Neuroscience and Biobehavioral Reviews 33 (2009) 81–88
Contents lists available at ScienceDirect
Neuroscience and Biobehavioral Reviews
journal homepage: www.elsevier.com/locate/neubiorev
Review
Claude Bernard and the heart–brain connection: Further elaboration
of a model of neurovisceral integration
Julian F. Thayer a,b,*, Richard D. Lane c
a
The Ohio State University, Department of Psychology, 1835 Neil Avenue, Columbus, OH 43210, USA
Mannheim Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, Heidelberg University,
Ludolf-Krehl-Street 7-11, D-68167 Mannheim, Germany
c
University of Arizona, Department of Psychiatry, Tucson, AZ 85724-5002, USA
b
A R T I C L E I N F O
A B S T R A C T
Keywords:
Cognition
Emotion
Heart rate variability
Inhibition
Prefrontal cortex
The intimate connection between the brain and the heart was enunciated by Claude Bernard over 150
years ago. In our neurovisceral integration model we have tried to build on this pioneering work. In the
present paper we further elaborate our model. Specifically we review recent neuroanatomical studies
that implicate inhibitory GABAergic pathways from the prefrontal cortex to the amygdala and additional
inhibitory pathways between the amygdala and the sympathetic and parasympathetic medullary output
neurons that modulate heart rate and thus heart rate variability. We propose that the default response to
uncertainty is the threat response and may be related to the well known negativity bias. We next review
the evidence on the role of vagally mediated heart rate variability (HRV) in the regulation of physiological,
affective, and cognitive processes. Low HRV is a risk factor for pathophysiology and psychopathology.
Finally we review recent work on the genetics of HRV and suggest that low HRV may be an
endophenotype for a broad range of dysfunctions.
! 2008 Elsevier Ltd. All rights reserved.
Contents
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Cortical control of cardiac activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The importance of inhibition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Inhibition and the right prefrontal cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Physiological regulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Emotional regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Cognitive regulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The genetics of HRV. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HRV as an endophenotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Summary and conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
‘‘Claude Bernard also repeatedly insists, and this deserves
especial notice, that when the heart is affected it reacts on the
brain; and the state of the brain again reacts through the
pneumo-gastric (vagus) nerve on the heart; so that under any
excitement there will be much mutual action and reaction
between these, the two most important organs of the body’’
(Darwin, 1999, pp. 71–72, originally published in 1872).
* Corresponding author at: The Ohio State University, Department of Psychology,
1835 Neil Avenue, Columbus, OH 43210, USA. Tel.: +1 614 688 3450;
fax: +1 614 688 8261.
E-mail address: [email protected] (J.F. Thayer).
0149-7634/$ – see front matter ! 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neubiorev.2008.08.004
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The work of the great French physiologist Claude Bernard is
considered by some to have laid the foundations for modern
neuroscience (Conti, 2002). His work was some of the first to
systematically investigate the connections between the peripheral
organs including the heart, and the brain. His keen insights and
reliance on experimental methods are widely acknowledged to
have influenced the course of medical research. Much of modern
medicine owes a debt to Claude Bernard. We too owe a great debt
to Claude Bernard. Some years ago we published a paper in which
we put forward the outlines of a model of neurovisceral integration
in the context of emotion regulation and dysregulation (Thayer and
Lane, 2000). The above statement from Darwin, based on the work
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J.F. Thayer, R.D. Lane / Neuroscience and Biobehavioral Reviews 33 (2009) 81–88
of Claude Bernard, perfectly encapsulates the key idea of that
neurovisceral integration model. Thus, we must admit that we are
not the first to examine this topic. However, we hope to be able to
build upon the pioneering work of Claude Bernard and to elaborate
some of his ideas. In this paper we seek to provide some meat for
the skeleton that we proposed in 2000. In particular we want to
provide a review of the recent evidence supporting key aspects of
the model. We had proposed that there are direct and indirect
connections between the brain and the heart and in this paper we
more fully explicate those pathways. In addition, we proposed that
the complex mix of physiological, behavioral, emotional, and
cognitive processes involved in self-regulation and adaptability
might have a common basis such that indices of heart rate
variability (HRV) would be associated with all of these various
forms of regulation. As such here we provide an overview of the
recent evidence supporting a role for individual differences in HRV
in physiological, affective, and cognitive regulation. We emphasized the importance of inhibition and in this paper further detail
the ways in which inhibition is critical to effective functioning in a
complex environment. Finally we end the present paper with a
discussion of both the behavioral and molecular genetics of HRV
and propose that low HRV should be examined as a possible
endophenotype for a broad range of dysfunctions spanning
psychopathology and pathophysiology. However, we start with
the crux of the model, the cortical control of heart rate.
