Neurogastroenterol Motil (2009) 21, 1155–e98
doi: 10.1111/j.1365-2982.2009.01348.x
Personality differences affect brainstem autonomic responses to visceral pain P. PAINE ,* S. F. WORTHEN , L. J. GREGORY ,* D. G. THOMPSON * & Q. AZIZ
*Department of Gastrointestinal Sciences, Hope Hospital, University of Manchester, UK Wingate Institute of Neurogastroenterology, Barts and the London, School of Medicine and Dentistry, Queen Mary College, University of London, UK
active and passive defence repertoires. Prevalence and clinical relevance of these endophenotypes as vulnerability factors for pain and emotion disorders warrant further exploration.
Abstract Brainstem autonomic nuclei integrate interoceptive inputs including pain, with descending modulation, to produce homeostatic and defence outputs. Cardiac Vagal Control is especially implicated in psychophysiological processes for both health and disease and is indexed non-invasively by heart rate variability. The study aim was to determine the nature of psychophysiological response profiles for visceral pain. Nineteen healthy subjects had electrocardiographic recordings at rest and during 10 painful oesophageal balloon distensions. Cardiac Vagal Control originating from nucleus ambiguus (CVCNA) was determined by polynomial filter application to the electrocardiogram inter-beat interval series. Heart rate and ÔCardiac Sympathetic Index (CSI)Õ were also determined. Psychological state and trait, including neuroticism and extroversion, were assessed. Subjects who increased CVCNA to pain were more neurotic, anxious and sensory sensitive than those who decreased CVCNA. Cluster analysis identified two psychophysiological groups: Group 1 (n = 11) demonstrated lower baseline CVCNA (P = 0.0001), higher heart rate (P = 0.02) and CSI (P = 0.015), pain tolerance at lower balloon volumes (P = 0.04), but attenuated heart rate response to pain (P = 0.01). Group 2 (n = 8) had the converse profile. Neuroticism scores were higher (P = 0.0004) and extroversion lower (P = 0.01) for group 1 than group 2. Two distinct psychophysiological response profiles to visceral pain exist that are influenced by personality. These may reflect different psychobiological bases for
Keywords autonomic, defence, psychophysiology, visceral pain.
BACKGROUND Pain comprises sensory-discriminative, affective-motivational, and cognitive-evaluative dimensions and evokes behavioural and physiological responses.1 Pain is a common clinical problem but often medically unexplained. Chronic visceral pain syndromes, including irritable bowel, are frequently co-morbid with affective disorders.2 Pain was recently described as a Ôhomeostatic emotionÕ which overlaps, interacts and shares psychological, neuroanatomical and physiological features with other emotions.3 This shared psychobiology includes the autonomic nervous system in a common Ôemotional motor systemÕ.4 Pain threshold differences occur between healthy and chronic pain groups but wide inter-individual variations make these diagnostically insensitive.5 Improved biomarkers and mechanistic understanding of inter-individual differences in pain perception and psycho–physiological response are needed for studies in health and disease. Brainstem autonomic nuclei integrate incoming interoceptive signals such as pain, with descending modulation, homeostatic and defence motor outputs.6 Selective, non-invasive, functionally relevant and event time-locked measurement of brainstem nuclei activity is possible indirectly via autonomic outputs. Electrocardiographic heart rate variability for example reflects nucleus ambiguus Cardiac Vagal Control (CVCNA).7
Address for correspondence Qasim Aziz, Professor of Neurogastroenterology, Director Wingate Institute of Neurogastroenterology, 26 Ashfield Street, London E1 2AJ, UK. Tel: +44 (0)207 882 2630; fax: +44 (0)207 375 2103; e-mail:
[email protected] Received: 29 January 2009 Accepted for publication: 26 April 2009
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gives rise to respiratory sinus arrhythmia – the basis for most CVCNA measures (Fig. 1).13 Nucleus ambiguus Cardiac Vagal Control modulation also occurs via the amygdala in emotional responses; periaqueductal grey matter in defence responses; the hypothalamus for other homeostatic functions; and facial and laryngeal receptors in communication7,14 (Fig. 1). Nucleus ambiguus Cardiac Vagal Control abnormalities were observed in relation to Ôorganic diseaseÕ; unstable infant temperaments; neonatal pain reactivity differences; emotional reactivity; and in chronic pain and affective disorders.15–17 Nucleus ambiguus Cardiac Vagal Control is therefore a psychophysiological Ômind-body interfaceÕ for which heart rate variability affords an indirect non-invasive window.17 Personality traits are dimensions of individual difference with evidence for a biological basis of which the best characterized are extroversion-introversion and neuroticism-emotional stability.18,19 Neuroticism is a measure of negative emotionality18 which correlates inversely with heart rate variability under genetic influence.20 Personality differences have also been found in pain sensitivity and coping in experimental and clinical settings.21–24 Personality traits and heart rate variability are therefore promising inter-related biomarkers for individual differences in pain perception and response. The study aim was to determine if endophenotypic psychophysiological profiles exist for pain, in particular whether personality influences visceral pain induced brainstem autonomic responses.
