Brain Heart Interactions - Physiology and Clinical Implications (Silvani Et Al 2016)

Brain–heart interactions:
physiology and clinical

rsta.royalsocietypublishing.org
implications
Alessandro Silvani1 , Giovanna Calandra-Buonaura2,3 ,
Review Roger A. L. Dampney4 and Pietro Cortelli2,3
1 PRISM Lab, and 2 Autonomic Unit, Department of Biomedical and
Cite this article: Silvani A,
Downloaded from https://royalsocietypublishing.org/ on 04 January 2024
Calandra-Buonaura G, Dampney RAL, Cortelli Neuromotor Sciences, University of Bologna, Bologna, Italy
P. 2016 Brain–heart interactions: physiology 3 IRCCS, Institute of Neurological Sciences of Bologna, Bellaria
and clinical implications. Phil. Trans. R. Soc. A University Hospital, Block G, Via Altura 3, 40139 Bologna, Italy
374: 20150181. 4 School of Medical Sciences (Physiology) and Bosch Institute for
http://dx.doi.org/10.1098/rsta.2015.0181 Biomedical Research, University of Sydney, Sidney, New South
Wales, Australia
Accepted: 19 January 2016
AS, 0000-0003-3992-3892; PC, 0000-0002-3633-8818
One contribution of 16 to a theme issue The brain controls the heart directly through the
‘Uncovering brain–heart information through sympathetic and parasympathetic branches of the
advanced signal and image processing’. autonomic nervous system, which consists of multi-
synaptic pathways from myocardial cells back
Subject Areas: to peripheral ganglionic neurons and further to
biomedical engineering central preganglionic and premotor neurons. Cardiac
function can be profoundly altered by the reflex
activation of cardiac autonomic nerves in response to
Keywords:
inputs from baro-, chemo-, nasopharyngeal and other
brain–heart interactions, autonomic nervous receptors as well as by central autonomic commands,
system, physiology, human disease including those associated with stress, physical
activity, arousal and sleep. In the clinical setting,
Author for correspondence: slowly progressive autonomic failure frequently
results from neurodegenerative disorders, whereas
Pietro Cortelli
autonomic hyperactivity may result from vascular,
e-mail: pietro.cortelli@unibo.it inflammatory or traumatic lesions of the autonomic
nervous system, adverse effects of drugs and
chronic neurological disorders. Both acute and
chronic manifestations of an imbalanced brain–heart
interaction have a negative impact on health. Simple,
widely available and reliable cardiovascular markers
of the sympathetic tone and of the sympathetic–
parasympathetic balance are lacking. A deeper
understanding of the connections between autonomic
cardiac control and brain dynamics through advanced
signal and neuroimage processing may lead to
invaluable tools for the early detection and treatment
of pathological changes in the brain–heart interaction.
2016 The Author(s) Published by the Royal Society. All rights reserved.
1. Physiology of the brain–heart interactions 2
(a) Physiological effects of sympathetic and parasympathetic nerve activities on the heart
rsta.royalsocietypublishing.org Phil. Trans. R. Soc. A 374: 20150181

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(i) Effects of sympathetic activity
The cardiac sympathetic innervation originates from sympathetic preganglionic neurons (S1N)
in the upper thoracic segments of the spinal cord, which synapse with neurons (S2N) in
the cervical and upper thoracic ganglia. Sympathetic postganglionic fibres innervate the
cardiac conduction system more prominently than the working myocardium [1], releasing
noradrenaline (norepinephrine) and neuropeptide Y. Noradrenaline binds to cardiac beta-
1 adrenergic receptors, increasing intracellular levels of cyclic adenosine monophosphate
(cAMP). In myocytes of the sinoatrial node, which is the physiological cardiac pacemaker,
increased cAMP levels hasten diastolic depolarization by increasing the inward ‘funny’ (If)
cation current gated by hyperpolarization-activated cyclic nucleotide-gated channels [2]. As
a result, the heart period (HP) shortens almost linearly with the frequency of sympathetic
postganglionic discharge [3]. This response is delayed by 1.7 s and the frequency response
essentially filters out the fluctuations of sympathetic activity faster than 0.15 Hz [4], which
are typically associated with breathing [5]. By itself, decreases in HP raise ventricular
contractility [6] and relaxation rate [7]. These effects are further enhanced by the increased
cAMP levels, which increase sarcoplasmic reticulum calcium reuptake because of protein
kinase A-dependent phosphorylation of phospholamban [8]. The decrease in HP also increases
atrioventricular conduction time, but this effect is counteracted by sympathetic activity [9].
Sympathetic innervation of cardiac automatic, conduction and contractile tissue follows parallel
yet distinct intrapericardial pathways [10], which are the basis for selective effects [11].
Sympathetic activity is also associated with ventricular repolarization heterogeneity, as indexed
by T-wave alternans in subjects with coronary artery disease [12] and by QT interval
variability in dogs with experimental heart failure [13]. The sympathetic nervous system also
controls the heart by promoting adrenal medullary release of adrenaline (epinephrine), whose
plasma threshold for decreasing HP is in the range of plasma levels attained during active
standing [14].
(ii) Effects of parasympathetic activity

The parasympathetic preganglionic neurons (P1N) involved in the control of cardiac function
are located in the medulla oblongata within and ventrolateral to the nucleus ambiguus
(NAmb), and to a much lesser extent in the dorsal motor nucleus of the vagus nerve (DMNX)
and in the reticular formation between these two nuclei [15]. All of these neurons project
through the vagus nerves to a complex set of epicardial ganglionated plexi [16], which
display functional selectivity for the effects on HP, conduction time and contractility [17], and
receive synaptic contacts by local sensory neurons [18]. Parasympathetic postganglionic fibres
widely innervate the cardiac conduction system as well as the atrial and ventricular working
myocardium [1,16], releasing acetylcholine and vasoactive intestinal peptide. Acetylcholine
decreases cAMP levels in myocardial cells by binding to M2 muscarinic receptors [8]. These
receptors also open specific potassium channels that gate a hyperpolarizing current, particularly
in conditions of marked parasympathetic activity [19]. As a result, HP lengthens almost linearly
with parasympathetic preganglionic discharge rate [3]. Resting HP values are higher than
the intrinsic HP in the absence of autonomic control [20], highlighting the prominence of
the cardiac parasympathetic tone over the cardiac sympathetic tone. Sinoatrial responses to
acetylcholine occur with minimal delay and keep up with modulations at least up to 0.4 Hz [4].
Parasympathetic activity also lengthens atrioventricular conduction time [9] and decreases
atrial and ventricular contractility [16] and ventricular relaxation rate [21], but does not affect
ventricular repolarization heterogeneity as indexed by T-wave alternans [12] or QT interval
variability [13].
(iii) Sympathetic–parasympathetic interactions 3
The sympathetic and parasympathetic cardiac controls are antagonistic in that they exert

