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HeartRateVariabilityBerntsonandCaciop po
Heart Rate Variability: A Neuroscienti~c Perspective
for Further Studies
Gary G. Berntson1and John T. Cacioppo2
1The Ohio State University, Columbus, OH;
and 2The University of Chicago, Chicago, IL
Heart rate variability (HRV) has proven to be a useful
tool for studies of autonomic control and its central
integration. Technical and analytical developments
continue to advance the available methods for extract-
ing accurate estimates of the components of heart rate
variability, and two international committees of scien-
tists have now recognized the potential utility of these
measures for both research and clinical applications
[1,2]. Additional research is necessary, however, to
more fully elucidate the mechanisms of HRV and to
re~ne approaches to the interpretation of these meas-
ures.
Neuroscienti~c Background
As noted by Malliani, Montano and Pagani [3] in the
previous (1997) issue on Noninvasive Cardiac Electro-
physiology, neural regulation of the heart entails a
complex interplay of central integrating mechanisms
and peripheral feedback loops. The dynamic interac-
tions of these processes result in rhythmical _uctu-
ations in heart rate within several frequency bands.
The high frequency (HF) band (⬃0.15–0.4 Hz in
adults), associated with respiratory sinus arrhythmia
(RSA), is considered to re_ect vagal modulation of the
heart, as sympathetic sinoatrial synapses and their in-
tracellular signaling pathways effectively ~lter out pe-
riodic _uctuations beyond about 0.15 Hz [1–5]. At
lower frequencies, however, sympathetic as well as va-
gal rhythms can translate into periodic _uctuations in
heart rate. Consequently, lower frequency rhythms in
heart rate in the low frequency (LF) range (⬃0.05–0.15
Hz; also referred to as the 0.1 Hz rhythm) or the very
low frequency range (⬃0.003–0.05 Hz) can re_ect the
joint action of both sympathetic and parasympathetic
neural in_uences.
Although HF rhythms in heart rate can reasonably
be interpreted to re_ect _uctuations in vagal cardiac
control, there remain important caveats in interpreta-
tion. These _uctuations arise from the inspiratory-re-
lated inhibition of vagal out_ow, and thus would be
expected to correlate with the overall level of vagal
control. But vagal inhibition may not be complete with
typical inspiratory volumes, so the magnitude of vagal
_uctuations and associated HRV is also a function of
tidal volume [6]. Moreover, higher frequency respira-
tory _uctuations in vagal control are not as effectively
transferred to variations in heart rate as are lower
frequency respiratory rhythms [7]. Finally, respiratory
frequencies can sometimes fall below the typical 0.15
Hz band pass for HF variability, and thus appear in
lower frequency bands. These considerations indicate
the need for greater attention to respiratory parame-
ters in interpreting HF variability [2].
Interpretation of HRV at lower frequencies is even
more problematic. Although measures of LF vari-
ability are sometimes considered an index of sympa-
thetic control, both sympathetic and parasympathetic
branches can contribute to these rhythms. In fact, va-
gal blockade with atropine can dramatically reduces
LF variability [8]. A proposed interpretive approach is
based on the fact that the two autonomic branches are
often reciprocally controlled, with increases in the ac-
tivity of one branch associated with decreases in the
other [3]. To the extent to which a reciprocal relation-
ship holds among the autonomic branches, it is argued
that the problem of specifying the state of autonomic
control may be reducible to a bipolar dimension of sym-
pathovagal balance, an index of which (LF/HF ratio)
may be derivable from HRV measures [3,9]. An exam-
ple of reciprocal regulation can be found in basic brain-
stem re_exes such as baroreceptor heart rate re_ex,
although this is not an invariant pattern. Hypoxia
[10,11] or atrial stretch [12,13], for example, can yield a
re_ex coactivation of both autonomic branches. This
raises an important issue for measures of sympathova-
gal balance.
Although there are important feedback in_uences
on HRV, the crucial role of central integrative mecha-
nisms is increasingly recognized, and these mecha-
nisms are not limited to the brainstem [14,15]. In fact,
basic cardiovascular re_ex substrates can be modu-
lated or even bypassed by rostral neural systems.