Pain and defence research has traditionally emphasized behavioural activation (e.g. fight-flight) and sympathetic response; however, hierarchical superiority of inhibition by prefrontal cortices and the parasympathetic nervous system is increasingly recognized.8 Inhibition facilitates a spectrum of freeze and affiliative (e.g. bonding) behaviours, whilst dis-inhibition facilitates behavioural activation.7,9–11 In Polyvagal theory, for example, phylogenetic comparison shows progressive elaboration of mammalian brainstem cardiac vagal control that enables increasing behavioural complexity.7 The vagus has a sensory nucleus (nucleus of the solitary tract) and two brainstem motor nuclei. The dorsal motor vagal nucleus innervates the heart and lower gut via unmyelinated slow effector neurones, producing ÔprimitiveÕ immobilization behaviours and bradycardia.7 The nucleus ambiguus by contrast innervates the heart (CVCNA), larynx and upper gut via myelinated fast-effector neurones, allowing modest heart rate slowing for subtler behavioural inhibition and bonding (Fig. 1). Nucleus ambiguus Cardiac Vagal Control withdrawal produces a faster heart-rate by reducing sino-atrial node constraints, facilitating behavioural activation.7 Physiologically, CVCNA functions primarily to control Ôbeat-to-beatÕ heart rate for blood pressure regulation by a vago-vagal reflex involving arterial baroreceptors.12 Additionally, Ôbreath-to-breathÕ CVCNA regulation occurs via lung stretch receptors, arterial chemoreceptors and respiratory neurones, that
Figure 1 Figure showing the central processes and neurophysiological control of Cardiac Vagal Control together with its cardiorespiratory influences and effects. PAG, periaqueductal grey matter; BP, blood pressure; SVR, systemic vascular resistance; CO, cardiac output; HR, heart rate; NTS, nucleus of solitary tract; CVM, cardiac vagal motoneurones; SA, stretch, RÕs, receptors). Figure adapted from Julu.14
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METHODS
(i) Heart rate. R waves, part of the QRS complex, are the first upwards deflection from electrical baseline on the ECG representing ventricular depolarisation. Powerlab HRV analysis software (AD Instruments) applied an R-wave detection algorithm to ECG offline, allowing recognition, detection and correction on-screen of misidentified R wave peaks. The R–R interval series (milliseconds) and heart rate were subsequently derived. The minimum duration for statistically reliable respiratory sinus arrhythmia (RSA) measures by international standards is 1 min.30 Continuously aquired ECG during the study was therefore divided into 1-min epochs for RSA derivation comprising 20-s prestimulus and 40-s poststimulus. Inter-stimulus interval was also 1-min duration. The ECG from the middle minute of a 3-min preintubation baseline period was taken subsequently as the comparator for changes from baseline. (ii) Cardiac Vagal Control from Nucleus Ambiguus. MXEDIT is a 31,32 DOS software RSA-based measure of CVC. A particular advantage of the MXEDIT technique over others such as spectral analysis is that it does not assume stationary activity (stationarity) which might be a problem when a stimulus is delivered during the epoch being measured. In brief, MXedit firstly converts the R–R series to time-based data by resampling; then applies a moving polynomial filter (Porges-Bohrer) producing a smoothed template series; subsequently subtracts this from the original series producing a residual time series; then applies a digital bandpass filter to extract variance in the frequency band of 12–40 Hz (the frequency of spontaneous breathing); and finally natural logarithm transforms this to quantify RSA [units are ln (ms2)]. This process truncates the original R–R series by 12–15 s at either end. Normal data for lnRSA has been published and is a well validated measure of CVCNA.33 (iii) Cardiac Sympathetic Index (CSI). This is a putative measure of sympathetic influence on heart rate,34 obtained by importing R–R series into the ÔCMETÕ program.13 CSI has been validated as a sympathetic cardiometric in humans by pharmacological blockade studies.34 It is a ratio of R–R intervals and has no units. It is a novel measure and relatively untested beyond the initial validation study, however other ÔestablishedÕ cardiometrics purported to measure sympathetic activity, such as the low frequency component of spectral analysis and thereby Ôsympathovagal balanceÕ, have been largely discredited.35 (iv) Protocol. All studies were performed in a sound and temperature-controlled room adjusted to subject comfort levels. Subjects completed a Spielberger State Anxiety Questionnaire and were then seated comfortably in a chair reclined to 45 degrees with their head supported. ECG electrodes were attached and a 3-min resting autonomic activity recording obtained. The middle minute of this period was used subsequently as baseline comparator. Subjects swallowed the oesophageal balloon catheter then rested a further 10 min. Autonomic responses were continuously recorded during 10 painful oesophageal balloon distensions, with 1-min inter-stimulus interval. Onset of balloon stimuli was marked digitally with Powerlab (AD instruments) and separate notes of time recorded by a second investigator. Subjects completed the Psychological Trait Questionnaires on a separate occasion supervised by the investigator.