.........................................................
opposite effects on myocardial cAMP levels, and thereby on HP, atrioventricular conduction
time, ventricular contractility and relaxation rate. Evidence that sympathetic noradrenaline
release is decreased by ongoing parasympathetic activity also suggests an inhibitory presynaptic
interaction [22]. The autonomic control of the mean values of heart rate (i.e. 1/HP) displays
accentuated nonlinear antagonism in that even high levels of sympathetic activity exert
negligible effects when parasympathetic activity is also high [23]. This nonlinear interaction
is much less prominent with respect to values of atrioventricular conduction time [23] and
even of the mean values of HP [3], which are well explained by a linear summation of
sympathetic and parasympathetic effects [24]. As far as autonomic modulations are concerned,
activity of each autonomic branch enhances the fluctuations of heart rate resulting from
the modulation of the other branch [25]. This synergistic interaction suggests that the high-
frequency fluctuations of heart rate that constitute respiratory sinus arrhythmia are enhanced
by sympathetic activity and, therefore, do not result solely from parasympathetic modulation,
as would be expected from the frequency response properties detailed previously [25]. In
contrast to this suggestion, however, analysis of HP fluctuations has shown that beta-adrenergic
blockade increases respiratory sinus arrhythmia in human subjects [26]. Taken together, these
discrepancies highlight that the interactions between sympathetic and parasympathetic activities
on cardiac function are complex and still incompletely understood, and that differences between
analyses based on HP and analyses based on heart rate may contribute to the variability in the
reported results.
(b) Central pathways regulating the autonomic outflow to the heart

(i) The central autonomic network
The autonomic outflow to the heart is regulated by a central autonomic network (CAN) of
interconnected brain structures, which includes the medial prefrontal cortex (MPFC) and insular
cortex, the amygdala and the bed nucleus of the stria terminalis (BNST), the lateral region of
the hypothalamus and the paraventricular nucleus (PVN) and dorsomedial hypothalamic (DMH)
nucleus, the periaqueductal grey (PAG) matter of the midbrain, the parabrachial Kölliker–Fuse
region of the lateral pons, as well as several regions of the medulla, which partly overlap with
those involved in respiratory control [27]. The MPFC comprises the anterior cingulate cortex
and the prelimbic and infralimbic areas and is involved in both cognitive and visceromotor
functions, thus being of potential great relevance for psychosomatic medicine [28]. The insula
is a viscerosensory and visceromotor region [29] and plays a key role in physiological and
pathological cardiovascular control [30]. In humans, the right (non-dominant) anterior insular
cortex is involved in the generation of the mental image of one’s physical state, which underlies
basic emotional states [31]. The amygdala is primarily involved in the information processing
related to negative emotions, whereas positive emotions tend to reduce amygdala activation [32].
The insular cortex, the central nucleus of the amygdala and the BNST constitute a cortico-
striatal–pallidal circuit that processes emotional information with autonomic responses [27]
and projects to the hypothalamic behaviour control column [33]. The PVN is a master
controller of the autonomic nervous system, providing specialized innervation to all autonomic
relay centres [27], and together with the DMH it integrates neuroendocrine, homeostatic and
stress responses [34]. The PAG takes part in regulating autonomic responses to physical and
psychological stressors [35]. The medullary nucleus of the tractus solitarius (NTS) and the
pontine parabrachial and Kölliker–Fuse nuclei are reciprocally connected and relay visceral
afferent information to other CAN structures [36]. In the medulla, the CAN includes the NAmb
and DMNX, the rostral (RVLM) and caudal portions of the ventrolateral medulla, and the
rostral ventromedial medulla (RVMM), which comprises the midline medullary raphe and
the parapyramidal area [36].
insular 4
MPFC cortex cortex

.........................................................
subcortical
PVN amygdala
forebrain
l,vl PAG midbrain
baroreceptors, nasopharyngeal
chemoreceptors, receptors
group III/IV muscle NTS
afferents
central MDH
NAmb/DMNX
inspiratory
neurons medulla
cardiac parasympathetic
outflow
Figure 1. Schematic diagram showing the major central pathways regulating the cardiac parasympathetic outflow. No
distinction is made between excitatory and inhibitory connections. DMNX, dorsal motor nucleus of the vagus nerve; l, lateral;
MDH, medullary dorsal horn of the trigeminal nucleus; MPFC, medial prefrontal cortex; NAmb, nucleus ambiguus, NTS, nucleus
of the tractus solitarius; PAG, periaqueductal grey; PVN, hypothalamic paraventricular nucleus; vl, ventrolateral.
(ii) Cardiac parasympathetic preganglionic neurons

Each cardiac P2N receives inputs from only a single active P1N [37]. Accordingly, the functional
specificity of cardiac P2N is matched by that of the P1N in the NAmb, separate groups of
which selectively and independently control HP, atrioventricular conduction and ventricular
contractility [38]. The P1N in the NAmb have myelinated B-fibre axons, while those in the DMNX
have unmyelinated slow-conducting C-fibre axons. The P1N in the DMNX may regulate to some
extent coronary blood flow or cardiac contractility, but, in contrast to P1N in the NAmb, they have
relatively little effect on HP [39]. The P1N in the DMNX have a low level of ongoing activity that
is not related to cardiac or respiratory activity, and are unaffected by baroreceptor inputs [40],
although they are activated by stimulation of pulmonary C-fibre afferents [41]. Conversely, the
P1N in the NAmb have a relatively high level of activity that shows a distinct cardiac and
respiratory modulation [42]. Inputs from baroreceptors, chemoreceptors and nasopharyngeal
receptors converge on individual P1N in the NAmb [37] and are gated by inspiratory-related
inputs, with the result that the reflex bradycardia normally evoked by stimulation of these
receptors is greatly attenuated during inspiration [43] (figure 1). The inspiratory gating of reflex
bradycardic responses is one of the mechanisms responsible for respiratory sinus arrhythmia and
is believed to have the effect of improving the ventilation–perfusion relationship in the lungs [44].
Apart from inputs from peripheral receptors and central inspiratory neurons, the P1N in the
NAmb or DMNX also receive inputs from other sources at all levels of the brain, including direct
projections from the hypothalamic PVN [45] and the lateral (l) and ventrolateral (vl) parts of the
midbrain PAG (figure 1) [46]. The main cortical areas that regulate HP are the MPFC, which is
thought to promote cardiac parasympathetic activity [28,47], and the insular cortex, which can
increase or decrease HP depending on the stimulated site [30]. The insular cortex sites where
stimulation decreases HP and increases arterial blood pressure densely innervate the MPFC and
amygdala [48]. In most of these studies, it is not completely clear if the changes in HP are due
to sympathetic or parasympathetic effects. Studies using the retrograde trans-synaptic transport
of viral vectors revealed indirect descending pathways by which the MPFC and insular cortex
may regulate the activity of P1N in the NAmb or DMNX, involving the amygdala, PAG and
NTS [49] (figure 1).
MPFC insular cortex cortex 5