1. Cortical control of cardiac activity
Heart rate is determined by intrinsic cardiac mechanisms and
the joint activity of the sympathetic nerves and parasympathetic
(vagus) nerves at the sinoatrial node. In healthy systems both
branches of the autonomic nervous system are tonically active
with sympathetic activity associated with heart rate acceleration
and parasympathetic activity associated with heart rate deceleration (Jose and Collison, 1970; Levy, 1990). Importantly, heart rate
in many species including humans is under tonic inhibitory control
peripherally via the vagus (Levy, 1990; Uijtdehagge and Thayer,
2000). Consistent with Claude Bernard’s statement both animal
and human data suggests that cortical activity modulates
cardiovascular function. An extensive body of research has been
directed at identifying the pathways by which this neural control is
achieved. For example, Benarroch (1993, 1997) has described the
central autonomic network (CAN). The output of the CAN has
connections to the sinoatrial node of the heart via the stellate
ganglia and the vagus nerve. Importantly, the output of the CAN is
under tonic inhibitory control via GABAergic neurons in the
nucleus of the solitary tract (NTS). Despite well documented
species differences, in many mammals including primates and
humans there appear to be both direct and indirect pathways
linking the frontal cortex to autonomic motor circuits responsible
for both the sympathoexcitatory and parasympathoinhibitory
effects on the heart (Balaban and Thayer, 2001; Barbas et al., 2003;
Barbas and Zikopoulos, 2007; Grace and Rosenkranz, 2002;
Rempel-Clower, 2007; Resstel and Correa, 2006; Saha, 2005; Saha
et al., 2000; Shekhar et al., 2003; Spyer, 1994; Ter Horst and
Postema, 1997; Thayer and Lane, 2000; Wong et al., 2007). Figure
one provides a composite model based upon the extant literature.
[A similar model has been proposed for the cortical regulation of
blood pressure (Gianaros, 2008).] In this model prefrontal cortical
areas including the orbitofrontal cortex (OFC) and medial
prefrontal cortex (mPFC) tonically inhibit the amygdala via
pathways to intercalated GABAergic neurons in the amygdala
(Barbas et al., 2003; Shekhar et al., 2003). Moreover, activation
(disinhibition) of the central nucleus of the amygdala (CeA: the
major efferent source of modulation of cardiovascular, autonomic,
and endocrine responses) may lead to increased HR and decreased
HRV by three routes: (1) activation (disinhibition) of tonically
active sympathoexcitatory neurons in the rostral ventrolateral
medulla (RVLM) by decreased inhibition from tonically active
neurons in the caudal ventrolateral medulla (CVLM) leading to a
net increase in sympathetic activity; (2) inhibition of neurons in
the NTS which leads to inhibition of tonically active nucleus
ambiguus (NA) and dorsal vagal motor nucleus (DVN) neurons
leading to a net decrease of parasympathetic activity; and (3)
direct activation of sympathoexcitatory RVLM neurons leading to a
net increase in sympathetic activity (Saha, 2005, Fig. 1, p. 453).
However, this last route is a minor pathway associated with only a
small percentage of the fibers connecting the CeA with the
medullalary ANS outputs. Thus, decreased activation of the
prefrontal cortex would lead to disinhibition of the tonically
inhibited CeA. This in turn would lead to a simultaneous
disinhibition of sympathoexcitatory neurons in the RVLM via
route number one above and an inhibition of parasympathoexcitatory neurons via route number two above. Both of which would
lead to an increase in HR and a concomitant decrease of vagally
mediated HRV.
Importantly and as suggested by Claude Bernard, modern
retrograde viral staining studies in rodents have identified similar
pathways to be specifically involved in the forebrain parasympathetic regulation of heart activity (Ter Horst and Postema, 1997).
Specifically, following pseudorabies virus injections into the
ventricular myocardium, labeled cardiac vagal motorneurons
and higher order command cells were found in the DVN, the
NA, the NTS, the area postrema, the ventrolateral reticular
formation, the locus ceruleus, parabrachial nucleus (PBN), the
periaquaductal gray (PAG), several regions of the hypothalamus,
the bed nucleus of the stria terminalis, the CeA, the anterior
cingulate (ACC), the insula, and the frontal cortex, among others.
Consistent with the above neural pathways we showed that
anterior cortical activity tonically inhibits cardioacceleratory
circuits in humans based on an increase in HR and a decrease of
HRV during pharmacological inactivation of either cerebral
hemisphere (Ahern et al., 2001).