Subjects Nineteen healthy volunteers participated (8 male, ages 22–54). Ethics approval was given by Central Manchester Local Research Ethics Committee (ref 07/Q1407/3). Full informed consent was obtained. Subjects with current or chronic pain, gastrointestinal, neurological or psychiatric medical problems or taking medication affecting GI, pain or neuropsychological function were excluded.
Psychological traits and state Subjects completed validated questionnaires including the Big Five Inventory, a 44-item Personality Questionnaire25 for which subscales of neuroticism and extroversion were used in subsequent analysis. State and trait anxiety were assessed using the Spielberger state-trait anxiety scores, and also anxiety and sensory sensitivity scores.26–28 Trait anxiety is the likely dominant subfactor of neuroticism;29 anxiety sensitivity focuses on bodily sensations of anxiety whereas sensory sensitivity focuses on ÔeverydayÕ sensations.
Painful oesophageal balloon distension Oesophageal balloons were hand assembled from 3-cm lengths of thin silicone tubing (medasil UK, Leeds, UK) tied and glued 0.5 cm at each end over perforations 2 cm from the tip of a commercially available nasogastric tube (2.7 mm, 120 cm; Pennine Healthcare Ltd, Derby, UK) thus creating a 2-cm diameter balloon. The tube was swallowed per-orally or trans-nasally according to subject preference and the balloon positioned 30 cm ab orus (mid/lower oesophagus). No local anaesthetic was used for intubation but passage was eased through the nasopharynx with a water-based lubricant jelly (KY jelly; Johnson & Johnson, Langhorn, PA, USA). The balloon was manually inflated by syringe at a rate of 2 mL s)1 until subjects indicated that pain tolerance threshold was reached. Subjects were instructed this was the level beyond first pain sensation at which further increases were not tolerated. This was equivalent to a rating of 7/10 on a Visual Analogue Scale ranging from 0 (no sensation) to 10 (extreme pain). The balloon was immediately deflated when pain tolerance threshold was indicated. Manual balloon inflation was used in preference to an automated method to allow Ôreal timeÕ changes in the input intensity of each stimulus. In other words, with manual inflation the balloon volume could be closely titrated to changes in subject symptom report and tolerance whereas currently available automated techniques require preset volumes which cannot be altered like this during stimulation. This ensured that pain tolerance threshold (and not a lesser pain level) could be reached each time.
Autonomic measures
Statistical analysis
Electrocardiographic (ECG) measures The skin was prepared by light excoriation to reduce impedance (Nuprep; DO Weaver & Co, Aurora, CO, USA), and electrodes placed (Cleartrace; Conmed Corporation, NY, USA) with conducting gel (Spectra 360 electrode Gel; Parker Laboratories, Fairfield, NJ, USA) in areas for standard 3 lead ECG placements (right, left sub-clavicular fossae and cardiac apex). ECG was acquired at 2 kHz using a commercial biosignals acquisition system (Powerlab; AD instruments, Chalgrove, Oxfordshire, UK).
