Experimental Physiology Celebrating 100 years
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Experimental Physiology 93.9 pp 1022-1028
DOI: 10.1113/expphysiol.2007.039461
© The Physiological Society 2008
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
93/9/1022    most recent
expphysiol.2007.039461v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Google Scholar
Right arrow Articles by Green, A. L.
Right arrow Articles by Paterson, D. J.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Green, A. L.
Right arrow Articles by Paterson, D. J.
Related Collections
Right arrow Hot Topic Reviews
Right arrow Cardiovascular control

Hot Topic Review

Identification of neurocircuitry controlling cardiovascular function in humans using functional neurosurgery: implications for exercise control

 Alexander L. Green1 and David J. Paterson2

1 Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK 2 Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford OX1 3PT, UK


   Abstract
Top
 Abstract
Introduction
 References
 
The neurocircuitry underlying human cardiovascular control during exercise has yet to be fully elucidated. Functional imaging studies and animal studies have so far identified potential circuits that might be involved in the cardiovascular response to exercise, so-called ‘central command’. This brief review highlights neurocircuits that may have functional significance as judged from direct recordings of electrical activity during exercise in patients with implanted deep brain stimulating electrodes. Of particular interest is the periaqueductal grey area (PAG), where electrodes are implanted in humans to treat chronic pain. This area is known to be important in the exercise pressor reflex in animals. Our studies have shown that changes occur in this region during anticipation of exercise, indicating a possible role in the central command of cardiovascular variables before and during exercise. This leads us to suggest that the PAG may be an ‘integrating area’ between the feedback signals from muscle and the feedforward signals from higher centres. The role of the PAG in cardiovascular control in humans, with reference to electrical stimulation experiments, is also described.

(Received 6 February 2008; accepted after revision 3 June 2008; first published online 20 June 2008)
Corresponding author A. L. Green: Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK. Email: alex.green{at}physiol.ox.ac.uk


   Introduction
Top
 Abstract
 Introduction
References
 
The concept that the cardiovascular system is ‘controlled’ by neurocircuitry is not a new one. In fact, as early as 1840, Henle suggested that muscle tone in the walls of blood vessels is under the control of nerve fibres (see Montastruc et al. 1996). Since that time, this topic has attracted a considerable amount of research interest, from the actions (and indeed discovery) of individual neurotransmitters (Loewi, 1921), through brainstem control and the discovery of the rostroventrolateral medulla (Guertzenstein & Silver, 1974), to the study of integrative systems such as Hilton's efferent pathway from the amygdala to the brainstem, involved in the defence–arousal system in cats (Hilton & Zbrozyna, 1963). A detailed history of this topic is out of the scope of this article, but has been comprehensively reviewed by Coote (2007). This hot topic review will concentrate on how the use of functional neurosurgery has aided in the identification of central nervous system circuitry that may be important in controlling the cardiovascular responses to exercise in humans, so-called ‘central command’.

Neural circuitry determining blood pressure

This area has been widely researched and reviewed and therefore we will only flag key areas that are essential to this review. The medulla contains the major nuclei that control heart rate, blood pressure and respiration. Information from the peripheral arterial and cardiopulmonary baroreceptors and chemoreceptors passes, via the glossopharyngeal and vagus nerves, to the caudal nucleus of the tractus solitarius (NTS; Jordan & Spyer, 1977; Ciriello & Calaresu, 1981; Loewy & Spyer, 1990). In addition, renal afferents provide an important influence on the activity of brainstem regions that control blood pressure. In exercise, the exercise pressor reflex is an important contributor of afferent ‘feedback’ from exercising muscles and therefore an additional influence on the control of cardiovascular parameters. Efferents from the brainstem are both parasympathetic (mainly cholinergic), which alter contractility of the heart and heart rate via the vagus, and from three types of sympathetic efferent (barosensitive, thermosensitive and glucosensitive) that innervate blood vessels, heart, kidneys and adrenal medulla. The parasympathetic system is activated by the nucleus ambiguus (NA) and the dorsal motor nucleus of the vagus nerve (DMNV), but it is the sympathetic system that is thought to be far more influential in blood pressure control. This latter system is largely activated by nuclei within the rostral ventrolateral medulla (RVLM). Also, neurones from RVLM provide sympathetic innervation to the heart, particularly influencing myocardial contractility, but also heart rate. These peripheral circuits are more comprehensively reviewed elsewhere (Guyenet, 2006).