Specifically, we have shown in a series of studies using both
pharmacological and neuroimaging approaches that prefrontal
cortical activity is associated with vagally mediated HRV (Ahern
et al., 2001; Lane et al., 2001, 2007, 2008; Nugent et al., 2007,
2008). For example, human evidence for the inhibitory role of the
frontal cortex comes from a study of HR and HRV before and after
right and left side intracarotid sodium amobarbital (ISA) injection
(Ahern et al., 2001). Qualitatively similar changes in HR were
observed during each hemisphere’s injection. During 10-min
inactivations of either hemisphere, HR increased, peaked at about
minute three, and gradually declined toward baseline values.
These data support the notion that cortical activity tonically
inhibits brainstem cardioacceleratory circuits. However, differential hemispheric effects appeared, with larger and faster HR
increases during right hemisphere inactivations. Concomitant
with these HR increases, vagally mediated HRV decreased,
mirroring the HR changes with respect to differential hemispheric
effects. Specifically, vagally mediated HRV decreases were greater
in the right hemisphere inactivations. These results support the
anatomical and physiological findings that right hemispheric
autonomic inputs to the heart are associated with greater cardiac
chronotropic control.
Using neuroimaging we (Lane et al., 2007, 2008; Nugent et al.,
2007, 2008) and others (Gianaros et al., 2004) have provided
evidence that activity of the prefrontal cortex is associated with
vagal function. For example, Lane et al. (in press) have presented
evidence that medial prefrontal activity is associated with HRV. To
J.F. Thayer, R.D. Lane / Neuroscience and Biobehavioral Reviews 33 (2009) 81–88
explore its central neural substrates we correlated a spectrally
derived index of vagally mediated HRV (HF-HRV) with measures of
cerebral blood flow (rCBF) derived from positron emission
tomography (PET) in twelve healthy women. Happiness, sadness,
disgust, and three neutral conditions were each induced by film
clips and recall of personal experiences. Interbeat intervals from
the electrocardiogram during six emotion and six neutral scans
were derived and analyzed. Across all conditions, HF-HRV
correlated with blood flow in the right superior prefrontal cortex
(BA 8,9), the left rostral anterior cingulate cortex (BA 24, 32), the
right dorsolateral prefrontal cortex (BA 46), and the right parietal
cortex (BA 40). Emotional arousal was associated with a decrease
in HRV and concomitant decreases in brain activation in these
regions. These findings are consistent with a general inhibitory role
for the prefrontal cortex via the vagus as suggested by Ter Horst
(1999). Taken together these pharmacological blockade and
neuroimaging studies provide support for the role of the prefrontal
cortex in the modulation of subcortical cardioacceleratory circuits
via an inhibitory pathway that is associated with vagal function
and can be indexed by HRV.
The frontal lobe areas identified in this study have been
implicated in different aspects of conscious processing of emotional responses (Lane, 2008). The neurovisceral integration model
holds that the conscious experience of emotion requires the
transmission of subcortical affective information to the cerebral
cortex and that top-down inhibitory influences have a modulatory
effect on the subcortical centers that shapes the nature of
subjective experience. New evidence from Williams et al., 2006
indicates that top-down feedback from cortical to subcortical
structures is necessary for conscious emotional experience to
occur. This is consistent with the more general principle that
inhibition serves to ‘sculpt’ excitatory neural action at all levels of
the neuraxis to produce context appropriate responses to
environmental demands (Knight et al., 1999; Thayer, 2006; Thayer
and Lane, 2005).
It has been proposed that the prefrontal cortex is taken ‘‘offline’’ during threat to let automatic, prepotent processes regulate
behavior (Arnsten and Goldman-Rakic, 1998). This selective
prefrontal inactivation may be adaptive by facilitating predominantly non-volitional behaviors associated with subcortical neural
structures such as the amygdala to organize responses without
delay from the more deliberative and consciously guided
prefrontal cortex. In modern society, however, inhibition, delayed
response, and cognitive flexibility are vital for successful adjustment and self-regulation, and prolonged prefrontal inactivity can
lead to hypervigilance, defensiveness, and perseveration.
