ? 18 - 19 - 20

Thomsen et al. 1995

? 21 - ? 22 - 23 - 24 + - 25 - 26

Tubani et al. 2003

- 27 ? - - 28 + + - -
Volono et al. 2013
+ + - - 29 - 30 ? 31 + +

a
Participants taking medications for cardiovascular control, such as beta-blockers, were excluded, no analgesics for any reason within 12 hours, no
permanent medication reported.
bA
void exercise or use of any caffeine, tobacco, or alcohol products 30 minutes prior.
c
Large SD in age (> 10 years).
d
Dominantly female.
e
Mixed sample of migraine and tension-type headache (TTH).
f
Any duration longer than six months.
g
No prophylactic drugs.
h
No headache or use of alcohol three days before the investigation.
i
Dominantly female.
j
Not reported in detail but similar age of onset.
k
Asked to refrain from consuming alcohol or caffeine for 24 hours prior to the tests.
l
Dominantly female.
m
Migraine without aura (MwoA) and migraine with aura (MwA).
n
Mean migraine duration of 7.6 (4.5) years with similar intensity.
o
Ceased taking prophylactic medication for at least one month.
p
Large SD in age (> 10 years).
q
Dominantly female.
r
MwoA and MwA, majority MwoA.
s
0.5 to 12 attacks per month with a duration of 2 to 72 hours.
t
One to 35 years.
u
Not allowed to take ergotamine or morphinomimetics 48 hours prior to examinations, sumatriptan 24 hours prior and weak analgesics six hours
prior to examinations.
v
Headache medication but no restrictions on smoking etc.
w
19 to 66 years.
x
Dominantly female.
y
0.1 to 75 attacks per year.
z
One to 49 years.
aa
Allowed to use.
bb
26 to 42 years.
cc
Large SD in age (> 10 years).
dd
Dominantly female.
ee
MwoA but with comorbid sleep-related headaches.

headache patients (52). Except for one study (52), none analysis to provide a more objective assessment of the
of the studies on HF-HRV initially reported significant extant literature.
differences between headache patients and HCs Results from subgroup analysis on diagnosis of
(48,50,53). This further highlights the utility of meta- headache disorder revealed lower vagal activity in
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10 Cephalalgia 0(0)

migraineurs compared to mixed samples of patients included studies reported only mixed (women and
with a variety of headache disorders, including men) samples. Lastly, we compared short- (<1 hour)
migraine and TTH, and patients with cluster headache. with long-term recordings (24 or 48 hours) using meta-
These findings provide first the evidence for a unique regression, but found no significant differences. It is
association of migraine and vagal activity, lending fur- noted that guidelines for the measurement of HRV
ther support for our hypothesis that reduced vagal (45) suggest that spectral analysis of 24-hour long-
activity may provide a physiological pathway linking term HRV (where spectral estimates are calculated
migraine and CVD. However, it is important to note over long data epochs that are not likely to be station-
that there are insufficient data to determine robust dif- ary) may not accurately reflect autonomic modulation,
ferences in vagal activity comparing different diagnosis which may be better captured by estimates based on
of primary headache disorders. Regarding a potential shorter data epochs. Future studies should take this
pathway linking HRV and CVD in headache patients, into account. Furthermore, no study recording HRV
the distinction between different headache disorders is for at least 24 hours (49–51) addressed potential differ-
crucial, as different diagnoses are associated with dif- ences between awake and sleep periods. The data by
ferent risk factors for CVD (60), and it is proposed that Vollono et al. (52) show that such analyses may be
different mechanism underlie the elevated CVD risk in important to address the involvement of the vagus
MwA in comparison to other headache types (61,62). nerve, as during nighttime, movement artifacts are
In general, symptom history and frequency—both minimized and the contribution of sympathetic influ-
important diagnostic qualities—are inadequately ences is low, in particular when further exploring
reported in most of the included studies, and as a sleep-related headache.
result we did not have sufficient data to perform The present systematic review and meta-analysis
meta-regression on symptom/attack frequency. In fact faces several limitations that need to be addressed in
only two studies provided adequate reporting of head- future research, especially given the availability of pri-
ache frequency (49,52) and headache history (52,53). mary research on this topic. Overall, this analysis was
We analyzed the reported mean duration of headache performed on a relatively small data set, including only
symptoms as a potential covariate on RMSSD but seven studies, all with high risk of bias (Table 3). We
found no significant differences. Given that, in most were not able to retrieve one full-text of a study con-
cases, studies on migraine patients did not distinguish ducted in Poland (73) that compared 40 headache
between MwA and MwoA symptoms, we were not able patients to 62 HCs. One study conducted in children
to address the potential impact of migraine aura. and adolescents (74) with potential data of interest, that
Critically, past research demonstrates that the associ- also reviewed the existing literature without taking a
ation of migraine and CVD might depend on the pres- meta-analytical approach, did not report the respective
ence of aura symptoms (63). One of the included studies indices of interest (HF-HRV or RMSSD) and we were
explicitly addressed differences in MwA and MwoA not able to obtain the data. Two studies published in
patients (54), but found no significant differences. 1993 by the same group of authors, investigating ANS
Given that we were not able to address differences in function in patients with TTH (75) and migraine (76),
vagal activity between MwoA and MwA using meta- did not report sufficient baseline data (i.e. a graphical
analysis, future studies on differences between the two display only instead of reporting exact means and SDs)
etiologies are encouraged. Thus, future studies are on vagal indices of HRV, and again, we were not able
needed to (i) compare different diagnosis of primary to obtain the data. Another three studies, two by
headache disorders, (ii) investigate the association of Zigelman et al. (77,78) and one by Appel et al. (79)
symptom severity (i.e. frequency, intensity, duration were insufficient in terms of reporting data of interest,
of attacks) and vmHRV, as well as (iii) the (longitu- and we were unable to contact the authors. Pierangeli
dinal) association of headache history and vmHRV, and colleagues (80) explored differences in cardiovascu-
and (iv) address differences in MwA and MwoA. lar responses to the tilt test and Valsalva maneuver in
While we found age not to be a significant covariate HCs compared to patients with MwoA and MwA, but
of HF-HRV, interpretations should be drawn with cau- provide data on HF as a graphical display only and we
tion given the relatively small mean differences in age were unable to contact the authors. Within a commen-
between samples (Table 1) included in the present ana- tary to a paper by Kurth et al. (10), Perciaccante et al.
lysis. HRV decreases with age (64–67) and future stu- (81) report some preliminary findings on HRV differ-
dies should investigate age as an important ences in headache patients compared to HCs. Again,
covariate—in particular linking the age of onset of however, we were not able to obtain the necessary data
symptoms and age at time of HRV recording. We to include the study in the present meta-analysis. The
were unable to explore potential gender differences in study by Shechter et al. (82) reported RR variation but
HRV that have recently been reported (68–72) as no indices of vmHRV, and we were not able to obtain
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Koenig et al. 11