osmoreceptors
.........................................................
subcortical
PVN DMH amygdala forebrain
midbrain
l,vl PAG somatosensory
receptors
baroreceptors,
NTS chemoreceptors,
group III/IV
muscle afferents
RVMM CVLM RVLM medulla
cardiac sympathetic outflow spinal cord
Figure 2. Schematic diagram showing the major central pathways regulating the cardiac sympathetic outflow. No distinction
is made between excitatory and inhibitory connections. CVLM, caudal ventrolateral medulla; DMH, dorsomedial hypothalamus;
RVLM, rostral ventrolateral medulla; RVMM, rostral ventromedial medulla (for more abbreviations, refer to figure 1).
(iii) Cardiac sympathetic premotor neurons

The major input to the cardiac S1N arises from sympathetic premotor neurons (S0N) in the
RVMM, RVLM, A5 area in the pons and hypothalamic PVN [50] (figure 2). These cell groups differ
with respect to their anatomical connections and functional properties. As will be discussed in
more detail below, S0N in the RVMM are activated during arousal and stress but do not generate
cardiac responses to baroreceptor or chemoreceptor inputs. By contrast, S0N in the RVLM are
critical for the expression of cardiac reflex responses to baroreceptor, chemoreceptor and other
inputs [36], but do not appear to have a major role in the generation of cardiac responses in
stress and arousal [51]. Much less information is available about the precise functional role of
S0N in the A5 area and PVN, although in regard to the latter it is likely that they are essential for
generating cardiac sympathetic responses to inputs associated with changes in blood volume or
plasma osmolality [52]. The chemical properties of the S0N in the different regions are also highly
varied. For example, many of the S0N in the RVMM contain serotonin, while those in the RVLM
are mainly adrenergic neurons of the C1 group. The S0N in the A5 group in the pons synthesize
noradrenaline, and in the PVN many of the S0N contain oxytocin, corticotropin-releasing factor,
vasopressin or angiotensin [50]. Neurons at all levels of the brain regulate the activity of the S0N,
but many of the descending pathways to the S0N in the medulla include synapses in other nuclei
(figure 2). As described above, the MPFC and insular cortex may regulate HP through changes in
cardiac sympathetic or parasympathetic activity. Activation of neurons in the MPFC may also
decrease vasomotor sympathetic activity [53]. The descending pathways from the MPFC and
insular cortex to the S0N in the medulla are not clearly defined. Anatomical studies in animals
have revealed direct descending projections to the RVLM as well as potential indirect projections
to both the RVMM and RVLM that include synaptic connections in the amygdala, PAG and
NTS [35,53] (figure 2).
(c) Reflex control of the autonomic outflow to the heart

Cardiac function can be profoundly altered by the reflex activation of cardiac autonomic nerves
in response to inputs from receptors including baroreceptors, chemoreceptors, receptors from
skeletal muscles and nasopharyngeal receptors. Cardiac sympathetic and parasympathetic nerve
activities are reciprocally altered in response to baroreceptor stimulation, whereas in response
6
to stimulation of chemoreceptor and nasopharyngeal inputs, both cardiac sympathetic and
parasympathetic activities are increased [54].

.........................................................
(i) Baroreceptor reflex
The physiological advantage of reciprocal baroreflex control of the heart by sympathetic
and parasympathetic nerves is that it allows for rapid and large compensatory responses to
perturbations in blood pressure [54]. The essential central circuits that mediate the baroreceptor
reflex control of the heart have been well defined [36]. Primary baroreceptor and chemoreceptor
afferent fibres terminate in the NTS on separate and spatially distinct subgroups of the second-
order neurons. From the NTS, baroreceptor signals are transmitted via excitatory glutamatergic
projection neurons directly to cardiac P1N in the NAmb (figure 1) or to the caudal ventrolateral
medulla, where they synapse with GABAergic neurons. In turn, these neurons project to and
inhibit S0N in the RVLM, which control the sympathetic outflow to the heart and different
vascular beds (figure 2). There is good evidence that the S0N in the RVLM that control the
sympathetic outflow to different vascular beds form separate subgroups [55]. It also seems likely
that cardiac S0N in the RVLM are distinct from sympathetic vasomotor S0N, given that the cardiac
and vasomotor sympathetic activities are reflexly regulated in a differentiated manner, according
to the afferent input [36].
(ii) Chemoreceptor reflex

The physiological cardiac response to the chemoreceptor reflex has the advantage of maximizing
oxygen conservation, while at the same time maintaining an adequate perfusion pressure for the
brain and the heart. This is achieved largely by a vagally evoked bradycardia (which reduces
cardiac oxygen consumption), while co-activation of cardiac sympathetic outflow maintains an
optimum stroke volume and cardiac output to meet the essential metabolic needs of the brain
and heart [54]. Chemoreceptor signals are transmitted from the NTS via direct projections to P1N
in the NAmb (figure 1) and to S0N in the RVLM [56,57] (figure 2). Given that chemoreceptor
stimulation evokes parasympathetic and sympathetic co-activation, it seems likely that both of
these projections are excitatory, presumably glutamatergic. In addition, chemoreceptor signals
are also transmitted indirectly to the RVLM via the Kölliker–Fuse nucleus in the pons [56].
(iii) Exercise pressor reflex

The mechanical distortion and interstitial accumulation of metabolites produced by skeletal
muscle contraction stimulate group III/IV thin fibre afferents from skeletal muscles, which
elicit the exercise pressor reflex. This reflex supports muscle perfusion by raising arterial blood
pressure as a result of increased sympathetic outflow to the heart and systemic vasculature and of
decreased parasympathetic outflow to the heart [58]. The neural pathway of the exercise pressor
reflex is not known with certainty, except for the site of the first synapse, which is in the spinal
cord dorsal horn [58]. However, neurons responsive to group III muscle afferents have been
demonstrated in the NTS [59], suggesting that the NTS is a key relay also for this reflex.
(iv) Diving reflex