2. The importance of inhibition
Sympathoexcitatory, cardioacceleratory subcortical threat circuits are under tonic inhibitory control by the prefrontal cortex
(Amat et al., 2005; Thayer, 2006). As outlined above, the amygdala,
which has outputs to autonomic, endocrine, and other physiological
regulation systems, and becomes active during threat and uncertainty, is under tonic inhibitory control via GABAergic mediated
projections from the prefrontal cortex (Thayer, 2006; Davidson,
2000). Importantly, we have proposed that the default response to
uncertainty, novelty, and threat is the sympathoexcitatory preparation for action commonly known as the fight or flight response. This
default threat response may be related to the well known negativity
bias in which negative information is given priority over positive
information in guiding behavior (Cacioppo et al., 1999). In support of
the important role of the amygdala in this process, it has recently
been shown that whereas the ‘‘default’’ mode of amygdala activation
serves a vigilance function for biologically relevant positive and
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negative information, amygdala activation is context-sensitive
albeit with a bias toward negative information (Cunningham
et al., 2008). From an evolutionary perspective this represents a
system that errs on the side of caution – when in doubt prepare for
the worst – thus maximizing survival and adaptive responses
(LeDoux, 1996). However, in typical daily life this response has to be
tonically inhibited and this inhibition is achieved via top-down
modulation from the prefrontal cortex. Thus, under conditions of
uncertainty and threat critical areas of the prefrontal cortex become
hypoactive. This hypoactive state is associated with disinhibition
of sympathoexcitatory circuits that are essential for energy
mobilization. However, when this state is prolonged it produces
the excess wear and tear on the system components that has been
characterized by McEwen as allostatic load (McEwen, 1998). It is also
important to note that psychopathological states such as anxiety,
depression, post-traumatic stress disorder, and schizophrenia are
associated with prefrontal hypoactivity and a lack of inhibitory
neural processes as reflected in poor habituation to novel neutral
stimuli and therefore a failure to recognize safety signals, a preattentive bias for threat information including an increased
negativity bias, deficits in working memory and executive function,
and poor affective information processing and regulation (Thayer
and Friedman, 2004; Shook et al., 2007a,b). Relatedly, we have
recently shown that greater resting HRV is associated with a smaller
negativity bias and with greater willingness to approach positive
novel objects (Shook et al., 2007b). Therefore proper functioning of
inhibitory processes is vital to the preservation of the integrity of the
system and therefore is vital to health. Importantly for our
discussion, these inhibitory processes can be indexed by measures
of vagal function such as HRV as we will illustrate below.
Several things are noteworthy about our previous pharmacological blockade and neuroimaging results. First, as suggested by
Claude Bernard, it appears that this modulation of cardiac activity
by the cortex is vagally mediated. This was shown by a decrease in
vagally mediated HRV during cortical inactivations. Second,
consistent with the known neuroanatomy, the effects of the
pharmacological blockade were more pronounced on the right
cerebral hemisphere than on the left. Retrograde viral staining
studies in both rodents and primates indicate that right-sided
neural fibers are preferentially involved in the cortical innervation
of the myocardium (Ter Horst and Postema, 1997; Chuang et al.,
2004). For example, Chuang et al. (2004) reported that following
administration of horseradish peroxidase into the sinoatrial node
of the monkey 75% of the labeled neurons in the nucleus ambiguus
were right sided whereas only 25% were left sided. In our blockade
study we showed that the increase in HR was larger and peaked
earlier during the right-sided inactivations compared to the leftsided inactivations. Moreover, our neuroimaging study (Lane et al.,
in press) found that in the across all conditions analysis three of the
four significant activations were right sided. Third, our previous
results implicated the anterior portions of the cerebral hemispheres in cardiac control as the area of inactivation induced by the
ISA is largely restricted to these areas (Ahern et al., 1994; Hong
et al., 2000; Ojemann and Kelley, 2002). Again, our neuroimaging
study found that three of the four significant associations were in
anterior regions in the across all conditions analysis (Lane et al., in
press). Fourth, our results are largely consistent with a growing
body of evidence from neuroimaging studies that have examined
the neural substrates of cardiac control. We and others have
found several regions of the prefrontal cortex associated with HR
and/or HRV (Lane et al., 2001, 2007; Gianaros et al., 2004; Critchley
et al., 2003; Nugent et al., 2007, 2008). Taken together the
literature and our previous results suggest that right-sided anterior
neural structures are preferentially involved in cardiac chronotropic control via a vagally mediated pathway.
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simultaneous increase in SCL is consistent with the present model
(Nagai et al., 2004).
