Affective Modulation of Nociception in Individuals at Differential Risk for Developing
Hypertension
A thesis presented to
the faculty of
the College of Arts and Sciences of Ohio University
In partial fulfillment
of the requirements for the degree
Master of Science
Sarah T. McGlone
August 2009
© 2009 Sarah T. McGlone. All Rights Reserved.
2
This thesis titled
Affective Modulation of Nociception in Individuals at Differential Risk for Developing
Hypertension
by
SARAH T. MCGLONE
has been approved for
the Department of Psychology
and the College of Arts and Sciences by
Christopher R. France
Professor of Psychology
Benjamin M. Ogles
Dean, College of Arts and Sciences 3
ABSTRACT
MCGLONE, SARAH T., M.S., August 2009, Psychology
Affective Modulation of Nociception in Individuals at Differential Risk for Developing
Hypertension (131 pp.)
Director of Thesis: Christopher R. France
Hypoalgesia is common in persons with and at risk for hypertension (Ghione,
1996; France, 1999) and may result from dampened affective responses to painful stimuli
(Wilkinson & France, 2009; Jorgensen et al., 1996). Generally, pleasant affective stimuli decrease pain, whereas unpleasant affective stimuli increase pain (Rhudy et al., 2005). In the current study, it was hypothesized that the buffering effect of positive affect and the exacerbating effect of negative affect on pain would be less for those at increased risk for developing hypertension. Participants (N=117) were stimulated at 120% of their nociceptive flexion reflex (NFR) threshold while viewing pleasant, unpleasant, and neutral images. Electromyographic response magnitudes, pain ratings, valence ratings, and arousal ratings were obtained. The hypothesis was not supported, possibly because the valence and arousal ratings showed little variability as a function of hypertension risk.
It appears that dampened affect is not the mechanism of hypoalgesia in those at risk for hypertension.
Approved: ______
Christopher R. France
Professor of Psychology 4
TABLE OF CONTENTS
Page
Abstract ...... 3
List of Tables ...... 8
List of Figures ...... 10
Introduction ...... 12
Hypertension and Pain ...... 13
Hypertension ...... 13
Laboratory Animals ...... 15
Humans ...... 20
Conclusions ...... 27
Risk for Hypertension and Hypoalgesia ...... 28
Laboratory Animals ...... 29
Humans ...... 30
Mechanical Nociceptive Stimulation ...... 33
Thermal Nociceptive Stimulation ...... 34
Multiple Forms of Nociceptive Stimulation ...... 34
Electrocutaneous Stimulation ...... 36
Real-World Nociceptive Paradigms ...... 38
Conclusions ...... 39
Mechanisms of Hypoalgesia in Hypertensives ...... 40
Affective Modulation of Pain in Hypertension ...... 43
Conclusions ...... 46 5
Affective Modulation of Pain ...... 47
Pain and Olfactory Affect Induction ...... 47
Pain and Auditory Affect Induction ...... 50
Pain and Visual Affective Induction ...... 52
Written Narrative ...... 52
Video ...... 52
Still Image ...... 54
The Current Study ...... 59
Overview ...... 59
Hypotheses ...... 60
Method ...... 66
Overview ...... 66
Power Analysis ...... 66
Participants ...... 66
Apparatus ...... 67
Measures ...... 69
International Affective Picture System (IAPS) ...... 69
Numerical Pain Rating Scale ...... 69
Affective Valence and Arousal Scales ...... 72
Parental Blood Pressure History Screening ...... 72
Procedure ...... 72
Preparation ...... 72
Phase 1: Assessment of NFR Threshold ...... 74 6
Phase 2: Presentation of Affective Stimuli ...... 76
Phase 3: Resting Blood Pressure Measurement ...... 77
Grouping of Participants ...... 77
Data Analysis and Reduction ...... 79
Results ...... 80
Characteristics of Participants ...... 80
Affective Modulation of Nociception and Pain ...... 83
EMG Responses ...... 83
Pain Ratings ...... 85
Hypertension Risk and IAPS Modulation of Valence and Arousal ...... 85
Valence Ratings ...... 85
Arousal Ratings ...... 90
Hypertension Risk and IAPS Modulation of Nociception and Pain ...... 94
EMG Responses ...... 94
Pain Ratings ...... 98
NFR Threshold Assessment ...... 102
NFR Threshold Magnitudes ...... 102
Pain Ratings during NFR Threshold Assessment ...... 105
Discussion ...... 105
Affective Modulation of Pain ...... 106
NFR Thresholds ...... 107
Risk for Hypertension and Nociception, Pain, and Gender ...... 108
Risk for Hypertension and Affective Modulation of Pain ...... 110 7
Limitations and Future Directions ...... 112
Conclusions ...... 115
References ...... 116
Appendix A: Ohio Blood Pressure History Survey forms ...... 130
8
LIST OF TABLES
Page
Table 1: Summary of Studies Examining the Relationship between…………………16 Hypertension and Pain Perception in Laboratory Rats
Table 2: Summary of Studies Examining the Relationship between…………………21 Hypertension and Pain Perception in Humans
Table 3: Chronological Presentation of Studies Linking Hypoalgesia……………….31 and Parental History (PH) of Hypertension
Table 4: Chronological Summary of Studies Examining Affective…………………..48 Modulation of Pain
Table 5: Affective Norms of IAPS Images (Lang, Bradley, & Cuthbert, 2001)……...70
Table 6: Timeline of Experimental Protocol………………………………………….73
Table 7: Order of IAPS Stimuli……………………………………………………….78
Table 8: Mean (± SD) Age, Body Mass Index (BMI), Systolic Blood Pressure…...…82 (SBP), Diastolic Blood Pressure (DBP), Heart Rate, and Gender Composition as a Function of Parental Histories of Hypertension and Resting Systolic Blood Pressure
Table 9: Results of 2 Parental History of Hypertension (positive or negative) x……..87 2 SBP (above or below the median for one’s gender) x 2 Gender (male or female) x 3 Valence (unpleasant, neutral, or pleasant affective valence of IAPS images) x 2 Stimulation (present or absent) repeated measures ANOVA for Affective Valence Ratings
Table 10: Mean Affective Valence Ratings as a Function of IAPS Image Type,…….88 Presence or Absence of an Electrocutaneous Stimulation, Systolic Blood Pressure, and Gender
Table 11: Results of 2 Parental History of Hypertension (positive or negative)……...91 x 2 SBP (above or below the median for one’s gender) x 2 Gender (male or female) x 3 Valence (unpleasant, neutral, or pleasant affective valence of IAPS images) x 2 Stimulation (present or absent) repeated measures ANOVA for Arousal Ratings
Table 12: Mean Arousal Ratings as a Function Gender, Presence or Absence……….92 of an Electrocutaneous Stimulation, and Affective Valence of IAPS Image
9
Table 13: Results of 2 Parental History of Hypertension (positive or negative)……...96 x 2 SBP (above or below the median for one’s gender) x 2 Gender (male or female) x 3 Valence (unpleasant, neutral, or pleasant affective valence of IAPS Images repeated measures ANOVA for EMG Responses
Table 14: Mean EMG Responses during Unpleasant, Neutral, and Pleasant IAPS...... 97 Images as a function of Gender and Parental History of Hypertension
Table 15: Results of 2 Parental History of Hypertension (positive or negative)...…..100 x 2 SBP (above or below the median for one’s gender) x 2 Gender (male or female) x 3 Valence (unpleasant, neutral, or pleasant affective valence of IAPS Images repeated measures ANOVA for Pain Ratings
Table 16: Results of 2 Parental History of Hypertension (positive or negative)…….103 x 2 SBP (above or below the median for one’s gender) x 2 Gender (male or female) ANOVA for NFR Thresholds
10
LIST OF FIGURES
Page
Figure 1: Affective modulation of pain ratings and NFR magnitudes…………………56 in the Rhudy et al. (2005) study
Figure 2: Hypothesized relationship between NFR magnitude and affective………….60 valence of IAPS images for all participants.
Figure 3: Hypothesized relationship between pain ratings and affective………………61 valence of IAPS images for all participants
Figure 4: Hypothesized relationship between hypertension risk and affective………...62 valence ratings of IAPS images.
Figure 5: Hypothesized relationship between hypertension risk and arousal….………62 ratings of all IAPS images
Figure 6: Hypothesized relationship between hypertension risk, affective……………63 valence of IAPS images, and NFR magnitude
Figure 7: Hypothesized relationship between hypertension risk, affective……………64 valence of IAPS images, and pain ratings
Figure 8: Hypothesized relationship between hypertension risk and NFR…………….65 threshold
Figure 9: Hypothesized relationship between hypertension risk and pain……………..65 ratings at NFR threshold level
Figure 10: Electrode placement on the left leg for NFR detection…………………….68
Figure 11: Sample pleasant, unpleasant, and neutral IAPS images……………………71
Figure 12: An example NFR…………………………………………………………...75
Figure 13: Flowchart of participants’ attrition from the study…………………………81
Figure 14: Mean (± S.E.M.) EMG response of the biceps femoris as a function……...84 of affective valence of IAPS images presented during electrocutaneous stimulation of the sural nerve
Figure 15: Mean (± S.E.M.) pain ratings as a function of affective valence of………..86 IAPS images presented during electrocutaneous stimulation of the sural nerve 11
Figure 16: Mean arousal ratings (± S.E.M.) as a function of affective……………….93 valence of IAPS images and gender
Figure 17: Mean arousal ratings (± S.E.M.) as a function of electrocutaneous………95 stimulation (presence or absence) and gender
Figure 18: Mean (± S.E.M.) EMG response magnitudes as a function………………..99 of parental history of hypertension among female participants
Figure 19: Mean (± S.E.M.) pain ratings as a function of parental history of……...... 101 hypertension and systolic blood pressure
Figure 20: NFR threshold as a function of parental history of hypertension…………104 and SBP
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INTRODUCTION
Past research has linked hypertension and risk for hypertension with decreased
pain perception, known as hypoalgesia (for reviews see Ghione, 1996; France, 1999).
The mechanism(s) responsible for hypoalgesia in those with and at risk for hypertension
is not well understood, due in part to the complexity of the pain experience. Pain is a
multidimensional construct, consisting of three components: sensation of a nociceptive
stimulus, affective reaction to the experience of the painful stimulus, and cognitive
evaluation of the experience. Owing to this complex interplay of factors, the same
nociceptive stimulus can be perceived differently over time and across people depending
upon individual differences in cognitive and affective reactions. Because hypertension
and risk for hypertension have long been associated with affective blunting, particularly
of negative affect (for a review see Jorgensen et al., 1996), it is possible that
hypertension-related hypoalgesia may result, at least in part, from decreased affective
responsivity to noxious stimuli.
Accordingly, the present study sought to determine if affective stimuli
differentially modulate pain ratings and nociceptive flexion reflex (NFR) responses in
individuals with differing degrees of risk for developing hypertension. Using the emotional control of nociception (ECON) paradigm developed by Rhudy and colleagues
(Rhudy et al., 2005; Rhudy et al., 2006; Rhudy, McCabe, & Williams, 2007; Rhudy et al.,
2008), NFR and pain responses were examined during presentation of standardized visual images known to evoke pleasant, unpleasant, and neutral affective responses. Although prior research indicates that pain and NFR responses decrease when viewing pleasant pictures and increase when viewing unpleasant pictures, it was anticipated that those at 13 increased hypertension risk would show reduced modulation to both pleasant and unpleasant visual stimuli. That is, relative to those with lower hypertension risk, those with higher risk would show smaller reductions in pain and nociception during pleasant pictures and smaller increases in pain and nociception during unpleasant pictures due to inhibited affective responsivity to the images.
In the following sections, the existing research linking both hypertension and risk for this disorder and pain perception will be examined. Next, the relationship between affect and pain perception will be presented. Finally, the specific design and hypotheses for the proposed study will be provided.
Hypertension and Pain
Hypertension
Hypertension is defined as having a systolic blood pressure of 140 mmHg or higher and/or a diastolic blood pressure of 90 mmHg or higher; persons with a systolic blood pressure of greater than 120 mmHg but less than 140 mmHg and/or a diastolic blood pressure of greater than 80 mmHg but less than 90 mmHg are considered prehypertensive (JNC VII, 2004). Hypertension has become an epidemic in the United
States, with at least 50 million Americans suffering from high blood pressure (Hajjar &
Kotchen, 2003). Approximately 30% of Americans with hypertension are unaware that they have high blood pressure; more than 40% of those aware of their hypertension are not being treated (JNC VII, 2004). The need for better understanding and control of hypertension is critical, as hypertension is linked to coronary heart disease, stroke, end- stage renal disease, and a host of other causes of morbidity and mortality (JNC VII,
2004). 14
In particular, the association between high blood pressure and cardiovascular
disease is well-documented. Risk of mortality from stroke or heart disease increases
linearly with blood pressure levels starting at 115 mmHg (systolic) and 75 mmHg
(diastolic) (JNC VII, 2004). Indeed, for each increase of 20 mmHg in systolic blood
pressure or 10 mmHg diastolic blood pressure, the probability of death from heart disease
or stroke doubles (JNC VII, 2004).
Due to the possible negative outcomes of hypertension, prevention and early
detection of the disorder are critical. There are a number of factors that influence the
odds that a person might have or later develop hypertension. Some of the more overt
risks include a family history of hypertension, a high resting blood pressure, and increased cardiac reactivity (France & Ditto, 1996). Other factors that increase the
likelihood of developing hypertension include obesity, high sodium intake, low levels of
physical activity, high levels of alcohol consumption, and not eating enough fruits,
vegetables, and/or potassium (Whelton et al., 2002). The risk of developing hypertension
also increases with age (JNC VII, 2004).
Despite the importance of early detection of high blood pressure, numerous
persons with hypertension do not receive an early diagnosis. This may be due to the fact
that many persons with hypertension do not experience any overt symptoms to warn them
that their blood pressure is too high. Interestingly, many studies (for a review, see
Ghione, 1996; France, 1999) have demonstrated that both animals and humans with
hypertension show a decreased perception of painful stimulation, also known as
hypoalgesia. The presence of hypoalgesia in those with high blood pressure may actually
discourage treatment-seeking behavior, as decreased pain perception may reduce the 15
likelihood of seeing a doctor. Indeed, hypertension is linked to increased risk of both
recognized and unrecognized myocardial infarction (MI) (Kannel et al., 1985).
Hypertensives with coronary heart disease are less likely to experience angina during
day-to-day activities than normotensives with this disorder (Ditto et al., 2007; Falcone et al., 1997). Siegel et al. (1992) found that approximately 25% of older hypertensive males without past coronary heart disease symptoms experience silent myocardial ischemia,
which is an unrecognized reduced blood flow to the heart. Additionally, individuals with
hypertension have an increased likelihood of experiencing silent myocardial ischemia
during exercise (Krittayaphong & Sheps, 1996; Falcone et al., 1997). The increased risk
of silent or unrecognized cardiovascular disease in persons with high blood pressure may
result in significant damage to the hearts of these individuals prior to receiving an initial
coronary diagnosis.
It is clear that hypoalgesia may be an indicator of the presence of high blood
pressure, which may serve as an important marker of this disorder in those individuals without other symptoms of hypertension. The pain perception of hypertensives has been thoroughly researched in both animal and human studies, and this research will be
examined in detail in the following sections.