The diving reflex is perhaps the most powerful autonomic reflex known, as it is associated
with intense sympathetically mediated vasoconstriction and profound vagally mediated
bradycardia [60]. Like the chemoreceptor reflex, it has the effect of conserving oxygen during
submersion. In non-diving animals such as rabbits, a very similar reflex is evoked by irritant
vapours [61]. In both cases, nasopharyngeal receptors innervated by trigeminal afferents trigger
the reflex responses. There is evidence for both a direct projection from trigeminal afferents to the
NAmb region that contains cardiac P1N, as well as indirect projections relayed via the medullary
dorsal horn of the trigeminal nerve [60] (figure 1).
(d) Integrative regulation of the autonomic outflow to the heart 7
(i) Physical activity

.........................................................
Physical exercise, either dynamic or static (isometric), entails a decrease in HP, which is abrupt
in onset, maintained or even enhanced while exercise occurs, and progressively reversed after
exercise is over [62]. The changes in HP at the onset and offset of exercise result primarily
from parasympathetic withdrawal and reactivation, respectively [62,63]. During steady-state
dynamic exercise, the decrease in HP results from a continuum of balanced sympatho-vagal
control, with parasympathetic withdrawal playing the greater role the lower the workload [64].
These autonomic changes result from the integration of the baroreceptor and exercise pressor
reflexes with central autonomic commands [65]. These commands are classically defined as feed-
forward modulation of P1N and S1N exerted by the descending somatic motor pathways, but
also incorporate feedback components associated with the perception of effort [66]. The neural
structures that issue the central autonomic commands associated with physical exercise are
still uncertain, and have been suggested to overlap with those of the CAN at the level of the
NTS, PVN, PAG, insular cortex and MPFC [62,65]. In this last respect, a remarkable study that
coupled magnetic resonance neuroimaging with measurements of HP, muscle sympathetic nerve
activity and arterial blood pressure in human subjects provided evidence that decreased activity
of the ventral MPFC is involved in the central commands that cause parasympathetic cardiac
withdrawal during static handgrip exercise [67]. During exercise, both central commands and the
exercise pressor reflex reset the operating point of the arterial baroreceptor reflex towards higher
values of blood pressure and heart rate [65]. There is evidence that this resetting is mediated
by neuronal circuitry in the NTS [59]. Chronotropic incompetence, i.e. the failure to increase
heart rate to a level commensurate with increased workload, may occur in patients with heart
failure because sympathetic overactivation desensitizes myocardial beta-adrenergic receptors,
and portends a poor prognosis [68]. Aerobic exercise training may decrease sympathetic
activation and ameliorate chronotropic incompetence in patients with heart failure [68,69]. The
mechanisms of this beneficial effect are thought to involve inhibition of the NFκB-dependent
inflammatory cascade, angiotensin II receptor expression and oxidative stress in RVLM and PVN
neurons [69].
(ii) Stress and arousal

Stress may be defined as a condition in which expectations, whether genetically programmed,
learned or deduced, do not match perceptions of the internal or the external environment, this
discrepancy eliciting compensatory responses [70]. The concept of arousal is state-dependent,
and, during wakefulness, it refers to the cerebral, autonomic and behavioural activation in
response to internal and environmental stimuli [71]. In the immediate response to a novel
psychological stress (e.g. air-puff stress), the changes in HP are often biphasic, due to co-activation
of cardiac sympathetic and parasympathetic nerves, consistent with an orienting response to the
arousing stimulus [54,72]. With repeated exposures, however, there is a decrease in HP which
is due predominantly to cardiac sympathetic activation [54]. There is good evidence that S0N
located in the RVMM (especially the midline raphe) generate stress-evoked increases in cardiac
sympathetic activity [73]. The midline raphe receives a direct projection from the DMH, a region
that is critical for the expression of the cardiovascular response to stress [72,73], and from the
lPAG [74], which as mentioned above is a region that generates cardiovascular responses to
physical stressors [35,72]. In addition, both the DMH and lPAG receive direct inputs from the
amygdala and direct or indirect inputs from the insular cortex (figure 2), both of which are
also involved in generating responses to physical stressors [35,72]. Furthermore, air-puff stress
induces an increase in c-Fos expression (a marker of neuronal activation) in the RVMM, but
not in the RVLM, which, as mentioned above, is activated when cardiac sympathetic activity
is reflexly increased by inputs from peripheral receptors [51]. The RVMM contains more S0N
than any other brain region [50]. The descending pathway from the DMH to the RVMM is
functionally asymmetric, such that disinhibition of the right DMH induces significantly larger
8
decreases in HP and increases in cardiac contractility and number of ectopic beats than those
evoked from the left DMH [75]. Thus, the pathway from the right DMH to the RVMM may

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contribute to stress-related increases in cardiac sympathetic activity [75], which is a main cause of
malignant tachyarrhythmias [76], and further explains the fact that intense emotional stress can
cause sudden death (see, for example, [77]), as also discussed in §2d(iv). Finally, vagally mediated
heart rate variability may also decrease with stress, and according to a remarkable meta-analysis
of neuroimaging studies may index the extent to which threat representations encoded in the
amygdala are inhibited by the ventral MPFC based on the external and internal perceptions of
safe contexts [47].
(iii) Sleep
The transition from wakefulness to non-rapid eye movement (non-REM) sleep brings about
an increase in HP [78], which is attributed to an increase in parasympathetic activity [79]. On
passing from non-REM sleep to REM sleep, which accounts for approximately 20% of total
sleep time, HP generally shows a mild tonic decrease, which is superimposed on large transient
changes in HP associated with bursts of rapid eye movements, phasic increases in the activity of
the pyramidal tract, ponto-geniculo-occipital waves, and acceleration of the hippocampal theta
rhythm (reviewed in [78]). These sleep-related changes in HP are best explained by sleep-related
central autonomic commands, which override or reset baroreflex function [80]. The hypothalamic
suprachiasmatic nucleus (SCN) is the master pacemaker responsible for the circadian rhythms of
wake–sleep states [81] and of blood pressure and HP [82]. Neurons in the SCN may issue circadian
autonomic commands involving sympathetic and parasympathetic outflows by projecting to the
PVN [83], which, as mentioned previously, is a master autonomic controller in the CAN [27].
However, the main SCN contribution to the circadian cardiovascular rhythms is thought to
come indirectly from the circadian rhythms of rest and activity [84] or, more precisely, of
wakefulness, non-REM sleep and REM sleep [85], each of which appears associated with specific
central autonomic commands [86]. The central autonomic commands during non-REM sleep
may involve inhibitory projections from sleep-active neurons of the hypothalamic ventrolateral
preoptic nucleus to the S0N of the PVN [87], central thermoregulatory pathways including
the RVMM, central baroreflex pathways including the NTS, the parabrachial and Kölliker–Fuse
nuclei, and command neurons in the pedunculopontine tegmental (PPT) nucleus [86]. During
REM sleep, central autonomic commands may involve the PAG, the pontine sublaterodorsal and
PPT nuclei, and the vestibular and raphe obscurus medullary nuclei [86].
2. Clinical implications of the brain–heart interactions