The cardiovascular responses are also integrated with respiratory responses at the level of the medulla (Spyer & Gilbey, 1988; Haselton & Guyenet, 1989). One particular area is the retrotrapezoid nucleus, which contains pH-sensitive neurones that influence breathing (see Guyenet et al. 2008 for review). Although these mechanisms are essentially a reflex to maintain cardiovascular homeostasis (Fig. 1), clearly neural control of the cardiovascular system is more complicated than this. For example, maintenance of a narrow blood pressure range would not account for the increases required at times of heightened activity, nor would it account for increases associated with arousal or anxiety. Early work on midbrain centres included the hypothalamus, which was identified as an important centre for the integration of the visceral and somatic components of the ‘alerting response’ in the rat (Abrahams et al. 1960; Hilton & Zbrozyna, 1963). Since the work of Hilton and colleagues, many other higher areas have been shown to connect to areas of cardiovascular regulation and, in some instances, to contain pressor or depressor regions. These areas include prefrontal cortex (Bandler et al. 2000), insular cortex (Hilton & Spyer, 1980), cingulate cortex (Burns & Wyss, 1985) and thalamus (Risold et al. 1997). These areas are involved in cardiovascular regulation associated with changes in behaviour; not only the arousal response, but also emotion (Berntson et al. 1998). It is the midbrain areas, particularly the periaqueductal grey area (PAG), that we are particularly concerned with in this review.


Figure 1
View larger version (61K):
[in this window]
[in a new window]

  		Figure 1.  Neural control of the cardiovascular system
The medulla contains areas rich in cells that are involved in the baroreceptor reflex and represents the termination of inputs from end-organs such as the heart and arterial smooth muscle. These areas, in turn, are influenced by higher areas up to the telencephalon. Abbreviations: AHN, anterior hypothalamic nucleus; LHA, lateral hypothalamic nucleus; PVN, paraventricular nucleus of the hypothalamus; LPBN, lateral parabrachial nucleus; PAG, periaqueductal grey; NTS, nucleus of the tractus solitarius; CVLM, caudal ventrolateral medulla; RVLM, rostral ventrolateral medulla; NA, nucleus ambiguus, DMNV, dorsal motor nucleus of the vagus; AP, area postrema; and IML, intermediolateral cell column. Adapted with permission from Wyss et al. (2004).

 
‘Central command’ and exercise

Identification of neurocircuitry in animal models is made possible by being able to manipulate the relevant central nervous system centres directly using, for example, electrical or chemical stimulation or to trace connections using injected tracer materials. In humans, direct manipulation is more difficult, although electrical and magnetic stimulation are possible. One particular area of research that led the way in human physiology is the work on ‘central command’ during exercise. This is a concept first introduced by Krogh & Lindhard (1913), although they called it ‘cortical irradiation’ and its name was later changed. Central command is the concept that higher brain centres ‘control’ the cardiorespiratory system (arterial blood pressure, heart rate, ventilation etc.) in a top-down manner to meet the anticipated metabolic demand of contracting muscles. For example, as shown by Krogh and Lindhard, perception of exercise results in a cardiorespiratory response that is related to the perceived work rate. Although traditionally central command of the cardiovascular system (via cardiovascular centres) has been intimately linked with parallel feedforward mechanisms involving the motor systems, Williamson and colleagues have proposed that ‘central command during exercise may actually involve the simultaneous activation of two separate networks, one for central motor control and one for central cardiovascular control’ (Williamson et al. 2006). Evidence for this comes from experiments where humans' perception of exercise, rather than the exercise itself, has been shown to determine the cardiorespiratory response (Mitchell, 1990) as well as experiments using hypnotically induced subjects (Morgan et al. 1976; Thornton et al. 2001). In these experiments, cardiorespiratory parameters are altered but without the usual feedback from exercising muscles.