3. Inhibition and the right prefrontal cortex
Fig. 1. A composite schematic diagram showing the pathways by which the
prefrontal cortex might influence control of heart rate. The prefrontal, cingulate,
and insula cortices form an interconnected network with bi-directional
communication with the amygdala. The amygdala is under tonic inhibitory
control via prefrontal vagal pathways to intercalated cells in the amygdala. The
activation of the central nucleus of the amygdala (CeA) inhibits the nucleus of the
solitary tract (NTS: solid square) which in turn inhibits inhibitory caudal
ventrolateral medullary (CVLM) inputs to the rostral ventrolateral medullary
(RVLM) sympathoexcitatory neurons (solid square), and simultaneously inhibits
vagal motor neurons in the nucleus ambiguus (NA) and the dorsal vagal motor
nucleus (DVN). In addition, the CeA can directly activate the sympathoexcitatory
neurons in the RVLM. The net effect of pharmacological blockade of the prefrontal
cortex would be a disinhibition of the CeA leading to disinhibition of medullary
cardioacceleratory circuits and an increase in heart rate. Figure adapted from
Gianaros (2008).
In summary, the pathways via which the prefrontal cortex can
control cardiac functions such as HR and thus HRV have been
described (see Fig. 1). Both branches of the ANS are tonically active
in the control of HR leading to both a tonic acceleratory drive as
well as a tonic deceleratory drive to the heart. When the tonic
inhibitory control of the output of the CeA by the frontal cortex is
reduced such as by pharmacological blockade, CeA activation
(disinhibition) produces increased HR via decreased inhibition of
sympathoexcitatory neurons in the RVLM as well as by inhibition
of vagal motor outputs in the NA and DVN. These multiple
mechanisms of HR control allow for a fine grained regulation of HR
in response to changing environmental demands. That these
circuits are under tonic inhibitory control by the prefrontal cortex
has also been supported by the autonomic concomitants of the socalled ‘‘default mode’’ brain state (Raichle et al., 2001). For
example, the observation that skin conductance level (SCL) is
inversely correlated with activity in the ventromedial PFC and the
OFC, that these regions are part of the ‘‘default’’ brain state, and
that they become deactivated during cognitive demands with a
One of the primary functions associated with the prefrontal
cortex is that of inhibition. Inhibitory processes are a component of
many tasks associated with so-called executive functions including working memory, attentional set-shifting, and response
inhibition. The prefrontal cortex has also been implicated in
affective processes including emotional regulation, affective setshifting, and extinction, all of which also rely heavily on inhibitory
processes. It has been suggested that there is a common inhibitory
network associated with a wide range of processes (Aron et al.,
2004; Chikazoe et al., 2007). As noted above, there are pathways
that have linked the prefrontal cortex with inhibition of medullary
cardioacceleratory circuits. The Neurovisceral Integration Model
proposes that all of these processes of cognitive regulation,
affective regulation, and physiological regulation may be related to
each other in the service of goal-directed behavior (Thayer and
Lane, 2000). In support of this idea, we have shown that cognitive,
affective, and physiological regulation are all associated with
vagally mediated cardiac function as indexed by HR and HRV
(Thayer and Brosschot, 2005). Importantly these inhibitory
functions have been linked with right hemisphere prefrontal
activity (Ahern et al., 2001; Aron et al., 2004; Kalisch et al., 2005).
There is a growing body of literature that suggests that the
right prefrontal cortex is preferentially related to inhibitory
processes across a wide range of cognitive, motor, and affective
tasks (Aron et al., 2004; Garavan et al., 1999; Konishi et al., 1999;
Chambers et al., 2006; Kalisch et al., 2005; Lieberman et al., 2007).
A recent report that directly compared different modalities
suggests that the right prefrontal cortex is involved in response
inhibition across response modalities (Chikazoe et al., 2007).
Given the predominant right hemispheric innervation of the
sinoatrial node of the heart we have proposed that the well known
right hemisphere advantage for emotion may be secondary to the
relative right hemisphere innervation of the heart (Ahern et al.,
2001). Similarly we have proposed that the relationship between
executive function performance and HRV is related to the
common neural basis for both functions (Thayer and Lane,
2000, 2005; Thayer and Brosschot, 2005). Therefore the right
hemisphere may be a critical player in inhibitory processes
involved in cognitive, affective, and physiological regulation
(Thayer and Lane, 2000; Thayer and Brosschot, 2005).