These systems include the hypothalamus, the amyg-
dala and the medial prefrontal cortex, which have been
Preparation of this manuscript was supported in part by grant
HL54428 from the National Institutes of Health, Heart Lung and
Blood Institute.
Address correspondence to: Gary G. Berntson, Ph.D., Ohio State
University, 1885 Neil Avenue, Columbus, OH 43210. E-mail:
berntson.2@osu.edu
279
Cardiac Electrophysiology Review 1999;3:279–282
© 2000 Kluwer Academic Publishers. Printed in the Netherlands.
shown to issue monosynaptic projections to brainstem
re_ex networks as well as autonomic source nuclei [16].
Rostral systems appear to be more _exible in the pat-
tern of autonomic control that they exercise, and can
yield reciprocal, independent, or coactive changes in
the activities of the autonomic branches [17,18].
Even in cases where rostral in_uences foster a gen-
eral reciprocal mode of autonomic control, there ap-
pears to be an important difference from the pattern of
reciprocal control exerted by baroreceptor re_exes.
Selective pharmacological blockades revealed that an
orthostatic challenge and standard psychological stres-
sors (e.g., mental arithmetic, reaction time task) yield
a similar pattern of reciprocal sympathetic activation
and vagal withdrawal in human subjects, when consid-
ered at the group level [19]. The response to ortho-
static stress displayed minimal individual variation, so
the reciprocal changes in the autonomic branches were
highly correlated across subjects. In contrast, psycho-
logical stressors, typical of those encountered in daily
life, yielded wide individual differences in the mode of
response, with some subjects consistently showing
predominantly sympathetic activation, others primar-
ily vagal withdrawal, and still others a reciprocal pat-
tern of autonomic response [19].
These neurobehavioral in_uences highlight the
need for a more comprehensive and realistic frame-
work for models of central autonomic control. The
neurobiological perspective also focuses on a relatively
neglected source of variance in autonomic regulation,
related to the feedback consequences of autonomic
state on the operations of rostral neural systems
[16,20]. Peripheral feedback loops in basic autonomic
re_exes are central concepts in cardiovascular physiol-
ogy, but the role of ascending visceral afference in the
functions of higher neural control systems has received
less attention. In fact, there are relatively direct as-
cending pathways, such as the noradrenergic projec-
tion from the locus coeruleus and the corticopetal
cholinergic projection of the basal forebrain, whereby
activities in autonomic source nuclei and brainstem
re_ex networks can modulate higher neural processes
[16,20]. These relationships have important implica-
tions for future studies.
Directions for Further Studies
1. Improved methods for quanti~cation
of HRV components
There are many analytical challenges in decomposing
HRV into functional components that relate meaning-
fully to basic physiological mechanisms and processes
[1,2]. Nonstationarities in RR-interval series, the pres-
ence of arrhythmias in clinical populations, and even
the accurate measurement of cardiac events pose
methodological problems for HRV studies. These is-
sues are important for future studies, but will not be
further dealt with here, as they are considered else-
where in this volume. At least as important, however,
are empirical and conceptual developments in our un-
derstanding of the mechanisms of HRV.
2. Origins and mechanisms of
autonomic control
Although much is known of the multiple mechanisms
contributing to HRV, the relative contributions of cen-
tral and peripheral processes has not been fully settled
[2,15,24]. Adding complexity to this issue is the fact
that central cardiovascular control systems extend be-
yond the brainstem to the highest level of the neuraxis.
Whereas the construct of sympathovagal balance may
have applicability in limited contexts, it is less mean-
ingful in situations where nonreciprocal patterns of
control manifest [17,18,21]. The latter mandate more
comprehensive models of autonomic control, and stra-
tegically derived measures that tap critical features of
the broader cardiovascular control system. This does
not imply that the construct of sympathovagal balance
is meaningless—only that it is incomplete. In this re-
gard, two important directions for future research are
a) the delineation of conditions under which reciprocal
and other patterns of autonomic control manifest, as
well as the functional bases of these patterns of control,
and b) the further development of measures that re-
_ect more closely the broader underlying neurophysi-
ology of cardiovascular control [21,22].