What is the underlying neurocircuitry of central command in humans? Most of the data come from functional imaging studies. Positron emission tomography (PET) studies have provided evidence of increases in regional cerebral blood flow in a number of areas during the supposed activation of central command. For example, Nowak and colleagues have shown that activation of the bilateral insular cortex (as well as cerebellum) occurs in paraplegics who attempt to lift a foot in addition to when they are performing hand-grip exercises (Nowak et al. 2005). Motor and sensory cortices are only activated in the latter situation. The insular cortex is not known to receive afferents from exercising muscles and therefore its activation in the absence of motor cortex activation but in the context of attempted exercise and cardiovascular changes is thought to be related to central command. Insular activation has similarly been found using PET and other functional imaging studies (King et al. 1999; Williamson et al. 1999).

Another higher area that has been implicated in cardiovascular control is the cingulate cortex. Williamson et al. (2006) have proposed that, since the cingulate region is involved with discrimination of peripheral somatosensory input during exercise, its role in central command could be to interpret an individual's level of central command, or ‘effort sense’. This theory is supported by the work of King and colleagues, who found this region (that they refer to as ‘medial prefrontal cortex’) to be activated during hand-grip exercise and associated with cardiovascular activation (King et al. 1999).

Direct recording from the human brain: the role of deep brain stimulation

Although these eloquent studies reveal regions of the brain that have increased (or decreased) activity in different states of cardiovascular regulation, they do not provide direct electrophysiological recordings in the intact human brain. Neither do they provide direct manipulation of human brain areas, to corroborate previous animal experiments using electrical stimulation techniques. This is where a technique called ‘deep brain stimulation’ (DBS) has the potential to aid research in this area. Deep brain stimulation is a therapeutic intervention in which one or more electrodes are passed into deep brain nuclei and are used to electrically stimulate the area (Fig. 2).


Figure 2
View larger version (86K):
[in this window]
[in a new window]

  		Figure 2.  A deep brain stimulator system in situ
A shows the typical trajectories of electrodes targeted at the periaqueductal grey area. The positions are based on postoperative magnetic resonance scans. Abbreviations: PAG, periaqueductal grey; RN, red nucleus; SC, superior colliculus; PVG, periventricular grey; and PC, posterior commissure. Inset shows a photograph of the electrode. Each electrode consists of 4 circumferential contacts. B, the procedure involves inserting the electrode through a 2.7 mm ‘twist drill’ hole in the operating theatre under local anaesthetic. C, a postoperative coronal magnetic resonance image showing an electrode in situ.

 
Each electrode consists of four circumferential contacts, and current can be passed between any combination of them (‘bipolar’ stimulation) or between the contact(s) and the ‘implantable pulse generator’ (IPG). The IPG is a power source/device for altering the electrical properties of the stimulation that sits in a subcutaneous pocket beneath the skin and is connected to the electrode(s). Conditions treated with DBS include Parkinson's disease, dystonia (a neurological condition that results in abnormal postures/movements), tremor, pain, psychiatric conditions such as depression, Tourette's syndrome and ‘obsessive–compulsive disorder’. The mechanisms of action of DBS are complex, but in general, high-frequency stimulation (such as subthalamic nucleus stimulation at 130 Hz in Parkinson's disease) probably inhibits activity of the nucleus, whereas low-frequency stimulation (e.g. 20 Hz stimulation of the periaqueductal grey in pain) probably drives it (McIntyre et al. 2004).