Our position however is to not overstate the evidence for right
hemispheric control of cardiac function. For example, the outstanding work of Bud Craig (2005) has suggested that cortical
regulation of vagal function is predominantly left-sided. It should
be noted that patterns of cortical activation associated with even
the simplest of tasks is incredibly dynamic and distributed (Gevins
et al., 1999). Thus, simplistic models of hemispheric activations
based on neuroanatomical and neuroimaging studies that do not
take into account these spatial and temporal patterns are bound to
be incomplete. Thus, we have suggested that a dynamical systems
framework might be appropriate (Thayer, 2006; Thayer and Lane,
2005). In this context we have proposed that a flexible network of
neural structures that can be differentially recruited in response to
challenges leads to ‘‘emergent’’ functional networks that are
context specific (Thayer and Lane, 2000).
In summary, the neurovisceral integration model has identified
a flexible neural network associated with self-regulation and
adaptability that might provide a unifying framework within
which to view the diversity of observed responses across domains.
Thayer and Lane (2000) suggested that a common reciprocal
J.F. Thayer, R.D. Lane / Neuroscience and Biobehavioral Reviews 33 (2009) 81–88
inhibitory cortico-subcortical neural circuit serves as the structural
link between psychological processes like emotion and cognition,
and health-related physiological processes, and that this circuit
can be indexed with HRV. Thus, because of these reciprocally
interconnected neural structures that allow prefrontal cortex to
exert an inhibitory influence on sub-cortical structures, the
organism is able to respond to demands from the environment,
and organize their behavior effectively. In the next sections we
briefly review the evidence for the relationship of HRV to physiological, affective, and cognitive regulation.
4. Physiological regulation
The regulation of physiological systems that are important for
health and disease has been linked to vagal function and HRV.
Thayer and Sternberg (2006) have recently summarized data
linking HRV to glucose regulation, hypothalamic–pituitary–adrenal axis function, and inflammation. In addition, Thayer and Lane
(2007) have recently reviewed the literature on the relationship
between vagal function and the risk for cardiovascular disease
(CVD) and stroke. The National Heart, Lung, and Blood Institute of
the US National Institutes of Health list eight risk factors for heart
disease and stroke (http://www.nhlbi.nih.gov/hbp/hbp/hdrf.htm).
Six of these factors are considered to be modifiable. Three of these
modifiable risk factors are associated with what could be called
biological factors. They are high blood pressure (hypertension),
diabetes, and abnormal cholesterol. Three others listed as
modifiable could be considered lifestyle factors and are tobacco
use (smoking), physical inactivity (exercise), and overweight
(obesity). Two factors are considered as non-modifiable. These
are age and family history of early heart disease or stroke. It is
interesting to note that there is at least some data to suggest that
each of these risk factors is associated with decreased vagal
function as indexed by HRV. Furthermore, emerging risk factors for
CVD and mortality such as inflammation and psychosocial factors
are also associated with decreased HRV (e.g., Thayer and Fischer,
2005; Brosschot et al., 2007). In addition, several large epidemiological studies have shown that reduced HRV is a risk factor for allcause mortality and morbidity (Liao et al., 2002). Taken together
there is growing evidence for the important role that the vagus
nerve serves in the regulation of a wide range of physiological
systems. As such, HRV in part due to its relationship with physical
health and physiological regulatory systems, may be of special
relevance to researchers in medicine and biology. Another area
that will be of great importance is emotional regulation.
5. Emotional regulation
We and others have recently reviewed the literature on the
relationship between HRV and emotional regulation (Thayer and
Brosschot, 2005; Appelhans and Luecken, 2006). Emotional
regulation is a valuable skill that has clear implications for health.
Emotions represent a distillation of an individual’s perception of
personally relevant environmental interactions, including not only
challenges and threats but also the ability to respond to them
(Frijda, 1988). Viewed as such, emotions reflect the status of one’s
ongoing adjustment to constantly changing environmental
demands. When the affective system works properly, it promotes
flexible adaptation to shifting environmental demands. In another
sense, an adequate emotional response represents a selection of an
optimal response and the inhibition of less functional ones from a
broad behavioral repertoire, in such a way that energy use is
matched to fit situational requirements. Resting HRV represents a
type of resource that can be brought to bear in situations where
emotional regulation is called for. We have investigated the role of
85
HRV in emotional regulation at two different levels of analysis. One
level is at the trait or tonic level where individual differences in
resting HRV have been associated with differences in emotional
regulation. We have shown that individuals with higher levels of
resting HRV, compared to those with lower resting levels, produce
context appropriate emotional responses as indexed by emotionmodulated startle responses, fear-potentiated startle responses,
and phasic heart rate responses in addition to behavioral and selfreported emotional responses (Melzig et al., in press; Ruiz-Padial
et al., 2003; Thayer and Brosschot, 2005). Another level of analysis
is at the state or phasic level where HRV values increase during the
successful regulation of emotion during emotion regulation tasks.