Laboratory Animals
Numerous animal studies have demonstrated a link between animals with high
blood pressure and hypoalgesia (see Table 1). In one early study, Dworkin and
colleagues (1979) found that, when hypertension was induced in rats using
phenylephrine, the animals demonstrated a decrease in a learned behavior (treadmill
running) to avoid a noxious trigeminal nucleus stimulus relative to normotensive rats. 16
Table 1. Summary of Studies Examining the Relationship between Hypertension and Pain Perception in Laboratory Rats
Method of Hypertension Reference Induction Nociceptive Paradigm Result Effect Size Dworkin et al., Phenylephrine Learned behavior Hypertensive rats N/A 1979 infusion (treadmill running) (HR) > latency to avoid Normotensive rats noxious trigeminal (NR) nucleus stimulation Zamir & Segal, Renal artery Paw lick response HR > NR N/A 1979 clipping latency (RL) to hot plate Zamir et al., 1980 Renal artery Paw lick RL HR > NR d=1.15 clipping
Paw pinch pressure HR > NR d=2.04 tolerated
Deoxycorticosterone Paw lick RL HR > NR d=1.22 acetate salt administration (DOCA) Saavedra, 1981 Sponatenously Tail flick RL SHR > NR N/A hypertensive rats (SHR) Wendel & Bennett, SHR Jumping RL to hot SHR > NR d=2.79 1981 plate
Tail flick RL SHR > NR d=3.94 Maixner et al., SHR Paw lick RL SHR > NR N/A 1982 Barres et al., 1983 Renal artery Tail flick RL n.s. N/A clipping Sisten & de Jong, SHR Paw lick RL SHR > NR d=3.53 1983 Renal artery Paw lick RL n.s. d=0.30 clipping DOCA Paw lick RL n.s. d=0.15 Gaida et al., 1983 Stroke-prone SHR Paw lick RL n.s. N/A (SHRSP) SHR Paw lick RL SHR > NR Sisten & de Jong, SHR Hot plate RL SHR > NR d=1.50 1984 Renal Artery Clip Hot plate RL n.s. d=0.07
DOCA Hot plate RL n.s. d=-.06 Friedman et al., Salt sensitive rats on Tail flick RL n.s. N/A 1984 low salt diet Flinch jump n.s. N/A Salt sensitive rats on Tail flick RL Salt sensitive > N/A high salt diet Salt resistant Flinch jump Salt sensitive > N/A Salt resistant 17
Table 1 (continued)
Method of Hypertension Reference Induction Nociceptive Paradigm Result Effect Size Naranjo & Isolation Tail flick RL HR > NR d=1.98 Fuentes, 1985 Paw pinch RL HR > NR d=3.11
Tsai & Lin, 1987 SHR Paw lick RL SHR > NR d=3.35
Renal artery clip Paw lick RL n.s d=0.09
DOCA Paw lick RL n.s. d=-0.68 Van den Buuse et SHR Hot plate RL SHR > NR N/A al., 1988 Eilam et al., 1991 Hypothalamic graft Paw lick RL HR > NR d=2.46 from SHR Lin et al., 1993 SHR Hot plate RL SHR > NR d=1.28
SHRSP Hot plate RL SHRSP > NR d=1.42
Hoffman et al., SHR Hot plate RL SHR > NR N/A 1998 Taylor et al., 2001 SHR Hot plate RL SHR > NR N/A
18
Zamir and Segal (1979) found that rats with hypertension experimentally induced by constriction of one of the renal arteries showed hypoalgesia in the form of a significantly delayed paw lick response to contact with a hot plate [M=23.1 s, SD= 2 versus M=10-13 s
(no SD provided) in sham operated rats]. In another study, Zamir and colleagues (1980)
found that rats had increased paw lick latencies when hypertension was induced by either renal artery clipping (M=25.9 s, SD=18 versus M=11 s, SD=4.1) or by administration of the salt deoxycorticosterone acetate (DOCA) (M=17.8 s, SD=8.0 versus M=10.2 s,
SD=3.61). Friedman et al. (1984) determined that Dahl rats that were bred to be salt- sensitive showed increased tail flick latency [M=11 s versus M=5 s (no SD provided)] when placed on a hypertension-inducing high salt diet. Additionally, Naranjo and
Fuentes (1985) induced hypertension in rats via isolation; these animals showed increased tail flick latency (M=2.8 s, SD=0.45 versus M=2.1 s, SD=0.22) and increased tolerance of paw pinching (M=155 g, SD=20.12 versus M=99 g, SD=15.65) as compared to non-isolated rats. It is clear that numerous methods of inducing hypertension are associated with hypoalgesia in animals. However, not all studies have replicated this phenomenon. For example, several researchers found that hypertension induced by renal artery clipping or DOCA was not linked with hypoalgesia (Barres et al.,1983; Sisten & de
Jong, 1983; Sisten & de Jong, 1984; Tsai & Lin, 1987). These negative results may indicate that experimental methods of inducing hypertension do not always result in hypoalgesia. Instead, it may be that experimental interventions to induce high blood pressure may only work in specific at-risk groups. For instance, in the Friedman et al.
(1984) study, DOCA administration was only effective at bringing about hypoalgesia in rats bred to be salt sensitive. 19
The relationship between nociceptive responding and hypertension has also been extensively examined in spontaneously hypertensive rats (SHR). These animals have
been selectively bred for their risk of developing hypertension. Though they are
normotensive at birth, SHR go on to develop high blood pressure between 6 and 10
weeks of age (van den Buuse et al., 1988). By age 10 weeks, the mean arterial pressures
(MAP) of SHR rats are 40 mmHg higher than control rats on the average (van den Buuse
et al., 1988). Saavedra (1981) conducted one of the earliest studies examining the
relationship between pain and hypertension using SHR. In this study, SHR showed
increased tail flick latency as compared to normotensive rats [M=9 s versus M=4 s (no SD
provided)]. In numerous other studies, SHR showed delayed paw licking or jumping in
response to hot plate stimulation (Wendel & Bennett, 1981; Maixner et al., 1982; Sitsen
& de Jong, 1983; Gaida et al., 1983; Sitsen & de Jong, 1984; Tsai & Lin, 1987; van den
Buuse et al., 1988; Lin et al., 1993; Taylor et al., 2001). Interestingly, Eilam et al. (1991)
found that, when grafts from the hypothalamus of SHR were implanted in normotensive
adult rats, these rats showed an increase in blood pressure of 30% as well as a two-fold
increase in paw lick latencies (M=28 s, SD=6.71 versus M=14 s, SD= 4.47).
Despite the impressive literature supporting the link between hypoalgesia and
SHR, one study failed to do so. Gaida et al. (1983) found that the paw lick latency of
stroke-prone SHR (SHRSP) did not differ from that of normotensive rats. It is possible
some difference between SHRSP and SHR led the SHRSP to have more typical pain
perception in this case, although SHRSP in other studies have shown hypoalgesia (e.g.,
Lin et al., 1993). 20
In general, research in the animal model supports a relationship between hypertension that is either experimentally-induced or naturally-occurring and decreased pain perception. This relationship has also been observed in human studies, and these findings are presented next.
Humans
Many studies have examined pain perception in both persons with high blood pressure and those at increased risk for hypertension. In this section, literature on pain perception in individuals with high blood pressure will be presented, followed by a discussion of research on those at risk for hypertension.
Similar to the animal model, the connection between hypertension and decreased pain perception has also been well-established across different forms of noxious stimulation in human studies (see Table 2). Much of the research in this area has used dental stimulation to determine differences in sensory threshold (level of stimulation required to perceive sensation), pain threshold (level of stimulation at which it becomes painful), and/or pain tolerance (level of stimulation at which the participant requests it be stopped) between hypertensives and normotensives. In the earliest study of this phenomenon, Zamir and Shuber (1980) reported that, in a sample of 55 men, 21 unmedicated hypertensives had both higher sensory thresholds (M=76.4 volts, SD=27.04 versus M=33.0 volts, SD=19.24) and pain thresholds (M=97.1 volts, SD=29.33 versus
M=50.1 volts, SD=23.32) for electrical tooth-pulp stimulation as compared with the 34 normotensive controls. Similar results have been found in samples comprised of both men and women (Ghione et al., 1985; Rosa et al., 1994).
21
Table 2. Summary of Studies Examining the Relationship between Hypertension and Pain Perception in Humans
Reference Nociceptive Paradigm Result Effect Size Zamir & Shuber, 1980 Dental pulp stimulation Sensory threshold HBP > NT d=1.85 Pain threshold HBP > NT d=1.77
Ghione et al., 1985 Dental pulp stimulation Sensory threshold HBP > NT d=1.43 Pain threshold HBP > NT d=1.07
Rosa et al., 1986 Dental pulp stimulation Sensory threshold BHBP > NT d=1.95 Pain threshold BHBP > NT d=1.75
Ghione et al., 1988 Dental pulp stimulation Sensory threshold BHBP > NT d=0.94 HBP > NT d=1.00 Pain threshold BHBP > NT d=0.97 HBP > NT d=0.73 Sheps et al., 1992 Thermal stimulation (forearm) Pain threshold HBP > NT N/A Pain tolerance HBP > NT N/A
Rosa et al., 1994 Dental pulp stimulation Sensory threshold HBP > NT d=1.15 Pain threshold HBP > NT d=2.93 Supraorbitalis nerve stimulation Blink reflex threshold HBP > NT d=1.90
Cutaneous electrical stimulation (hand) Sensory threshold HBP > NT d=0.88 Pain threshold HBP > NT d=1.20 Pain tolerance HBP > NT d=1.47
Guasti et al., 1995 Dental pulp stimulation Pain threshold BHBP > NT d=0.66 HBP > NT d=0.76
Pain tolerance BHBP > NT d=1.00 HBP > NT d=0.70
Schobel et al., 1996 Mechanical stimulation (earlobe, hand, feet) Pain ratings BHBP < NT d=1.50 Pain threshold BHBP > NT d=0.75 Schobel et al., 1998 Mechanical stimulation (earlobe, hand, feet) Pain ratings BHBP < NT d=1.24
22
Table 2 (continued)
Reference Nociceptive Paradigm Result Effect Size Guasti et al., 1998 Dental pulp stimulation Pain threshold HBP > NT d=1.37 Pain tolerance n.s. d=0.21
Guasti et al., 1999 Dental pulp stimulation Pain threshold HBP > NT d=0.58 Pain tolerance HBP > NT d=0.43
Nyklicek et al., 1999 Cutaneous electrical stimulation (forearm) Pain threshold HBP > NT d=0.75 Pain tolerance HBP > NT d=0.63
Guasti et al., 2002 Dental pulp stimulation Pain threshold HBP > NT d=0.50 Pain tolerance n.s. d=0.19 Ditto et al., 2007 Exercise Pain ratings HBP < NT N/A
Note. Significant results for female participants only.
HBP indicates hypertensive persons; NT, normotensive persons; BHBP, borderline hypertensive persons
23
In a more recent study, the pain thresholds and pain tolerances of male
hypertensives (N=25) and normotensives (N=14) were compared (Guasti et al., 1998).
The hypertensive men had higher pain thresholds [M=29 relative units (rU), SD=6] than
then men with normal blood pressure (M=22 rU, SD=4); the hypertensives also had higher pain tolerances than the normotensives, though this difference failed to reach statistical significance (M=48 rU, SD=18 versus M=44 rU, SD=20).
In another study, Guasti and colleagues (1999) again examined pain threshold and pain tolerance using a larger sample consisting of 130 hypertensives and 51 individuals with normal blood pressure. Uniquely, in this study, participants’ ambulatory blood pressure was monitored for 24 hours. Those with high blood pressure had significantly higher pain thresholds and pain tolerances than normotensives (pain threshold: M=25.58 rU, SD=8.29 versus M=21.62 rU, SD=4.89; pain tolerance: M=42.24 rU, SD=17.15 versus M=35.41 rU, SD=14.71).
In a more recent study, Guasti et al. (2002) again examined pain perception during dental pulp stimulation in a sample of 45 unmedicated hypertensive and 28 normotensive male participants. After pain threshold and tolerance for electrical dental stimulation were obtained for each participant, 24-hour ambulatory blood pressure was assessed. Consistent with their prior studies, higher 24-h systolic blood pressure was associated with increased pain threshold (r=0.30, p<.05); however, in this study, blood pressure was unrelated to pain tolerance.
Rosa et al. (1986) extended the research on pain perception in hypertensives to persons with borderline hypertension (persons with systolic blood pressure between 140
and 160 mmHg and/or diastolic blood pressure between 90 and 95 mmHg). In a sample 24
of men and women, 19 borderline hypertensives had significantly lower sensory and pain
thresholds of dental pulp stimulation than 39 normotensives (sensory threshold: M=42.7
volts, SD=7.3 versus M=28.4 volts, SD=7.4; pain threshold: M=61.2 volts, SD=11.4
versus M=40.4 volts, SD=12.3). Additionally, Ghione et al. (1988) demonstrated
increased sensory and pain thresholds for tooth-pulp stimulation in both 42 hypertensives
(sensory threshold: M=40.2 volts, SD=7.6; pain threshold: M=58.7 volts, SD=13.3) and
34 borderline hypertensives (sensory threshold: M=39.8 volts, SD=7.7; pain threshold:
M=61.5 volts, SD=12.3) as compared to 80 normotensives (sensory threshold: M=32.1
volts, SD=8.63; pain threshold: M=48.7 volts, SD=14.0). Guasti et al. (1995) found that
persons with high blood pressure (N=20; pain threshold: M=3.33 ln rU, SD=0.34; pain
tolerance: M=3.81 ln rU, SD=0.48) or borderline high blood pressure (N=13; pain
threshold: M=3.28 ln rU, SD=0.28; pain tolerance: M=3.93 ln rU, SD=0.36) had higher
pain thresholds and pain tolerances than normotensives (N=34; pain threshold: M=3.11 ln rU, SD=0.23; pain tolerance: M=3.55 ln rU, SD=0.4).
In two more recent studies, differences in pain perception between normotensives and borderline hypertensives were assessed by Schobel and colleagues (1996, 1998). In the first study, pain thresholds were determined for nociceptive pressure applied to skin
folds of the left earlobe and the interdigital webs between the second and third fingers of
the left hand and between the second and third toes of both feet (Schobel et al., 1996).
After at least 30 minutes, MAP and subjective pain ratings were obtained from 10 normotensive and 13 borderline hypertensive participants while they were stimulated at their pain thresholds for 2 minutes, with 8 minutes between each stimulation site. Pain ratings were reported every 10 seconds during each type of stimulation. Participants 25
were instructed to provide a rating of 100 when stimulation was just starting to be
painful, and then to double or triple this value when the pain was twice or three times
more intense, respectively. There were significant and negative correlations between
resting MAP and pain ratings for both normotensive (r=-0.47, p<.01) and borderline
hypertensive participants (r=-0.38, p=.01): as blood pressure increased, pain ratings
decreased in both groups. There were important differences between the groups,
including lower overall pain ratings (M=161, SD=28.84 versus M=204, SD=28.46) and increased time to reach pain thresholds (M=8 s, SD=10.82 versus M=2 s, SD=3.16) in the borderline hypertensive group relative to the normotensive control group.
The second study by Schobel et al. (1998) again used a mechanostimulation nociceptive paradigm to examine differences in pain responses between normotensives
(N=9) and borderline hypertensives (N=12). A negative correlation between MAP and pain ratings was again observed (r=-0.58, p<.01), and mean pain ratings were lower in the borderline hypertensives (M=160, SD=27.71 versus M=194, SD=27.0). The difference between the two studies is that the former examined the role of baroreceptor stimulation in the pain perception in hypertension, and the later investigated the role of endogenous opioids. How baroreceptors and endogenous opioids may serve as mechanisms for the decreased pain perception of hypertensives will be discussed in a later section.
The link between hypoalgesia and hypertension has been established using nociceptive paradigms other than dental pulp stimulation as well. In a study by Sheps et al. (1992), thermal stimulation was applied to the forearms of 10 hypertensive and 10 normotensive men. The results demonstrated that blood pressure was significantly and 26 positively correlated with both pain thresholds (r=0.44) and pain tolerances (r=0.64).
Rosa et al. (1994) used supraorbitalis nerve electrical stimulation to examine eye blink reflex threshold in male and female participants both with (N=8) and without (N=8) hypertension. Those individuals with high blood pressure had significantly greater blink reflex thresholds than the normotensive participants (M=4.8 mA, SD=1.6 versus M=2.4 mA, SD=0.8).
Another method that has been used to examine pain perception differences between hypertensives and normotensives is cutaneous electrical stimulation. When cutaneous stimulation was delivered to the back of the hand, Rosa et al. (1994) found that
77 participants with high blood pressure had higher sensory thresholds, pain thresholds, and pain tolerances than 64 persons with normal blood pressure (sensory threshold:
M=1.7 mA, SD=0.7 versus M=1.2 mA, SD=0.40; pain threshold: M=4.1 mA, SD=1.7 versus M=2.5 mA, SD=0.78; pain tolerance: M=6.5 mA, SD=2.4 versus M=3.75 mA,
SD=1.1). Nyklicek et al. (1999) used electrical stimulation of the forearm on 42 hypertensives and 21 normotensives of both genders. Surprisingly, only female hypertensives demonstrated significantly higher pain thresholds (M=2.25 mA, SD=0.89 versus M=1.64 mA, SD=0.74) and marginally significantly higher pain tolerances
(M=3.00 mA, SD=1.11 versus M=2.28 mA, SD=1.18) for the electrical stimulation than normotensive female participants; no significant differences existed between the males with and without hypertension (pain threshold: M=2.32 mA, SD=0.56 versus M=2.74 mA, SD=0.78; pain tolerance: M=3.59 mA , SD=0.89 versus M=3.74 mA, SD=0.86).
Recently, Ditto et al. (2007) examined the relationship between blood pressure and a naturalistic pain stimulus: exercise stress tests used to assess possible myocardial 27 ischemia. A large sample of 425 men and 482 women completed the McGill Pain
Questionnaire (MPQ) before and after undergoing a stress test, and their blood pressure was monitored before, during, and after exercising as well. Those with higher systolic blood pressure during exercise reported less pain on the MPQ, F(1,876)=58.98, p=.003.
Conclusions
Evidence from both laboratory animal and human literatures demonstrate a relationship between high blood pressure and decreased nociceptive responding.
However, interpretation of that relationship remains difficult. In laboratory rats, hypertension is either induced experimentally or through selectively breeding spontaneously hypertensive rats (SHR). Applying findings from the former group of hypertensive rats to humans is challenging due to its dissimilarity to how high blood pressure develops in people. However, even the findings linking hypoalgesia to SHR do not generalize completely to humans; genetic factors are only one component in the myriad of factors that contribute to development of hypertension, and research with SHR cannot take into account various lifestyle choices that may help or hinder the development of hypertension in people.
Naturally, studies investigating high blood pressure in humans are more applicable to other persons. Though it is important to note that some nociceptive paradigms used in laboratory research with humans bear little resemblance to painful stimuli encountered in everyday life, one real-world link between hypoalgesia and high blood pressure cannot be ignored: those with hypertension are at increased risk of unrecognized myocardial infarction. Additionally, evidence of positive and significant correlations between pain threshold/ tolerance and blood pressure have been found in 28
both hypertensives and borderline hypertensives (e.g. Sheps et al., 1992; Ghione et al.,
1988; Guasti et al., 1995). Importantly, this may be an indication that increasing blood pressure is associated with decreasing pain perception, regardless of diagnostic status.
This is supported by research finding that resting blood pressure is inversely related to pain ratings (Bruehl et al., 1992; Maixner et al., 1997; Bruehl et al., 2002) and positively
related to both pain threshold (Maixner et al., 1997; Bruehl et al. 2002) and pain tolerance
(Maixner et al., 1997) among normotensives.
Another possibility to be considered is that simply being at risk for hypertension may be linked with decreased pain perception. Individuals at risk for hypertension are currently normotensive, but they have an increased chance of developing hypertension later in life. Commonly identified risk factors for later hypertension development are having a parental history of hypertension and high normal resting blood pressure. The research examining the pain perception of those at risk for high blood pressure now will be presented.