Using DBS patients, insights into neural circuitry involved in cardiovascular regulation in humans have come about from two aspects of the technique. First, with an electrode implanted into the human brain, there is a period of time when it is not connected to the IPG, either intra-operatively or for a week postoperatively. This period of time before implantation of the whole system is so that if the DBS has no effect, it is simply explanted and the patient is not left with a stimulator system in situ. During this time, it is possible to record ‘local field potentials’ (LFPs) from the brain area in question. Second, whether the system is internalized or not, DBS can be used to stimulate an area to see what effects it has on clinical parameters, such as those of the cardiovascular system.

Exercise, arterial blood pressure and the role of the periaqueductal grey

Animal studies have defined a role of the midbrain, including the PAG, in the exercise pressor reflex. For example, muscle contraction increases PAG neuropeptide Y and enkephalin release in cats (Williams, 1996). In addition, c-Fos expression identified the activation of PAG neurons during dynamic treadmill exercise in rats (Iwamoto et al. 1996), and muscle contraction increases PAG neuron discharge (Kramer et al. 1996). This feedback mechanism is thought to be an important peripheral ‘sensor’ that is important in modulating central command control of the cardiovascular system, although it does not imply that the PAG itself is a ‘centre’ for central command.

Using LFP recordings, our group has shown that there are significant changes in the LFPs in the PAG during ‘anticipation’ of exercise in patients who had PAG stimulators for treatment of chronic pain (Fig. 3 ; Green et al. 2007). These changes did not occur in the sensory thalamus (another brain area used in DBS for chronic pain treatment). These results demonstrate, for the first time, that human midbrain activity is altered in ‘anticipation’ of exercise, at the same time as increases in blood pressure, heart rate and respiratory rate, but prior to exercise. They therefore provide direct neurophysiological evidence for a role of the PAG in supraspinal control of exercise-related cardiorespiratory changes without evidence that it is involved in control of locomotion. We can therefore suggest a putative role of command signals emanating from the PAG in mediating the cardiovascular responses associated with anticipation of exercise. This is compatible with the classical ‘parallel activation’ of locomotor and cardiovascular systems, although it is unclear whether the PAG is a ‘central command’ site as such.


Figure 3
View larger version (25K):
[in this window]
[in a new window]

  		Figure 3.  Changes in local field potentials during ‘central command’
In this experiment, electrical activity was measured in the PAG of patients with implanted deep brain stimulator electrodes in three different conditions: resting; ‘anticipation’ of exercise whilst an investigator was ‘counting down’ to exercise; and exercise. There were significant increases in activity during anticipation of exercise, compared with rest, suggesting that brain activity increases during ‘central command’. Reproduced with permission from Green et al. (2007)).

 
This putative role for the PAG in exercise is supported by evidence that this area is important for control of blood pressure itself (Fig. 4 ; Green et al. 2005). Thus, the functional brain circuitry necessary for central command has been shown to exist. Could the changes we have found in the PAG simply be a ‘stress’ response, related to anxiety or fear? Although fear has been described in relation to human PAG (Nashold et al. 1969), fear or anxiety were not seen in any of our subjects during recording. Another confounding factor would be the recording from axons of passage, such as those in Hilton's pathway, rather than PAG neurons themselves. Without histological sections of the brain, this is difficult to refute, although connections between PAG and higher centres involved in cardiovascular regulation have been demonstrated in animal models (see subsection on ‘The PAG in animals: comparison of our findings’).


Figure 4
View larger version (49K):
[in this window]
[in a new window]

  		Figure 4.  Arterial blood pressure changes seen with stimulation of PAG
A, mean changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), R–R interval and maximal rate of change of ventricular pressure (maximal dP/dt) for seven patients who had a reduction in BP during stimulation (yellow area) of ventral periventricular grey. Stimulation was started at 100 s and stopped at 400 s. The grey area denotes ± 1 S.E.M. B, the same mean changes for six patients with an increase in SBP on stimulation of dorsal periventricular grey. Reproduced with permission from Green et al. (2005).