3. Validation of HRV indices as markers
of physiological processes
It is important to progressively advance HRV meas-
ures from the status of outcomes of a state or process
to markers of that state or process [23]. Both outcome
measures and markers capture the predictive relation
from a physiological state to an experimental measure,
but a marker also permits inferences concerning the
physiological state from the experimental index,
whereas outcome measures do not. The mere fact that
a physiological state may be re_ected in an experimen-
tal measure is not suf~cient to infer the presence of
that physiological state from the measured index. At
this point, RSA may be considered a marker of vagal
control of the heart, because if variables such as age,
respiratory rate and depth, and other known determi-
nants are taken into account, a change in RSA can be
used to index changes in vagal control [1,2]. Although
the LF/HF measure of sympathovagal balance may
vary in the expected direction with reciprocal changes
in activities of the autonomic branches during ortho-
static challenges [3], a change in this index in other
contexts does not necessarily imply a reciprocal change
in autonomic control [2,21].
Outcome measures may be useful under some con-
ditions, but the ultimate utility of experimental meas-
ures relates to their validity as a markers of physiologi-
cal states, a status that has not yet been established for
indices of sympathovagal balance [2,21,24,25]. One ap-
280 Berntson and Cacioppo CEPR 1999; Vol. 3, No. 4
proach to this issue is to identify more thoroughly the
contextual determinants of patterns of HRV, as what
might otherwise be an outcome measure could assume
the status of a marker within a clearly de~ned set of
conditions. Another approach is to more fully elucidate
the physiological mechanisms that underlie these rela-
tions, including the in_uences of rostral neurobehavio-
ral systems, which would permit a more critical evalu-
ation and selection of relevant measures.
4. Clinical applications
Patterns of heart rate variability have proven effective
in risk strati~cation in premature infants, after myo-
cardial infarction, and in other cardiovascular dysfunc-
tions, and may have utility for diagnosis as well as
elucidation of the basic pathophysiology of a range of
disorders [1,2,26,27]. Moreover, because psychosocial
factors can impact on autonomic control [26,28], HRV
measures may offer the basis for clinical interventions
[29]. Because clinical issues are considered elsewhere
in this volume, we limit out attention to two perspec-
tive for future studies. One important focus for further
research concerns the speci~c cellular events and proc-
esses that mediate the links between patterns of auto-
nomic control, HRV, and clinical outcomes. Another
entails a broader perspective. Although the autonomic
nervous system, the hypothalamic-pituitary-adrenal
axis, and the immune system have been viewed as
distinct functional domains, this view is no longer vi-
able. It is now recognized, or example, that (a) the
autonomic nervous system innervates immune tissues,
(b) neuroendocrine hormones and immune-tissue cy-
tokines impact on the central nervous system and auto-
nomic functions, and (c) that central corticotropin-re-
leasing-hormone systems exert important regulatory
in_uences over a wide spectrum of behavioral, auto-
nomic, neuroendocrine, and immune processes
[30,31,32]. In view of these considerations, autonomic
control can not be divorced from the broader range of
physiological systems with which it is integrally linked.
Patterns of autonomic control are both modulated by
rostral neural systems and in turn impact on higher
levels of the neuraxis [16], and these relations may
have substantial health implications. For example, re-
search in psychoneuroimmunology reveals that exag-
gerated heart rate reactivity to laboratory stressors
can predict immune reactions, including the immune
response to an in_uenza vaccine [33]. But recent re-
search reveals that it is the sympathetic component of
heart rate response, rather than heart rate reactivity
per se, that underlies this predictive relationship [33].
Moreover, peripheral immune responses have been
shown to impact importantly on central autonomic
regulation (in part via a vagal afferent pathway) [32].
The complexity of the bidirectional in_uences between
central systems and peripheral functional states may
seem daunting, but the broader health implications of
autonomic control and HRV may require attention to
this complex interplay.
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