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The autonomic data were normally distributed therefore comparisons were performed using two-tailed paired StudentÕs t-tests. Mann–Whitney U-tests were used for the psychological scores. Hierarchical cluster analysis was performed to determine best-fit cluster solution then k-wise cluster analysis was performed with this solution to identify sub-groups and determine means of the parameters. Input functions for cluster analyses were baseline
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2.01 ± 0.17 vs pain CSI 3.02 ± 0.2, P £ 0.0001). CVCNA did not change during pain compared with baseline at group level (baseline CVCNA 6.6 ± 0.32 ln (ms2) vs pain CVCNA 6.6 ± 0.28 ln (ms2), P = 0.9).
CVCNA, CVCNA in pain, neuroticism, extroversion and CSI (STATS-DIRECT and SPSS software; Altrincham, Cheshire, UK).
RESULTS
Psychological salience of CVCNA individual pain response differences Approximately half the subjects increased CVCNA during pain and half reduced it when expressed individually as percentage change from baseline (Fig. 2 panel A). Neuroticism, sensory sensitivity and anxiety trait scores were higher for subjects who increased CVCNA (n = 10) to oesophageal pain than those who reduced CVCNA (n = 9) to oesophageal pain (all P < 0.05). Anxiety state was not significantly different between the two groups (Fig. 2 panel B).
Pain tolerance thresholds No adverse events occurred and no subjects withdrew. Subjects indicated pain tolerance threshold was reached on each occasion. Consistent with the phenomenon of habituation, the balloon volume for pain tolerance threshold increased from first to 10th distension (mean ± SEM 23.5 mL ± 1.2 vs 27.7 mL ± 1.3, P = 0.004).
Autonomic measures
Correlation analysis of personality and autonomic measures (i) Personality. Neuroticism and extroversion were negatively correlated (r -0.47, P = 0.042). Additionally, neuroticism correlated positively with
Group HR, CSI and CVCNA, during pain Heart rate and CSI increased during pain compared with baseline (baseline heart rate 69.95 ± 2.44 vs pain heart rate 72.73 ± 2.31 beats min)1, P = 0.03; baseline CSI
A
B
Figure 2 (A) Individual differences in percentage change from baseline of Cardiac Vagal Control by nucleus ambiguus (CVCNA) to oesophageal balloon distension. Solid black line indicates baseline. Half of subjects increased whereas the other half decreased CVCNA relative to baseline during pain. (B) Psychological trait differences were seen between subjects increasing CVCNA to oesophageal pain (n = 10, greater levels of anxiety sensitivity, sensory sensitivity, neuroticism and trait anxiety, all P < 0.05) vs those reducing (n = 9). Error bars represent SEM values.
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sensory sensitivity (r 0.5, P = 0.028) anxiety trait (r = 0.75, P = 0.0002) and anxiety sensitivity (r 0.62, P = 0.004) confirming a strong relationship between measures of anxiety and neuroticism. Neuroticism correlated negatively with baseline CVCNA i.e. the higher the neuroticism score the lower the baseline CVCNA (Fig. 3 panel A). Extroversion correlated positively with heart rate change during pain i.e. more extrovert subjects had brisker heart rate increases (Fig. 3 panel B). Extroversion correlated positively with balloon volume - in other words more introvert individuals reported pain tolerance at lower balloon volumes (Fig. 3 panel C). (ii) CVCNA. Baseline CVCNA correlated negatively with absolute change in CVCNA during pain, in other words those with lower baseline CVCNA tended to increase CVCNA during pain whereas those with higher baseline CVCNA tended to withdraw CVCNA (Fig. 3 panel D). CVCNA change during pain correlated negatively with heart rate change during pain i.e. subjects who increased CVCNA during pain tended to have a blunted or reduced heart rate response (Fig. 3E).
A
C
Cluster analysis A hierarchical cluster analysis was performed for the whole group (n = 19) to determine optimal cluster size solution. Input parameters were baseline CVCNA and CSI, CVCNA in pain, neuroticism and extroversion scores. Cluster options solution freedom was given for 2–4 clusters. The optimal cluster size was two clusters, indicated by dendritic distance. K-wise cluster analysis was performed using the two group solution with the same input parameters. Eleven subjects were placed in one cluster (group 1) and eight subjects in a second cluster (group 2), allowing further comparison of means between the two groups. The group means of the psychological trait and physiological parameters were compared for these two groups (Table 1). Group1 (n = 11) compared with group 2 (n = 8) at baseline demonstrated lower baseline CVCNA but higher HR and CSI. During pain, group1 became intolerant at lower balloon volumes, increased CVCNA but had an attenuated HR response. They had higher neuroticism and lower extroversion.