 
In addition to the findings in PAG, the subthalamic nucleus (STN) was found to be involved during exercise (mainly the {gamma}-frequency, 60–90 Hz) but was associated mainly with decreased activity during anticipation of exercise (Green et al. 2007). A previous study demonstrated that electrical stimulation of the STN in humans leads to increases in heart rate and arterial blood pressure (Thornton et al. 2002). This is compatible with the classic studies by Eldridge et al. (1981), who showed that stimulation of the STN can drive locomotion and cardiorespiratory responses in decorticate cats, independent of feedback from exercising muscles. Since the STN projects to areas that affect cardiovascular function as well as to the thalamus for movement control (Verberne & Owens, 1998), it is likely that it is important in the circuitry necessary for exercise-related cardiovascular function but not the changes seen with anticipation, i.e. central command. Of course, these are not the only human brain areas likely to be important in cardiovascular control, but we are restricted to recording from sites that are being used therapeutically.

The PAG in animals: comparison of our findings

The finding of blood pressure changes with PAG stimulation, at least in animals, is not new. In 1935, Kabat and co-workers demonstrated it in the cat (Kabat et al. 1935). Later, in 1956, Hunsperger described the ‘defence’ reaction (Hunsperger, 1956). This is an integrated response that is associated with survival in the wild. For example, if escape from danger is possible, the response involves a ‘fight or flight’ reaction that includes raised blood pressure and heart rate, non-opioid-mediated analgesia and emotional effects, such as fear (Carrive & Bandler, 1991a). Conversely, if escape is not possible and it is safer to remain undetected, the reaction consists of lowered blood pressure, opioid-mediated analgesia and a ‘withdrawal reaction’ as well as fear (Johnson et al. 2004). Furthermore, the columns of the PAG are functionally distinct and opposite; activation of the dorsomedial and dorsolateral columns evokes the ‘fight or flight’ response, and activation of the lateral and ventrolateral columns produces the passive coping responses described above (Carrive & Bandler, 1991b).

How does this fit with our findings of PAG activation in ‘anticipation’ of exercise? It could be that under ‘normal’ circumstances, the PAG acts as a relay centre for central command (from higher centres, such as the insular or cingulate cortices) but in times of stress, i.e. when a defence reaction is employed, it acts as a de novo centre for cardiovascular control, omitting the need for higher centres. Also of note, the LFP recordings were averages, and it is possible that reductions may occur in ventral PAG activity at the same time as dorsal PAG activations. If this is the case, the average increases in activity may reflect the larger increase in dorsal PAG activity. However, we are not able to test this hypothesis because of the crude nature of LFP recordings.

Summary

There is a wealth of animal data identifying neural circuitry involved in cardiovascular control. Translating this research into humans has, until recently, mainly involved the use of functional imaging techniques. More recently, the advent of DBS has allowed us to look at the activity of brain regions in cardiovascular experiments as well as giving us the opportunity to stimulate the human brain, thus comparing animal with human data. In the future, these findings may lead to therapies directed at cardiovascular modulation.

Ethical approval

All human studies performed by the authors and referred to in this article were passed by the local ethics committee (Oxfordshire Regional Ethics Committee ‘C’) and written informed consent obtained from all patients. The methodology conforms to the Declaration of Helsinki.


   References
Top
 Abstract
 Introduction
 References
 
Abrahams VC, Hilton SM & Zbrozyna A (1960). Active muscle vasodilatation produced by stimulation of the brain stem: its significance in the defence reaction. J Physiol 154, 491–513.[Free Full Text]

Bandler R, Keay KA, Floyd N & Price J (2000). Central circuits mediating patterned autonomic activity during active vs. passive emotional coping. Brain Res Bull 53, 95–104.[CrossRef][Medline]

Berntson GG, Sarter M & Cacioppo JT (1998). Anxiety and cardiovascular reactivity: the basal forebrain cholinergic link. Behav Brain Res 94, 225–248.[CrossRef][Medline]

Burns SM & Wyss JM (1985). The involvement of the anterior cingulate cortex in blood pressure control. Brain Res 340, 71–77.[CrossRef][Medline]