(a) Autonomic hyperactivity versus autonomic failure
Neurodegenerative disorders frequently cause slowly progressive failure of the autonomic
control, mainly concerning its sympathetic component, resulting in multiple clinical
manifestations (orthostatic hypotension, impaired sweating, neurogenic bladder with erectile
dysfunction in men, gastrointestinal dysmotility), which may be subtle due to compensatory
mechanisms [88]. Conversely, vascular, inflammatory or traumatic lesions of the autonomic
nervous system and drug adverse effects most often manifest acutely with signs of autonomic
hyperactivity, including abnormal excessive control of the cardiovascular system. Sustained and
chronic autonomic hyperactivity may also appear in association with other chronic neurological
disorders, in particular sleep disorders [89]. Both acute and chronic manifestations of an
imbalanced brain–heart interaction represent a risk factor for the development of cardiovascular
diseases or acute cardiovascular events, which can also lead to sudden cardiac death. It may be
quite difficult to separate out the cardiac component in these clinical conditions. By contrast,
viewing derangements of the brain–heart interaction from the perspective of the underlying
Table 1. Manifestations of sympathetic and parasympathetic hyperactivity.
9
sympathetic hyperactivity parasympathetic hyperactivity

.........................................................
hypertension hypotension
..........................................................................................................................................................................................................
tachycardia bradycardia
..........................................................................................................................................................................................................
hyper- or hypothermia lacrimation and sialorrhoea

..........................................................................................................................................................................................................
hyperhidrosis yawning
..........................................................................................................................................................................................................
mydriasis miosis
..........................................................................................................................................................................................................
Table 2. Manifestations and complications of paroxysmal autonomic hyperactivity.
paroxysmal autonomic hyperactivity

manifestations complications
hypertension intracerebral haemorrhage, vasogenic cerebral oedema
..........................................................................................................................................................................................................
labile blood pressure compromised cerebral perfusion

..........................................................................................................................................................................................................
neurogenic cardiac injury apical ballooning syndrome (takotsubo syndrome)

..........................................................................................................................................................................................................
tachyarrhythmias ventricular tachycardia and fibrillation

..........................................................................................................................................................................................................
bradyarrhythmias asystole
..........................................................................................................................................................................................................
neurogenic lung injury pulmonary oedema, hypoxia

..........................................................................................................................................................................................................
hyperthermia worse neurological recovery

..........................................................................................................................................................................................................
hyperhidrosis dehydration
..........................................................................................................................................................................................................
muscle rigidity rhabdomyolysis, acute tubular necrosis

..........................................................................................................................................................................................................
autonomic syndromes may provide key pathophysiological insights and therapeutic success.
Given these clinical implications, in the present section we will characterize the clinical features,
the supposed pathogenetic mechanisms, and the common causes of autonomic hyperactivity,
focusing on its cardiovascular consequences.
(b) Effects of sympathetic and parasympathetic hyperactivity

Autonomic hyperactivity is characterized by excessive sympathetic activation, either in isolation
or in association with excessive parasympathetic activation (table 1) [90]. Excessive sympathetic
activity may result from activation of descending sympathoexcitatory pathways, disinhibition
of sympathoexcitatory reflexes [91], sympathetic activation by hypoxia or ischaemia [92], loss of
baroreflex buffering [93] or loss of inhibitory GABAergic control at diencephalic [94], brainstem
or spinal levels [95]. Sympathetic overactivity is thought to be the common phenomenon
that links the major cardiac pathologies seen in neurological catastrophes [96] (table 2). In
general, when physical or psychological stressors challenge the body, a transient sympathetic
overactivity, mainly with active coping mechanisms, is adaptive as part of the short-term survival
machinery. This has been referred to as ‘allostasis’, which is the re-establishment of homeostasis
through change in the level of operation of the physiological system (see [70]). By contrast,
chronic stress states produce passive or withdrawal coping mechanisms and elicit a long-term
autonomic response referred to as a ‘hyperarousal state’, characterized by chronic sympathetic
and hypothalamo-pituitary–adrenocortical system activation. The consequences of overactivity
of the allostatic systems are referred to as ‘excessive allostatic load’, which is maladaptive and
leads to chronic diseases (table 3).
Table 3. Disorders associated with chronic autonomic hyperactivity.
10
chronic autonomic hyperactivity-

.........................................................
associated disorders
obesity
..........................................................................................................................................................................................................
diabetes, insulin resistance

..........................................................................................................................................................................................................
hypertension
..........................................................................................................................................................................................................
insomnia and anxiety

..........................................................................................................................................................................................................
hyperthermia
..........................................................................................................................................................................................................
high energy expenditure

..........................................................................................................................................................................................................
muscle wasting
..........................................................................................................................................................................................................
increased susceptibility to infection

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impairment of memory
..........................................................................................................................................................................................................
(c) Common causes of paroxysmal sympathetic hyperactivity

(i) Severe head injury
Episodes of paroxysmal sympathetic hyperactivity frequently occur in the setting of severe diffuse
axonal injury and in the post-resuscitation period after severe anoxic–ischaemic brain insults [97].
These paroxysms usually start 5–7 days after injury and follow a regular pattern (1–3 times per
day, lasting 1–10 h). Over time, the episodes tend to become less frequent and more prolonged
and are associated with poor outcome. Release of hypothalamic CAN structures from cortical
inhibitory control may explain acute episodes of autonomic hyperactivity of diencephalic origin,
which may occur after closed-head injury associated with a decorticate state and widespread
axonal damage [27].
(ii) Subarachnoid haemorrhage

Subarachnoid haemorrhage is associated with acute and massive sympathetic hyperactivity [98].
This may produce electrocardiographic changes indicative of cardiac injury [99,100] and
different arrhythmias, particularly supraventricular tachyarrhythmias such as atrial fibrillation.
Acute hydrocephalus after subarachnoid haemorrhage may cause episodes of acute autonomic
hyperactivity linked to disinhibition of hypothalamic CAN structures such as the PVN [27].
Mechanical and chemical stimulation of the insular cortex has also been postulated as a
mechanism for autonomic derangements caused by subarachnoid haemorrhage in the Sylvian
fissure [30].
(iii) Insular stroke