B
E
D
Figure 3 Correlations between psychological and autonomic parameters. (A) Neuroticism correlated negatively with baseline Cardiac Vagal Control by nucleus ambiguus (CVCNA) i.e. more neurotic individuals had lower baseline CVCNA. (B) Extroversion correlated positively with change in heart rate during pain i.e more extrovert subjects tended to have a greater heart rate increase during pain. (C) Extroversion correlated positively with mean balloon volume at pain tolerance levels i.e. more extrovert subjects tolerated larger volumes whereas introvert subjects tolerated lower. (D) Baseline CVCNA correlated negatively with absolute CVCNA change during pain i.e. subjects with lower baseline CVCNA tended to increase CVCNA during pain whereas those with higher baseline CVCNA tended to reduce. (E) Change in CVCNA during pain correlated negatively with change in heart rate i.e. subjects who increased CVCNA during pain tended to have a smaller increase or even a decrease in heart rate.
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independent personality dimensions (e.g. neuroticismemotional stability and extroversion-introversion) or temperamental categories (neurotic-introvert vs emotionally stable-extrovert).24,39 Our results however lend support to both approaches in that the correlation analysis results favour a spectrum of responses whereas the cluster analysis suggests categorical/ dichotomous response patterns (i.e. 2 ÔbinaryÕ groups).
Table 1 Comparisons between mean ± SEM of two sub-groups identified by cluster analysis for psychological and physiological parameters. Comparisons performed used two-sided unpaired t-tests
Measure Baseline CVCNA Baseline HR Baseline HR Balloon volumes (pain threshold) Pain delta CVCNA Pain delta HR Neuroticism Extroversion
Group 1
Group 2
5.69 ± 0.28
7.81 ± 0.31
74.77bpm ± 2.97 2.34 ± 0.2 23.57 mL ± 1.46
63.32bpm ± 2.86 1.55 ± 0.13 28.38 mL ± 1.64
+0.26 ± 0.2 0.42 ± 1.4 3.1 ± 0.2 3.1 ± 1.7
Significance level P = 0.0001 P = 0.02 P = 0.015 P = 0.045
)0.3 ± 0.2
P = 0.1
6 ± 1.4 1.7 ± 0.2 3.94 ± 0.27
P = 0.016 P = 0.0004 P = 0.016
Central control of autonomic patterned defence responses In mammals binary defence responses can be elicited from periaqueductal grey (PAG) matter. In particular ventrolateral PAG (VLPAG) receives inputs from nucleus of the solitary tract and from spinal dorsal horn. Ventrolateral periaqueductal grey stimulation elicits similar autonomic responses to group 1: reduced sympathetic activity including hypotension, increased parasympathetic activity and blunted heart rate response/bradycardia.11,38 Ventrolateral periaqueductal grey lesions prevent freezing defence behaviour and therefore this region may be responsible for passive coping.11 Conversely, lesions in dorsolateral/lateral PAG block fight-flight responses but stimulation elicits tachycardia, sympathetic activation and parasympathetic withdrawal i.e. a pattern similar to group 2. Dorsolateral PAG can be activated by higher centres and does not receive input from NTS or spinal cord. Lateral PAG receives input from dorsal horn but is usually activated by superficial cutaneous pain rather than visceral.11 Recent work suggests that in addition to binary fight-flght or flaccid-freeze responses, inhibitory VLPAG outputs can be blended with activation outputs of dorsolateral/lateral PAG to produce ÔtonicfreezeÕ in which activation is temporarily constrained whilst awaiting disinhibition.38
CVCNA, Cardiac Vagal Control (Nucleus Ambiguus); HR, heart rate; bpm, beats per minute.
DISCUSSION In healthy subjects, we have employed novel techniques and a novel pluralistic approach that encompasses psychological traits, psychological state, visceral pain stimuli and selective but diverse physiological responses. Our study has for the first time demonstrated psychological salience for CVCNA response to visceral pain and provides evidence for two different endophenotypic psychophysiological response profiles.