Carrive P & Bandler R (1991a). Control of extracranial and hindlimb blood flow by the midbrain periaqueductal grey of the cat. Exp Brain Res 84, 599–606.[Medline]

Carrive P & Bandler R (1991b). Viscerotopic organization of neurons subserving hypotensive reactions within the midbrain periaqueductal grey: a correlative functional and anatomical study. Brain Res 541, 206–215.[CrossRef][Medline]

Ciriello J & Calaresu FR (1981). Projections from buffer nerves to the nucleus of the solitary tract: an anatomical and electrophysiological study in the cat. J Auton Nerv Syst 3, 299–310.[CrossRef][Medline]

Coote JH (2007). Landmarks in understanding the central nervous control of the cardiovascular system. Exp Physiol 92, 3–18.[Abstract/Free Full Text]

Eldridge FL, Millhorn DE & Waldrop TG (1981). Exercise hyperpnea and locomotion: parallel activation from the hypothalamus. Science 211, 844–846.[Abstract/Free Full Text]

Green AL, Wang S, Owen SLF, Xie K, Liu X, Paterson DJ, Stein JF, Bain PG & Aziz TZ (2005). Deep brain stimulation can regulate arterial blood pressure in awake humans. Neuroreport 16, 1741–1745.[CrossRef][Medline]

Green AL, Wang S, Purvis S, Owen SL, Bain PG, Stein JF, Guz A, Aziz TZ & Paterson DJ (2007). Identifying cardiorespiratory neurocircuitry involved in central command during exercise in humans. J Physiol 578, 605–612.[Abstract/Free Full Text]

Guertzenstein PG & Silver A (1974). Fall in blood pressure produced from discrete regions of the ventral surface of the medulla by glycine and lesions. J Physiol 242, 489–503.[Abstract/Free Full Text]

Guyenet P (2006). The sympathetic control of blood pressure. Nat Rev Neurosci 7, 335–346.[Medline]

Guyenet PG, Stornetta RL & Bayliss DA (2008). Retrotrapezoid nucleus and central chemoreception. J Physiol 586, 2043–2048.[Abstract/Free Full Text]

Haselton JR & Guyenet PG (1989). Central respiratory modulation of medullary sympathoexcitatory neurons in rat. Am J Physiol Regul Integr Comp Physiol 256, R739–R750.[Abstract/Free Full Text]

Hilton SM & Spyer KM (1980). Central nervous regulation of vascular resistance. Annu Rev Physiol 42, 399–441.[CrossRef][Medline]

Hilton SM & Zbrozyna AW (1963). Amygdaloid region for defence reactions and its efferent pathway to the brain stem. J Physiol 165, 160–173.[Free Full Text]

Hunsperger RW (1956). Affective reaction from electric stimulation of brain stem in cats [in German]. Helv Physiol Pharmacol Acta 14, 70–92.[Medline]

Iwamoto GA, Wappel SM, Fox GM, Buetow KA & Waldrop TG (1996). Identification of diencephalic and brainstem cardiorespiratory areas activated during exercise. Brain Res 726, 109–122.[CrossRef][Medline]

Johnson PL, Lightman SL & Lowry CA (2004). A functional subset of serotonergic neurons in the rat ventrolateral periaqueductal gray implicated in the inhibition of sympathoexcitation and panic. Ann N Y Acad Sci 1018, 58–64.[CrossRef][Medline]

Jordan D & Spyer KM (1977). Studies on the termination of sinus nerve afferents. Pflugers Arch 369, 65–73.[CrossRef][Medline]

Kabat H, Magoun HW & Ranson SW (1935). Electrical stimulation of points in the forebrain and midbrain. The resultant alteration in blood pressure. Arch Neurol Psych 34, 931–955.

King AB, Menon RS, Hachinski V & Cechetto DF (1999). Human forebrain activation by visceral stimuli. J Comp Neurol 413, 572–582.[CrossRef][Medline]

Kramer JM, Jarboe MO & Waldrop TG (1996). Periaqueductal gray neuronal responses to hindlimb muscle contraction in the cat. Soc Neurosci Abstr 22, 89.