Acute stroke can impair central autonomic control, resulting in myocardial injury,
electrocardiographic abnormalities, cardiac arrhythmias and ultimately sudden death. Cardiac
and renal diseases, diabetes and arrhythmogenic medications increase the risk of cardiac
morbidity and mortality after stroke [100]. Autonomic imbalance is more frequent after
infarcts involving the insular cortex, which is part of the CAN [30]. Despite evidence
indicating a lateralization of autonomic control by the insular cortex [27], there is no
obvious laterality in the impact of insular cortex stroke on cardiovascular response or stroke
prognosis [30].
(iv) Seizures 11
Focal seizures involving CAN structures such as the MPFC, insular cortex and amygdala

.........................................................
entail various autonomic manifestations [27] including sympathetic hyperactivity and cardiac
arrhythmias [101]. The most common cardiac manifestation is sinus tachycardia but paroxysmal
atrial fibrillation, supraventricular and ventricular tachycardia or ventricular fibrillation may
also occur. Other autonomic manifestations of temporal lobe seizures include paroxysmal
hypertension, ictal piloerection, sweating and facial flushing or pallor [102]. Temporal lobe
seizures, particularly originating from the left hemisphere, may also manifest with excessive
parasympathetic activity leading to ictal bradycardia and asystole which can cause syncope [103].
Seizure-related cardiac arrhythmias have been implicated as a potential pathogenetic mechanism
of sudden unexpected death in epilepsy. However, ictal asystole usually has a self-limiting
course, and postictal rather than ictal arrhythmias together with respiratory abnormalities seem
of greater importance to the pathophysiology of sudden unexpected death in epilepsy [104]. In
seizures occurring during sleep, as in nocturnal frontal lobe epilepsy, an increase in sympathetic–
parasympathetic balance, similar to that associated with physiological arousal from sleep, usually
precedes the onset of the motor manifestations. This suggests a role of autonomic activation,
which is part of the arousal response, in triggering seizures [105].
(v) Brainstem lesions

Sympathetically mediated hypertension, cardiac arrhythmias or myocardial injury may occur as
a consequence of brainstem lesions, particularly those involving the lateral medulla [106]. Rarely,
paroxysmal sympathetic activity may be the presentation of baroreflex failure due to bilateral
involvement of the NTS [107].
(vi) Baroreflex failure syndrome

The baroreflex failure syndrome refers to the cardiovascular manifestations resulting from
interruption of the afferent limb of the baroreflex at the level of the carotid sinus, baroreceptor
afferents or medulla. The main clinical manifestations of baroreflex failure are acute hypertension
or fluctuating hypertension with or without orthostatic hypotension or orthostatic tachycardia.
Episodes of severe bradycardia and hypotension, referred to as malignant vagotonia, may also
occur [108].
(vii) Autonomic dysreflexia in spinal cord injury

Autonomic dysreflexia refers to episodes of massive sympathetic hyperactivity triggered by
reflex stimuli below the lesion in patients with cervical or thoracic spinal cord injury above T5.
These episodes occur upon recovery from the acute spinal shock [109] and are characterized
by severe hypertension that may result in hypertensive encephalopathy, intracranial or retinal
haemorrhage, seizures or even sudden death [110]. Headache, anxiety, facial flushing and
extensive diaphoresis above the level of the lesion often precede the onset of the hypertensive
crisis. The most common stimuli originate from the bladder or rectum.
(viii) Guillain–Barré syndrome

Sympathetic or parasympathetic hyperactivity or hypofunction in different combinations
may be detected in about two-thirds of patients with Guillain–Barré syndrome [111,112].
Autonomic hyperactivity may manifest with sinus tachycardia, sustained or paroxysmal
hypertension, episodes of flushing, orthostatic hypotension and cardiac arrhythmias including
cardiac arrest. The main mechanism of cardiovascular instability in Guillain–Barré syndrome is
impaired baroreflex modulation of the sympathetic cardiovascular output due to demyelination
of baroreceptor afferents [112]. Episodes of severe paroxysmal hypertension may result
in subarachnoid haemorrhage or posterior leukoencephalopathy syndrome or takotsubo
syndrome [113], whereas some patients are at risk of severe vagally mediated bradycardia and
12
asystole in response to reflex stimuli such as tracheal suction [112].

.........................................................
(ix) Sepsis
The systemic inflammatory response to infection includes tachycardia in a context of sympathetic
overactivity and myocardial contractile dysfunction, which converts into autonomic failure
preceding shock in severe cases [114]. Inflammatory mediators act directly on the heart to cause
tachycardia in experimental sepsis [115]. However, the sympathetic outflow to the heart also
markedly increases in these conditions [116]. Cardiac sympathetic activation during sepsis may
result from disinhibition of the DMH and the RVMM caused by prostaglandin E2 binding to
neurons in the medial preoptic hypothalamus [116,117]. This is a dramatic example of the complex
and still poorly understood interactions between the brain, autonomic activity and the immune
system, which are a burgeoning area of research [118].
(x) Iatrogenic causes

Several drugs can trigger syndromes characterized by mental status changes, increase of muscle
tone, hyperthermia and autonomic hyperactivity. These include the neuroleptic malignant
syndrome, which may be elicited by dopamine D2 receptor blocking antipsychotics [119];
malignant hyperthermia, which is a hypermetabolic response to volatile anaesthetics or to
succinylcholine driven by excessive calcium release in the skeletal muscle [120]; the serotonin
syndrome, which results from overactivation of central and peripheral serotonin receptors,
often by antidepressant drugs [121]; and the anticholinergic syndrome, which results from the
inhibition of muscarinic cholinergic neurotransmission [122]. The brain structures responsible for
autonomic hyperactivity associated with these iatrogenic causes are still unclear.
(d) Causes of chronic and sustained sympathetic hyperactivity