Thus, it has been shown that phasic increases in HRV in response to
situations that require emotional regulation facilitates effective
emotional regulation. In an early study, we showed that HRV
increased in recovering alcoholics in response to alcohol cues but
only if they later reported an increased ability to resist a drink.
Those recovering alcoholics that later reported an urge to drink did
not exhibit increased HRV during the alcohol cues (Ingjaldsson
et al. (2003). A recent replication and extension of this work
reported increased HRV during the successful regulation of
emotion by either reappraisal or suppression (Butler et al.,
2006). We have recently shown that the increase in HRV associated
with emotional regulation is accompanied by concomitant
cerebral blood flow changes in areas identified as being important
in emotional regulation and inhibitory processes (Lane et al.,
2008). Taken together these findings suggest that HRV functions at
both the trait and state levels as a resource that can be utilized in
the service of emotional regulation. Future research is directed at
assessing if this resource can be depleted and thus lead to
subsequent failures of emotional regulation. The relationship
between HRV and emotional regulation will have important
implications for those that study the link between emotional states
and dispositions such as depression, anxiety, anger and hostility,
alexithymia, and physical health. Yet another area of active
research by our group and others involves research on cognitive
functioning and HRV.
6. Cognitive regulation
We have also recently reviewed our research on the relationship between HRV and cognitive regulation (Thayer and Johnsen,
2004; Thayer et al., 2005). Attentional regulation and the ability to
inhibit prepotent but inappropriate responses are important for
health in a complex environment. Many tasks important for
survival in today’s world involve cognitive functions such as
working memory, sustained attention, behavioral inhibition, and
general mental flexibility. These tasks are all associated with
prefrontal cortical activity (Arnsten and Goldman-Rakic, 1998).
Deficits in these cognitive functions tend to accompany aging, and
are also present in negative affective states and dispositions such
as depression and anxiety. In a series of studies we showed that
compared to individuals with low levels of resting HRV, those with
higher resting levels, performed better on tasks that required
executive function such as the Stroop task and the n-back task
(Johnsen et al., 2003; Hansen et al., 2003). Furthermore, we showed
that when resting HRV levels were decreased by aerobic detraining, performance on executive function tasks suffered
(Hansen et al., 2004). Stress can also impair cognitive function
and may contribute to the cognitive deficits observed in various
mental disorders. We have also shown that persons with higher
resting HRV performed equally well under threat of shock or nonthreat conditions whereas those with lower resting HRV
performed more poorly on certain tasks in threat conditions
(Hansen et al., in press). In addition those with lower resting HRV
86
J.F. Thayer, R.D. Lane / Neuroscience and Biobehavioral Reviews 33 (2009) 81–88
showed larger cortisol responses to mild cognitive challenge that
persisted into the recovery period compared to those with high
resting HRV (Johnsen et al., 2002).
We have recently expanded these studies to more ecologically
valid situations. In one recent experiment we showed that those
police officers with higher resting HRV had higher situational
awareness and therefore performed better in a police shoot-noshoot virtual reality task (Saus et al., 2006). Moreover, in this study
a brief situational awareness training program was associated with
a smaller decrease in HRV during the shooting task suggesting a
decreased mental workload. Taken together these studies suggest
that those with higher resting HRV are better able to perform tasks
that involve executive and inhibitory functions over a wide range
of laboratory and real-life situations. They also suggest that
behavioral training and aerobic de-training can affect both HRV
and cognitive performance. However, it is also clear that there is a
significant genetic contribution to HRV.
7. The genetics of HRV
The investigation of the genetics of HRV is currently an area
of very active exploration both by our group and by others. Both
behavioral and molecular genetic studies suggest that there is a
significant genetic component to the individual differences in
HRV including stress induced HRV changes (Boomsma et al.,
1990; Wang et al., in press). Kupper et al. (2004) reported
heritabilities for the time domain indices of SDNN (35–47%) and
RMSSD (40–48%) in a large twin study of 772 participants across
four time periods during the day. Wang et al. (2005) in a large
study of African American and European American youth
reported that SDNN, RMSSD, and HF were highly significantly
correlated (r > 0.80). Moreover, this combined factor had a
heritability of 70%. We also reported that African Americans had
greater HRV than European Americans but did not differ in their
heritabilities. In addition we have recently shown that two
indices of HRV were significantly greater in females than in males
but the genders did not differ in their heritabilities (Snieder et al.,
2007).