Risk for Hypertension and Hypoalgesia
Most commonly, risk for hypertension has been defined as a parental history of the disorder and/or high-normal blood pressure. It is important to remember that persons at risk for hypertension are nevertheless normotensive. There have been numerous studies examining pain perception in the context of risk for hypertension, particularly in the human model. The results of these studies generally support a link between hypoalgesia and risk for hypertension. The animal and human studies on this topic will be presented, followed by a discussion of potential common mechanisms of decreased pain perception in hypertensives and those at risk for developing high blood pressure. 29
Laboratory Animals
In an early study, Wendel and Bennett (1981) examined pain sensitivity in young
(30-70 days of age) rats using age-matched spontaneously hypertensive rats (SHR) that are bred to develop hypertension and normotensive Wistar-Kyoto (WK) control rats.
Importantly, the systolic blood pressures of the SHR and WK rats were not significantly different, meaning both rat strains were normotensive at the time of the experiment.
Despite being normotensive, the young SHR showed significantly less pain perception in response to nociceptive stimulation than the WK rats. The SHR had a mean jump latency of 45 s (SD=10) when placed on a hot plate, whereas the WK rats had a faster mean jump latency of 21 s (SD=10). Additionally, SHR had significantly longer tail-flick latency
(M=8.8 s, SD=0.5) than WK rats (M=7.3 s, SD=0.2).
In another study comparing age-matched SHR and WK rats, Maixner et al. (1982) used the hot plate method to assess pain sensitivity in both 4 week old and 16 week old rats. At 4 weeks of age, the mean arterial blood pressures (MAP) of the SHR and WK rats did not differ significantly. However, the SHR had longer paw-lick/jump latencies in response to the hot plate than the WK rats [M=17 s versus M=8 s (no SD provided)]. By age 16 weeks, the SHR had significantly higher MAP than the WK rats, and the difference in paw-lick/jump latencies persisted: SHR had an average latency of 33 s (no
SD provided) whereas WK rats had an average latency of just 14 s (no SD provided).
Similarly, Sitsen and de Jong (1983) found that both young SHR that were still
normotensive and adult SHR with hypertension showed hypoalgesia in paw lick
responses to being placed on a hot plate and electric stimulation. These authors 30
concluded that genetic risk for hypertension may be responsible for hypoalgesia seen
both prior to and after the onset of high blood pressure.
Whether or not risk for hypertension is a causal agent of hypoalgesia, as Sitsen and de Jong (1983) postulate, has yet to be determined. Regardless of the direction of
causality, these animal studies show a link between hypoalgesia and genetic risk for hypertension. The relationship between these factors has been explored in many studies with human subjects, and these studies will now be described.
Humans
In a recent study of 1160 male former medical students followed longitudinally from young adulthood into their 90s, Wang et al. (2008) found that parental history of hypertension increases the risk of developing hypertension along the following lines: those with both parents having hypertension are 2.4 times more likely to develop high blood pressure than those with normotensive parents; those with a father having hypertension are 1.8 times more likely to develop hypertension than those with normotensive fathers; and those with a hypertensive mother are 1.5 times more likely to develop high blood pressure than those with normotensive mothers. Given the association between parental hypertension and later development of the disorder, it is not surprising that many of the studies that have examined pain perception in those at increased risk for high blood pressure have tested the biological children of individuals
with established essential hypertension as participants. As the following studies will describe, persons who have a positive parental history of hypertension (meaning one or both of their biological parents have been diagnosed with high blood pressure) generally show lower levels of pain perception than the offspring of normotensives (see Table 3). 31
Table 3 Chronological Presentation of Studies Linking Hypoalgesia and Parental History (PH) of Hypertension
Nociceptive Pain Measures Reference Paradigm Result Effect Size Ghione et al., 1988 Electrical (tooth) Sensory threshold PH+ = PH- d=0.33 Pain Threshold PH+ = PH- d=0.22 France et al., 1991 Mechanical (thigh)
Positive pressure Pain Threshold PH+ > PH- d=0.27 Numerical Pain PH+ < PH- d=0.66 Ratings
Negative pressure Pain Threshold PH+ > PH- d=0.49 Num. Pain Ratings PH+ < PH- d=0.60
France et al., 1994 Venipuncture (arm) Num. Pain Ratings Females: PH+ < PH- d=0.67 Males: PH+ = PH- d=0.00
France & Stewart, Cold (hand) McGill Pain Ratings PH+ < PH- d=0.51 1995 Num. Pain Ratings PH+ = PH- N/A
Ischemia (arm) McGill Pain Ratings PH+ < PH- d=0.52 Num. Pain Ratings PH+ = PH- N/A al’Absi et al., 1996 Cold (hand) McGill Pain Ratings PH+ < PH- d=0.53 Num. Pain Ratings PH+ = PH- N/A
Stewart & France, Cold (hand) McGill Pain Ratings PH+ < PH- d=0.48 1996 Num. Pain Ratings PH+ = PH- N/A
Ischemia (arm) McGill Pain Ratings PH+ < PH- d=0.45 Num. Pain Ratings PH+ = PH- N/A
Bragdon et al., Heat (arm) Pain Threshold PH+ > PH- d=0.84 1997 Pain Tolerance Females w/ low N/A MAP: PH+ > PH-
Ditto et al., 1997 Electrocutaneous Num. Pain Ratings Females w/high (arm) MAP: PH+ < PH- d=0.81 McGill Pain Ratings PH+ = PH- N/A
Cold (hand) Num. Pain Ratings PH+ = PH- N/A McGill Pain Ratings PH+ = PH- N/A
Page & France, NFR (ankle) Pain Threshold PH+ > PH- d=0.61 1997 NFR Threshold PH+ > PH- d=0.56
McGill Pain Ratings PH+ = PH- d=0.00
32
Table 3 (continued)
Nociceptive Pain Measures Reference Paradigm Result Effect Size Ditto et al., 1998 Mechanical pressure Among those with (finger) high-normal resting BP: Pain Tolerance PH+ > PH- d=0.42 Num. Pain Ratings PH+ < PH- d=0.85
D’Antono et al., Cold (hand) Num. Pain Ratings PH+ < PH- d=0.54 1999 Mechanical (finger) McGill Pain Ratings PH+ < PH- d=0.50 Respiratory Sinus PH+ < PH- d=0.53 Arrhythmia
France & NFR (ankle) NFR Threshold PH+ > PH- d=0.58 Suchowiecki, 2001
Campbell et al., Mechanical (finger) Max. Pain Intensity PH+ < PH- N/A 2002 Avg. Pain Intensity PH+ < PH- N/A Pain Tolerance Not reported N/A
France et al., 2002 NFR (ankle) NFR Threshold PH+ > PH- d=0.59 Pain Threshold PH+ = PH- d=0.11 Pain Tolerance PH+ = PH- d=0.21 McGill Pain Ratings PH+ = PH- d=-0.23
Cook et al., 2004 Acute exercise Num. Pain Ratings PH+ = PH- d=0.17 (quadriceps) Max. Exertion PH+ = PH- d=0.05 Muscle Pain PH+ < PH- d=0.80 Exponent
France et al., 2005 NFR (ankle) NFR Threshold PH+ = PH- N/A Num. Pain Ratings PH+ < PH- d=0.31 McGill Pain Ratings PH+ = PH- N/A
Electrocutaneous Pain Threshold PH+ > PH- d=0.27 (ankle)
33
Mechanical Nociceptive Stimulation
In an early study of pain perception in persons at risk for hypertension, France,
Ditto, and Adler (1991) showed that, relative to men without a parental history of high
blood pressure (N=24), males with hypertensive parents (N=21) gave lower pain ratings
in response to both positive (M=2.6, SD=2.29 versus M=4.3, SD= 2.81) and negative thigh-cuff pressure (M=2.8, SD=2.29 versus M=4.2, SD=2.34). Pain ratings were on a 0 to 10 scale, with 0 meaning no pain and 10 meaning extreme pain. Persons at risk for high blood pressure also had higher pain thresholds for both types of thigh-cuff pressures
(positive: M=234 mmHg, SD=41.24 versus M=223 mmHg, SD=39.19; negative: M=235 mmHg, SD=36.66 versus M=215 mmHg, SD=44.09).
In the first of three landmark studies all using the same sample of males, Ditto et al. (1998) found that, among 88 14-year old boys, those with both a parental history of hypertension and normally elevated resting blood pressure reported significantly less pain during finger pressure, F(1,84)=10.86, p=.001. These individuals also had somewhat higher pain tolerances, F(1,84)=2.62, p=.109. These participants were examined again at age 19, and those with a positive parental history of hypertension were associated with lower maximum (r=.29, p<.05) and average (r=.53, p<.01) pain ratings of finger pressure relative to those whose parents did not have high blood pressure (Campbell et al., 2002).
Campbell and colleagues also reported that blood pressure at age 14 was unrelated to pain ratings at age 19. However, systolic blood pressure (SBP) at age 14 was the most significant predictor (as compared to parental hypertension history and body mass index) of blood pressure increases from age 14 to 19, and in turn higher SBP at age 19 was associated with higher pain tolerances (r=0.32, p<.01) and lower maximum (r=-0.30, 34 p<.01) and average (r=-0.31, p<.01) pain ratings. The 24 hour ambulatory blood pressures and heart rates of the participants from the Ditto et al. (1998) study were examined again when they reached age 22 (Campbell et al., 2003). Importantly, hypoalgesia observed in these subjects at age fourteen was associated with elevated blood pressure at age 19 and age 22 (Campbell et al., 2002; Campbell et al., 2003), which these authors interpret as an indication that hypoalgesia may be an marker of hypertension that will develop later in life.
Thermal Nociceptive Stimulation
Bragdon et al. (1997) examined the pain perception of 52 persons with and without an established parental history of hypertension using heat applied to the forearm.
These authors found that those persons at increased risk for hypertension had significantly higher pain thresholds both when at rest and after a speech stressor, F(1, 43)
= 8.89, p<.01. Additionally, women with a low mean arterial pressure who lacked a parental history of high blood pressure had lower pain tolerances than women with both low MAP and a history of hypertension. This finding is complimented by the finding of
Ditto, France, and France (1997) that women (N=48) with a parental history of hypertension and high MAP reactivity to a stressful videogame demonstrated hypoalgesia to forearm shock, F(1, 41)=7.48, p=.01. At least among women, cardiovascular reactivity to stress and parental risk of high blood pressure may interact to determine whether or not hypoalgesia is observed.
Multiple Forms of Nociceptive Stimulation
Some studies have examined familial risk for hypertension and pain perception using more than one type of nociceptive paradigm. For example, France and Stewart 35
(1995) examined pain perception of both ischemia of the dominant arm and the cold pressor task in a sample of 40 males with and 40 males without a parental history of high
blood pressure. In this study, positive parental history for hypertension, along with high
cardiac reactivity and high mean arterial pressure, were predictors of lower retrospective
pain ratings obtained using the McGill Pain Questionnaire (MPQ). However, numerical
pain ratings using a 0-100 scale (0=no pain, 100=worst pain imaginable) determined
while ischemia and cold pressor were occurring did not differ on the basis of parental
history of hypertension. It may be that, as the MPQ assessed pain retrospectively, it
better reflected the increasing differences between the pain ratings of the groups that
occurred over the course of the nociceptive tasks (5 minutes of ischemia and 2 minutes of
cold pressor) as compared to the numerical pain ratings that were assessed at regular
intervals throughout each task (France & Stewart, 1995). A similar pattern of results has been found in other studies (al’Absi et al., 1996; Stewart & France, 1996).
D’Antono et al. (1999) also studied the relationship between pain, current blood
pressure, and hypertension risk in a sample of 80 women. These authors found that
women with hypertensive parents who had high-normal systolic blood pressure reported
lower pain ratings during both finger pressure and the cold pressor task, F(1,76)=5.75,
p=.019. Risk for hypertension also was linked with lower retrospective McGill Pain
Questionnaire ratings, F(1,76)=4.94, p=.029. In addition to these more traditional pain measures, respiratory sinus arrhythmia (RSA) responses to nociception were assessed.
The authors describe RSA as a measure of heart rate variability in relation to breathing that has been hypothesized to vary with emotionality, with greater intensity of emotion linked with higher levels of RSA. Women with a parental history of high blood pressure 36 had lower levels of RSA, F(1,76)=5.56, p=.021, which may be indicative of decreased emotionality relative to the control group. However, the exact relationship between RSA and emotionality is uncertain. Butler, Wilheim, and Gross (2006) found that elevated
RSA was associated with increased negative emotion, supporting the findings of
D’Antono and colleagues, but they also found that increased RSA was linked with emotional suppression. Clearly, more research on the association between RSA and emotion is warranted.
D’Antono et al. (1999) conducted a second study with this sample of women to assess their pain experiences in everyday life in order to examine the generalizability of their findings. Pain sensitivity as measured in the lab had a significant and positive correlation with daily pain reports on days when participants were not menstruating, r=0.34, p=.042. This relationship was no longer present when participants were menstruating, which the authors hypothesized was due to generally elevated pain reports during this time.
Electrocutaneous Stimulation
Page and France (1997) used the nociceptive flexion reflex (NFR) to study pain perception differences in sample of 116 men and women at differential risk for hypertension. The NFR is a spinal reflex that allows for withdrawal from nociceptive stimulation, and it is considered an objective measure of pain threshold. It is elicited by applying electrical stimulation to the sural nerve at the ankle and measuring the resulting electromyography (EMG) activity over the biceps femoris muscle on the back of the upper leg. Page and France observed that both men and women with a parental history of hypertension required more stimulation for NFR to occur (men: M=16.6 mA, SD= 6.4 37
versus M=13.3 mA, SD=4.9; women: M=13.5 mA, SD=4.8 versus M=10.9 mA, SD=4.9).
Additional assessment of group differences in subjective ratings of the electrical stimulation produced similar results, with the offspring of hypertensive parents showing higher pain thresholds than those without a parental history of hypertension (men:
M=11.7 mA, SD=5.4 versus M=8.6 mA, SD= 4.0; women: M=9.8 mA, SD=5.1 versus
M=7.5 mA, SD=2.9). Separate stepwise regression analyses revealed that parental history of hypertension and resting systolic blood pressure (SBP) were independent
predictors of both NFR threshold and pain threshold, with both a positive parental
hypertension history and increasing SBP associated with higher NFR and pain thresholds.
However, there were no differences in McGill Pain Questionnaire retrospective pain
ratings between those with and without a parental history of hypertension (PH+: M=16.9,
SD=13.0; PH -: M=16.9, SD=8.3).
France and Suchowiecki (2001) also used NFR to examine pain perception in normotensive men and women at differential risk for high blood pressure. NFR thresholds were determined in 54 participants at risk for hypertension and 59 individuals without a parental history of hypertension before, during, and after forearm ischemia.
Results indicated that those with a parental history of hypertension (M=19.6 mA,
SD=6.7) had higher mean NFR thresholds than those without a parental history of the disorder (M=15.8 mA, SD=6.4).
Later, France, Froese, and Stewart (2002) observed similar results when NFR threshold was measured before, during, and after a math stressor: parental history of high blood pressure was linked with higher NFR thresholds (M=22.6 mA, SD=8.4 versus
M=17.5 mA, SD=9.0). Resting SBP was also a significant and independent predictor of 38
NFR threshold when assessed pre-math and post-math. However, those with and without a parental history of hypertension did not differ on pain threshold, pain tolerance, or
McGill Pain Questionnaire pain ratings.
Another study examining NFR, as well as electrocutaneous stimulation, in those
with or without a parental history of high blood pressure was conducted by France et al.
(2005). The results found no difference in NFR thresholds or retrospective McGill Pain
Questionnaire pain ratings on the basis of parental history of hypertension. Nevertheless, those with a parental history of high blood pressure had lower subjective pain ratings of
NFR stimulation while it was occurring (M=35.1, SD=29.9 versus M=43.5, SD=24.0).
Additionally, those with a positive parental history of hypertension had higher electrocutaneous ankle stimulation pain thresholds (M=20.9 mA, SD=14.2) compared to the offspring of normotensives (M=17.5 mA, SD=11.2).
Real-World Nociceptive Paradigms
Two studies in particular have used nociceptive stimulations common in everyday life to study pain perception in those at risk for hypertension. In one, novice female blood donors (those with zero or one prior donations) who had parents with hypertension had lower venipuncture pain ratings than those without a parental history of hypertension
(France et al., 1994). However, there were no significant differences in the pain ratings of novice male blood donors with and without a familial history of high blood pressure.
The authors posit that novice male donors exhibited a floor effect, as men provided uniformly low venipuncture pain ratings regardless of donation experience. Additionally, there were no differences in pain ratings between those with differential parental histories 39
of hypertension among more experienced blood donors, regardless of gender, which
France and colleagues hypothesize may be due to habituation and self-selection factors.
Cook et al. (2004) also conducted a study that demonstrated the external validity
of the link between hypertension risk and hypoalgesia. These authors studied quadriceps
muscle pain that resulted from cycling exercise in a sample of 34 normotensive African
American women, 18 with and 16 without a parental history of high blood pressure. The
cycling was a maximal exercise test with increasing resistance until the participant could
no longer continue. The muscle pain of women with a parental history of hypertension
increased more slowly than the muscle pain of women without a parental history of
hypertension (d=0.80).
Conclusions
Given the evidence linking hypoalgesia with risk for hypertension, it is likely that
decreased pain perception may serve as a marker for future hypertension development.
Though it is worth noting that some studies have failed to find a link between parental
hypertension and hypoalgesia, in general this research indicates a relationship between parental history of high blood pressure and hypoalgesia in both animals and humans. In some human studies, the hypoalgesia observed in those at risk for hypertension was best explained not by parental history of hypertension alone, but by an interaction of parental history and elevated resting blood pressure (France & Stewart, 1995, Page & France,
1997; Ditto et al., 1998; D’Antono et al., 1999, France et al., 2002). Indeed, some studies have found an inverse relationship between resting blood pressure and pain perception without taking parental history of hypertension into account (Bruehl, Carlson, &
McCubbin, 1992; Maixner et al., 1997; Bruehl et al., 2002). Additionally, in many 40
studies, those at risk for hypertension do not differ from control participants in all aspects of nociception measured. For instance, France et al. (2002) found that those at risk for
high blood pressure had higher NFR thresholds than those without a parental history of
hypertension, but pain threshold, pain tolerance, and MPQ pain ratings did not differ
between groups, and Maixner et al. (1997) found that those with elevated SBP had higher
thermal pain tolerances but not pain thresholds than those with lower SBP. Findings like these make it apparent that the relationship between pain perception and risk for
hypertension is complex in nature. Though it is complex, it is worth unraveling the link
between hypoalgesia and hypertension risk, as it may help to identify those who are most
at risk for developing hypertension among children of hypertensives and normotensives
with mild blood pressure elevation (France, 1999). One way to explore this relationship
is to examine the potential mechanisms that lead to hypoalgesia in those with and at risk
for hypertension. These will now be presented.
Mechanisms of Hypoalgesia in Hypertensives
Unfortunately, although the relationship between hypoalgesia and hypertension is
well-established, the mechanism(s) responsible are only somewhat understood. In
general, there are three mechanisms typically used to explain the link between pain
perception and hypertension: baroreceptors, endogenous opioids, and descending
inhibition of pain. First, one possible explanation for decreased pain perception in hypertensives is a lack of sensitivity to information from baroreceptors, which are sensors that respond to changes in pressure in the body. In some studies, baroreceptor stimulation lowered forearm shock pain thresholds in normotensive males but raised it in borderline hypertensive men (Elbert et al., 1988; Rockstroh et al., 1988). However, 41
France et al. (1991) found that carotid baroreceptor stimulation during thigh-cuff pressure
did not bring about different pain ratings between 24 male normotensives and 21 males with a positive parental history for high blood pressure. Schobel et al. (1996) found that
baroreceptor activation was not significantly different between normotensives and
borderline hypertensives. Presently, researchers have concluded that baroreceptors alone
may be unable to account for the hypoalgesia seen in persons with or at risk for
hypertension.
Another possible mechanism is lessened sensitivity to endogenous opioids
(McCubbin et al., 2006). Endogenous opioids are naturally occurring substances created
by the body to ease the effects of pain or stress, with one well-known example being
endorphins. It has been hypothesized that endogenous opioid levels increase to high levels in the hypothalamus of persons with or at risk for hypertension because the brain has a lessened sensitivity to endogenous opioids (France & Ditto, 1996). In turn, increased endogenous opioid levels are associated with higher pain tolerances (Rosa et al., 1988). Increased levels of one endogenous opioid, beta endorphins, have been found in both people with high blood pressure and the children of hypertensives as compared to normotensive controls (Fontana et al., 1994; Guasti et al., 1996). However, research about the role of endogenous opioids in the pain perception of those with and at risk for hypertension has been mixed. McCubbin et al. (2006) found that persons at risk for hypertension showed increases in pain ratings during a cold pressor task when the opioid antagonist naltrexone was administered. These authors speculated that their findings are an indication of a relationship between hypoalgesia in persons at risk for hypertension and endogenous opioid exaggeration. However, France et al. (2005) had different results 42
when administering naltrexone to participants: women had increased pain ratings of NFR
stimulation, whereas men had higher electrocutaneous pain thresholds. Participants’
differential risk for hypertension did not impact these results, which France and
colleagues interpreted to mean that hypoalgesia in those at risk for hypertension is not
mediated by endogenous opioids. Another study found that, when opioid antagonist
naloxone was administered to borderline hypertensives, pain ratings of noxious
mechanostimulation did not change from baseline levels (Schobel et al., 1998). These
mixed results make it difficult to determine what, if any, role endogenous opioid
sensitivity may play in the pain perception in those at risk for hypertension.
Yet another possible cause of hypoalgesia in hypertensives and persons at risk for
hypertension is increased inhibition of pain perception at the supraspinal level (France &
Suchowiechi, 1999). It may be that people at risk for hypertension have an exaggerated
and/or prolonged central inhibition of ascending pain signals. In a sample of 83 men and
women, France and Suchowiechi (1999) found that reduction of blood flow to the
forearm, known as forearm ischemia, led to a reduction of the nociceptive flexion reflex
(NFR) in both genders, which may indicate activation of supraspinal pain modulation in the form of diffuse noxious inhibitory controls (DNIC). However, later research by these
authors with 113 male and female participants showed similar reductions in NFR during
forearm ischemia for persons at risk for hypertension and normotensive controls,
indicating that DNIC do not vary based on differential risk of high blood pressure (France
& Suchowiechi, 2001).
In sum, currently there is much uncertainty regarding potential mechanisms of hypoalgesia in those with and at risk for high blood pressure. The present study will 43
attempt to shed light on the issue by examining how interpretation of the pain experience
itself may differ between those at differential hypertension risk.
Affective Modulation of Pain in Hypertension
The nature of pain is complicated, as it is comprised of sensory input, affective
experience, and cognitive evaluation of nociceptive stimulation. Melzack and Wall
(1965) describe the complexity of the pain experience using their Gate Control Theory,
which posited a physiological “gate” in the spinal cord that may be relatively opened or closed to the perception of pain. Whereas nociceptive sensory information typically opens the gate, allowing transmissions of signals that may be perceived as pain, ongoing cognitive and/or affective activity is also capable of modulating the gate and thereby
influencing the ultimate perception of pain. Therefore, differential affective reaction or
cognitive evaluation of the same nociceptive sensory input may result in individuals
regarding the same painful stimulus differently.
In the current study, the influence of affect on nociception and pain perception
will be examined. Although the definition of affect and emotion have long been a source
of debate in psychology, in the present context the term affect will be used because we
are focused exclusively on the subjective experience of the hedonic and arousing qualities
of presented visual stimuli. This use of the term is consistent with Russell’s (2003)
definition of affect as a consciously accessible state that is a relatively simple and
unreflective combination of hedonic (pleasure-displeasure) and arousing (sleepy-
activated) values; affect may be either free-floating or attributable to a specific stimulus.
Russell explains that affect alone does not account for the full range of an emotional
experience, which must also include an antecedent event, attribution, appraisal, some 44
form of instrumental action, physiological and expressive changes, metacognition,
categorization of oneself as experiencing a specific emotion, and emotional regulation.
It is hypothesized that differences in the affective processing of pain may
contribute to decreased pain perception in those with and at risk for high blood pressure.
Previous research has demonstrated that those with high blood pressure show affective
dampening (Jorgensen et al., 1996). This dampening may occur while experiencing pain,
and, therefore, those with and at risk for hypertension may have a decreased affective
response to nociception, leading to cognitive evaluation of pain as less than that of a
person who is a not at risk for high blood pressure. This process may result in the
hypoalgesia commonly observed in those with and at risk for hypertension.
Indeed, there is a great deal of research indicating that persons with high blood pressure may experience and express affect differently from normotensives. In a meta- analysis summarizing much of this information, 83 studies with 295 effect sizes and a total of 25,469 participants were examined by Jorgensen et al. (1996). These authors found that hypertension was significantly linked with lower levels of affect expression, higher levels of negative affect, including anxiety and guilt, and increased defensiveness, which is blocking of hostile impulses. Because this study was a meta-analysis, affective expression, negative affect, and defensiveness were assessed differently in each study.
Generally, affective expression was assessed using interpersonal assessments like role playing or self-reported overt reactions to negative affect, negative affect was assessed by self-report of how frequently/intensely negative affect was experienced, and defensiveness was assessed by self-reported use of repressive coping and denial of hostility. There were numerous moderator variables in this meta-analysis, including 45
awareness of blood pressure status and age. Awareness of having high blood pressure
was linked with higher negative affectivity, and hypertensives of a younger age were
more likely to have lower levels of affect expression than older hypertensives. The
authors also mention that, though there was a significant relationship between
hypertension and increased negative affect, this relationship was weak and changed in
direction for different subgroups of participants. For example, among Black individuals,
hypertension was unrelated to negative affectivity, and among students and white collar
workers, hypertension was associated with decreased negative affectivity. Overall, the
results of this meta-analysis demonstrate that hypertensives are affective blunters: though
they may experience higher levels of negative affect, they have lower levels of affect
expression, indicating that these persons have smaller reactions to their affective states than normotensives.
A recent study of normotensive participants examined the relationship between affect and resting blood pressure (Pury et al., 2004). Participants viewed thirty-six affectively laden images (16 pleasant, 16 unpleasant, and 4 neutral) from the International
Affective Picture System (IAPS) while their resting blood pressure was monitored. The
results indicated that resting systolic blood pressure was negatively correlated with
affective ratings of a series of both pleasantly (r=-0.26) and unpleasantly (r=-0.35)
valenced IAPS pictures. This demonstrates a clear link between blood pressure and
affect: having elevated resting blood pressure is associated with affective blunting.
There is some evidence that the link between high blood pressure and affective
blunting may extend to persons at increased risk for hypertension. Wilkinson and France
(2009) found that, when 116 participants viewed affectively laden IAPS images, 46
individuals with a positive parental history of hypertension show dampened affective
valence to both pleasant and unpleasant IAPS images. That is, these individuals had affective valence ratings that were closer to neutral than persons without a parental history of high blood pressure. This lends preliminary support to the idea that, similar to hypertensives, those with a parental history of hypertension demonstrate affective
blunting.
Conclusions
Though the link between risk for hypertension and hypoalgesia is strong, exactly
what constitutes this link is less well-understood. It is possible that decreased affective
response to nociception may be part of the mechanism by which decreased pain
perception occurs in those with and at risk for hypertension. If this is the case, over time
these individuals might develop a tonic descending inhibition of nociceptive inputs, as
their lessened affective reactions to pain would cause them to experience hypoalgesia
whenever pain is encountered. This may shed light on why hypertensives have an
increased likelihood of having a myocardial infarction without even realizing it (Kannel
et al., 1985): the blunted affective reactions to the physical sensations of pain
hypertensive individuals experience over their lifetime may lead to the inability to
perceive much of the nociception they experience, including the pain associated with a
heart attack.
In order to better understand how affect influences pain perception in those at risk
for hypertension, first the relationship between pain and affect in normal populations
must be examined. An overview of this research is presented next. 47
Affective Modulation of Pain
In general, research with normal populations has shown that stimuli that evoke negative affect are linked with increased pain perception, whereas stimuli that elicit positive affect are related to decreased pain perception. Studies examining the impact of various types of affective stimuli on pain perception are described below and in Table 4.
However, this review will focus primarily on visual stimuli because pictures of differential affective valence will be used in the present study.
Pain and Olfactory Affect Induction
Olfaction is important in affect, as the sense of smell is linked with the limbic system, an
area of the brain critical to affective expression (Villemure & Bushnell, 2002). As such,
olfactory mood inductions can influence pain perception. Jahangeer and colleagues
(1997) examined this hypothesis using mice. The animals were exposed to positive
(feces of mice who had eaten sugar water), negative (cat feces), and neutral odors
(banana). In the first experiment, mice that were not habituated to the various odors
showed no group differences in nociception to electric shock. However, in the second
experiment, the mice were habituated for 20 days to the positive, negative, or neutral
odor, depending on their group assignment. After odor habituation occurred, the neutral
odor did not impact nociception, whereas the positive odor decreased and negative odor
increased nociceptive reactions, such as jumping, attempting to escape, and squeaking.
At low levels of electric shock, mice exposed to positive odors showed a 36.0% decrease in nociceptive behavior, whereas mice exposed to negative odor had a 28.1% increase in nociceptive behavior; at high levels of shock, the nociception of the former group decreased by 12.4% and the nociception of the latter group increased by 10.9%. 48
Table 4. Chronological Summary of Studies Examining Affective Modulation of Pain
Affect Nociceptive Pain Measures Effect Reference Paradigm Paradigm Result Size Cogan et al., Audiotapes Mechanical Pain Threshold Humor > Control N/A 1987 Humor (arm) Relaxing > Control Relaxing Humor > Attention Attention Control
Zelman et al., Written Cold pressor Pain Tolerance + > Baseline N/A 1991 statements - < Baseline Numerical Pain + = - = Baseline Ratings
Zillman et al., Video Cold pressor Pain tolerance + > - d=0.52 1996 Mechanical + > - d=0.85 (arm) Jahangeer et al, Olfactory Electric Nociceptive Non-habituated to N/A 1997** Shock response odor: behaviors + = - Habituated to odor: + < Baseline - > Baseline
Weisenberg, Video Cold pressor Pain tolerance + > Baseline N/A Raz, & Hener, Num. Pain + < Baseline 1998 Ratings de Wied & Still Image Cold pressor Pain Tolerance + > Neutral d=0.50 Verbaten, 2001 (IAPS) - < Neutral d=0.20
Meagher et al., Still Image Cold pressor Pain Threshold + > Baseline N/A 2001 (IAPS) - < Baseline Pain Tolerance - < Baseline + = Baseline
Rhudy & White noise Radiant Heat Pain Threshold Women: d=-1.23 Meagher, 2001 (90 dB) - > Baseline Men: d=1.11 - < Baseline
Villemure et Olfactory Heat Pain + < - d=0.90 al., 2003 Unpleasantness Ratings Pain Intensity + = - d=0.55 Ratings
49
Table 4 (continued)
Affect Nociceptive Pain Measures Effect Reference Paradigm Paradigm Result Size Rhudy et al., Still Image NFR NFR Magnitude + = Neutral d=0.85 2005 (IAPS) + < - d=1.33 - = Neutral d=0.49
Num. Pain + < Neutral d=1.25 ratings + < - d=1.73 - = Neutral d=0.47
Rhudy et al., Still Image NFR NFR Magnitude Cue: 2006a (IAPS) n.s. d=0.18 Uncued: + < Neutral d=0.56 + < - d=1.10 - > Neutral d=0.53
No effect for cued vs. uncued Num. Pain + < Neutral <- d=1.25 Ratings Rhudy et al., Still Image Cold pressor Pain Threshold + > Neutral = - d=1.06 2006b (IAPS) Pain Tolerance + = Neutral > - d=0.74
Rhudy, Still Image NFR Autonomic + < - d >0.66 McCabe, & (IAPS) Reaction + < Neutral d > 0.66 Williams, 2007 - = Neutral d=0.11
Rhudy et al., Still Image NFR NFR Magnitude + (food) = Neutral d<.30 2008 (IAPS) + (erotic) < Neutral N/A + (food, erotic) < N/A - (loss, attack) - (loss) = Neutral d=.38 - (attack) > Neutral d=.59
Num. Pain + (erotic) = Neutral d=.10 ratings + (food) = Neutral d=.03 + (erotic, food) = d=.12 - (loss, attack) - (attack) = Neutral d=.07 - (loss) = Neutral d=.06
** Study conducted with mice. All other studies in the table have human participants.
+ indicates positive affect group; -, negative affect group
50
The role of odor in pain perception has also been examined in humans by
Villemure and colleagues (2003). A sample of 15 males smelled 27 different odors and provided preference rankings of each; the most preferred and the least preferred scents of each subject were selected as their positive and negative odors for the experiment.
Participants then experienced a thermal heat stimulus, and the temperature that resulted in moderate pain was selected. Next, participants experienced the thermal and olfactory stimuli simultaneously and completed an intensity discrimination task with a focus on either the painful or the olfactory stimulus. The results indicated that the scents altered mood and pain unpleasantness ratings but did not influence perceived pain intensity.
Specifically, positive odors were linked with positive affect and negative odors were linked with negative affect. Analyses showed that these affective changes, rather than the odors themselves, were associated with pain unpleasantness ratings being lower for those who experienced positive odors and higher for those who smelled negative odors.
Interestingly, when subjects focused on the nociceptive stimulation rather than the odors, pain intensity and unpleasantness measures increased, which may indicate that attention plays a role in altering pain perception that is separate from the role of affect.
Pain and Auditory Affect Induction
An important early study examining the relationship between pain and affect was conducted by Cogan and colleagues (1987). In Study 1, pain perception was assessed in
40 male and female participants after listening to one of three types of 20-min recordings: laughter-inducing, relaxation-inducing, or dull-narrative. Participants who listened to either laughter- or relaxation- inducing audio tapes had higher pain thresholds for mechanical pressure of the upper arm than persons in the control group. In a second 51
study, these authors matched 40 females participants on pressure pain thresholds, and
then participants received one of several interventions: 1) listening to a tape that was a) laughter-inducing, b) interesting, or c) uninteresting; 2) completing multiplication problems, or 3) no intervention. The pain thresholds for the women after listening to a laughter-inducing tape increased, but the thresholds of persons in the other groups did not change after experiencing their particular intervention. The findings of Cogan et al.
(1987) demonstrate that positive affect, like relaxation and mirthfulness, results in decreased pain perception. The findings of the second study seem to counter those of
Villemure et al. (2003): that is, positive affect led to hypoalgesia, but attentional interventions did not impact pain perception.
Good (1996) reviewed the literature on the effectiveness of using pleasant music to reduce pain perception in individuals after undergoing surgery. In most studies, music
was able to successfully reduce negative affect and observed pain in postoperative
patients. However, it is important to note that the use of pain medication and sensory
pain experienced by persons who listened to music after surgery was not different from
control groups.
A study by Rhudy and Meagher (2001) examined whether or not negative affect-
inducing stimuli would affect pain perception. These authors exposed 40 male and
female participants to loud bursts of white noise (90 dB) in an attempt to induce fear.
Radiant heat thresholds were assessed both before and after white noise exposure. In
women, radiant heat thresholds increased after the white noise bursts, but thresholds
following the noises decreased in men. An explanation for this result is found in
differences in the affect elicited by white noise: female participants found the noise to be 52
fear-inducing, whereas males found the noise to be surprising, but not fear-eliciting. This result supports the hypothesis that less intense negative affect, such as mild to moderate fear or anxiety (such as surprise) enhances pain perception, whereas more intense levels of negative affect result in hypoalgesia. This indicates a curvilinear relationship between pain perception and unpleasant affect, with pain increasing with negative affect to a point, past which negative affect is associated with decreased pain. In a later paper,
Rhudy et al. (2008) comment that the inhibitory effects of negative affect on pain perception would be more likely when affectively-laden stimuli represent an imminent threat to participants.
Pain and Visual Affective Induction
Written Narrative
After initially undergoing the cold pressor task, 65 participants in a study by
Zelman et al. (1991) study read statements that were positive, negative, or neutral in
affective tone. These individuals then repeated the cold pressor task. Both the length of
time participants were able to keep their hands in the cold water (pain tolerance) and
verbal pain reports (pain ratings) given before and after affect induction were compared.
The pain tolerances of individuals who experienced the negative affect induction
decreased, whereas the pain tolerances of those who had positive affect induction
increased. However, pain ratings given before and after affect induction did not differ
across the groups.
Video
In a study of 72 male undergraduate students, Zillmann et al. (1996) examined the
impact of viewing a 15-minute film segment on pain sensitivity to both arm cuff pressure 53
and a cold-pressor task. Prior to viewing the film, a blood pressure cuff on the
participants’ arm was inflated until they pushed a button when it began to be painful.
Then, participants were randomly assigned to view one of five possible film clips; two
film segments depicted positive affect in the form of sexual scenes, two film segments
depicted negative affect by way of violent scenes, and one film segment depicted neutral
affect by describing the development of the National Geographic Society. After viewing
the film clip, participants repeated the arm cuff pressure task, and also a cold-pressor task
(the arm cuff task was performed first for the first half of participants, and the cold-
pressor task was first for the second half of participants). Zillmann and colleagues found
that participants reported decreased pain sensitivity after viewing film clips that elicited
positive affect: they were able to withstand higher levels of arm cuff pressure as
compared to before the film, and they were able to keep their hands immersed in ice
water longer than participants in the neutral and negative affect groups. However, the
group that viewed the negative film clips showed increased pain perception, as they were
able to withstand less arm pressure than before viewing the film segment, though not
significantly less pressure than the control group. The participants who viewed the negative film clip kept their hand in ice water for a similar amount of time as the control group.
Weisenberg, Raz, and Hener (1998) used film to assess affective modulation of pain in a large sample of participants (N=200). Individuals first viewed one of nine different films: there were three types of films (a positive affect-inducing humorous film, a negative affect-inducing holocaust film, or a neutral film) of one of three different durations (15, 20, or 45 min). Additionally, a control group viewed no film at all. 54
Participants underwent the cold pressor task immediately after viewing the film
(baseline) and then again 30 minutes later. Those who viewed the humorous film showed increased pain tolerances from their baseline levels. Additionally, regardless of the affect of the film, increased duration of film clips was associated with increased pain tolerances, which may be evidence of attention moderating the experience of pain.
The possibility that expectation of benefiting from positive affect results hypoalgesia was examined by Mahony, Borroughs, and Hieatt (2001). In this study, pain thresholds for upper arm pressure were measured for 134 participants. They then viewed either a humorous video or a relaxation video. One half of participants were told that the video would increase their pain threshold, and the other half were told it would decrease their pain threshold. The results demonstrated that expectations did significantly influence pain thresholds: those who were told their pain thresholds would increase had higher pain thresholds than a control group, and those who were told their pain thresholds would decrease had lower pain thresholds than the control group. Based on their findings, Mahony and colleagues argue that the hypoalgesia commonly observed after a positive affect manipulation may be just a placebo effect, albeit an effective one.
Still Image
Meagher et al. (2001) used still images from the International Affective Picture
System (IAPS) to examine how viewing a slideshow of images that were affectively pleasant (e.g., nudes), unpleasant (e.g., violent scenes, mutilated bodies), or neutral (e.g., a dustpan, a basket) would impact perception of the cold pressor task. Fifty male and female undergraduate students were tested individually. Each participant viewed one of the slide shows as they held their hand in ice water until it became “intolerable.” 55
Additionally, pain thresholds were determined by participants indicating when they first
felt pain. Relative to participants viewing neutral slide shows, participants who saw fear-
related unpleasant images had lower pain thresholds and tolerances on the cold pressor task, whereas those who viewed slides showing pleasant erotic scenes had increased pain thresholds but pain tolerance was unchanged. de Wied and Verbaten (2001) had similar results using IAPS images in combination with the cold pressor task. Participants who viewed pleasant IAPS images had an average pain tolerance that was 39 seconds longer than those who viewed neutral images (pleasant, M=119.75 s, SD=91.23; neutral,
M=80.31 s, SD=64.94), alternatively, those who saw unpleasant images had pain tolerances than were 12 seconds shorter than participants viewing neutral images
(unpleasant, M=68.49 s, SD=54.83).
Recent studies using the nociceptive flexion reflex (NFR) have found similar results to studies using thermal and pressure stimuli. Rhudy et al. (2005) conducted a study in which 28 male and female participants had their NFR activity assessed while viewing affectively-laden (pleasant, neutral, or unpleasant) images from the IAPS. When pictures with a pleasant affective valence (i.e., erotic scenes) were viewed, NFR activity was significantly lower than that observed while viewing IAPS pictures with a unpleasant affective valence (i.e., human and animal attack images); there were no differences in
NFR activity between neutral (i.e., mushrooms, a basket) and either pleasant or unpleasant images. Pain ratings obtained when viewing pleasant images were significantly lower than those obtained while either neutral or unpleasant images were viewed; there were no significant differences between pain ratings given while viewing unpleasant and neutral images. Figure 1 provides a summary of these results. 56
Figure 1. Affective modulation of pain ratings and NFR magnitudes in the Rhudy et al. (2005) study.
Note: Figure from “Affective modulation of nociception at spinal and supraspinal levels” by Rhudy et al., 2005, Psychophysiology, 42, 579-587. Copyright 2005 Society for Psychophysiological Research.
57
Rhudy and his colleagues stated that the affective valence, but not the arousal caused by viewing the pictures, was responsible for their findings, as arousal ratings were uncorrelated with either NFR responses or pain ratings. These results were replicated with the same IAPS images by Rhudy et al. (2006a) with 50 male and female participants. However, when the pain-inducing stimuli were preceded by a cue, only pain ratings and not NFR magnitudes were modulated by the affective valences of the pictures viewed. These authors hypothesized that viewing affective pictures results in descending modulation of spinal nociception when the nociceptive stimuli are unpredictable.
Another study by Rhudy et al. (2006b) investigated the affective modulation of pain with IAPS images in a sample of 37 veterans, 27 of whom were either alcohol or cocaine dependent. Over the course of three sessions, participants viewed affect-eliciting
IAPS images, and then placed their arms in 33°F water until they could no longer tolerate the cold. Previous findings that positive affect decreases pain perception and negative affect increases pain perception were validated; affective modulation of pain was not affected by alcohol/cocaine addiction.
Rhudy, McCabe, and Williams (2007) further expanded the research on NFR and affective modulation using IAPS images by examining autonomic responses (skin conductance and heart rate acceleration) to NFR stimulation. The authors explained that, under motivational priming theory (Lang et al., 1990), pleasant stimuli decrease reactions to aversive stimuli and unpleasant stimuli increase these reactions. The authors hypothesized that this relationship would hold true for autonomic responses. In a study of 53 male and female undergraduate participants, autonomic reactions during NFR stimulation were significantly smaller while viewing pleasant images compared to 58 unpleasant images; autonomic reactions to both unpleasant and pleasant images were larger than reactions to neutral images. These findings may indicate that autonomic measures are an effective way to ensure affective modulation is occurring during nociceptive stimulation. Unfortunately, any possible differences in NFR magnitude on the basis of affective content of IAPS images were not examined in this study.
Recently, Rhudy and colleagues (2008) examined the effects of different types of pleasant (erotic and food) and unpleasant (attack and mutilation) IAPS images on nociceptive reactions. Though NFR responses were greater during unpleasant images relative to pleasant ones regardless of the specific type of unpleasant or pleasant images used, only NFR responses during attack images were larger than NFR responses during neutral images, and only NFR responses during erotic images were smaller than NFR responses during neutral images. Contrary to the postulation of Rhudy et al. in the 2005 paper, these results indicate that arousal does play a role in affective pain modulation, as attack images were rated as more arousing than loss images (p<.001, d=.92) and erotic images had slightly higher arousal ratings than food images (p=.10, d=.57). These results indicate the erotic pleasant images and unpleasant images involving human and animal attacks are the most effective at bringing about affective modulation of nociception, and that arousal and valence work together to cause affective pain modulation.
Generally, the research reviewed here supports the hypothesis that affect modulates the experience of pain: stimuli that evoke positive affect tend to decrease pain perception, whereas stimuli that bring about negative affect often lead to an increase in pain perception. The research on both the decreased pain perception of those with and at 59
risk for hypertension and the affective modulation of pain will now be integrated as the
current study and its hypotheses are described.
The Current Study
The impact of positive and negative affect on pain perception in normal
populations has been examined extensively (e.g., Rhudy et al., 2005; Rhudy et al., 2006a;
Rhudy et al., 2006b; Rhudy, McCabe, & Williams, 2007; Rhudy et al., 2008). In
addition, the decreased pain perception of those with and at risk for hypertension has
been well-documented (Ghione, 1996; France, 1999), as has the propensity for these
individuals to show affective blunting (Jorgensen et al., 1996). It is possible that
affective blunting may account for the hypoalgesia in those with and at risk for hypertension. However, to date there has been no research examining the effect of affective modulation on pain perception in those at increased risk for high blood pressure.
The goal of the current study is to bridge this gap.
Overview
Male and female college students with and without a parental history of hypertension were recruited for participation in this study. First, the NFR threshold level for each participant was determined. Once the NFR threshold was determined, participants viewed 24 images from the IAPS that have been normatively rated as pleasant, unpleasant, or neutral in affective valence. Participants were stimulated at
120% of their NFR threshold during one half of the images of each affective valence, as well as during some intertrial periods. Participants provided pain ratings and NFR magnitudes were recorded during each electrocutaneous stimulation. After participants 60 viewed an image, they provided ratings of affective valence and arousal as well. At the end of the session, resting blood pressure and heart rate were monitored.
Hypotheses
The current study tested the following hypotheses:
Hypothesis 1:
Affective valence of IAPS stimuli will modulate pain perception.
(a) Across all participants, NFR magnitudes will be significantly less when
pleasant IAPS images are viewed relative to when unpleasant IAPS images are
viewed.
High NFR Magnitude
Low Unpleasant Neutral Pleasant Valence of IAPS Image
Figure 2. Hypothesized relationship between NFR magnitude and affective valence of IAPS images for all participants.
(b) Across all participants, pain ratings will be lower when pleasant IAPS images
are viewed relative to when unpleasant IAPS images are viewed. 61
High Pain Ratings
Low
Unpleasant Neutral Pleasant Valence of IAPS Image
Figure 3. Hypothesized relationship between pain ratings and affective valence of IAPS images for all participants.
Hypothesis 2:
Participants at increased hypertension risk will show decreased affective responding to IAPS images relative to participants with lower hypertension risk.
(a) Participants at increased hypertension risk will rate pleasant IAPS images as
less pleasant and unpleasant IAPS images as less unpleasant than participants at
lower risk of developing high blood pressure. 62
+ Low Risk High Risk Ratings Affective Valence Affective Valence
-
Pleasant Unpleasant Valence of IAPS Image
Figure 4. Hypothesized relationship between hypertension risk and affective valence ratings of IAPS images.
(b) Participants at increased hypertension risk will rate all IAPS images as less
arousing than participants with lower high blood pressure risk.
High
High Risk Low Risk IAPS Arousal Ratings
Low
Unpleasant Neutral Pleasant Valence of IAPS Images
Figure 5. Hypothesized relationship between hypertension risk and arousal ratings of all IAPS images.
63
Hypothesis 3:
Affective modulation of nociception and pain will be less in participants at increased risk for hypertension relative to those at lower risk of developing hypertension.
(a) Compared to participants at decreased risk for hypertension, those with a
hypertensive parent(s) and/or elevated blood pressure will show less of a decrease
in NFR magnitudes when pleasant IAPS images are viewed, and they will show
less of an increase in NFR magnitude when unpleasant IAPS images are viewed.
High Low Risk High Risk NFR Magnitude
Low
UnpleasantPleasant Neutral UnpleasantPleasant Valence of IAPS Image
Figure 6. Hypothesized relationship between hypertension risk, affective valence of IAPS images, and NFR magnitude.
(b) Compared to participants with neither a parental history of hypertension nor
elevated blood pressure, those with hypertensive parent(s) and/or elevated blood
pressure will show less of a decrease in pain ratings when pleasant IAPS images
are viewed, and they will show less of an increase in pain ratings when unpleasant
IAPS images are viewed. 64
High Low Risk High Risk Pain Ratings
Low
UnpleasantPleasant NeutralPleasant Unpleasant Valence of IAPS Image
Figure 7. Hypothesized relationship between hypertension risk, affective valence of IAPS images, and pain ratings.
Hypothesis 4:
Consistent with prior studies, during initial NFR assessment, individuals with a
parental history of hypertension and/or elevated blood pressure will have
significantly higher NFR thresholds and lower pain ratings at NFR threshold as
compared to those without both a parental history of high blood pressure and
elevated blood pressure. 65
High NFR Thresholds
Low
Low HBP Risk High HBP Risk
Figure 8. Hypothesized relationship between hypertension risk and NFR threshold.
High Pain Ratings
Low
Low HBP Risk High HBP Risk
Figure 9. Hypothesized relationship between hypertension risk and pain ratings at NFR threshold level.
66
METHOD
Overview
The current study used a mixed factorial design with three between-subjects factors and one within-subject factor. The between-subjects factors were parental history of hypertension (positive or negative), gender (male or female), and systolic blood pressure (above or below the median for one’s gender). The within-subject factor was valence of the IAPS slide (pleasant, negative, and unpleasant). The study uses the same design as Rhudy et al. (2005, 2006a, 2006b, 2007, 2008) in order to permit comparisons with prior findings.
Power Analysis
In order to determine the necessary sample size, a power analysis was conducted.
The mean effect size of parental history on pain perception was calculated to be d=0.432
(see Table 3); this is a medium effect size. The mean effect size of affective valence on pain perception was d=0.682 (see Table 4), which is a large effect size. The former effect size was used in the power analysis to determine the most conservative estimate of sample size required. To achieve a medium effect size of d=0.432 in the current study,
116 participants were needed in order to obtain a power of .80 at the α = .05 level for the repeated measures ANOVA analyses to be conducted. These analyses will be described in more detail in a later section.
Participants
In order to ensure adequate sample size, a total of 100 men and 100 women were recruited from Ohio University Psychology Department online pool of participants. To be eligible, participants had to be between 18-25 years of age, have no major health 67
issues (including cardiovascular, renal, and/or pulmonary disease), and have no history of
knee or hip replacement surgery (which could affect the NFR threshold assessment).
Participants received two research credits used towards fulfilling a requirement in basic
psychology classes at Ohio University
Apparatus
Data collection and the presentation of stimuli were accomplished using a
Gateway personal computer (Model E-4610S), an IBM ThinkPad laptop (Model #1844),
and two Gateway flat panel monitors (Model # TFT1980PS+). One monitor was located
in an equipment room and was used by the experimenter to monitor physiological data.
The other monitor was located 0.5 m in front of the participant in an adjacent testing
room and used by the participant to view stimuli and provide pain and affective ratings
using a computer mouse. Labview 7 Express software was used to control timing of
stimulus presentation and to record pain, valence, and arousal ratings. A Micro1401
analog-to-digital convertor and Spike2 software was used to record NFR data. NFRs
were elicited using a Nicolet bar electrode, anode inferior, attached over the retromalleolar pathway of the sural nerve of the left leg (see Figure 10). Electrical stimulation was delivered using a Digitimer, DS7A constant-current stimulator.
Electromyographic (EMG) activity was recorded using a DelSys, Bagnoli-2 differential
EMG amplifier. In order to detect NFRs, an EMG electrode was placed over the left biceps femoris muscle, 10 cm above the popliteal fossa, and a reference electrode was placed over the lateral epicondyle of the femur. Both systolic and diastolic blood
pressure (in mm Hg) as well as heart rate [in bpm) were measured from the left arm using
an automated Critikon, Dinamap (Compact T) blood pressure monitor. 68
Stimulating electrode attached over the retromalleolar pathway of the sural nerve
EMG electrode attached over the biceps femoris muscle
Reference electrode placed over the lateral epicondyle of the femur
Figure 10. Electrode placement on the left leg for NFR detection.
69
Before all electrodes in this study were applied, the skin was slightly abraded at the placement sites to reduce resistance below 10,000 Ohms.
Measures
International Affective Picture System (IAPS)
Consistent with Rhudy et al. (2005, 2006a, 2006b, 2007), 24 digital pictures from the IAPS (Lang, Bradley, & Cuthbert, 2001) were selected for presentation to participants based on the affective responses that they elicit. The IAPS images have normative affective ratings based on a 1-9 scale with 1=“complete unhappiness” and 9= “complete happiness.” Table 5 provides the affective norms of each IAPS image used in this study.
Of the twenty-four pictures, eight elicit pleasant affect via erotic images, eight elicit unpleasant affect via human and animal attack images, and eight elicit neutral affective responses (i.e., rating=5) (see Figure 11). The pictures were shown in a predetermined randomized order to all participants.
Numerical Pain Rating Scale
On the monitor in front of the participant, the computer displayed a numerical rating scale to rate the pain level of each electrical stimulation. Participants were asked to rate each stimulation from 0 to 100 with the following points as anchors: 0 (no sensation perceived), 1 (just noticeable sensation), 25 (uncomfortable), 50 (pain), 75
(very painful), and 100 (maximum tolerable pain). If at any time a participant gave a stimulation a rating of 100, the experimental session was terminated, regardless of whether or not an NFR has been elicited. Participants provided pain ratings for each
stimulation delivered.
70
Table 5. Affective Norms of IAPS Images (Lang, Bradley, & Cuthbert, 2001)
IAPS Picture Image Affective Mean Affective # Description Valence Valence Ratings (SD)* 5500 Mushroom Neutral 5.42 (1.58) 7040 Dust Pan Neutral 4.69 (1.09) 4660 Erotic Couple Pleasant 7.40 (1.36) 1050 Snake Unpleasant 3.46 (2.15) 7080 Fork Neutral 5.27 (1.09) 4800 Erotic Couple Pleasant 6.44 (2.22) 4689 Erotic Couple Pleasant 6.90 (1.55) 1930 Shark Unpleasant 3.79 (1.92) 6510 Attack Unpleasant 2.46 (1.58) 4659 Erotic Couple Pleasant 6.87 (1.99) 1120 Snake Unpleasant 3.79 (1.93) 5530 Mushroom Neutral 5.38 (1.60) 4687 Erotic Couple Pleasant 6.87 (1.51) 6350 Attack Unpleasant 1.90 (1.29) 5520 Mushroom Neutral 5.33 (1.49) 1300 Pit Bull Unpleasant 3.55 (1.78) 7010 Basket Neutral 4.94 (1.07) 4658 Erotic Couple Pleasant 6.62 (1.94) 3530 Attack Unpleasant 1.80 (1.32) 4681 Erotic Couple Pleasant 6.69 (1.82) 5510 Mushroom Neutral 5.15 (1.43) 7030 Iron Neutral 4.69 (1.04) 6260 Aimed gun Unpleasant 2.44 (1.54) 4670 Erotic Couple Pleasant 6.99 (1.73)
* Note that these ratings are on a scale of 1= “complete unhappiness” to 9 = “complete happiness.”
71
Pleasant IAPS Image # 4660
Unpleasant IAPS Image # 6260
Neutral IAPS Image # 5500
Figure 11. Sample pleasant, unpleasant, and neutral IAPS images. 72
Affective Valence and Arousal Scales
Each time a participant viewed an image, regardless of whether or not they received electrical stimulation while looking at it, they rated both the affective valence and arousal level the image elicited. Both items were rated on a 1-9 scale. The anchors of the affective valence scale were: 1= complete unhappiness, 5= complete neutrality, and 9=complete happiness. The anchors of the arousal scale were: 1= complete calm, 5= complete neutrality, and 9= complete arousal.
Parental Blood Pressure History Screening
The biological parents of those who participated in the study were mailed the
Ohio Blood Pressure History Survey (Page & France, 2001). This survey (see Appendix
A) requests the following information from the parents: age, amount of time since their last blood pressure screening, typical blood pressure (if known), if a doctor has diagnosed them as hypertensive (if so, age at diagnosis, whether it was pregnancy-related, and if hypertension medication was prescribed were asked), if they have diabetes or kidney disease, if they have any other significant health problem (and if so, what), and whether their mother, father, sister(s), and/or brother(s) have hypertension. The Ohio Blood
Pressure History Survey has been shown to be a valid self-report measure of hypertension history, with an overall accuracy of 94.2%, a sensitivity of 95.4% and a specificity of
92.4% as compared to medical records (Page & France, 2001).
Procedure
Preparation
The entire procedure for this study took 90 minutes to complete (see Table 6).
73
Table 6. Timeline of Experimental Protocol
Time Task Pain Cardiovascular Affect (min) Measures Measures Measures 5 Review informed consent 5 Inclusion criteria questionnaire, obtain parental address(es) 5 Height and weight assessment 15- Electrode 20 attachment 5 Move to reclining chair, familiarization of pain rating scale, application of BP/HR cuff 10- NFR threshold NFR; pain 15 assessment ratings (0-100 scale) 10- Affective NFR; pain Valence and 15 modulation of ratings (0-100 arousal ratings (1- NFR/pain ratings scale) 9 scale) with IAPS images 15- Resting BP and HR Blood Pressure & 20 monitoring Heart Rate
74
Participants were asked not to use nicotine, caffeine or alcohol, or to exercise vigorously
for four hours prior to participation. Additionally, participants were instructed not to take
analgesic medication for 24 hours prior to participation in the study. After arriving in the
laboratory, participants were asked to provide informed consent to all procedures, and
they then completed a questionnaire to ensure all inclusion criteria were met. Participants
also provided the mailing address(es) of their biological parents so that the experimenters
could send their parents the Ohio Blood Pressure History Survey. Next, participants’
height and weight were measured. Participants then were prepped for electrode
placement, and electrodes were placed on the participants’ left leg as follows: a
stimulating bar electrode over the retromalleolar pathway of the sural behind the ankle,
an EMG electrode over the biceps femoris muscle 10 cm above the popliteal fossa, and
an EMG reference electrode over the literal epicondyle of the femur (see Figure 10).
After all the electrodes were applied, the participants moved to a reclining chair with
their knees at a 60-degree angle, and they were familiarized with the pain rating scale.
Phase 1: Assessment of NFR Threshold
The NFRs were elicited by electrically stimulating the sural nerve and measuring the resulting EMG activity in the biceps femoris muscle. A NFR was defined as a mean
EMG response in the 91-150 ms interval after the stimulus that exceeds the mean EMG
activity during the 60-ms before the stimulus is presented by at least 1.38 standard
deviations (see Figure 12). The 91-150-ms poststimulus interval is selected to avoid
possible contamination by the low-threshold cutaneous flexor reflex (RII), which is non-
nociceptive, the startle reflex, and/or any voluntary movements or startle reactions that
may begin as early as 150 ms post-stimulation (Dowman, 1991, 1992). 75
Time (in s)
Figure 12. An example NFR.
76
The NFR threshold for each participant was determined using the procedure described by
Rhudy and France (2007). Electrical stimulation of the sural nerve was repeated using an
interval of 8-12 seconds to avoid both habituation and predictability. During each
electrical stimulation, five rectangular wave pulses of 1-ms duration and 3-ms
interstimulus interval were administered. The trial started with 0 mA of stimulation and
increased by 4 mA steps until an NFR was elicited. The stimulus intensity then
decreased in 2 mA steps until the NFR disappeared. The up-down staircase method was
repeated twice more with 1 mA steps. Average stimulus intensity in mA of the last two
peaks and troughs was multiplied by 1.2 to determine the intensity of stimulation to be
used throughout the picture viewing. If a participant’s NFR threshold could not be
reliably elicited, they were given the option of either repeating the threshold-determining
procedure or ceasing participation in the study. Participants were prompted to give pain
ratings after each stimulation.
Phase 2: Presentation of Affective Stimuli
During Phase 2, participants were asked to focus on the computer monitor, and they were told that they would receive stimulation randomly both during and in between the display of the images. Participants were familiarized with the affective valence and arousal scales. Stimulation at 120% of the NFR threshold value determined in Phase 1 was delivered during the viewing of four out of the eight pictures of each affective valence and also during nine intertrial periods. Images were presented in a pre- determined randomized order developed with the condition that no more than two pictures of the same affective valence were permitted to be viewed consecutively (see
Table 7). All pictures were viewed for six seconds with the time between images ranging 77
from 12-22 s. Electrical stimulation was delivered 3-5 s after the picture onset and 11-21 s after intertrial period onset. After viewing each image, participants rated both the affective valence and arousal the picture elicited. Each time that electrical stimulation was presented during an image, the participants were asked to provide a pain rating after
providing the affective valence and arousal ratings.
Phase 3: Resting Blood Pressure Measurement
In the third phase of the study, all electrodes were removed from the participants,
and then a blood pressure cuff was applied over the upper left arm. Participants then were seated quietly for fifteen minutes as their resting blood pressure and pulse rate were monitored at three minute intervals (i.e., 0, 3, 6, 9, 12, 15 min). After the conclusion of
the blood pressure monitoring, the participants’ mean systolic blood pressure was
determined using the average of the last three readings.
Grouping of Participants
For a participant to be assigned to the positive parental history of hypertension
group, they must have at least one parent with a prior diagnosis of high blood pressure
that was treated with medication. If neither parent had been previously diagnosed with
hypertension, they were assigned to the negative parental history of hypertension group.
Participants were not included in the current research if either of their biological parents
reported a prior diagnosis of hypertension but no medication, or if they had a history of
renal disease or diabetes. The first exclusion was to limit the sample to clearly diagnosed
patients, and the second was to limit the positive parental history group to the children of
parents with essential hypertension.
78
Table 7. Order of IAPS Stimuli
Trial # IAPS Picture # Affective Stimulation Stimulation Valence during picture after picture 1 5500 Neutral No No 2 7040 Neutral Yes No 3 4660 Pleasant Yes No 4 1050 Unpleasant No No 5 7080 Neutral No Yes 6 4800 Pleasant No Yes 7 4689 Pleasant No No 8 1930 Unpleasant Yes Yes 9 6510 Unpleasant No No 10 4659 Pleasant No No 11 1120 Unpleasant Yes No 12 5530 Neutral No Yes 13 4687 Pleasant Yes Yes 14 6350 Unpleasant No Yes 15 5520 Neutral Yes No 16 1300 Unpleasant Yes No 17 7010 Neutral Yes No 18 4658 Pleasant Yes No 19 3530 Unpleasant No No 20 4681 Pleasant No No 21 5510 Neutral Yes Yes 22 7030 Neutral No No 23 6260 Unpleasant Yes Yes 24 4670 Pleasant Yes Yes
79
For a participant to be assigned to the elevated blood pressure group, they must have a resting systolic blood pressure (SBP) that was above the median for their gender.
Separate assignment within each gender was conducted, as men typically have higher average resting blood pressure levels then women; in the current study, the median systolic blood pressure for men was 111.2 mmHg, and the median for women was 102.0 mmHg.
Data Analysis and Reduction
Before conducting any statistical analyses, the data were examined for outliers, which were defined as scores falling two standard deviations or more from the mean.
Outliers were identified among the mean EMG responses elicited during unpleasant
(n=4), neutral (n=2), and pleasant (n=3) IAPS images; there were also outliers among mean affective valence ratings of neutral IAPS images both in the presence (n=3) and absence (n=5) of electrocutaneous stimulation. All analyses were conducted with and without the outliers. Because the significance of the results did not change as a function
of outlier exclusion, all data were included in the reported analyses.
The EMG values reported reflect the mean EMG activity during the 91-150 ms
period post-stimulation. Pain ratings refer to the actual pain ratings provided by
participants during electrocutaneous stimulation on a 0-100 scale. Valence and arousal
ratings refer to the actual participant ratings of the IAPS images on the respective 1-9
scales.
All analyses were conducted using SPSS version 15.0 software (SPSS, Inc.,
Chicago, IL). In all repeated measures ANOVAs, the Greenhouse-Geisser corrected 80
degrees of freedom were used to control for potential violations of sphericity. All
pairwise comparisons were least significant difference comparisons.
RESULTS
Characteristics of Participants
Although 200 undergraduates participated in the study, analyses are based on a
final sample of 117. This subsample excluded participants who did not complete the
protocol (n=22) or whose parental history of hypertension could not be confirmed (n=61).
Participant attrition is illustrated in Figure 13.
Mean ages, body mass indexes, systolic blood pressures, diastolic blood
pressures, and heart rates are displayed in Table 8 as a function of parental history of
hypertension and resting systolic blood pressure; the number of men and women in each
group is also reported. Participants had an overall mean age of 19.2 years (SD=1.3) and
an overall average body mass index (BMI) of 24.0 kg/m² (SD=3.5). The mean systolic blood pressure was 108.6 mmHg (SD=11.1), and the mean diastolic blood pressure was
60.1 mmHg (SD=7.1). The mean heart rate was 64.6 bpm (SD=10.3). The sample was predominantly non-Hispanic White (90.6%), 4.3% were non-Hispanic Black, 3.4% were
Asian or Pacific Islander, and 1.7% were identified as other.
To determine if hypertension risk status was associated with differences in demographic characteristics, separate 2 parental history of hypertension (positive or negative parental history of hypertension) x 2 median systolic blood pressure (above or below median systolic blood pressure) analyses of variance (ANOVA) were performed
on age, body mass index, systolic blood pressure, diastolic blood pressure, and heart rate.
There were no significant findings for age or heart rate. 81
Recruited for the study (n=200)
Excluded (n=22)
Rating of 100 during NFR threshold assessment (n=14)
Unable to determine NFR threshold (n=5)
Equipment problems (n=3)
Completed study protocol (n=178)
Excluded (n=43)
Parental Ohio Blood Pressure Surveys not returned
Parental Ohio Blood Pressure Surveys returned (n=135)
Excluded (n=18)
Parental history of hypertension
Final data set (n=117)
Positive parental history of
hypertension (n=46)
Negative parental history of hypertension (n=71)
Figure 13. Flowchart of participants’ attrition from the study. 82
Table 8. Mean (± SD) Age, Body Mass Index (BMI), Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Heart Rate, and Gender Composition as a Function of Parental Histories of Hypertension and Resting Systolic Blood Pressure
Positive Parental History Negative Parental History Below Above Below Above Median SBP Median SBP Median SBP Median SBP (n=21) (n=25) (n=39) (n=32) Mean Age (years) 19.3 (1.5) 19.2 (1.0) 18.9 (1.4) 19.3 (1.1)
Mean BMI (m/kg ²) 23.2 (3.2) 25.7 (3.7) 23.4 (3.3) 23.8 (3.5)
Mean SBP (mmHg) 101.0 (5.7) 118.0 (10.4) 101.0 (6.4) 115.5 (8.6)
Mean DBP (mmHg) 57.7 (5.4) 64.9 (7.7) 56.7 (5.9) 62.3 (6.4)
Mean Heart Rate (bpm) 62.7 (7.6) 62.0 (11.6) 66.0 (9.9) 66.1 (11.1)
Men 10 13 21 18
Women 11 12 18 14
83
For body mass index, a significant main effect for systolic blood pressure was
observed, F(1,113)=4.67, p<.05, ηp²=.04, indicating that those who were above the
median systolic blood pressure for their gender had significantly higher body mass
indexes (M = 24.7 kg/m²) than those who were below the median systolic blood pressure
of their gender (M = 23.3 kg/m²). Additionally, a main effect for the median split of
systolic blood pressure was observed for both systolic blood pressure [F(1,113)=110.60,
p<.001, ηp²=.50] and diastolic blood pressure [F(1,113)=27.94, p<.001, ηp²=.20].
Affective Modulation of Nociception and Pain
EMG Responses
To examine the first hypothesis that affective valence of IAPS images would
modulate nociceptive responses, with pleasant images blunting and unpleasant images
exacerbating nociception, a 3 valence (unpleasant, neutral, and pleasant affective valence
of IAPS images) repeated measures ANOVA was conducted on EMG response
magnitudes obtained while participants viewed IAPS images and received stimulation at
120% of their NFR threshold. In accordance with Hypothesis 1, there was evidence that
the affective valence of IAPS images modulated nociceptive responses, with a significant
difference observed across the affective valences of the IAPS images, F(1.65,
189.52)=18.55, p<.001, ηp²=.14 (see Figure 14). Least significant difference pairwise
comparisons were then conducted to determine how EMG response magnitudes varied as
a function of the affective valence of the IAPS images. EMG responses were
significantly lower when participants were stimulated during pleasant IAPS images relative to both neutral (p<.001) and unpleasant (p<.001) images. However, EMG responses did not differ during neutral images as compared to unpleasant images (p=.12). 84
7 V) μ
(in 6
5
4
3
2 Mean EMG Response Magnitudes EMG Mean 1
0 Unpleasant Neutral Pleasant
Affective Valence of IAPS Images
Figure 14. Mean (± S.E.M.) EMG response of the biceps femoris as a function of affective valence of IAPS images presented during electrocutaneous stimulation of the sural nerve.
85
Pain Ratings
To examine the hypothesis that affective valence of IAPS images would modulate pain perception, a 3 valence (unpleasant, neutral, and pleasant affective valence of IAPS images) repeated measures ANOVA was conducted on pain ratings. Results of the
ANOVA revealed that affective valence significantly influenced mean pain ratings,
F(1.95, 226.51)=49.58, p<.001, ηp²=.30 (see Figure 15), and least significant difference pairwise comparisons revealed that pain ratings were lower during pleasant images relative to both neutral (p<.001) and unpleasant (p<.001) images. Pain ratings were also lower during neutral images as compared to unpleasant images (p<.001).
Hypertension Risk and IAPS Modulation of Valence and Arousal
To determine if individuals with increased risk of developing hypertension show blunted affective responding to the IAPS images, separate 2 parental history of hypertension (positive or negative) x 2 SBP (above or below the median for one’s gender) x 2 gender (male or female) x 3 valence (unpleasant, neutral, or pleasant affective valence of IAPS images) x 2 stimulation (present or absent) repeated measures ANOVA were conducted on affective valence ratings and arousal ratings.
Valence Ratings
Table 9 summarizes the observed main effects and interactions of the ANOVA conducted on valence ratings, and Table 10 provides mean valence ratings. A main effect for stimulation indicated that participants rated images as more unpleasant when receiving electrocutaneous stimulation as compared to non-stimulation trials.
86
50
40
30
20 Mean Pain Ratings
10
0 Unpleasant Neutral Pleasant
Affective Valence of IAPS Images
Figure 15. Mean (± S.E.M.) pain ratings as a function of affective valence of IAPS images presented during electrocutaneous stimulation of the sural nerve
87
Table 9. Results of 2 Parental History of Hypertension (positive or negative) x 2 SBP (above or below the median for one’s gender) x 2 Gender (male or female) x 3 Valence (unpleasant, neutral, or pleasant affective valence of IAPS images) x 2 Stimulation (present or absent) repeated measures ANOVA for Affective Valence Ratings
Source F value p value ηp²
Parental History of Hypertension (PH) .48 .49 .00 SBP 1.53 .22 .01 Main Effects Gender 21.88 .001 .17 Valence 275.73 .001 .72 Stimulation 6.99 .01 .06
PH x SBP 1.61 .21 .01 PH x Gender .02 .89 .00 PH x Valence .17 .80 .00 PH x Stimulation .86 .36 .01 Two-Way SBP x Gender .01 .94 .00 Interactions SBP x Valence 3.23 .05 .03 SBP x Stimulation 1.69 .20 .01 Gender x Valence 7.09 .001 .06 Gender x Stimulation 2.65 .11 .02 Valence x Stimulation 10.95 .01 .09
PH x SBP x Gender .38 .54 .00 PH x SBP x Valence .79 .43 .01 PH x SBP x Stimulation .05 .83 .00 Three-Way PH x Gender x Valence .51 .57 .00 Interactions PH x Gender x Stimulation .17 .68 .00 PH x Valence x Stimulation 1.71 .18 .01 SBP x Gender X Valence .65 .50 .01 SBP x Gender x Stimulation 2.38 .13 .02 SBP x Valence x Stimulation .11 .89 .00 Gender x Valence x Stimulation .03 .97 .00
PH x SBP x Gender x Valence .45 .60 .00 Four-Way PH x SBP x Gender x Stimulation 1.61 .21 .01 Interactions PH x SBP x Valence x Stimulation .26 .76 .01 PH x Gender X Valence x Stimulation .01 .99 .00 SBP x Gender x Valence x Stimulation 2.20 .12 .02
Five-Way PH x SBP x Gender x Valence x .37 .68 .00 Interaction Stimulation
88
Table 10. Mean Affective Valence Ratings as a Function of IAPS Image Type, Presence or Absence of an Electrocutaneous Stimulation, Systolic Blood Pressure, and Gender
Male Participants
Below the Median SBP Above the Median SBP
Stimulation Non- Stimulation Non- Trials Stimulation Trials Stimulation Trials Trials
Valence Mean SD Mean SD Mean SD Mean SD Unpleasant 3.2 (1.1) 3.1 (1.1) 3.5 (1.1) 3.3 (1.1)
Neutral 4.7 (1.1) 4.9 (0.9) 4.6 (0.8) 5.0 (0.6)
Pleasant 6.2 (0.8) 6.3 (0.6) 6.3 (1.0) 6.2 (0.9)
Female Participants
Below the Median SBP Above the Median SBP
Stimulation Non- Stimulation Non- Trials Stimulation Trials Stimulation Trials Trials
Valence Mean SD Mean SD Mean SD Mean SD Unpleasant 2.1 (1.0) 2.0 (0.8) 2.6 (1.2) 2.8 (1.1)
Neutral 4.8 (1.3) 5.2 (0.9) 4.5 (0.9) 5.0 (0.6)
Pleasant 5.8 (1.5) 5.7 (1.5) 5.3 (1.4) 5.7 (1.3)
89
Finally, a significant main effect of gender indicated that, overall, males rated the images more positively than females did. Caution must be taken in interpreting the main effects just reported, as they were all involved in significant two-way interactions. The first was between SBP and valence.
Follow-up analyses revealed that the main effect of SBP was significant for negatively valenced images, F(1, 115)=5.17, p<.05, ηp²=.04. Least significant difference pairwise comparisons determined that those with lower SBP rated unpleasant images as more unpleasant (M=2.6) than those who had higher SBP (M=3.1), partially supporting the hypothesis that those at increased risk for hypertension would show blunted affective valence ratings. There was no main effect of SBP for neutral [F(1, 115)=.15, p>.05,
ηp²=.00] or pleasant images [F(1, 115)=.10, p>.05, ηp²=.00].
The second two-way interaction was between valence and gender. Follow-up analyses determined that men and women had significant differences in their ratings of both unpleasant [F(1, 115)=22.97, p<.001, ηp²=.17] and pleasant images [F(1,
115)=10.39, p<.01, ηp²=.08]. Specifically, women rated unpleasant images as more unpleasant than did men (M=2.4 and 3.3, respectively), and men rated the pleasant images as more pleasant than did women (M=6.3 and 5.6, respectively). Gender did not influence valence ratings of neutral images, F(1, 115)=.35, p>.05, ηp²=.00.
The third two-way interaction was between valence and stimulation. Follow-up analyses revealed that affective valence ratings did not differ as a function of electrocutaneous stimulation for unpleasant images [F(1.00, 116.00)=1.07, p>.05,
ηp²=.01] or pleasant images [F(1.00, 116.00)=0.41, p>.05, ηp²=.00], but participants rated 90 neutral images more positively when they were not stimulated (M=5.01) as compared to when they were stimulated (M=4.65), F(1.00, 116.00)=24.10, p<.001, ηp²=.17.
Arousal Ratings
A 2 parental history of hypertension (positive or negative) x 2 SBP (above or below the median for one’s gender) x 3 valence (unpleasant, neutral, or pleasant affective valence of IAPS images) x 2 stimulation (present or absent) repeated measures ANOVA was conducted on arousal ratings. Table 11 summarizes the observed main effects and interactions, and mean arousal ratings are provided in Table 12. There was a main effect of parental history of hypertension on arousal ratings. Contrary to the hypothesis, individuals with hypertensive parents reported higher arousal (M=4.89) while viewing
IAPS images as compared to those without a parental history of hypertension (M=4.42).
There were also significant main effects for valence and stimulation, though interpreting them requires caution as they are involved in higher-order interactions. For the valence main effect, least significant difference pairwise comparisons revealed that arousal ratings were higher for unpleasant images (M=5.8) than both pleasant (M=5.5) and neutral (M=2.6) images, and arousal ratings for pleasant images were higher than for neutral images. The stimulation main effect indicated that participants reported higher arousal ratings on stimulation trials (M=4.8) relative to non-stimulation trials (M=4.5).
Significant two-way interactions were observed between gender and valence and gender and stimulation. Although examination of the simple main effects failed to isolate the gender by valence interaction, as seen in Figure 16 pairwise comparisons revealed that women reported higher arousal ratings during unpleasant versus pleasant images
(p<.001) but men did not (p=.73). 91
Table 11. Results of 2 Parental History of Hypertension (positive or negative) x 2 SBP (above or below the median for one’s gender) x 2 Gender (male or female) x 3 Valence (unpleasant, neutral, or pleasant affective valence of IAPS images) x 2 Stimulation (present or absent) repeated measures ANOVA for Arousal Ratings
Source F value p value ηp²
Parental History of Hypertension (PH) 4.10 .05 .04 SBP 1.37 .25 .01 Main Effects Gender .45 .50 .00 Valence 264.46 .001 .71 Stimulation 30.90 .001 .22
PH x SBP .05 .82 .00 PH x Gender .19 .66 .00 PH x Valence .58 .53 .01 PH x Stimulation .04 .85 .00 Two-Way SBP x Gender .00 .95 .00 Interactions SBP x Valence 1.11 .32 .01 SBP x Stimulation .01 .94 .00 Gender x Valence 3.71 .04 .03 Gender x Stimulation 5.06 .03 .04 Valence x Stimulation 1.02 .36 .01
PH x SBP x Gender .36 .55 .00 PH x SBP x Valence 3.02 .06 .03 PH x SBP x Stimulation .42 .52 .00 Three-Way PH x Gender x Valence .51 .56 .01 Interactions PH x Gender x Stimulation 2.07 .15 .02 PH x Valence x Stimulation 1.11 .33 .01 SBP x Gender X Valence .07 .90 .00 SBP x Gender x Stimulation 1.65 .20 .01 SBP x Valence x Stimulation .74 .47 .01 Gender x Valence x Stimulation .53 .58 .01
PH x SBP x Gender x Valence .62 .51 .01 Four-Way PH x SBP x Gender x Stimulation .05 .83 .00 Interactions PH x SBP x Valence x Stimulation 1.94 .15 .02 PH x Gender X Valence x Stimulation .60 .54 .01 SBP x Gender x Valence x Stimulation .93 .39 .01
Five-Way PH x SBP x Gender x Valence x Stimulation 1.14 .32 .01 Interaction
92
Table 12. Mean Arousal Ratings as a Function Gender, Presence or Absence of an Electrocutaneous Stimulation, and Affective Valence of IAPS Image
Males
Stimulation Trials Non-Stimulation Trials
Valence Mean SD Mean SD Unpleasant 5.7 (1.8) 5.5 (1.8)
Neutral 2.5 (1.3) 2.3 (1.2)
Pleasant 5.7 (1.5) 5.4 (1.8)
Females
Stimulation Trials Non-Stimulation Trials
Valence Mean SD Mean SD Unpleasant 6.3 (1.5) 5.7 (1.6)
Neutral 3.1 (1.6) 2.5 (1.3)
Pleasant 5.5 (1.7) 5.1 (1.7)
93
Males Females 6
4
Mean Arousal Ratings Arousal Mean 2
0 Unpleasant Neutral Pleasant
Affective Valence of IAPS Images
Figure 16. Mean arousal ratings (± S.E.M.) as a function of affective valence of IAPS images and gender
Though follow-up analyses of the gender by stimulation interaction revealed 1) simple main effects of stimulation for both men and women and 2) no simple main effects of 94 gender within stimulation or non-stimulation trials, examination of Figure 17 reveals that women provided somewhat higher arousal ratings during stimulation trials than men did.
Hypertension Risk and IAPS Modulation of Nociception and Pain
To determine if differential risk for developing hypertension was associated with differential affective modulation of nociception and pain, a 2 parental history of hypertension (positive or negative) x 2 SBP (above or below the median) x 2 gender
(male or female) x 3 valence (unpleasant, neutral, and pleasant affective valence of IAPS images) repeated measures ANOVA was conducted separately on both EMG response magnitudes and pain ratings elicited while participants were electrocutaneously stimulated as they viewed IAPS images.
EMG Responses
Results of the ANOVA on EMG responses revealed a significant main effect for valence and a significant 3- way interaction among parental history of hypertension, gender, and valence (see Table 13 for F statistics and Table 14 for means and standard deviations). The main effect for valence replicated the results reported earlier: EMG responses during pleasant images were smaller than responses during unpleasant images.
Follow-up analyses of the three-way interaction revealed a significant interaction between valence and parental hypertension history for females [F(1.73, 91.56)=3.27, p<.05, ηp²=.06], but not for males [F(1.55, 91.55)=.93, p>.05, ηp²=.01]. 95
5.4
5.2 Males Females 5.0
4.8
4.6
Mean Arousal Ratings 4.4
4.2
4.0 Stimulation No Stimulation Presence or Absence of Electrocutaneous Stimulation
Figure 17. Mean arousal ratings (± S.E.M.) as a function of electrocutaneous stimulation (presence or absence) and gender 96
Table 13. Results of 2 Parental History of Hypertension (positive or negative) x 2 SBP (above or below the median for one’s gender) x 2 Gender (male or female) x 3 Valence (unpleasant, neutral, or pleasant affective valence of IAPS Images repeated measures ANOVA for EMG Responses
Source F value p value ηp²
Parental History of Hypertension .14 .71 .00 (PH) Main Effects SBP 3.39 .07 .03 Gender .55 .46 .01 Valence 17.23 .001 .14
PH x SBP .25 .62 .00 PH x Gender 3.61 .06 .03 Two-Way PH x Valence 1.39 .25 .01 Interactions SBP x Gender 1.76 .19 .02 SBP x Valence .38 .65 .00 Gender x Valence .96 .37 .01
PH x SBP x Gender .32 .57 .00 Three-Way PH x SBP x Valence .38 .64 .00 Interactions PH x Gender x Valence 3.30 .05 .03 SBP x Gender X Valence 2.06 .14 .02
Four-Way PH x SBP x Gender x Valence 1.13 .32 .01 Interaction
97
Table 14. Mean EMG Responses during Unpleasant, Neutral, and Pleasant IAPS Images as a function of Gender and Parental History of Hypertension
Males
Positive Parental History Negative Parental History
EMG (in μV) EMG (in μV)
Valence Mean SD Mean SD Unpleasant 4.01 (2.35) 6.14 (8.08)
Neutral 3.90 (2.64) 5.54 (5.60)
Pleasant 3.25 (1.74) 4.31 (4.71)
Females
Positive Parental History Negative Parental History
EMG (in μV) EMG (in μV)
Valence Mean SD Mean SD Unpleasant 7.18 (5.91) 4.86 (2.93)
Neutral 5.38 (3.98) 5.18 (3.13)
Pleasant 4.60 (4.58) 3.39 (1.93)
98
As shown in Figure 18, women with a parental history of hypertension had marginally larger EMG responses during unpleasant images as compared to women with a negative parental history of hypertension (p=.06); however, there were no parental history differences for either neutral or pleasant slides.
Since electrocutaneous stimulation intensity varied as a function of NFR threshold, with those having higher NFR thresholds receiving higher stimulation levels throughout the IAPS image viewing protocol, a 2 parental history of hypertension x 2
SBP x 2 gender x 3 valence repeated measures ANCOVA was conducted on EMG responses with NFR threshold as a covariate. The results were the same: a significant main effect for valence and a significant three-way interaction between parental history, gender, and valence.
Pain Ratings
The results of the 2 parental history of hypertension x 2 SBP x 2 gender x 3 valence repeated measures ANOVA conducted on pain ratings are summarized in Table
15. In addition to the main effects of valence and gender, there were significant two-way interactions between parental history of hypertension and SBP as well as parental history and gender. As seen in Figure 19, follow-up analyses of the parental history by SBP interaction revealed that SBP was not associated with pain differences for those without a parental hypertension history; however, for those with a parental history of hypertension, having an SBP above the median was associated with higher pain ratings than for those whose SBP was below the median (M=44.6 and 28.97, respectively, F(1, 44)= 4.51, p<.05, ηp²=.09). 99
10 Positive Parental History of Hypertension (females only) Negative Parental History of Hypertension (females only) 8
6
4 Mean EMG Responses EMG Mean
2
Unpleasant Neutral Pleasant Affective Valence of IAPS Images
Figure 18. Mean (± S.E.M.) EMG response magnitudes as a function of parental history of hypertension among female participants
100
Table 15. Results of 2 Parental History of Hypertension (positive or negative) x 2 SBP (above or below the median for one’s gender) x 2 Gender (male or female) x 3 Valence (unpleasant, neutral, or pleasant affective valence of IAPS Images repeated measures ANOVA for Pain Ratings
Source F value p value ηp²
Parental History of Hypertension (PH) 2.24 .14 .02 Main Effects SBP 1.95 .17 .02 Gender 25.18 .001 .19 Valence 44.48 .001 .29
PH x SBP 9.03 .01 .08 PH x Gender 5.04 .03 .04 Two-Way PH x Valence .67 .51 .01 Interactions SBP x Gender 1.85 .18 .02 SBP x Valence .52 .59 .01 Gender x Valence 2.10 .13 .02
PH x SBP x Gender .04 .85 .00 Three-Way PH x SBP x Valence .01 .99 .00 Interactions PH x Gender x Valence 1.07 .34 .01 SBP x Gender X Valence .09 .91 .00
Four-Way PH x SBP x Gender x Valence .23 .79 .00 Interaction
101
50
40
30
20 Mean Pain Ratings Positive Parental History of Hypertension 10 Negative Parental History of Hypertension
0 Below the Median SBP Above the Median SBP Systolic Blood Pressure
Figure 19. Mean (± S.E.M.) pain ratings as a function of parental history of hypertension and systolic blood pressure
102
Follow-up analysis of the parental history by gender interaction revealed that parental history of hypertension did not influence pain ratings for men, F(1, 60)= 0.39, p<.05, ηp²=.00, but for women parental history of hypertension was associated with higher pain ratings as compared to women without a parental history of hypertension
(M=51.2 and 36.4, respectively, F(1, 53)= 5.05, p<.05, ηp²=.09.
A 2 parental history of hypertension x 2 SBP x 2 gender x 3 valence repeated measures ANCOVA also was conducted on pain ratings with NFR threshold as a covariate, as those with higher NFR thresholds received more intense stimulations than those with lower thresholds. The results were unchanged.