Endophenotypic psychophysiological response profiles Group 1 can be classified as Ôneurotic-introvertÕ with low resting CVCNA, high resting heart rate and CSI, increase in CVCNA during pain but blunted heart rate response in other words a sympathetic predominant resting state with paucity of parasympathetic tone at rest but mainly parasympathetic defence response. Group 2 can be classified as Ôextrovert-emotionally stableÕ with high resting CVCNA, low resting heart rate and CSI, a withdrawal of CVCNA during pain and a brisker heart rate response in other words a parasympathetic predominant resting state but mainly sympathetic defence response. Patterned physiological defence responses similar to these have been seen in differentially anxious rodents and birds.36,37 The parasympathetic predominant defence response pattern seen in group 1 has been characterized as a ÔpassivecopingÕ or Ôtonic-immobilisationÕ response whereas that in group 2 as a Ôfight-flightÕ or Ôactive-copingÕ response.11,38 Debate exists as to whether the psychobiological differences underlying personality are best captured by
Correspondence to clinical and healthy subject studies The parasympathetic nervous system has an antinociceptive role40 and low CVCNA has been reported in chronic pain conditions and affective disorders.17,41 A study in Functional Dyspepsia found two psychophysiological autonomic sub-groups with some correspondence to but not identical with ours, however there was no healthy control group.42 Given therefore that our study was of acute pain in healthy volunteers extrapolation to clinical populations should be guarded until similar studies are performed in clinical populations who may respond differently.
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In other healthy volunteer studies, greater sympathetic reactivity is related to higher pain thresholds/ better pain tolerance43 whereas blunted sympathetic responses to pain are associated with greater neuroticism, somatic44 and rectal45 pain sensitivity.
rather than direct neurophysiological measures. Nonetheless, in this study, personality variables do have some explanatory power for the variance seen in pain related ANS responses and perception.
Future areas of exploration and application Personality and neurobiology
Further confirmation of pain induced ANS response pattern stability and of the distribution of these patterned responses in a larger cohort, studied serially on multiple occasions is now warranted. The effect of sex and age on the CVCNA response patterns also warrants systematic exploration. The clinical relevance of these endophenotypes seen in healthy volunteers is speculative before clinical populations are directly studied, nonetheless it is interesting to note that neurotics are overrepresented in functional medical syndromes including Irritable Bowel (IBS) and fibromyalgia which are overlapping syndromes of pain, emotion and autonomic disturbance.50,51 Furthermore it is known that premorbid neuroticism score is strongly predictive for development of postinfectious IBS.50 If the surge in CVCNA, seen during pain with a neurotic profile, were matched by a general parasympathetic increase, subjects might experience diarrhoea since parasympathetic activity is promotile for the colon.12 In conclusion, this study for the first time has found supportive evidence of psychophysiological endophenotypes in health for visceral pain with personality type as a major contributory factor. Future work should be aimed at establishing the prevalence, stability, genetic contributions and clinical relevance of these endo-phenotypes.
In our study, the extroversion-introversion personality dimension related more to sympathetic reactivity whereas the neuroticism-emotional stability personality dimension related more to parasympathetic reactivity. Links between extroversion and higher pain thresholds are well established46 and it is possible therefore that this is mediated in part through brisk sympathetic responses. Neuroticism is linked to limbic reactivity, is associated with lower resting parasympathetic activity/slower parasympathetic return to baseline, and to choline transporter and serotenergic genetic polymorphisms.47,48 The CVCNA response pattern in this study and its link to broader personality traits, is consistent with a central psychophysiological role for CVCNA and prefrontal cortex inhibition.7,9 The influential GreyMcNaughton personality model is explicitly based on behavioural inhibition and activation systems and incorporates fight-flight-freeze defence responses. It is claimed this more closely reflects the underlying biological basis of personality than neuroticism and extroversion which are Ôsurface traitsÕ.10 Better psychophysiological ÔfitÕ for visceral pain might be obtained therefore by using Grey-McNaughton measures or personality sub-trait measures such as sensation seeking/sensory sensitivity which may relate more closely to pain processing.23,29 To expect precise mapping of personality constructs and neurobiology may however be naieve.49 In particular, somewhat inconsistent relationships between brain, autonomic, endocrine and immune physiology with psychological traits and processes suggest that exact correspondence is unlikely. CVCNA itself is multiply determined (Fig. 1) and it should also be noted that non-invasive measures such as heart rate variability are themselves indirect indexes of CVCNA
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ACKNOWLEDGMENTS Cancer research UK funded Dr Paine and the study. Professor Aziz is funded by Career Establishment Grant from the Medical Research Council.
CONFLICT OF INTEREST No conflicts of interest.
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