Several molecular genetic studies have also been reported with
significant associations found with the angiotensin converting
enzyme insertion/deletion gene (Busjahn et al., 1998; Thayer et al.,
2003) and the choline transporter gene among others (Neumann
et al., 2005). Several research groups are continuing to explore
possible candidate genes associated with HRV and much future
work is needed. Molecular genetic studies have their limitations as
many candidate gene studies have conspicuous failures to
replicate. However, another approach exists which seeks to
identify a level between the genotype and the phenotype. This
approach involves the identification of what are called endophenotypes.
8. HRV as an endophenotype
It is possible that low vagally mediated HRV, as an index of
activity in a set of neural structures involved in physiologic,
affective, and cognitive regulation, may serve as a useful endophenotype for a range of physical and psychological disorders
including psychopathology. For example in the context of
psychopathology, the endophenotype concept represents an
alternative to the traditional nosological categorization of disease
as exemplified by the Diagnostic and Statistical Manual (Gottesman
and Gould, 2003). Endophenotypes are markers on the pathway
between genes and behavior that allow for more explicit
characterization of the dysfunction associated with various
neuropsychiatric disorders. Gottesman and colleagues have
enumerated a number of criteria for an endophenotype (Gottesman and Gould, 2003; Gould and Gottesman, 2006). These include
(1) association with the illness, (2) heritability, (3) state
independence, (4) co-aggregation of the endophenotype and
illness within families, and (5) the endophenotype is found in nonaffected family members at rates higher than in the general
population. Whereas a review of the evidence for low HRV as an
endophenotype for psychopathology is beyond the scope of the
present paper much of this evidence in the case of panic disorder
has been summarized previously (Friedman and Thayer, 1998a;
Friedman, 2007). Specifically (1) low HRV is associated with panic
disorder (Friedman and Thayer, 1998a,b), (2) HRV is heritable
(Wang et al., 2005; Snieder et al., 2007; Thayer et al., 2003), (3) low
HRV in panic disorder is state independent, that is, is present in the
absence of panic symptoms (Friedman et al., 1993; Friedman and
Thayer, 1998b), (4) within families low HRV and panic disorder
co-aggregate (Friedman and Thayer, 1998a; Friedman, 2007), and
(5) lower HRV is found in children of patients with panic disorder
compared to children of healthy controls (Srinivasan et al., 2002).
Moreover, there is a continuum with some endophenotypes being
closer to the genes and some being closer to the phenotype or
behavior. For HRV, candidate genes such as the ACE I/D gene have
been identified and this same genotype has been linked to
psychopathology in general (Gard, 2002) and panic disorder in
particular (Olsson et al., 2004). Furthermore Grillon and colleagues (Cornwell et al., 2006) have proposed context-specific startle
modification as an endophenotype for some sub-types of
pathological anxiety. We have recently shown that contextspecific startle modification varies as a function of resting HRV
(Melzig et al., in press). Thus, low HRV may be an endophenotype
for a more general susceptibility that may include contextspecific startle modification as a marker (Melzig et al., in press).
Clearly much more evidence is needed before low HRV is
confirmed as an endophenotype for panic disorder or psychopathology more generally but it is certainly a viable candidate.
Importantly, low HRV may be an endophenotype for a broad range
of dysfunctions involving physiological, affective, and cognitive
regulation. Future work is directed at assessing the potential for
HRV to be a useful marker across a spectrum of physical and
mental health domains.
9. Summary and conclusions
In 1865 Claude Bernard delivered a lecture at the Sorbonne on
the physiology of the heart and its connections with the brain
(Bernard, 1867). Therefore, we suspect that he would not be
surprised to see the extensive evidence for the connections
between the heart and the brain that we have reviewed here. In
the neurovisceral integration model we have proposed that the
relationship between HRV and important physiological, cognitive,
and emotional regulation functions is due to the ability of HRV to
index activity in a flexible network of neural structures that is
dynamically organized in response to environmental challenges.
The neuroanatomical, pharmacological blockade, and neuroimaging studies provide support for the forebrain influences on HRV
as implied by the pioneering work of Claude Bernard. In this
further elaboration of the neurovisceral integration model we
have tried to flesh out as it were the outline that we published in
2000. We and others continue to explore the implications of this
model as they pertain to organism adaptability to a constantly
changing environment. It is hoped that the present review will
help neuroscientists better appreciate and contribute to the
understanding of ‘‘the mutual action and reaction between these,
the two most important organs of the body’’ (Darwin, 1999, p. 72,
originally published 1872).
J.F. Thayer, R.D. Lane / Neuroscience and Biobehavioral Reviews 33 (2009) 81–88
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