(i) Fatal familial insomnia and agrypnia excitata
Fatal familial insomnia (FFI) is a rare familial prion disease whose clinical hallmark is the
agrypnia excitata syndrome [123]. Somatomotor abnormalities (e.g. pyramidal signs, myoclonus,
dysarthria/dysphagia and gait dysfunctions) also occur with variable latency and degree during
the disease course. The term agrypnia (from the Greek expression for ‘to chase sleep’), as
proposed by Lugaresi & Provini [124], describes an organic insomnia, which is characterized
by severe or complete lack of sleep, especially deep sleep. The sleep disorder is associated
with sympathetic and motor hyperactivation (excitata) and with episodes of a peculiar oneiric
behaviour (oneiric stupor) [125]. Agrypnia excitata is typical of but not specific for FFI [94]. At
rest, FFI patients show from the onset of agrypnia a progressive worsening of hypertension,
tachycardia and hyperthermia sustained for 24 h resulting in a progressive decline in the
amplitude of circadian oscillations of the autonomic parameters [126]. FFI is characterized by
unbalanced autonomic control with preserved parasympathetic activity but higher background
and stimulated sympathetic activity [127]. Clinico-pathological relations and functional imaging
in FFI implicate the anterior ventral and mediodorsal nuclei of the thalamus in the regulation
of the wake–sleep cycle and other autonomic functions, with sparing of hypothalamic and
brainstem structures [128]. The mediodorsal thalamic nucleus is an integral part of the circuits
that connect the hypothalamus with the amygdala and the MPFC components of the CAN [33].
The preferential thalamic lesions in FFI would act by disconnecting the limbic cortical areas
involved in the control of instinctive behaviour and the cortical and subcortical regions that
promote sleep and regulate autonomic functions. Such a disconnection syndrome results in a
shift to persistent wakefulness behaviour and sympathetic hyperactivation, which makes FFI the
paradigm of what can occur in humans if the arousal system cannot be shut off. Dysfunctions of
the medial thalamus and related limbic areas are believed to underlie also the agrypnia excitata
13
associated with delirium tremens, Morvan syndrome [123], and Whipple disease [129].

.........................................................
(ii) Obstructive sleep apnoea syndrome
The obstructive sleep apnoea syndrome (OSAS) is characterized by repetitive episodes of
complete (apnoea) or partial (hypopnoea) upper airway obstruction occurring during sleep,
which usually result in blood oxygen desaturation and often terminate with brief arousal. The
apnoeic episodes are associated with sympathetic hyperactivity and blood pressure increase, and
with HP increase at onset of apnoeas followed by tachycardia on resumption of breathing [130].
OSAS with this continuous repetition of obstructive respiratory events during the night is a
paradigm of how a sleep breathing disorder can lead to a permanent dysregulation of the
autonomic cardiovascular control resulting in sustained sympathetic hyperactivity. Recent data

on animal models highlight the key role played in this process by the NTS and PVN [131].
A remarkable functional imaging study on patients suggested that the elevated sympathetic
activity associated with OSAS may be driven by changes in activity in higher cortical regions,
such as the MPFC [132]. An increase in sympathetic tone is thought to underlie the cardiovascular
complications responsible for the increased mortality rate in patients with sleep apnoea [133].
In addition, inhibition of the excitatory pathway from the PVN to P1N during chronic
hypoxia/hypercapnia may decrease cardiac parasympathetic activity, further increasing the risk
of adverse cardiac events associated with OSAS [45]. At least in women, OSAS severity is
significantly associated with incident heart failure [134], which brings about cardiopulmonary
reflex desensitization and severe cardiac and renal sympathoexcitation [135]. The OSAS is
also related to the development of daytime hypertension [136] and to excessive daytime
sleepiness [137]. A reduced baroreflex sensitivity is also a well-documented feature of OSAS
before the onset of cardiovascular complications [138]. Daytime hypertension and excessive
daytime sleepiness may share a common underlying cause: the cardiovascular effects of OSAS
may be due to the top-down dysfunction of the baroreflex, while the reduced diurnal vigilance
may be explained by a bottom-up dysfunction of the baroreceptor afferent effect [71]. This
could be better understood from an allostatic perspective where the chronic hypertensive state
associated with OSAS might be viewed as the result of autonomic nervous system adaptation to
the episodic recurrence of sympathetic surges during the night. Therefore, the reduced baroreflex
sensitivity consistently described in OSAS could be an indirect index of an as yet unknown
maladaptive mechanism resulting in a decreased baroreflex function.
(iii) Autonomic effects of sleep debt and narcolepsy with cataplexy

Sleep has important homeostatic functions. Whether sleep deprivation and fragmentation is
due to sleep disorders such as restless legs syndrome [89] or anxiety or depression or a
hectic lifestyle, it may disturb many essential homeostatic mechanisms with adverse effects on
autonomic, hormonal and metabolic systems [139]. There is evidence that short sleep duration
is associated with cardiovascular morbidity in epidemiological surveys [140] and that sleep
deprivation profoundly affects the autonomic nervous system [141]. Acute [142] and chronic [143]
sleep deprivation are associated with increased sympathetic and decreased parasympathetic
cardiovascular modulation. Long-term sleep deprivation is a chronic stressor that may decrease
resting HP and increase systolic and diastolic blood pressure [144], entailing a modest but
independent increase in the risk of cardiac ischaemia, stroke and sudden cardiac death [145].
The central neural mechanisms responsible for the autonomic effects of sleep debt are still
unclear. However, it seems reasonable to surmise that they consist of altered function of those
same structures of the CAN which underlie the sleep-related central autonomic commands
(see §1d(iii)). Another sleep disorder with possible autonomic involvement is narcolepsy with
cataplexy, a chronic disorder of the sleep–wake behaviour associated with the loss of neurons
releasing hypocretin/orexin peptides [146]. Preliminary evidence indicates that autonomic
control of cardiac variability by baroreflex and central autonomic (feed-forward) mechanisms
is altered in narcolepsy with cataplexy patients during spontaneous sleep–wake behaviour, and
14
particularly during wakefulness before sleep [147]. The extent to which narcolepsy with cataplexy
entails derangements in the control of the cardiovascular system is still a matter of debate [146].

.........................................................
Interestingly, however, hypocretin/orexin neurons project to all of the brain structures that are
thought to underlie the sleep-related central autonomic commands [86].
(iv) Triggering of cardiovascular events by emotional stressors

After the pioneering work of Walter B. Cannon in 1942 [148] with an article proposing a scientific
basis for ‘voodoo’ death, several studies were performed to clarify the neurobiological basis
of the link between emotional and cardiovascular events that are a major cause of morbidity
and mortality in the developed world. Today we have strong evidence that cardiovascular
events can be triggered by acute mental stress caused by events such as an earthquake, a
televised high-drama soccer game, job strain or the death of a loved one [149]. Animal studies
suggest that stressors presumed to provoke acute negative emotions affect cardiovascular
physiological control and increase the risk of sudden cardiac death through haemodynamic and
electrophysiological pathways increasing sympathetic output, impairing endothelial function and
creating a hypercoagulable state [150]. Interestingly, post-traumatic stress disorder, which is an
anxiety disorder initiated by exposure to a traumatic event, is also independently associated with
increased risk of incident coronary heart disease and mortality [151].
3. Conclusion and perspectives