Krogh A & Lindhard J (1913). The regulation of respiration and circulation during the initial stages of muscular work. J Physiol 47, 112–136.[Free Full Text]

Loewi O (1921). Uber humorale Ubertragbarkeit der Herznervenwirkung. Pflugers Arch 189, 239–242.[CrossRef]

Loewy AD & Spyer KM (1990). In Central regulation of Autonomic Functions. Oxford University Press, New York.

McIntyre CC, Savasta M, Walter BL & Vitek JL (2004). How does deep brain stimulation work? Present understanding and future questions. J Clin Neurophysiol 21, 40–50.[Medline]

Mitchell JH (1990). J.B. Wolffe memorial lecture. Neural control of the circulation during exercise. Med Sci Sports Exerc 22, 141–154.[Medline]

Montastruc JL, Rascol O & Senard JM (1996). The discovery of vasomotor nerves. Clin Auton Res 6, 183–187.[CrossRef][Medline]

Morgan WP, Hirta K, Weitz GA & Balke B (1976). Hypnotic perturbation of perceived exertion: ventilatory consequences. Am J Clin Hypn 18, 182–190.[Medline]

Nashold BS Jr, Wilson WP & Slaughter DG (1969). Sensations evoked by stimulation in the midbrain of man. J Neurosurg 30, 14–24.[Medline]

Nowak M, Holm S, Biering-Sørensen F, Secher NH & Friberg L (2005). "Central command" and insular activation during attempted foot lifting in paraplegic humans. Hum Brain Mapp 25, 259–265.[CrossRef][Medline]

Risold PY, Thompson RH & Swanson LW (1997). The structural organization of connections between hypothalamus and cerebral cortex. Brain Res Brain Res Rev 24, 197–254.[CrossRef][Medline]

Spyer KM & Gilbey MP (1988). Cardiorespiratory interactions in heart-rate control. Ann N Y Acad Sci 533, 350–357.[Medline]

Thornton JM, Aziz T, Schlugman D & Paterson DJ (2002). Electrical stimulation of the midbrain increases heart rate and arterial blood pressure in awake humans. J Physiol 539, 615–621.[Abstract/Free Full Text]

Thornton JM, Guz A, Murphy K, Griffith AR, Pedersen DL, Kardos A, Leff A, Adams L, Casadei B & Paterson DJ (2001). Identification of higher brain centres that may encode the cardiorespiratory response to exercise in humans. J Physiol 533, 823–836.[Abstract/Free Full Text]

Verberne AJ & Owens NC (1998). Cortical modulation of the cardiovascular system. Prog Neurobiol 54, 149–168.[CrossRef][Medline]

Williams CA (1996). Neuropeptide Y-like substances are released from the rostral brainstem of cats during the muscle pressor response. J Physiol 495, 267–277.[Medline]

Williamson JW, Fadel PJ & Mitchell JH (2006). New insights into central cardiovascular control during exercise in humans: a central command update. Exp Physiol 91, 51–58.[Abstract/Free Full Text]

Williamson JW, McColl R, Mathews D, Ginsburg M & Mitchell JH (1999). Activation of the insular cortex is affected by the intensity of exercise. J Appl Physiol 87, 1213–1219.[Abstract/Free Full Text]

Wyss JM, Carlson SH & Oparil S (2004). The Pathogenesis of Hypertension. In Basic and Clinical Neurocardiology, ed. Armour JA and Ardell JL, pp. 375. Oxford University Press, New York.





This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
93/9/1022    most recent
expphysiol.2007.039461v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Google Scholar
Right arrow Articles by Green, A. L.
Right arrow Articles by Paterson, D. J.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Green, A. L.
Right arrow Articles by Paterson, D. J.
Related Collections
Right arrow Hot Topic Reviews
Right arrow Cardiovascular control

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS