Running Head: PAIN AND PSYCHOLOGICAL AROUSAL
Murdoch University
Honours Thesis in Psychology
The Relationship between Pain and Arousal:
The Modulation of Noxious Sensation by the Brain’s Alerting Network
This thesis is presented in partial fulfilment of the requirements for the degree of
Bachelor of Psychology (Honours), Murdoch University, 2017.
Amber L. English
Word Count: 9,587
PAIN AND PSYCHOLOGICAL AROUSAL ii
Declaration
I declare that this thesis is my own account of my research and contains as its main
content work that has not previously been submitted for a degree at any tertiary
educational institution.
Name: Amber L. English
Signature:
PAIN AND PSYCHOLOGICAL AROUSAL iii
Copyright Acknowledgement
I acknowledge that a copy of this thesis will be held at the Murdoch University Library.
I understand that, under the provisions of s51.2 of the Copyright Act 1968, all or part of
this thesis may be copied without infringement of copyright where such a reproduction is
for the purpose of study and research.
This statement does not signal any transfer of copyright away from the author.
Full Name of Degree: Bachelor of Psychology with Honours
Thesis Title: The Relationship between Psychological Arousal and
Pain in Healthy Adults
Author: Amber Lee English
Year: 2017
Signed:
PAIN AND PSYCHOLOGICAL AROUSAL iv
Table of Contents
Cover Page ..................................................................................................................... i
Declaration .................................................................................................................... ii
Table of Contents ......................................................................................................... iv
List of Figures .............................................................................................................. vi
List of Tables............................................................................................................... vii
Acknowledgements ................................................................................................... viii
Abstract ........................................................................................................................ ix
Introduction ................................................................................................................... 1
Psychological Arousal ........................................................................................... 2
Pain ........................................................................................................................ 4
Nociception ........................................................................................................... 5
The Dorsal Horn .................................................................................................... 6
Bidirectional Spinal Modulation ........................................................................... 6
The Noradrenergic System .................................................................................... 9
Pain Catastrophizing ........................................................................................... 12
Nociceptive Flexion Reflex................................................................................. 13
Pupillary Dilation Reflex .................................................................................... 15
The Present Study ............................................................................................... 16
Hypotheses .......................................................................................................... 17
Methods ....................................................................................................................... 18
Participants .......................................................................................................... 19
Design ................................................................................................................. 20
Measures and Apparatus ..................................................................................... 20
Procedure............................................................................................................. 22
Data Filtering and Reduction .............................................................................. 25
PAIN AND PSYCHOLOGICAL AROUSAL v
Data Analysis ...................................................................................................... 26
Results ......................................................................................................................... 28
Assumption Testing for MANOVAR ................................................................. 28
Pain Catastrophizing ........................................................................................... 29
Self-report Variables ........................................................................................... 29
Nociceptive Flexion Reflex Responses ............................................................... 32
Pupillary Responses ............................................................................................ 36
Discussion .................................................................................................................. 37
Hypothesis One: Pain Ratings and Arousal ........................................................ 38
Hypothesis Two: Nociceptive Reflex and Arousal ............................................. 39
Hypothesis Three: Pupillary Responses .............................................................. 42
Hypothesis Four: Pain Catastrophizing ............................................................... 43
Limitations .......................................................................................................... 44
Conclusions and Future Directions ..................................................................... 45
References .................................................................................................................. 46
Appendices ................................................................................................................. 66
Appendix A – Ethics Approval Letter ................................................................ 66
Appendix B – Sequence Order of Stimulus Presentation ................................... 67
Appendix C – Pain Catastrophizing Scale ......................................................... 68
Appendix D – Information Letter and Consent Form ......................................... 69
Appendix E – Univariate Normality and Violations ........................................... 72
Appendix F – Pupillary Response Means over Trials ......................................... 81
Appendix G – Summary of Project ..................................................................... 82
Appendix H – SPSS Output ................................................................................ 84
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List of Figures
Figure 1. Supra-spinal noradrenergic pathways ............................................................ 4
Figure 2. Brainstem mechanisms of pain modulation ................................................... 8
Figure 3. Measurement of the Nociceptive Flexion Reflex ........................................ 14
Figure 4. Electrode placement..................................................................................... 20
Figure 5. Staircase method for the Nociceptive Flexion Reflex ................................. 22
Figure 6. Experimental design .................................................................................... 23
Figure 7. Stimulus timing in experimental conditions ................................................ 24
Figure 8. Measurement of pupil size ........................................................................... 25
Figure 9. Mean pain ratings over trials ....................................................................... 29
Figure 10. Means for subjective self-ratings ............................................................... 31
Figure 11. Mean response rate over trials ................................................................... 33
Figure 12. Means for response rate and magnitude. ................................................... 34
Figure 13. Means for pupil size................................................................................... 36
PAIN AND PSYCHOLOGICAL AROUSAL vii
List of Tables
Table 1. Descriptives for Reflex Response Rate ......................................................... 33
Table 2. Descriptives for Reflex Response Magnitude ............................................... 35
Table 3. Descriptives for R3 Response Latency ......................................................... 36
PAIN AND PSYCHOLOGICAL AROUSAL viii
Acknowledgements
Firstly, I would like to acknowledge those who directly facilitated this thesis
project. Thank you to my supervisor, Professor Peter Drummond, for your wealth of
knowledge and for always making time for me. Thank you to Paul Mckay for all your
insight and help with my pupillometry data. Additionally, a big thanks to Mann Trac,
without you I don’t think most of the equipment would exist, let alone work!
Secondly, I would like to express my appreciation to all those who participated
in my study, for their time and ‘pain’. Thank you also to my fellow pain researchers,
especially the lovely Jessica Wright.
Thirdly, I would like to thank all my friends and family, who put up with the
eternally grumpy thesis-Amber. Thank you to my partner Shane Murphy for the late
nights at the lab, for being my guinea-pig, and for supporting me through this intense
year. A shout out to my psych squad, for the solidarity and sporadic good humour. And
all my love for the English family: Mama Kitty, Papa Bo and my little brother Jay.
Lastly, I would like to dedicate this thesis to those who departed from my life
this year: David English, Lilly, and Caitlyn Pickles. May you all rest in peace.
PAIN AND PSYCHOLOGICAL AROUSAL ix
Abstract
The literature indicates that pain is decreased by arousal in healthy individuals.
Conversely, arousal has been observed to increase pain in those with chronic pain. The
present study explored the relationship between psychological arousal and pain in healthy
adults (N=30). To elucidate this interaction, this study utilised an acoustic startle stimulus
and electrically-induced pain, while also manipulating stimulus timing. The acoustic
startle was presented prior to electrical stimulation, to act as the arousal induction. The
reverse stimulus timing, the acoustic startle presented after electrical stimulation, acted
as the experimental control. Using a repeated-measures design, timing effects were
evaluated according to physiological responses and subjective self-ratings. The main
hypothesis was that the presentation of the acoustic startle before electrical stimulation
would result in significantly lower pain ratings, in comparison to electrical stimulation
alone. Not only was this inhibitory effect supported but it extended to both pain and
sharpness ratings, in comparison to the reverse stimulus timing. In line with predictions,
pupillary responses supported that there was adequate physiological arousal in all
conditions. Contradictory to predictions, stimulus timing did not significantly alter
pupillary responses or spinal nociceptive reflexes. These physiological outcomes were
inconsistent with the interaction found between stimulus timing and participant ratings.
Additionally, Pain Catastrophizing did not correlate with the other pain measures and thus
was not included in the other analyses. Together, these findings suggest that prior
activation of arousal significantly inhibits the experience of pain in healthy individuals’,
at a purely supra-spinal level.
Keywords: pain, nociception, arousal, descending inhibition, spinal reflex, pupillometry
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The Relationship between Pain and Arousal:
The Modulation of Noxious Sensation by the Brain’s Alerting Network
There are stories of individuals achieving great feats while in severe pain, a
wounded soldier continues to run through the battlefield, a frostbitten climber continuing
to climb after hearing the rumble of an approaching avalanche. It is well known that a
state of arousal can greatly inhibit the intensity of pain in a healthy person (Vo, 2014).
Psychological arousal refers to the heightened alertness of brain areas involved in how
we perceive such experiences. Descending arousal pathways, from the brain to body, have
been implicated in both the reduction and amplification of pain (Millan, 2002; Pertovaara,
2006). Some theorists have cast arousal as an overarching mechanism which orients the
body to the most significant stimuli (Berridge & Waterhouse, 2003; Young et al., 2017).
For pain and arousal, a relationship is presumed but poorly understood (Dowman, Ritz,
& Fowler, 2016).
Where arousal reduces perceived pain intensity (Millan, 2002), it increases
physiological signs of pain (Kyle & McNeil, 2014). The literature demonstrates that it
broadly increases both autonomic activities (Chapman, Bradshaw, Donaldson, Jacobson,
& Nakamura, 2014) and pain withdrawal reflexes (Bradley, Moulder, & Lang, 2005; Koh
& Drummond, 2006; Kyle & McNeil, 2014). Further, while reducing pain in healthy
people, arousal has been shown to do the opposite in those with chronic pain (Drummond,
Finch, Skipworth, & Blockey, 2001; Drummond & Willox, 2013; Knudsen, Finch, &
Drummond, 2011).
Chronic pain affects nearly 20% of adults (Henderson, Harrison, Britt, Bayram,
& Miller, 2013). Living with persistent pain is associated with myriad challenges. It is
accompanied by both poorer mental health (Dersh, Polatin, & Gatchel, 2002; Forgeron et
al., 2010; Geisser, 2000; Snelling, 1994) and physical function (Henderson et al., 2013).
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In turn, practical difficulties threaten financial and vocational stability (van Leeuwen,
Blyth, March, Nicholas, & Cousins, 2006). All of these pressures are compounded by
social isolation (Forgeron et al., 2010; Snelling, 1994), and inadequate pain control
(Breivik, Collett, Ventafridda, Cohen, & Gallacher, 2006). Effective pain management is
rare, and many pain conditions are resistant to commonly administered pharmaceutical
treatments (Arnér & Meyerson, 1988; Blackburn-Munro & Blackburn-Munro, 2003).
Psychological arousal pathways are broadly implicated in the upregulation of pain in
chronic pain conditions (Taylor & Westlund, 2017). Hence, these mechanisms are a
promising target for research and treatment (Pertovaara, 2013).
This study aimed to enhance the future study of pain and associated conditions,
by exploring the functional relationship between pain and arousal in healthy participants.
This study provides a methodological framework and baseline data, to enable future
research to make valid comparisons between healthy and clinical populations.
Psychological Arousal
Psychological arousal is a broad construct referring to the general alertness of
brain areas responsible for how sensory input is perceived (Pfaff, 2006). This energised
state is normally induced by salient or biologically significant stimuli (Young et al., 2017).
It can be challenging to differentiate psychological arousal from overlapping mental
functions, such as attention (Coull, 1998), and parallel processes, such as physiological
arousal (Young et al., 2017). Arousal occurs without attention, but attention cannot
increase without arousal (Coull, 1998). The same applies to intense sensations (Rhudy,
Williams, McCabe, Russell, & Maynard, 2008), which are accompanied by arousal but
characterised by the involuntary reactions which occur in conjunction with them
(Samuels, Hou, Langley, Szabadi, & Bradshaw, 2007). The startle response is one such
set of reactions, occurring due to an intense and unexpected stimuli (Bradley et al., 2005).
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The startle-induced arousal state orients mental resources toward the stimuli and
suppresses irrelevant information, in order to enhance defensive processes (Dowman et
al., 2016). Sympathetic processes then mobilise the body, resulting in heightened
physiological arousal and rapid motor responses (Goldstein, 2013). Simultaneously,
psychological arousal activates higher processes and stimulates the sympathetic nervous
system.
Psychological arousal is communicated by networks of neurotransmitters, with
catecholamine systems the primary mediators (Lundberg, 2005). The catecholamine
noradrenaline is particularly important to psychological arousal as it innervates an
overarching alerting system (see Figure 1), composed of the Locus Coeruleus and regions
of the parietal and frontal cortex (Posner, 2008). This high-level psychological arousal
is relayed primarily via the noradrenergic system (Samuels & Szabadi, 2008a; Young et
al., 2017), whereas low-level arousal is mainly dopamine-mediated (Floresco, 2015).
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Figure 1. Supra-spinal noradrenergic pathways. Adapted from Higgins and George
(2009).
Pain
Pain is a dominating and unpleasant experience (Montes-Sandoval, 1999). It is
defined not only by sensation but also by pervasive thoughts and emotions (Weissman-
Fogel, Sprecher, & Pud, 2008). It does, however, serve important biological functions. It
alerts the body to threat or injury, enabling both protective and defensive processes
(Dowman et al., 2016). The unpleasantness of pain helps to protect the body by
conditioning avoidance of danger. Further, it initiates defensive operations in the nervous,
endocrine and immune systems which cooperatively minimise harm from danger
(Chapman, Tuckett, & Song, 2008).
Scientific understanding of higher pain processing has been revolutionised by
contemporary neuroimaging techniques. Many theorists point to a "Pain Matrix" of key
structures, due to consistent activation in frontal, parietal, somatosensory, insular, and
cingulate areas (Davis & Moayedi, 2013; Garcia-Larrea & Peyron, 2013). The evidence,
however, suggests that this network of activation is not unique to pain (Iannetti &
Mouraux, 2010; Salomons, Iannetti, Liang, & Wood, 2016). As a consequence, some
have returned to the more general "Neuro-matrix" theory (Melzack, 1999), in which pain
processing depends on multi-sensory and multi-modal integration (Legrain, Iannetti,
Plaghkib, & Mouraux, 2011; Mouraux, Diukova, Lee, Wise, & Iannetti, 2011). This
perspective emphasises the importance of functional pathways and relationships rather
than localised structures (Apkarian, Hashmi, & Baliki, 2011).
Nociception
Nociception refers to the detection of stimuli causing or potentially causing
damage, commonly termed "noxious stimuli" (Wiech, Ploner, & Tracey, 2008).
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Cutaneous pain, activated by noxious stimulation of the skin, is detected by nerves and
receptors in the peripheral nervous system and relayed to processing areas of the central
nervous system (CNS), which encompasses the spinal cord and brain (van Griensven,
Strong, & Unruh, 2013). The nerve fibres, termed nociceptors, respond preferentially to
noxious stimuli. Many are poly-modal, responding to chemical, thermal and mechanical
stimuli. The transmission of pain signals occurs along Aδ-fibres and C-fibres. Aδ-fibres
are highly myelinated, fast-conducting, and signal sharp pain. C-fibres, on the other hand,
are slow-conducting and signal dull, prolonged pain (Basbaum, Bautista, Scherrer, &
Julius, 2009). These afferent nerve fibres terminate in the spinal dorsal horn (Almeida,
2004). From there, inter-neurons relay information to sensory nerves in the CNS, for
higher processing, and motor nerves in the peripheral nervous system, for reflex reactions
(Snell, 2010).
The Dorsal Horn
The Dorsal Horn of the spinal cord is the first place that sensory inputs are
integrated (Le Bars, 2002). It is a multi-functional and multi-synaptic structure that is
organised into layers, termed laminae. Aδ nociceptors project primarily onto laminae I
and V, C-fibers project to laminae II and VI (Cordero-Erausquin, Inquimbert, Schlichter,
& Hugel, 2016). Within these layers, pain signals are inhibited or facilitated, especially
within laminae II, according to neural influences stemming from information about the
external and internal environment (Basbaum et al., 2009). These nociceptive signals are
relayed, via laminae VI, to the periphery as a part of reflex pathways (Snell, 2010). They
are also sent to higher structures for further processing, mainly via laminae I and V
(Cordero-Erausquin et al., 2016). Before higher processing, these nociceptive signals are
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further integrated by brainstem structures (Chapman et al., 2008). Information is relayed
from the spinal dorsal horn to various brain structures via two ascending tracts: the
spinothalamic tract, terminating in structures enabling the discrimination of pain qualities,
and the spinoreticular tract, which relays to limbic structures responsible for emotional
and cognitive elements of pain (Almeida, 2004).
Bi-directional Spinal Modulation
The relationship between nociceptive signals sensed in the periphery, and pain,
experienced in the brain, is a bidirectional one (Drummond, 2012). Current understanding
indicates that pain arises from the interaction between various networks in the spinal cord
and brain (Mendell, 2014). The dorsal horn does not passively transmit sensory messages
to higher structures. Rather, peripheral pain pathways interact with complex modulatory
mechanisms throughout the CNS (Millan, 2002). The seminal Gate Control theory of
Melzack and Wall (1965), and Melzack’s (1999) subsequent neuro-matrix theory,
crystalised contemporary understanding of pain communication throughout the body.
Melzack and Wall proposed that pain is "gated" by non-nociceptive stimuli, due to
competition between different forms of sensory input at various points in the spinal cord.
This mechanism is often referred to as "segmental" inhibition, as the distribution of pain
inhibition corresponds, anatomically, to segments of the dorsal horn (Clark & Proudfit,
1992). In addition to segmental modulation, pain signals can change as they cross the
spinal cord, proprio-spinally, or due to higher structures, supra-spinally (Sandkühler,
1996). Supra-spinal modulation can occur purely at the cortical level, involving processes
of perceptual appraisal (Rhudy et al., 2009). At the mid-level, ascending pain signals can
also be influenced by activity in the brainstem nuclei (Heinricher, Tavares, Leith, & Lumb,
2009; Schlereth & Birklein, 2008).
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Descending inhibition when greater than descending facilitation, “gates” pain
signals, resulting in analgesia (Millan, 2002). This suppression of pain signals is
particularly dominant following the detection of a dangerous or stressful stimulus.
Stressful conditions are frequently observed to lead to a range of adaptive responses and
general anti-nociception, presumably due to the biological imperative that pain does not
interfere with "fight or flight" (Chapman et al., 2008). This effect, known as stress-
induced analgesia, originates in cortical fear networks and modulatory systems in the
brainstem (Vo, 2014), through overlapping networks of stress and arousal (Valentino &
Van Bockstaele, 2008). Research suggests that it is mediated primarily by endogenous
opioids (Butler & Finn, 2009; Vo, 2014). Opioids exert their influence through the Peri-
aqueductal Grey (PAG) and Rostroventral Medulla (RVM), which connect directly to the
DH (Millan, 2002). Electrical stimulation and microinjection of opioid agents, into the
PAG and RVM, demonstrate that stress-induced analgesia can be abolished by blocking
these pathways or induced by their stimulation (Gebhart, 2004; Vo, 2014). However, this
analgesic effect is not mediated by opioids alone and a plethora of neuro-modulatory
mechanisms are involved (Butler & Finn, 2009). In particular, parallel inputs from
serotonergic and noradrenergic mechanisms are likely to be necessary for the full
expression of stress-induced analgesia (Millan, 2002). Serotonin, produced in the medulla,
forms part of an excitatory link between the PAG and RVM (Pertovaara & Almeida,
2006). Noxious stimulation activates both pro- and anti-nociceptive serotonergic
pathways and their effects rely heavily on stimulus parameters (Millan, 2002).
Noradrenaline shares a similar relationship with opioidergic pain modulation (see Figure
2), but unlike serotonin it is also demonstrated to exert independent effects on nociception
(Llorca-Torralba, Borges, Neto, Mico, & Berrocoso, 2016; Pertovaara, 2006, 2013).
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Figure 2. Brainstem mechanisms of pain modulation. Adapted from Brodin, Ernberg,
and Olgart (2016).
The Noradrenergic System
The Noradrenergic system is best known for its role in the initiation and regulation
of arousal (Berridge, 2008), though recent literature also emphasises its capacity for pain
modulation (Pertovaara, 2013). Through bi-directional transmission of noradrenaline in
the brain and spinal cord, this system coordinates general arousal, as well as specific
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responses to threat and reward (Young et al., 2017). Noradrenaline is a neurotransmitter
which enables rapid adaptive responses to stimulation (Bouret & Sara, 2005).
Noradrenaline acts directly on specific receptors, termed adrenoceptors, found throughout
the CNS. Physiological and pharmacological interventions demonstrate the arousal
effects of α1-adrenoceptor activation (Berridge, 2008; Berridge & Waterhouse, 2003).
The inhibitory influences of α2-adrenoceptors, on the other hand, are associated with
sedation and parasympathetic processes (Berridge & Waterhouse, 2003; Gyires, Zádori,
Török, & Mátyus, 2009). Similarly, central activation of α2-adrenoceptors usually exerts
an inhibitory influence over spinal nociception (Millan, 2002). To enable analgesia,
however, this inhibitory control must be greater than the pro-nociceptive influence of
spinal noradrenaline on α1-adrenoceptors (Drummond, 2012).
The Locus Coeruleus (LC) is a nucleus in the pons of the brainstem which directly
mediates psychological arousal (Carter et al., 2010) and indirectly regulates autonomic
arousal (Berridge, 2008). It is the primary source of noradrenaline in the brain (Wetzel,
Buttelmann, Schieler, & Widmann, 2016) and has projections throughout the cerebral
cortex, as well as directly to the dorsal horn (Szabadi, 2012). Noradrenaline directly
mediates arousal functions of the LC (Samuels & Szabadi, 2008b). The LC also exerts
indirect arousal modulation. Increased LC activity inhibits sedation-promoting GABA-
ergic neurons and excites alertness-promoting serotonergic and cholinergic systems
(Samuels & Szabadi, 2008a). The LC is robustly activated by specific stressors, such as
acoustic startle stimuli (Wetzel et al., 2016), and responds preferentially to noxious
stimulation (Irwin, Ahluwalia, & Anisman, 1986; Szabadi, 2012). Subsequently, LC-
mediated arousal directly controls reflex reactions such as the acoustic startle reflex and
pupillary reflex dilation (Szabadi, 2012). As these responses are also indicative of
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mechanisms involved in descending pain modulation, the LC-noradrenaline system is
broadly implicated in the intersection of arousal and pain (Chapman et al., 2014).
LC-mediated arousal contributes not only to analgesia, via inhibition of pain
signals, but also to hyperalgesia, due to pain facilitation (Millan, 2002). The timeframe
of activation binds the demonstrated effects of arousal on nociception. Arousal
inductions in healthy participants, such as body cooling, demonstrate the pro-nociceptive
influence of prolonged activation (Drummond, 2001). Similarly, prolonged pain appears
to activate unique mechanisms of the LC-noradrenaline system. While the injection of
spinal noradrenaline does little to alter basal pain in healthy people (Pertovaara, 2013), it
increases chronic pain (Ali et al., 2000). The LC-noradrenaline system is even referred
to as a "chronic pain generator", according to review of relevant neuro-chemical evidence
(Taylor & Westlund, 2017). Arousal is often investigated using neurochemical and
pharmacological interventions, but these often have wide-ranging limitations.
Pharmacological manipulation of arousal, for instance, has been argued to induce extra
effects that can produce false positives and compromise the validity of results
(Drummond et al., 2001). Functional research can provide the basic understanding of
these mechanisms that is needed before manipulation (Arendt-Nielsen, Curatolo, &
Drewes, 2007).
Recent studies have produced preliminary functional evidence for an inverse
relationship between LC-mediated arousal and chronic pain. Drummond and colleagues
(2001) demonstrated that various arousal stimuli decrease pain, to a subsequent thermal
pain induction, for healthy participants. A number of the same stimuli facilitated clinical
pain in those with Complex Regional Pain Syndrome. Acoustic startle stimuli, in
particular, have repeatedly been shown to increase pain ratings in those with chronic pain
(Drummond & Willox, 2013; Knudsen et al., 2011). Some have suggested that arousal
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can transform from analgesia to hyperalgesia, due to specific pathological changes in
noradrenergic mechanisms (Donello et al., 2011; Drummond, 2012; Rahman, D’Mello,
& Dickenson, 2008; Vanegas & Schaible, 2004). However, to explore and eventually
understand these relationships, further functional research is required.
Pain Catastrophizing
The interaction between arousal and pain intensity is not only bound by the temporal
properties of the activating stimuli (Schlereth & Birklein, 2008) but also the cognitive
and emotional state they are appraised in (Ploghaus et al., 1999). Emotional state
contributes up to 52% of the variance in perceived pain intensity, as indexed by both self-
report and physiological measures such as the Nociceptive Flexion Reflex (Rhudy et al.,
2008). While fear of an impending shock reduces pain intensity, anxiety has been shown
to amplify it (Ploghaus et al., 2001; Rhudy & Meagher, 2000). When this relationship
between stress and pain is pervasive, it likely indicates Pain Catastrophizing (Sullivan &
Neish, 1998).
Pain Catastrophizing is an exaggerated negative cognitive and affective state,
activated by nociceptive pain (Sullivan, Bishop, & Pivik, 1995). Many have highlighted
it as an important variable in the experimental measurement of pain (Edwards,
Haythornthwaite, Sullivan, & Fillingim, 2004; Quartana, Campbell, & Edwards, 2009;
Sullivan, Tripp, & Santor, 2000). It accounts for up to 31% of the variance in pain ratings
(Keefe, Rumble, Scipio, Giordano, & Perri, 2004), and is positively associated with
amplified pain responses in healthy (Seminowicz & Davis, 2006) and clinical populations
(Sullivan et al., 2001).
Sullivan and colleagues (Sullivan et al., 1995; 2001) proposed that catastrophizing
amplifies pain by altering spinal gating. This theory is supported by the negative
association between catastrophizing and diffuse noxious inhibition, a well-researched
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spinal pain modulating mechanism (Weissman-Fogel et al., 2008). On the other hand,
evidence suggests that it does not correlate with the Nociceptive Flexion Reflex (France,
France, al’Absi, Ring, & McIntyre, 2002; Rhudy et al., 2011; Terry, 2015). Hence, some
argue that catastrophizing is a purely supra-spinal mechanism (Rhudy et al., 2009; Rhudy,
Maynard, & Russell, 2007).
Nociceptive Flexion Reflex
Pain signals trigger many rapid bodily responses. While most autonomic
responses occur via relay stations in the brain, nociceptive input can also directly initiate
reflex movements via the dorsal horn (Benarroch, 2006). The nociceptive flexion reflex
of the lower limbs is one such response, often utilised as a measure of spinal nociception
(Dowman, 1991). It is consistently activated by painful nociceptive stimulation, acting to
withdraw the stimulated limb from a potentially harmful stimulus (Sandrini et al., 2005).
Withdrawal is accomplished by flexion at the ankle, knee and hip. The flexion reflex at
the knee, usually measured via the biceps femoris, is followed by a smaller reflex in the
hip, measured via the rectus femoris (Andersen, 2000; Arendt-Nielsen, Brennum, Sindrup,
& Bak, 1994; Hugon, 1973; Roby-Brami, & Brussels, 1987).
Electromyography (EMG) is the most common technique to measure this reflex,
which it does by recording the electrical signals that cause muscles to contract. The NFR
is characterised by three distinct phases of EMG activity; the tactile R2 component, the
nociceptive R3 component, and an involuntary movement response (Sandrini et al., 2005).
The latencies of the inconsistent R2 and more stable R3 correspond, respectively, to the
conduction velocities of the tactile Aβ fibres and the nociceptive Aδ fibres (Plaghki,
Bragard, Le Bars, Willer, & Godfraind, 1998). The R3 can only be invoked by stimulation
of Aδ fibres, though it recruits input from Aβ and C fibres (Skljarevski & Ramadan, 2002).
These signals are integrated proprio-spinally by wide dynamic range neurons in laminae
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V of the dorsal horn (Neziri et al., 2009). These neurons are multi-receptive to enable
rapid discrimination of the intensity and location of noxious stimuli to induce an effective
withdrawal reflex (Sandrini et al., 2005). Following the R2 and R3 is the associated startle
response, which is an involuntary movement response mediated by spinal and supra-
spinal pathways (Rhudy & France, 2007). The R3, on the other hand, is mediated
primarily at the spinal level (Cogiamanian et al., 2011; Rhudy et al., 2011).
The R3 has attracted significant interest in research as an "objective" measure of
pain processing (Sandrini et al., 2005). Usually measured via the ipsilateral brevis head
of the biceps femoris (see Figure 3), the magnitude of this response has been linearly
correlated with participant-rated pain intensity (Chan & Dallaire, 1989; Micalos,
Drinkwater, Cannon, Arendt-Nielsen, & Marino, 2008). The intensity of the activating
stimulus not only corresponds to the participants' subjective pain threshold, but the
maximum reflex response is associated with the level of "intolerable" pain intensity
(Skljarevski & Ramadan, 2002).
Figure 3. Measurement of the Nociceptive Flexion Reflex. Adapted from Baars et al.
(2009).
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This reflex highlights the complexity of spinal and supra-spinal pain mechanisms.
Supra-spinal mediators, such as Pain Catastrophizing, have been shown to disassociate
the flexion reflex from pain ratings (France et al., 2002). Further, the magnitude of this
reflex is mostly unaffected by cognitive influences strongly correlated with perceived
pain intensity (Jurth, Rehberg, & von Dincklage, 2014; Terkelsen, Andersen, Mølgaard,
Hansen, & Jensen, 2004). On the other hand, specific affective influences, such as fear,
are consistent with changes in both the flexion reflex and self-rated pain (Rhudy et al.,
2008).
There is some evidence that psychological arousal, via supra-spinal pathways,
may increase pain withdrawal reflexes (Bradley et al., 2005), even when it decreases self-
rated pain (Koh & Drummond, 2006; Szabadi, 2012). This has thus far only been
examined with the nociceptive blink reflex, however, and further study is required to
verify these findings.
Pupillary Dilation Reflex
The study of pupil size has been of increasing psychometric interest since its
emergence in the 1960’s. It provides a consistent method for verifying the interaction
between physiological arousal and wide-ranging mental activities (Laeng, Sirois, &
Gredebäck, 2012). Pupillary reflex dilation is an arousal response mediated by the
sympathetic nervous system (Diamond, 2001), described by some as an autonomous
orienting response (Einhäuser, Stout, Koch, & Carter, 2008; Gilzenrat, Nieuwenhuis,
Jepma, & Cohen, 2010).
Pupillary reflex dilation is controlled mainly by the noradrenergic system (Larson,
2001; Neuhuber & Schrödl, 2011). Noradrenaline, is understood to inhibit the
parasympathetic pathways responsible for pupillary light reflexes (Koss, 1986), and
excite the responsible sympathetic pathways (Szabadi, 2012). Research shows tight
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correlation between pupil dilation and increased activity in the LC. This has been
evidenced both in animals (Bouret & Sara, 2005; Rajkowski, Kubiak, & Aston-Jones,
1993; Rajkowski, Majczynski, Clayton, & Aston-Jones, 2004) and humans (Aston-Jones
& Cohen, 2005a, 2005b; Murphy, O'Connell, O'Sullivan, Robertson, & Balsters, 2014).
Pharmacological inductions of noradrenergic excitation have been shown to induce
parallel increases in pupil diameter and LC activity (Phillips, Szabadi, & Bradshaw, 2000),
while inhibitory drugs are shown to reduce them (Chapman et al., 2014). Functional
studies of pupillary reflex dilation demonstrate that it is highly responsive to both startling
(Wetzel et al., 2016) and noxious stimulation (Chapman, 1999; Chapman et al., 2014;
Kyle & McNeil, 2014).
The Present Study
This study aimed to explore the interaction of psychological arousal and pain
intensity. Specifically, this was tested using experimentally-induced arousal, evoked by
an acoustic startle, and unilateral limb pain, evoked by electrical stimulation.
Differing response types were assessed for each stimulus condition, to explore the
level of interaction. Each stimulus intensity was subjectively measured, to illuminate the
supra-spinal experience of each, including self-rated pain. The nociceptive flexion reflex
was used to index spinal processing, as it is considered a reliable indicator of spinal
nociception (Rhudy & France, 2007). Pupillary responses were used to provide a
methodological check of physiological arousal by each stimulus. Additionally, they were
indexed the intensity of processing at the level of the brainstem.
In this study, we intended not only to measure the outcomes of startle-induced
arousal and electro-cutaneous pain but also to discern the effect of their timing. The time
span of arousal has a pronounced effect on nociception (Drummond, 2001; Schlereth &
Birklein, 2008) but previous behavioural interventions fail to manipulate stimulus timing
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to elucidate them (Kyle & McNeil, 2014). Due to this, the present study included an
arousal induction followed by painful stimulation and an experimental control: an arousal
induction following painful stimulation.
The effect of a startle stimulus on pain perception is bound not only by stimulus
timing but also how it is perceived. Perceptual factors determine whether supra-spinal
arousal induces stress-induced analgesia or anxiety-induced hyperalgesia (Ploghaus et al.,
2001; Rhudy & Meagher, 2000). Due to this, the pain catastrophizing scale was included
as a measure of individual variability in pain perception.
Hypotheses
Hypothesis one: pain ratings and arousal. The primary hypothesis of was that
pain ratings would decrease when the acoustic startle was presented before the pain
stimulus, due to descending inhibition by supra-spinal arousal. These ratings were
predicted to be lower than those for painful stimulation alone. The control condition, of
pain followed by an acoustic startle, was expected to differ from painful stimulation alone.
However, due to the absence of such a control in the literature, the investigation of
responses was purely exploratory.
Hypothesis two: nociceptive reflex and arousal. The combination of the arousal
induction with painful stimulation was predicted to increase nociceptive reflex responses.
This increase was predicted due to the spinal summation of the sensory inputs, compared
to painful stimulation alone. The presentation of the startle, in the control condition, was
later than the expected response time of the R3, so an increase was anticipated only for
the involuntary movement response.
Hypothesis three: pupillary response. Pupil size was predicted to increase due
to both stimulus types. This methodological check was intended to demonstrate that the
stimuli were increasing arousal. The combination of the startle and pain stimulus was
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predicted to induce greater physiological arousal, as indexed by pupil dilation, compared
to either on their own.
Hypothesis four: pain catastrophizing. In line with prior studies, Pain
Catastrophizing was predicted to correlate positively with pain ratings but not with the
nociceptive reflex.
Methods
Participants
This study recruited 43 participants, 30.23% of whom failed to exhibit a reliable
Nociceptive Flexion Reflex response, within tolerable stimulation levels. Jensen, Biurrun
Manresa, and Andersen (2015) reported a failure rate of 29% for the present procedures.
While not consistently reported, this difficulty is evident in healthy volunteers (Biurrun
Manresa et al.) and chronic pain sufferers (Sterling, Hodkinson, Pettiford, Souvlis, &
Curatolo, 2008).
Of those recruited, 11 males and 19 females were successfully tested (N= 30).
Participants were aged between 18 and 36 years (M=23.53, SD=4.79). Volunteers were
primarily recruited through the Psychology Research Participant Portal. The remainder
were recruited via convenience sampling. Students were reimbursed with two hours of
research credit for their time. Participants recruited from the general populace were
compensated with a free coffee voucher.
The recruited sample was of physically and psychologically healthy participants,
between 18-60 years of age. It excluded those with chronic pain conditions, impaired
hearing, psychiatric conditions, or any illness for which analgesic medication is
prescribed. Additionally, pregnant women were excluded.
All participants gave informed written consent, according to procedures approved
by the Murdoch University Human Research Ethics Committee (see Appendix A).
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Design
This study had a repeated-measures design, in which experimental conditions
were presented in a pseudo-randomised predetermined order (see Appendix B). A within-
subjects single-session design was chosen due to the wide variability in nociceptive reflex
responses between participants and sessions (Sandrini et al., 2005).
Measures and Apparatus
Pain Catastrophizing Scale. This 13-item measure (see Appendix C) determines
individual levels of pain catastrophizing according to 3 factors; magnification, rumination,
and helplessness. It requires reflection on an earlier painful experience to rate the presence
and intensity of associated thoughts and feelings; from 0 (not at all) to 4 (all the time).
Scores were calculated by summing the individual responses to all thirteen items. The
total score ranges from 0-52.
The validity of this scale has been supported by comparison with convergent and
divergent measures (Osman, 1997; Osman et al. 2000). It demonstrates high internal
consistency (α = .87-.95), and test-retest reliability (r =.7- .75) (Osman et al., 2000;
Sullivan et al., 1995). Additionally, it has been validated in both healthy and chronic pain
populations (Osman et al., 2000; Van Damme, Crombez, Bijttebier, Goubert, & Van
Houdenhove, 2002)
Nociceptive Flexion Reflex. A Grass SD9 was used to deliver electrical
stimulation to invoke the flexion reflex. Stimulation was delivered using a custom-built
concentric electrode, composed of a ring-shaped stainless steel anode with a copper wire
cathode at its centre, with an outer anode diameter of 20mm and an inner diameter of
10mm. This stimulation was presented to one leg, with half of the participants tested on
their right and the other half on their left. The electrode was secured to the skin, behind
the lateral malleolus, over the sural nerve. The stimulus consisted of 10 square-waves, of
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1 ms duration, with 2 ms intervals, lasting a total of 30 ms. This stimulus format was
chosen to reliably invoke the flexion reflex at a reduced stimulus intensity (Arendt-
Nielsen, Brennum, Sindrup, & Bak, 1994; Khatibi, Vachon-Presseau, Schrooten, Vlaeyen,
& Rainville, 2014). The incremental duration was chosen to produce the perception of a
single stimulus (Skljarevski & Ramadan, 2002).
The reflex was detected via Electromyography (EMG), using two disposable
Cleartrode electrodes (ConMed Corporation, NY, USA) on each muscle group (see
Figure 4). For the rectus femoris, electrodes were placed 15 cm superior to the patella.
For the biceps femoris, they were placed 10 cm above the popliteal fossa. An inter-
electrode distance of 2 cm was used for both. Additionally, a ground electrode was placed
below the knee, to filter out electrical noise. Signals were amplified using an EMG
biopotential amplifier (Biopac Systems, Inc., USA). An MP 100 Biopac Systems
Analogue/Digital Channel receptor digitised the data at 2,000 Hz (Biopac Systems, Inc.,
USA).
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Figure 4. Electrode placement. Adapted from Herman (2016).
Visual Analogue Scale. Participants reported the intensity of perceived pain and
sharpness, verbally, according to a visual analogue scale, ranging from 0 (indicating no
pain/no sharpness) to 10 (indicating extreme pain/extreme sharpness).
The visual analogue scale has good convergent (r=.72- .95) and concurrent
validity (r=.71–.92), when compared with other pain scales (Good et al., 2001; Kelly,
2001; Ohnhaus & Adler, 1975). It also has good test-retest reliability (r= .71–.99) (Good
et al., 2001; Price, 1983).
Acoustic Startle Stimulus. Tone bursts were administered to both ears for all
participants. These were generated using a Biopac STM 100 module (Biopac Systems,
Inc., USA), at 110 dB for 50 ms. This intensity and duration consistently initiates a strong
startle response (Blumenthal, 1996). Loudness and discomfort were verbally rated on a
scale ranging from 0 (no loudness/discomfort) to 10 (extreme loudness/discomfort).
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Pupil Dilation Response. Pupillary responses were monitored in each trial.
Changes were captured using a pupillometer, with a macro lens and infrared attachment,
via an external trigger. Each trigger initiated a photo sequence, as well as the electrical
stimulus and/or the acoustic stimulus. Images were captured every 0.2 s, over 5 s duration,
with a total of 750 photos per participant. For each trial, 25 photos were directly uploaded
to a tethered computer. The pupillary response was defined as the difference between
mean pupil area (mm2), pre-stimulus, and maximum pupil area (mm2), post-stimulus.
Procedure
All testing was conducted by the student researcher (AE), in controlled laboratory
settings, at a constant temperature of 20 ± 1°c. Upon arrival at the laboratory, the
participant was presented with an information letter, explaining the nature and scope of
the study, with an attached consent form (see Appendix D). This was followed by the
Pain Catastrophizing Scale. Once these had been filled out, the participant was prepared
for the experiment. Due to the natural electrical resistance of human skin, which can be
compounded by dead skin and other debris (Fish & Geddes, 2009), the electrode sites
were shaved and cleaned using an abrasive soap and alcohol wipes.
The impedances, for both stimulating and output electrodes, were always below 15 kΩ.
Participants were seated for the remainder of the study, with their position adjusted so
that their knees were at an angle of 130° and ankles at an angle of 90°.
Nociceptive Reflex Calibration. Before data was collected, each participant was
tested for the level at which the nociceptive flexion reflex could be reliably induced. Once
seated, participants were administered three electrical stimuli to accustom them to
noxious sensations (Rhudy & France, 2007). To determine the participants’ threshold for
reflex activation, Willers’ staircase method was used (Willer, 1977). The electrical
stimuli were administered in pseudo-randomised intervals of 10-20 s, to avoid habituation
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(Lim, Sterling, Stone, & Vicenzino, 2011; von Dincklage, Olbrich, Baars, & Rehberg,
2013). Pain ratings were recorded after each administration. The stimulus intensity started
at 1 mA and was incrementally increased and decreased until the response was detectable
in 80% of trials (see Figure 5). The reflex was considered present if the mean peaks
exceeded 1.5 SD above the mean 60 ms pre-stimulus (Rhudy & France, 2007). The
experiment was discontinued if the intensity reached 10 mA, or the pain was rated
intolerable by the participant. The intensity of the last two peaks and troughs was
averaged, to get the threshold level, which was multiplied by 120%. The subsequent
supra-threshold level was employed for the remainder of the study.
Figure 5. Staircase method for the Nociceptive Flexion Reflex. Adapted from Hubbard
et al. (2011).
Experimental phase. For the experiment, each participant was directed to apply
headphones, for the acoustic stimulus. A sticker (5 mm) was placed below the right eye,
used as an absolute reference for pupil measurement. A forehead rest and chin rest were
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then adjusted to frame the participant’s pupils with the camera. They were directed to
lean forward and focus their sight on a label affixed to the wall behind the camera.
The participants were then administered the trials of stimulation (see Figure 6).
Figure 6. Experimental design.
Each of these conditions was initiated by the trigger, at varying delays following
the initiation of photo capture (see Figure 7). After each trial, the participant rated the
pain, sharpness, loudness and discomfort associated with the stimuli. There were 30 trials
in total with pseudo-randomised intervals of 30-60 seconds.
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Figure 7. Stimulus timing in experimental conditions.
Data Filtering and Reduction
Stimulus outputs, barring the changes in pupil size, were interpreted via the
Biopac System (Biopac Systems, Inc., USA), and filtered using the AcqKnowledge
software (Biopac Systems, Inc., USA). To remove electrical noise, EMG data were
filtered with a high pass filter, using a cut-off frequency of 20 Hz. Additionally, a band-
stop filter, ranging from 49 to 51 Hz, was applied to these waveforms.
A customised program was used to extract the response amplitude (i.e. area under
the curve (AUC)) for each component of the flexion reflex. The measured timeframe for
each component was 50 ms. There was 50 ms between measures of the R2 and R3, and
100 ms between the R3 and the involuntary movement response. The timeframes were
set manually per participant, around the highest peak for the R3. In keeping with the
findings of France, Rhudy, and McGlone (2009) responses were determined according to
normalized EMG scores; with reflex magnitude expressed as a percentage of the
participants’ maximum voluntary contraction (AUC).
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Additionally, the response latency of the R3 component was measured for each trial.
Responses were too variable for accurate latency measurements of each component.
Pupillary response data was first processed using customised software developed
by Paul McKay. This algorithm was designed to identify the height and width of each
pupil, per frame. Simultaneously, it identified the height and width of the comparison
sticker which served as an index, against which the absolute area (mm2) within each pupil
was quantified. For the purposes of this study, analyses were focused on the
measurements from left pupil. This side was chosen because it produced more exact
measurements, due to the positioning of the comparison sticker (see Figure 8).
Figure 8. Measurement of pupil size.
Data Analysis
Multivariate analysis of variance with repeated measures (MANOVAR) was run,
using an alpha level of .05, using the Statistical Package for the Social Science (V.240,
Chicago, USA) for each of the main dependent variables: self-report ratings, reflex
responses and pupillary responses. A number of authors recommend the use of
multivariate over the univariate approach, for repeated measures analysis (Gueorguieva
& Krystal, 2004; Keselman, Algina, & Kowalchuk, 2001). With due consideration to the
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trade-off of statistical power (Park, Cho, & Ki, 2009), this approach was chosen to
prioritise test validity (Stevens, 2012). The within-subject factors were: the conditions,
for stimulus timing, and the trials, over time. A small number of planned contrasts were
then used for each of these variables to confirm or deny specific hypotheses about the
relationship among the conditions. In keeping with the recommendations of Keppel and
Wickens (2004) the number of comparisons never exceeded 1 + ((3a - 1) / 2) – 2a (where
a=levels), to ensure an acceptable level of family-wise error. Lastly, a small number of
correlations were run to analyse pain catastrophizing.
Self-report variables. MANOVAR was run for each of the four self-report
variables: pain, sharpness, loudness and discomfort. First, analyses were conducted for
the experimental manipulation; for 10 trials of acoustic then electrical and 10 trials of
electrical then acoustic. Means for pain and sharpness were analysed for the electrical
only, acoustic-before and acoustic-after, conditions. Means for loudness and discomfort
were analysed for the acoustic only, acoustic-before and acoustic-after conditions.
Reflex responses. MANOVAR was conducted for each of the three reflex
components: the R2, the R3 and the involuntary movement response. First, due to the
inconsistency of the reflex response, the data was coded according to responses and non-
responses. Non-responses were determined when reflex AUC was below 10% of
maximum voluntary contraction. MANOVAR was conducted for the number of
responses, response magnitude and latency. The means were compared for the electrical
only, acoustic-before, and acoustic-after conditions.
Pupillary Responses. Pupillary responses were compared across conditions
using MANOVAR. Average pupil size was compared between baseline pre-stimulus and
maximum post-stimulus. These were also compared across stimulus conditions. Due to
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missing data, there were insufficient degrees of freedom to analyse the response across
trials.
Pain Catastrophizing. Catastrophizing was compared to the pain-specific R3
reflex response and self-rated pain scores. Pearson’s product-moment correlation
coefficient (r) was calculated for each of the conditions that satisfied normality.
Results
Assumption Testing for MANOVAR
The following analyses were completed to ensure the data satisfied the normality
assumptions underlying MANOVAR.
For univariate repeated-measures analysis, sphericity is assumed where there are
three or more dependent variables. Mauchly’s test revealed that this assumption was
violated across nearly all of the variables. As the multivariate analysis does not assume
sphericity, this supports the appropriateness of this approach (Scheiner & Gurevitch,
2001).
Due to the small sample size (N = 30), univariate normality was assessed using
Shapiro-Wilk and visual inspection of boxplots. On a small number of variables these
assumptions were not satisfied (see Appendix E). As MANOVAR is robust against mild-
moderate violations of normality, these abnormalities were not considered to be a threat
to the interpretation of analyses (Park et al., 2009; Tabachnick & Fidell, 2007). Further,
multivariate normality was considered satisfied from inspection of multivariate outliers.
The absence of multicollinearity, usually assumed by multivariate analysis, is not of
concern to MANOVAR, which is intended to analyse related factors (Nimon, 2012).
Additionally, the relationships evident between variables were deemed roughly linear,
from visual inspection of scatterplots.
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The homogeneity of variance-covariance matrices, usually tested with Box’s M,
could not be verified due to the singular cell matrices of repeated measures data (Potvin,
Lechowicz, & Tardif, 1990). Due to this Pillai’s test was used for all multivariate effects
as it is robust against such violations (Nimon, 2012; Scheiner & Gurevitch, 2001).
Pain Catastrophizing
A small number of correlations were performed to ascertain whether pain
catastrophizing was a significant covariate for the other pain measures, specifically the
subjective self-ratings of pain and the nociceptive R3 reflex. Firstly, some analyses were
run to ascertain whether the data satisfied the assumptions underlying correlational
analysis. Normal distribution was assessed using Shapiro-Wilk (see Appendix E).
Linearity and Homoscedasticity were evaluated using visual inspection of scatterplots.
Pain catastrophizing scores and self-rated pain scores met the assumptions of normality.
Pearson’s (r) was not significant for all of the conditions (PCS x Pain for Electrical only:
r(28) = .22, p = .248, PCS x Pain for Electrical then Acoustic: r(28) = .28, p = .135, PCS
x Pain for Acoustic then Electrical: r(28) = .09, p = .650). As the nociceptive reflex scores
violated the assumption of normality, they were analysed using Spearman’s rho, as
recommended by Tabachnick and Fidell (2007). This revealed that the relationship was
not significant, PCS x R3: rs = .12, p = .561. Catastrophizing scores were not included in
the other analyses, as all correlations were not significant.
Self-report Variables
Pain. Subjective ratings for pain differed significantly among the experimental
conditions (main effect for Condition: F(1, 29) = 40.84, p = .000, η2=.59) and over trials
(main effect for Trial number: F(9, 21) = 2.94, p = .020, η2=.56). However, there was no
significant interaction effect (Condition x Trial: F(9, 21) = 1.23, p = .33). Planned
contrasts revealed that pain ratings were lower when the acoustic startle was presented
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prior to the electrical stimulus than they were for the electrical stimulus followed by the
acoustic stimulus: F(1, 29) = 40.84 , p = .000, η2=0.59, and the electrical stimulus alone:
F(1, 29) = 17.94 , p = .000, η2=0.38. Additionally, there was a quadratic change in ratings
over trials: F(1, 29) = 11.65, p = .002, η2=.29. For depiction of effects over trials see
Figure 9, for descriptives see Figure 10.
Figure 9. Mean pain ratings over trials. Error bars denote standard error.
Sharpness. There was a significant difference between experimental conditions
(main effect for Condition: F(1, 29) = 6.80, p = .014, η2= .19) but no significant effects
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over trials (main effect for Trial: F(9, 21) = .93, p = .522, interaction effect for Condition
x Trial: F(9, 21) = 1.72, p = .148).
Planned contrasts revealed that sharpness ratings were significantly lower for the
acoustic-before than for the acoustic-after condition: F(1, 29) = 6.80, p = .014, η2=0.19.
They did not, however, differ from the electrical stimulus alone: F(1, 29) = .00, p = .984.
For descriptives see Figure 10.
Loudness. There was a significant effect for the experimental condition: F(1, 29)
= 5.93, p = .021, η2= .17. There were, however, no significant effects for the trial number
(main effect for Trials: F(9, 21) = 1.04, p = .440), or for their interaction (Conditions x
Trials: F(9, 21) = .96, p = .500).
Planned contrasts showed that the acoustic stimulus was rated to be significantly
louder when presented before electrical stimulation than it was for acoustic-after: F(1, 29)
= 5.93, p = .021, η2= 0.17, though not from the acoustic stimulus alone: F(1,29) = 3.41,
p =.075. For descriptives see Figure 10.
Discomfort. The discomfort ratings differed significantly between the
experimental conditions (main effect for Conditions: F(1, 29) = 4.43, p =.044, η2=.13).
However, there were no significant effects for the trial number (main effect for Trials:
F(9, 21) = 2.09, p = .079, interaction effect for Conditions x Trials interaction: F(9, 21)
= 1.23, p = .329).
Planned contrasts showed that discomfort to the acoustic startle was greater when
presented before, compared to after, electrical stimulation; F(1, 29) = 4.43, p = .044,
η2=0.13. It did not, however, differ significantly from the discomfort to the acoustic
stimulus alone: F(1, 29) = 1.86, p = .184. For descriptives see Figure 10.
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Figure 10. Means for subjective self-ratings. Error bars denote standard deviation.
Nociceptive Reflex Responses
Response Rate. The number of responses did not differ significantly among
conditions for any of the reflex components. There were no significant differences across
the electrical only, acoustic-before or acoustic-after conditions, for the R2: F(1, 29) =
2.36, p = .136, R3: F(1, 29) = 1.41, p = .244, or involuntary movement response: F(1, 29)
= .44, p = .514). For descriptives see Table 1.
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Table 1
Descriptives for Reflex Response Rate (%)
Condition R2 R3 Involuntary
M (SD) M(SD) M(SD)
Electrical 40.00 (46.01) 65.67 (42.24) 70.67 (38.95)
Acoustic then Electrical 28.00 (40.21) 63.33 (39.33) 72.67 (34.63)
Electrical then Acoustic 27.00 (43.48) 56.33 (44.84) 75.00 (37.67)
The number of responses differed significantly between the three reflex
components (main effect for NFR: F(2, 28) = 18.33, p = .000, η2= .57) and over trials
(main effect for Trials: F(9, 21) = 9.52, p = .000, η2= .80). However, there was no
interaction between the levels (NFR x Trial: F(17, 13) = 2.15, p = .083).
Planned contrasts revealed that the response rate was significantly lower for the
R2 component than the other two components: F(1, 29) = 29.89, p = .000, η2= .51.
Additionally, the R3 component was significantly lower than the involuntary movement
response F(1, 29) = 8.14, p = .008, η2= .22. Further, there was a significant linear decline
response rates over trials: F(1, 29) = 53.47, p = .000, η2= .65. For the depiction over trials
see Figure 11.
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Figure 11. Mean response rate over trials. Error bars denote standard error.
Response Magnitude. The magnitude of responses also did not differ
significantly between conditions. Across the electrical only, acoustic-before and acoustic-
after conditions there were no significant effects for the R2: F(2, 16) = 1.08, p = .364, R3:
F(1, 7) = 1.66, p = .239), or the involuntary movement response: F(1, 7) = 1.66, p = .239.
For descriptives see Table 2.
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Table 2
Descriptives for Reflex Response Magnitude (%)
Condition R2 R3 Involuntary
M (SD) M(SD) M(SD)
Electrical 26.78 (13.09) 29.30 (16.00) 31.93 (17.88)
Acoustic then Electrical 27.63 (9.77) 33.67 (20.66) 38.72 (25.68)
Electrical then Acoustic 25.92 (8.90) 27.35 (15.77) 28.55 (18.44)
None of the reflex components varied significantly over trials (main effect for
Trials: F(2, 10) = .81, p = .649) but they did differ significantly from each other (main
effect for NFR: F(2, 10) = 16.43, p = .001, η2= .77). Planned contrasts revealed that the
R2 had a significantly lower magnitude than the other two components: F(1, 11) = 36.07,
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p = .000, η2= .77), though there was no significant difference between the latter: F(1, 11)
= .98, p = .345. For descriptives see Figure 12.
Figure 12. Means for response rate and magnitude. Error bars denote standard deviation.
Response Latency. The latency of the R3 response differed significantly between
conditions: F(2, 21) = 5.502, p = .012, η2=.119. Planned contrasts revealed that the
response latency was significantly shorter when the acoustic was presented before the
electrical stimulus, compared to the other conditions: F(2, 21) = 9.21, p = .006, η2=.30.
For descriptives see Table 3.
Table 3
Descriptives for the R3 Response Latency
Condition Mean SD
Electrical 140.55 ms 27.04 ms
Acoustic then Electrical 127.88 ms 22.06 ms
Electrical then Acoustic 141.81 ms 26.80 ms
Pupillary Response
Pupil measurements, at baseline and maximum, differed significantly: F(1, 26) =
191.76, p = .000, η2=.88. Additionally, there was a significant effect for the stimulus
condition: F(3, 24) = 3.48, p = .031, η2=.30. There was, however, no interaction effect:
F(3, 24) = 1.84, p = .167.
Post-hoc analyses revealed that there was significant dilation across conditions.
This response was greater following the acoustic stimulus than it was for the electrical
stimulus: F(1, 26) = 4.56, p = .042, η2=.15. There was, however, no significant difference
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between the experimental conditions: F(1, 28) = .71, p = .406. For descriptives see Figure
13.
Figure 13. Means for pupil size. Error bars denote standard deviation.
Discussion
The current study aimed to explore the relationship between psychological arousal
and the healthy individual's experience of pain. The relationship was tested using the
combination of an arousal induction and pain evoked by electrical stimulation of the sural
nerve. The arousal induction, an acoustic startle stimulus, was presented before or after
the painful stimulus to explore timing effects. The acoustic startle and electrical stimulus
were also presented alone, in separate trials, as comparative measures. Additionally,
physiological measures were taken as a methodological check and to index different
levels of stimulus processing.
The literature shows that arousal can have a substantial inhibitory effect on pain
perception in healthy individuals (Millan, 2002). Conversely, it can have the opposite
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effect on those with chronic pain (Drummond et al., 2001; Drummond & Willox, 2013;
Knudsen et al., 2011). By increasing understanding of the functional relationship between
pain and arousal in healthy participants, future studies will be better equipped to clarify
pathophysiological mechanisms in chronic pain.
Hypothesis One: Pain Ratings and Arousal
The central hypothesis of the present study was that the acoustic startle stimulus
would have an inhibitory effect on the electrically-induced pain, due to the descending
influences of psychological arousal. In line with predictions, the presentation of an
acoustic startle stimulus before the electrical stimulus significantly reduced subjective
ratings of pain. In accordance with existing research, this reduction was significant in
comparison to pain ratings to the electrical stimulus alone. The exploratory investigation
revealed that this inhibition was specific to the stimulus timing, with pain rated
significantly lower for the acoustic-before than the acoustic -after condition. These
findings were further supported by the significant reduction in the sharpness ratings to
the electrical stimulus in the acoustic-before condition, compared to acoustic -after.
In addition to the difference between pain ratings, between conditions, there was
also a significant change over trials. The results reveal that pain ratings initially increased
and then progressively decreased over the remaining trials. This quadratic change was
likely due to the competing influences of sensitisation and habituation. Repeated
exposure to a noxious stimulus will generally result in the pain dulling or intensifying.
These opposing influences are mainly mediated at the supra-spinal level (Bingel, Schoell,
Herken, Büchel, & May, 2007; Rhudy, Bartley, & Williams, 2010) and relate to the
prioritisation of resources for homeostasis. Due to the biological imperative to protect a
threatened area from damage, pain signals can be amplified by sensitisation. However,
when a painful stimulus fails to invoke damage, pain signals can be inhibited by
PAIN AND PSYCHOLOGICAL AROUSAL
38
habituation (Eisenstein, 2001). The rise and fall of pain ratings in this study may reflect
initial sensitisation and then, in the absence of any signs of damage, habituation.
Additionally, the results show that the inhibitory influence of the arousal induction may
have interacted with these competing influences. In the acoustic -before condition
sensitisation was less pronounced and the habituation effect more dramatic.
Interestingly, while pain and sharpness ratings were lower in the acoustic-before
condition, the loudness and discomfort to the acoustic stimulus were higher. There was,
however, no significant difference in comparison to the acoustic stimulus alone. The
likeliest explanation is that pain signals inhibited acoustic intensity. Whether this
inhibition occurred at a spinal or supra-spinal level is, however, unclear. It is widely
accepted that pain has a substantial capacity to re-orient attention (Eccleston & Crombez,
1999), and is preferentially processed by the brain’s alerting network (Dowman et al.,
2016). However, it is also possible that the difference occurred due to a spinal effect, such
as pre-pulse inhibition. Pre-pulse inhibition refers to the inhibition of a startle response
due to sensorimotor gating by a weaker stimulus, presented 30-500ms prior (Braff, Geyer,
& Swerdlow, 2001). The “pre-pulse” can be in the same or different sensory modality
(Blumenthal, 1996), and has been previously demonstrated with electrical stimulation
(Blumenthal, Burnett, & Swerdlow, 2001). The observed effect could be due to the
electrical stimulus acting as a weaker pre-pulse gating the subsequent acoustic. Equally,
it could be due to the greater salience of the pain signals re-directing attention. The main
implication is that stimulus timing intrinsically binds that perceived intensity of sensation.
Hypothesis Two: Nociceptive Reflex and Arousal
The spinal nociceptive flexion reflex was measured to better understand how
spinal processing was involved, in the interaction between arousal and pain. It was
predicted that reflex responses would be stronger for the two experimental conditions
PAIN AND PSYCHOLOGICAL AROUSAL
39
than for the electrical stimulus alone, due to the summation of the sensory inputs.
Contrary to predictions, no significant differences were found between conditions for the
response magnitude, in any of the reflex components. The only significant effect that the
stimulus timing had on spinal responses was their latency, which was significantly shorter
in the acoustic-before condition. This increased responsiveness implies that there was
some effect from the descending influence of the arousal, induced by the acoustic startle.
The results did not support any effects of the startle stimulus at the spinal level. However,
the variability of the reflex responses may have compromised findings.
In keeping with the research, the tactile R2 component was significantly smaller
and less consistent than the other two components. However, the nociceptive R3 and
involuntary movement response also had variable response rates. This inconsistency
directly contradicts comprehensive review by Sandrini et al. (2005), which attests to the
reliability of Willers’ staircase method in activating the R3 component of the flexion
reflex. The observed inconsistency may be partially attributable to habituation effects.
The significant linear decline observed supports the presence of habituation across reflex
components, for both response rates and response magnitude. Usually, however, this
reduction is observable only for response size (Sandrini et al., 2005). It is only severe
enough to significantly affect response consistency when the habituation effect is
magnified, for instance with weaker stimulus intensities (von Dincklage et al., 2013). The
SD9 stimulator stimulator that was used in the present study restricted the strength of the
electrical stimulation, as it could only emit a maximum of 100 volts. This study
compensated for the reduced voltage in a couple of ways. Firstly, a more substantial
electrical stimulus of 10-square waves was chosen rather than the usual five. Secondly, a
single concentric electrode was selected, rather than two bipolar electrodes, to administer
PAIN AND PSYCHOLOGICAL AROUSAL
40
more concentrated stimulation. However, as this stimulated a smaller surface area, it may
have impacted upon the reliability of stimulating the nociceptive receptive field.
Due to the inconsistency of the induction procedures, non-responses could have
impacted significantly upon statistical power (Schafer & Graham, 2002). To address this
the rate of responses (vs. non-responses) was analysed to discern any significant effects
that may have influenced findings. There were no significant differences in response rate
between any of the conditions, implying that it was unlikely to have systematically altered
effects. As there is already a reduction in statistical power intrinsic to MANOVAR,
however, this study is still at a heightened risk of committing a type II error. The findings
failed to support any spinal interaction between pain and arousal, other than the priming
of a swifter R3 response by the arousal induction. While the lack of significant findings
contradicts previous research (Bradley et al., 2005; Koh & Drummond, 2006; Szabadi,
2012) the literature on this topic is severely limited. Additionally, inspection of the
univariate output indicated that there were no significant findings that went undetected
due to the multivariate approach. The lack of meaningful relationship between this
response and startle-induced arousal is consistent with the hypothesis that the observed
interaction between arousal and pain is psychological. The lack of association between
this spinal response and the significant supra-spinal effects introduces the possibility that
the relationship may be purely supra-spinal. Due to the inconsistency of the reflex
induction methods, however, further research is required to substantiate these
interpretations.
Hypothesis Three: Pupillary Response
PAIN AND PSYCHOLOGICAL AROUSAL
41
Pupil size was predicted to increase in all conditions. The dilation was expected
to be greater for the combination of acoustic and electrical stimulation, compared to either
on their own. Pupillary responses fulfilled their role as a methodological check but failed
to support predicted differences. The results show that there was consistent pupil dilation
in each stimulus condition, supporting that the stimuli were inducing the intended
physiological outcomes. Contradictory to prediction, the experimental conditions were
not significantly different from baseline. Additionally, they did not differ significantly
between each other. As pupillary reflex dilation is under direct control of the brainstems
Locus Coeruleus (Larson, 2001; Neuhuber & Schrödl, 2011), the null results imply that
stimulus timing did not affect mid-level processing. This supports that the observed
effects for self-ratings were likely supra-spinal. However, the quantity of missing
response data limits this interpretation. Due to participants’ movement during the
experiment, many of the pupil photos were not of a high enough quality to make accurate
pupil measurements and thus were discarded. The subsequent reduction in power may
have contributed to the null result of experimental conditions. Due to this, future
researchers are advised to secure the participants’ head during pupillometry.
Due to missing data, this response could not be explored over trials, using
MANOVA. However, inspection of univariate output and response means (see Appendix
F) showed a roughly linear decline in pupil size. This may indicate a habituation effect,
akin to that found for reflex responses
The only significant difference was between the single stimulus conditions, with
the acoustic startle alone inducing a significantly greater response than the electrical
stimulus alone. This finding implies that the acoustic startle may have been the more
perceptually intense stimulus. Overall, these results support the induction of arousal, but
any interaction between pain and arousal was likely supra-spinal.
PAIN AND PSYCHOLOGICAL AROUSAL
42
Hypothesis Four: Pain Catastrophizing
Pain Catastrophizing was predicted to correlate positively with pain ratings.
Conversely, catastrophizing was predicted to have no significant associations with
nociceptive reflex responses. The analyses revealed that it was not associated with either
of the pain-specific measures. The absence of a relationship between catastrophizing and
the nociceptive flexion reflex was in line with predictions and supports the argument of
Rhudy, France and colleagues(2002; 2009; 2011; 2007) that catastrophizing exerts a
supra-spinal and not spinal effect on the experience of pain. The lack of association with
pain ratings, however, contradicts predictions and previous findings. The Pain
Catastrophizing Scale is consistently associated with subjectively rated pain, in healthy
participants (Sullivan & Neish, 1998; Sullivan, Rouse, Bishop, & Johnston, 1997;
Sullivan et al., 2001; Sullivan et al., 2000), across a range of electrical intensities
(Seminowicz & Davis, 2006). In the present study, catastrophizing did not correlate with
pain ratings in any of the conditions. One possible explanation is that catastrophizing was
not appropriately measured. There is some evidence that the catastrophizing only
correlates significantly with pain scores when administered closely after painful
stimulation (Dixon, Thorn, & Ward, 2004; Edwards, Campbell, & Fillingim, 2005;
Edwards et al., 2004). Dixon et al. (2004) found that pre- and post-test measurements of
catastrophizing did not correlate well (r=0.46) with those taken during an experimental
pain induction. This scale conceptualises catastrophizing as an underlying trait or
disposition activated by painful experiences. The measurement of catastrophizing, before
the experiment, relied on the participants’ recall of a potentially distant referent (Quartana
et al., 2009). Future researchers are advised to administer the scale during experimental
proceedings, to ensure accurate interpretation of this factor.
Limitations
PAIN AND PSYCHOLOGICAL AROUSAL
43
Several limitations need to be considered in the interpretation of results. The first
significant weakness was the generalizability of the findings. As the sample relied
primarily on young-adult students, it is unclear whether findings apply to the broader
population. Additionally, the reported violations of normality may aggravate this.
MANOVA is robust against moderate violations, but some of the more severe violations
may have reduced statistical power.
A second limitation was the reliance on self-report measures to evaluate the
perceived stimulus intensities. However, to minimise potential biases, the participants
were blind to all hypotheses.
A third major limitation was the high failure rate associated with the nociceptive
reflex induction procedures. As nearly a third of participants failed to exhibit a
measurable nociceptive flexion response, the failure rate presents a significant threat to
the generalizability of results. While this rate is within the normative range, this limitation
is one that is frequently overlooked and under-reported in the literature (Jensen et al.,
2015). One recommendation to reduce failure rates, is to stimulate the medial arch of the
foot rather than the sural nerve, behind the ankle. Stimulation of this area while
participants are standing, has been shown to result in lower failure rates and lower
subjective ratings of discomfort (Jensen et al., 2015; Lewis, Rice, Jourdain, & McNair,
2012). It should be taken into consideration that the medial arch of the foot has a
significantly smaller nociceptive receptive field (Neziri et al., 2009), which would require
a more diffuse stimulation than that used in this study, to ensure constant stimulation.
This reflex induction method was not viable in the present study due to the required
positioning of participants for pupillometry. Without these restrictions, however, this
approach provides a promising avenue for the improvement of future research.
Conclusions and Future Directions
PAIN AND PSYCHOLOGICAL AROUSAL
44
The main finding of this study was that the presentation of an acoustic startle
before electrical stimulation reduced subsequent pain perception. This inhibitory effect
was significant in comparison to both electrical stimulation alone and the reverse stimulus
timing. The difference between the arousal induction and electrical stimulation alone is
in line with previous research, supporting that an interaction occurred. The presence of
an inhibitory effect only for the prior arousal induction suggests that the relationship is
temporally bound. This interaction was not evident in pupillary responses or nociceptive
reflex results, implying that the inhibitory mechanisms involved may be purely supra-
spinal.
This study supports the effect of descending inhibition, due to prior activation of
arousal systems, on the healthy individuals’ experience of pain. Due to the limitations
and restricted scope of this study more research is needed to understand this relationship
entirely. Despite the acknowledged limitations, this study provides a strong indication of
how arousal interacts with pain. This interaction is not only crucial to the general
understanding of healthy populations but could also have significant functional
implications for chronic pain. Preliminary evidence has already emerged for an inverse
relationship, between pain and arousal, in those with chronic pain. Is this interaction
similarly bound by the temporal properties of the activating stimulus? Is it restricted by
individual factors such as pain catastrophizing? And does the interaction occur at a spinal
or supra-spinal level? These questions are essential, not only to greater understanding but
also to the development of effective treatments.
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Appendix A
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Ethics Approval Letter
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Appendix B
Scoring Sheet with Sequence Order of Stimulus Presentation
1) A 2) E 3) EA 4) AE 5) AE 6) A 7) EA 8) E 9) AE 10) EA Series 1 Pain, Sharp
Loud, Discomfort
NFR
11) AE 12) EA 13) AE 14) E 15) EA 16) AE 17) A 18) EA 19) AE 20) A Series 2 Pain, Sharp
Loud, Discomfort
NFR
21) E 22) EA 23) E 24) AE 25) A 26) EA 27) AE 28) EA 29) AE 30) EA Series 3 Pain, Sharp
Loud, Discomfort
NFR
Key: A denotes acoustic stimulus only; E denotes electrical stimulus only; AE denotes the acoustic followed by
electrical stimulus; EA denotes the electrical followed by the acoustic stimulus.
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Appendix C
Pain Catastrophizing Scale
Everyone experiences painful situations at some point in their lives. Such experiences may include headaches, tooth pain, joint or muscle pain. People are often exposed to situations that may cause pain such as illness, injury, dental procedures or surgery. Instructions: We are interested in the types of thoughts and feelings that you have when you are in pain. Listed below are thirteen statements describing different thoughts and feelings that may be associated with pain. Using the following scale, please indicate the degree to which you have these thoughts and feelings when you are experiencing pain.
RATING 0 1 2 3 4
MEANING Not at all To a slight degree
To a moderate degree
To a great degree
All the time
When I am in pain….
No Statement Rating
1 I worry all the time about whether the pain will end.
2 I feel I can’t go on.
3 It’s terrible and I think it’s never going to get any better.
4 It’s awful and I feel that it overwhelms me.
5 I feel I can’t stand it anymore.
6 I become afraid that the pain will get worse.
7 I keep thinking of other painful events.
8 I anxiously want the pain to go away.
9 I can’t seem to keep it out of my mind.
10 I keep thinking about how much it hurts.
11 I keep thinking about how badly I want the pain to stop.
12 There’s nothing I can do to reduce the intensity of the pain.
13 I wonder whether something serious may happen. Copyright 1995 Michael J. L. Sullivan. Reproduced with permission. Source: Sullivan MJL, Bishop S, Pivik J. (1995). The pain catastrophizing scale: Development and validation. Psychol Assess, 7(4), 524-532.
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Appendix D
Information Letter and Consent Form
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Appendix F
Pupillary Response Means over Trials
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Appendix G
Thesis Summary
There are stories of individuals achieving great feats while in severe pain, a
wounded soldier continues to run through the battlefield, a frostbitten climber
continuing to climb after hearing the rumble of an approaching avalanche. It is well
known that a state of arousal can greatly inhibit the intensity of pain in a healthy person.
Psychological arousal refers to the heightened alertness of brain areas involved in how
we perceive such experiences. The activation of the arousal system is generally
associated with the reduction of pain in healthy individuals (Millian, 2002).
Interestingly, there is increasing evidence that it can have the opposite effect on those
with chronic pain (Drummond et al., 2001; Drummond & Willox, 2013; Knudsen et al.,
2011). As psychological arousal pathways, from brain to body, have been broadly
associated with the facilitation of chronic pain (Taylor & Westlund, 2017) they provide
an promising target for future research and treatment.
To understand the relationship in chronic pain, however, there must first be a
good understanding of this relationship in healthy individuals. The current research
provides evidence for the presence of an interaction but not the nature of it. Previous
research fails to show how it is effected by the arousal timing, or whether the interaction
occurs as the pain signals travel to the brain or in the brain itself.
This study aims to enhance the future study of pain and associated conditions,
by exploring the functional relationship between pain and arousal in healthy
participants. The relationship was tested using the combination of an arousal induction
and pain evoked by a brief electrical shock. The arousal induction, a startling noise, was
presented before or after pain to explore the effect of timing. The acoustic startle and
electrical stimulus were also presented alone, in separate trials, to provide baseline
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measures. Self-report measures were used to assess the pain and sharpness of the
electrical stimulus, as well as the loudness and discomfort to the acoustic stimulus.
Additionally, physiological measures were taken to indicate spinal pain processing,
according to the knee jerk reflex, and provide a methodological check for arousal, via
changes in pupil size. Prior to the experiment itself, Pain Catastrophizing was assessed,
as a measure of individual variation in pain perception.
The main finding of this study was that presentation of the startling noise before
electrical stimulation reduced subsequent pain. This inhibitory effect was significant in
comparison to both electrical stimulation alone and the reverse stimulus timing. The
difference between the arousal induction and electrical stimulation alone supports
previous research. However, the inhibitory effect of the arousal induction was only
present when timed before electrical stimulation, supports that the relationship was
bound by timing. The involvement of arousal was confirmed by pupillary responses.
Further, as there were almost no significant differences, between the conditions, for
spinal reflex responses it is suggested that the interaction may have occurred purely in
the brain. Pain catastrophizing scores were not found to correlate with the other pain
measures. However, this was likely due to measurement issues.
Despite its limitations, this study provides a strong indication of how arousal
interacts with pain. This is not only important to the general understanding of healthy
populations but could have significant functional implications for chronic pain.
Preliminary evidence for an inverse relationship has already emerged. Is this interaction
similarly bound by the temporal properties of the activating stimulus? Does the
interaction occur at the level of the spine or brain? These questions are essential, not
only to greater understanding but also to the development of effective treatments.
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Appendix H
SPSS Output
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