From the perspective of the clinician, the analysis of heart rate variability (HRV) based on
the electrocardiogram holds promise as an attractively simple tool for detecting autonomic
impairments and for predicting the prognosis of some neurological disorders through the
assessment of the brain–heart connections. Unfortunately, we are still far from the realization of
this very important unmet need. According to the Task Force on HRV evaluation (1996) [152],
there are only two clinical situations where HRV analysis should be performed: to assess
mortality risk in patients after myocardial infarction and to detect early evidence of cardiac
autonomic neuropathy in diabetic patients. In the light of the clinical relevance of the brain–heart
connection for so many diseases, this implies that what is really lacking to develop specific clinical
applications of the knowledge on heart–brain interactions are simple, widely available and
reliable cardiovascular markers of the sympathetic tone and of the sympathetic–parasympathetic
balance. Such markers would be invaluable for the early detection of signs of cardiovascular
dysautonomia, the treatment of which can avoid the occurrence of the life-threatening paroxysmal
or chronic autonomic hyperactivity.
This state of affairs highlights the need for a deeper physiological understanding of the
links between brain dynamics and the corresponding autonomic cardiac dynamics. The key
issue at stake here is to combine different sources such as: information on animal models
and human subjects, information on basic physiology and clinical disorders, but also, and
critically, information from different biosignals in each given setting. In the physiology
laboratory, key advances can be obtained by multi-modal recordings of electroencephalogram,
electrocardiogram, electromyogram, blood pressure and respiration in animal models with
congenital or acquired (viral vectors, drug-inducible expression systems) genetic modification
of brain circuits. Multi-modal recordings including beat-to-beat blood pressure (finger volume
clamp), respiration, muscle sympathetic nerve activity (peroneal nerve microneurography) and
body temperature are also desirable when investigating brain–heart interactions in the clinical
laboratory, in order to interpret cardiac control in its true physiological context. Taking advantage
of the recent developments in magnetic resonance neuroimaging, as well as in advanced
processing techniques of electroencephalographic, electrocardiographic and cerebrovascular flow
signals, interdisciplinary and multi-modal research approaches now have the chance of bringing
our understanding of the brain–heart interactions to the next level.
Authors’ contributions. A.S., G.C.-B., R.A.L.D. and P.C. carried out the bibliographic research, analysed the data,
15
interpreted the results and wrote sections of the paper. R.A.L.D. constructed the figure schemes. A.S. drafted
the full manuscript, which was reviewed by G.C.-B., R.A.L.D. and P.C. P.C. coordinated the project. All authors

.........................................................
gave final approval for publication.
Competing interests. We have no competing interests.
Funding. No specific funding was dedicated to this project.
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Brain–heart interactions:

physiology and clinical

rsta.royalsocietypublishing.org Phil. Trans. R. Soc. A 374: 20150181

(ii) Effects of parasympathetic activity

rsta.royalsocietypublishing.org Phil. Trans. R. Soc. A 374: 20150181

(b) Central pathways regulating the autonomic outflow to the heart

rsta.royalsocietypublishing.org Phil. Trans. R. Soc. A 374: 20150181

l,vl PAG midbrain

(ii) Cardiac parasympathetic preganglionic neurons

rsta.royalsocietypublishing.org Phil. Trans. R. Soc. A 374: 20150181

cardiac sympathetic outflow spinal cord

(iii) Cardiac sympathetic premotor neurons

(c) Reflex control of the autonomic outflow to the heart

rsta.royalsocietypublishing.org Phil. Trans. R. Soc. A 374: 20150181

(ii) Chemoreceptor reflex

(iii) Exercise pressor reflex

(iv) Diving reflex

rsta.royalsocietypublishing.org Phil. Trans. R. Soc. A 374: 20150181

(ii) Stress and arousal

rsta.royalsocietypublishing.org Phil. Trans. R. Soc. A 374: 20150181

2. Clinical implications of the brain–heart interactions

rsta.royalsocietypublishing.org Phil. Trans. R. Soc. A 374: 20150181

hyper- or hypothermia lacrimation and sialorrhoea

Table 2. Manifestations and complications of paroxysmal autonomic hyperactivity.

paroxysmal autonomic hyperactivity

labile blood pressure compromised cerebral perfusion

neurogenic cardiac injury apical ballooning syndrome (takotsubo syndrome)

tachyarrhythmias ventricular tachycardia and fibrillation

neurogenic lung injury pulmonary oedema, hypoxia

hyperthermia worse neurological recovery

muscle rigidity rhabdomyolysis, acute tubular necrosis

(b) Effects of sympathetic and parasympathetic hyperactivity

rsta.royalsocietypublishing.org Phil. Trans. R. Soc. A 374: 20150181

diabetes, insulin resistance

insomnia and anxiety

high energy expenditure

increased susceptibility to infection

(c) Common causes of paroxysmal sympathetic hyperactivity

(ii) Subarachnoid haemorrhage

(iii) Insular stroke

rsta.royalsocietypublishing.org Phil. Trans. R. Soc. A 374: 20150181

(v) Brainstem lesions

(vi) Baroreflex failure syndrome

(vii) Autonomic dysreflexia in spinal cord injury

(viii) Guillain–Barré syndrome

rsta.royalsocietypublishing.org Phil. Trans. R. Soc. A 374: 20150181

(x) Iatrogenic causes

(d) Causes of chronic and sustained sympathetic hyperactivity

rsta.royalsocietypublishing.org Phil. Trans. R. Soc. A 374: 20150181

autonomic cardiovascular control resulting in sustained sympathetic hyperactivity. Recent data

(iii) Autonomic effects of sleep debt and narcolepsy with cataplexy

rsta.royalsocietypublishing.org Phil. Trans. R. Soc. A 374: 20150181

(iv) Triggering of cardiovascular events by emotional stressors

3. Conclusion and perspectives

rsta.royalsocietypublishing.org Phil. Trans. R. Soc. A 374: 20150181

2. Bucchi A, Baruscotti M, Robinson RB, DiFrancesco D. 2007 Modulation of rate by autonomic

rsta.royalsocietypublishing.org Phil. Trans. R. Soc. A 374: 20150181

mathematical model. Am. J. Physiol. Heart Circ. Physiol. 275, H1733–H1747.

rsta.royalsocietypublishing.org Phil. Trans. R. Soc. A 374: 20150181

rsta.royalsocietypublishing.org Phil. Trans. R. Soc. A 374: 20150181

rsta.royalsocietypublishing.org Phil. Trans. R. Soc. A 374: 20150181

hypothalamus. Eur. J. Neurosci. 23, 3284–3296. (doi:10.1111/j.1460-9568.2006.04860.x)