the data. We also requested details on the HRV meas- lying headache disorders and an increased risk for
ures taken in the study by Aygül et al. (83) that CVD in headache patients. Three potential models
reported only RR variation but not values for HF (61) may underpin the link between headache and
and RMSSD, but did not receive a response from the CVD: (i) the frequent experience of headache may
authors. Studies that illustrate but insufficiently report lead to lifestyle changes such as decreased physical
findings on vagal indices of HRV are inconsistent, activity, altered smoking habits or an unhealthy die-
reporting lower parasympathetic activity in headache t—all of which may reduce vmHRV—that elevate
patients compared to HCs (73) or no differences CVD risk; (ii): an unfavorable CVD risk profile is asso-
(74–76,79). Given the exclusion of these 11 studies ciated with reduced vmHRV, which could subsequently
(73–83) with potential data of interest, the present ana- lead to the development of headache; and (iii) genetic
lysis is limited and not completely reflective of the exist- or environmental causes common both to headache
ing evidence. and an unfavorable CVD risk profile may lead to
In addition, it is critical to note that all included reductions in vmHRV. Here we emphasize how
studies carry a potential high risk of bias (Table 3). vmHRV may relate to headache disorders and CVD;
In general, most studies failed to report medication in however, future research is needed to determine
sufficient detail, an important issue considering whether vmHRV is actually a mediating factor of
well-known effects on HRV (37,84). Furthermore, headache disorders and its relationship to CVD.
most studies failed to control for frequent comorbid Future studies are needed to: (i) carefully distinguish
conditions described in the context of headache dis- between different diagnosis based on established cri-
orders (i.e. anxiety and depression) that are also teria, (ii) examine homogenous samples of patients of
linked with HRV. We also found large methodological the same age, gender, with the same diagnosis, and
differences between studies regarding the recording of headache characteristics (i.e. frequency, intensity, head-
HRV. Specifically, some studies asked participants to ache history) that (iii) control for comorbid conditions,
avoid exercise, smoking or alcohol consumption prior and (iv) determine the impact of medication on vagal
to the recording of HRV, while others did not control activity, in addition to primary headache disorders and
for such influences. We addressed publication bias and comorbid conditions.
study heterogeneity excluding one study on RMSSD
(38), reporting an unlikely large effect and found the
Conclusion
main effect for RMSSD to hold.
Lower vagal activity, indexed by vmHRV, is asso- We demonstrate here that vmHRV is reduced in
ciated with an increased risk for CVD. Furthermore, patients with primary headache disorders, findings
lower vmHRV is associated with greater inflammation associated with a medium effect size. Future studies
and less inhibitory control in pain processing. Chronic are needed to further examine the association
pain patients show lower HRV, and vagus nerve stimu- between headache disorders—and migraine in
lation in chronic pain patients (including migraine and particular—vmHRV, common comorbid conditions
cluster headache) may lead to pain release and a sim- and risk for CVD. We emphasize the necessity of
ultaneous increase in HRV. Therefore, reduced future large-scale studies to further investigate these
vmHRV may reflect an important mechanism under- pathways.

Clinical implications
. This is the first meta-analysis on vagal activity indexed by heart rate variability in headache patients
compared to healthy controls.
. Vagal activity is reduced in headache patients compared to healthy controls.
. Lower vagal activity provides a mechanism linking headache disorders—in particular migraine—to cardio
vascular disease and comorbid depression.

Funding
This work was supported by FAPESP, a Brazilian research Acknowledgment
funding institution in the state of São Paulo, and by Ohio We thank Fiorella Pepe, executive secretary, Segreteria
State University, which has helped to initiate collaborative Società Italiana di Medicina Interna, for providing us with
activities between the authors of the current manuscript. the full text of one included paper.
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12 Cephalalgia 0(0)

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