NFR Threshold Assessment
NFR Threshold Magnitudes
The final hypotheses were that those at higher risk for hypertension would have
1) higher NFR thresholds and 2) lower pain ratings when stimulated at NFR threshold during NFR threshold assessment. These hypotheses were examined using 2 parental history of hypertension (positive or negative) x 2 systolic blood pressure (above or below the median for one’s gender) x 2 gender (male or female) between-group ANOVAs. The main effects and interactions for the NFR threshold analysis are shown in Table 16 and included a main effect of gender and a significant interaction between parental history of hypertension and SBP. The main effect of gender reflected higher NFR thresholds for women versus men (M=14.2 mA and 10.9 mA, respectively). As can be seen in Figure
20, the interaction between SBP and parental hypertension indicated that offspring of hypertensive parents had higher NFR thresholds than offspring of normotensive parents among those with above-average SBP, F(1,44)=5.82, p<.05, ηp²=.12. 103
Table 16. Results of 2 Parental History of Hypertension (positive or negative) x 2 SBP (above or below the median for one’s gender) x 2 Gender (male or female) ANOVA for NFR Thresholds
Source F value p value ηp²
Main Effects Parental History of Hypertension (PH) .46 .50 .00 SBP 3.80 .06 .03 Gender 7.44 .01 .06
Two-Way PH x SBP 4.52 .05 .04 Interactions PH x Gender 1.24 .27 .01 SBP x Gender 2.06 .16 .02
Three-Way PH x SBP x Gender 1.08 .30 .01 Interaction
104
Positive Parental History of Hypertension 20 Negative Parental History of Hypertension
15
10
5 Mean NFR Threshold (in mA) (in NFR Threshold Mean
0 Below the Median SBP Above the Median SBP Sytolic Blood Pressure
Figure 20. NFR threshold as a function of parental history of hypertension
and SBP
105
However, there was no significant effect of parental history among those with below- average SBP, F(1,69)=0.13, p>.05, ηp²=.00.
Pain Ratings during NFR Threshold Assessment
A 2 parental history of hypertension (positive or negative) x 2 systolic blood pressure (above or below the median for one’s gender) x 2 gender (male or female)
ANCOVA on pain ratings at NFR threshold was conducted using NFR threshold level as a covariate (as persons with higher NFR threshold received greater levels of stimulation during threshold assessment). No significant main effects or interactions were observed.
DISCUSSION
The current study examined nociceptive responses (defined by EMG activation) and pain ratings in response to electrocutaneous stimulation of the sural nerve while unpleasant, neutral, and pleasant IAPS images were viewed; additionally, valence and arousal ratings of the IAPS images were obtained. Consistent with the first hypothesis, we replicated previous findings that pleasant stimuli result in decreased nociception and pain whereas unpleasant stimuli result in increased nociception and pain (Rhudy et al.,
2005; Rhudy et al., 2006a; Rhudy et al., 2006b; Rhudy et al., 2008), as both pain ratings and EMG responses to electrocutaneous stimulation were lower during pleasant images versus unpleasant images. In contrast, the second hypothesis that risk for hypertension would be associated with blunted valence and arousal ratings of IAPS stimuli found little support; the only evidence for this hypothesis was that those with elevated SBP rated unpleasant images less negatively than those with lower SBP. Further, contrary to the third hypothesis, there was no evidence to support the notion of a differential affective modulation of nociception or pain as a function of risk of developing hypertension. 106
Finally, consistent with previous research (Page & France, 1997; France & Suchowiecki,
2001; France et al., 2002), there was some support for the hypothesis that those at increased risk of hypertension would have higher NFR thresholds. Specifically, those with both a parental history of hypertension and elevated SBP had the highest NFR thresholds. However, average pain rating at NFR threshold did not differ between the groups.
Affective Modulation of Pain
The replication of the affective modulation of pain is significant for several reasons. First, this was by far the largest test of the effect of affectively laden IAPS images on NFR responses undertaken to date; up until this point, the largest sample size used in this type of research was 50 (Rhudy et al., 2006a). By more than doubling the number of participants, the robustness of the finding that pleasant IAPS images decrease nociception and pain and unpleasant IAPS images increase nociception and pain is supported. Another important aspect of this replication is that we are the first researchers outside of Rhudy’s lab to find these results, further supporting the robust nature of the effects.
Rhudy et al. (2008) hypothesize that affective modulation of nociception and pain occurs via an interaction between valence and arousal of affective stimuli, with valence determining the direction of modulation and arousal determining the magnitude of the effect. The actual mechanism by which this interaction enacts its effects is likely to be descending inhibition or facilitation of nociception and pain by the brain, with the amygdala activating descending circuitry to either increase or decrease pain perception based on its processing of affective stimuli (Rhudy et al, 2005; 2006a). Evidence of 107 affective modulation of nociception and pain has important implications, including direct clinical relevance. For example, the robustness of this phenomenon supports the notion that current pharmacological interventions for patients with chronic or recurrent pain such as antidepressant medications may be effective, at least in part, via their direct effect on affective experience. Further, these findings confirm the potential benefit of cognitive and behavioral efforts that endeavor to help pain patients to reduce negative affective experiences and increase positive affective experiences. These findings also suggest that pleasant affective stimuli might be helpful in reducing more acute pain experiences, such as by viewing photos of loved ones while undergoing acute dental or medical procedures
(e.g., blood draws).
NFR Thresholds
The current finding that those with the highest risk for hypertension (i.e., those with both a parental history of hypertension and elevated SBP) had the highest NFR thresholds is supported by previous research (Page & France, 1997; France &
Suhowiecki, 2001; France et al., 2002). This result supports the link between increased hypertension risk and hypoalgesia, but only among those at the highest risk for hypertension. That is, these results indicate that neither positive parental history of hypertension nor elevated SBP alone were associated with hypoalgesia. However, given the low number of individuals with a positive parental history of hypertension in the current study, it is difficult to determine the full contribution of parental hypertension history to nociception and pain, which may partially explain the failure to replicate previous findings (Page & France, 1997; France & Suchowiecki, 2001; France et al.,
2002) that positive parental hypertension history is an independent predictor of increased 108
NFR thresholds. Another explanation for our inability to find a parental history of hypertension effect on NFR thresholds is that both false-positive and false-negative assignments to the parental hypertension history groups are likely to have occurred. As explained by France et al. (2005), false-positives are individuals with a positive parental history of hypertension who do not go on to develop high blood pressure; false-negatives are individuals identified as having a negative parental hypertension history, but their parents are either hypertensive and unaware of it or currently normotensive but go on to develop hypertension in the future. As it is impossible to know the false-positive and false-negative rates in a cross-sectional study involving parental history of hypertension, it is likely that some null effects are due to error in assigning participants to parental hypertension history groups. A final finding from the analyses of the NFR threshold data was that there were no differences in pain ratings of stimulations at NFR threshold level on the basis of hypertension risk.
Risk for Hypertension and Nociception, Pain, and Gender
Rather than showing decreased nociception and pain, women with a positive parental history of hypertension had larger EMG responses and pain ratings than women with a negative parental history of hypertension, and those with both elevated SBP and a positive parental history of hypertension had higher pain ratings than those with lower
SBP and a parental history of hypertension. In contrast, there were no differences in
EMG responses and pain ratings as a function of hypertension risk among men.
The research on nociception and pain in women at differential risk for hypertension has been mixed, with some research finding an association between risk for hypertension and hypoalgesia (France et al., 1994; D’Antono et al., 1999; France & 109
Suchowiecki, 2001; France et al., 2002; France et al., 2005) but other studies failing to do so. Of particular relevance to the current results, al’Absi et al. (1999) reported that women with a parental history of hypertension had higher pain ratings than women without a parental history during a cold pressor task. In a later study, al’Absi et al.
(2005) failed to find a difference in pain ratings or reflex thresholds of women with differential risk for hypertension when NFR was used as a nociceptive stimulus. al’Absi and colleagues suggest several explanations for the lack of hypoalgesia in women with a parental history of hypertension, such as hormonal fluctuations, decreased cardiovascular reactivity, or even a general decreased ability to modulate pain among women. However, in the current study, a potential contributor to greater nociceptive and pain responses among women with a positive parental history is that they had higher NFR thresholds
(M=15.9 mA) than women with a negative parental history (M=13.0 mA). Although this difference was not significant, F(1,53)=1.52, p=.23, ηp²=.03, it is nonetheless the case that women with hypertensive parents were stimulated at a higher intensity than women with normotensive parents. Indeed, when NFR threshold (which determined subsequent stimulation intensity) was included as a covariate in the ANOVA conducted on pain ratings during IAPS images, the effect of parental history of hypertension among women was no longer significant, F(1,52)=3.37, p=.07, ηp²=.06. Similarly, when NFR threshold was added as a covariate in the ANOVA conducted on women’s EMG responses, the difference in response magnitude as a function of parental history of hypertension was no longer significant, F(1,52)=1.29, p=.26, ηp²=.02. In sum, the apparently higher nociceptive and pain responses among women at risk for hypertension may be most 110 parsimoniously explained by differential stimulation intensities rather than endogenous differences in pain responsivity.
It is important to note that, regardless of parental history of hypertension, women had higher NFR thresholds than men. This finding is in contrast to prior reports wherein men generally have higher NFR thresholds than women (Page & France, 1997; France et al., 2002; France et al., 2005). In the present study, it is possible that women found the reflex testing procedure to be more stressful than men, resulting in higher levels of baseline muscle tension among women. Unfortunately, baseline muscle tension data was not captured during reflex testing. However, it was captured during the IAPS image viewing portion of the study, and the results of the ANOVA conducted on these baseline muscle tension data indicated that females (M=0.91 μV) had higher levels than males
(M=0.83 μV), F(1,115)=5.59, p<.05, ηp²=.05. In turn, elevated baseline muscle tension may contribute to higher NFR threshold levels as EMG activity during the 90-150 ms post-stimulus window must exceed baseline EMG activity by 1.38 SD in order for an
NFR to be identified. As a result, an elevated baseline level can make it more difficult to achieve an NFR response and in so doing can inflate NFR threshold levels.
Risk for Hypertension and Affective Modulation of Pain
As noted above, the main hypothesis that risk for hypertension would be associated with differential affective modulation of nociception and pain was not supported in the present study. It is clear that the failure to demonstrate a pain moderation effect is due, at least in part, to the fact that risk for hypertension was not associated with blunted affective ratings of IAPS stimuli in the current study. As a result, there was no opportunity for differential affective processing to influence the pain 111 experience. Although the finding that those with hypertension show affective blunting has been supported in the literature (Jorgenson et al. 1996; Pury et al., 2004), only one study to date has examined the relationship between risk of hypertension, as defined by parental history of hypertension and resting systolic blood pressure, and valence and arousal responses to IAPS stimuli. Wilkinson and France (2009) reported that those with a parental history of hypertension rated pleasant images as less pleasant and unpleasant images as less unpleasant than those with normotensive parents, and they also rated pleasant and unpleasant images as less arousing relative to those with a negative parental hypertension history. However, the IAPS images that were used in that study were different from those used in the current study. Wilkinson and France used a variety of image categories from the pleasant (erotic, children, nature images) and unpleasant
(mutilation, weapons, human and animal attack scenes) dimensions. Rhudy et al. (2008) reported that erotic pleasant images and unpleasant images depicting human and animal attack scenes are more arousing than other types of pleasant and unpleasant images respectively. Therefore, it is possible that the effects observed by Wilkinson and France are partially attributable to having images that elicit differential arousal levels grouped together. Nonetheless, regardless of the explanation for the observed differences between the studies, the results of the present research indicate that affective blunting was not a potential mechanism for the hypoalgesic NFR responses observed in those with a parental history of hypertension and high-normal resting blood pressure. Before this hypothesis is dismissed entirely, however, it would be advisable to replicate the current study using different affective stimuli. In the current study mean arousal ratings for unpleasant images (M=5.8) and pleasant images (M=5.4) were approximately one point above the 112 midpoint of the 1-9 scale. Rhudy et al. (2008) suggest that arousal intensity is related to magnitude of affective pain modulation, and therefore more arousing images may produce greater affective modulation of nociception and pain. Additionally, other forms of arousal manipulation, such as videos or recall of pleasant and unpleasant life events, may result in more intense affective pain modulation. However, it is possible that, among those with increased risk of developing hypertension, there is a limit to the amount of affective modulation of pain possible. That is, perhaps those with increased hypertension risk do show affective modulation of pain, but it may not increase with arousal level of stimuli as it does in those at lower risk for hypertension.
Limitations and Future Directions
There are a number of limitations that must be considered when interpreting the results of the current study. First, there were only approximately two-thirds as many individuals with hypertensive parents (n=46) as compared to normotensive parents
(n=71). The low number of individuals with a parental history of may provide a potential explanation for some of our non-significant results: low power. Our a priori power analyses indicated that a sample size of 116 would be required in order to have a power of .80 given our predicted medium effect size based on previous research. Though our actual sample size was 117, it was not evenly distributed between those with and without a parental history of hypertension. Therefore, it is possible that, with more participants having a positive parental history, more effects of parental hypertension would have been observed due to increased power. For example, the PH x SBP x Valence interaction for arousal ratings and the PH x Gender interaction for EMG responses both approached significance (both p=.06), and might have reached statistical significance with a larger 113 number of participants with a parental history of hypertension. Second, the relatively smaller size of the parental history of hypertension group is partially explained by another limitation of the study -- attrition. Although 200 people participated in this study, data from only 117 individuals were useable for analysis. Most of the attrition was due to problems with the parental blood pressure screening issues, including either the parental blood pressure history questionnaire was not returned (n=43) or parental hypertension history could not be determined based on the information provided on the survey (n=18).
It is likely that some of the 61 individuals who were not included in this analysis did indeed have a parental history of hypertension, but this could not be determined for the purposes of this study. Perhaps providing an incentive for parents to return the Ohio
Blood Pressure Survey, such as monetary payment, could enhance return rates. In addition, it might be helpful to try and administer the survey over the phone if parents do not return the original survey; unfortunately, this option was not available in the present study as we did not seek a priori IRB approval to contact parents in this manner
Additional limitations must be noted with regard to the study design. First, it is clear that the IAPS images were perceived differently across participants (e.g., in men versus women), and this may have contributed to a failure to show group differences in affective blunting. On the other hand, recently Rhudy et al. (2008) examined how different types of pleasant (erotic vs. food) and unpleasant (loss vs. attack) IAPS images modulated nociception and pain, and their results demonstrated that the largest effects were obtained with the exact images that we used. A separate methodological issue relates to the reliance on electrocutaneous stimulation as a nociceptive stimulus. This type of nociception is seldom experienced in daily life, making shock a somewhat 114 artificial pain stimulus and perhaps limiting generalizability to other forms of pain encountered in daily life. Indeed, electrocutaneous stimulation activates all types of nociceptors simultaneously, whereas more typically encountered noxious stimulations activate specific nociceptors. Heat is known to activate C-fiber mechano-heat nociceptors (CMH) and Type I and Type II A-fiber mechano-heat nociceptors
(AMH)(Raja et al., 1999). CMH are activated quickly, and are prone to both fatigue and sensitization. Type II AMH are responsible for the initial sharp pain accompanying heat, and Type I AMH activation is linked with the secondary burning sensation.
Mechanical/pressure also activate CMH and AMH, with A-fiber mechanically sensitive afferents (MSA) showing greater activation than C-fiber MSA and A-fiber mechanically insensitive afferents (MIAs), also known as high-threshold A-fibers, being the most accurate at distinguishing both size and intensity of stimulation. Cold is linked most strongly with the activation of A-delta nociceptors, though all A-fiber nociceptors fire when stimuli below 0°C are encountered. Perhaps most importantly, the physiological component of electrocutaneous stimulation differs from the physiology involved in myocardial ischemia, which many hypertensives experience silently. The pain associated with myocardial ischemia (i.e., angina pectoris) is associated with activation of A-delta and C-fibers (Wang et al., 2009). Given the differential physiological underpinnings of different types of nociception, it would be useful to attempt to replicate the current study with a range of nociceptive stimuli, such as mechanical stimuli, thermal heat stimulation, or cold pressor. A final issue is that resting blood pressure assessment occurred immediately after IAPS images and electrocutaneous stimulation, and therefore SBP,
DBP, and heart rate levels may have been elevated. To address this potential limitation, 115 we only used the last three SBP, DBP, and heart rate measurements to calculate means for each participant; nonetheless, it is possible that blood pressures and heart rates remained elevated throughout the 15 minute monitoring period, and this may be particularly true among those at greatest risk for hypertension (Steptoe & Marmot, 2005).
Accordingly, future studies should consider having separate testing sessions for nociceptive and resting blood pressure assessments.
Conclusions
The affective modulation of nociception and pain is a robust phenomenon, with pleasant stimuli decreasing the pain experience and unpleasant stimuli increasing it.
However, this effect does not appear to be moderated by risk for hypertension and therefore affective blunting was not supported as a potential explanation of hypoalgesia in those at increased risk for hypertension. Although methodological improvements and further testing are suggested before this hypothesis is fully discounted, other potential mechanisms of hypoalgesia in those at risk for hypertension should be explored with the ultimate goal of early identification and treatment of those who are most likely to go on to develop the disorder.
116
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APPENDIX A: OHIO BLOOD PRESSURE HISTORY SURVEY FORMS
FATHER’S FORM Because this study is concerned with the effects of a genetic history of hypertension (high blood pressure), this form should be completed by the biological father only.
1. What is your age? ______
2. How long has it been since you last had your blood pressure checked by your doctor?
___ 0 to 6 months ___ 6 to 12 months ___ 1 to 5 years ___ more than 5 years ___ never
3. If you know, what is your typical blood pressure now? ______systolic diastolic
4. Have you ever been told by a doctor that you had hypertension (high blood pressure)? Yes No Don't Know
If yes, how old were you when you received this diagnosis? ______
5. Has a doctor ever prescribed medication for you to treat hypertension (high blood pressure)? Yes No Don't Know
If yes, please list the medication(s): ______
6. Do you suffer from diabetes or kidney disease? Yes No Don't Know
If yes, please describe: ______
7. Do you suffer from any other significant health problems? Yes No Don't Know
If yes, please describe: ______
8. From the list below, please circle any of your biological relatives who were told by a doctor that they had hypertension (high blood pressure) before age 55:
Your Mother Your Father Your Sister(s) Your Brother(s)
131
MOTHER’S FORM Because this study is concerned with the effects of a genetic history of hypertension (high blood pressure), this form should be completed by the biological mother only.
1. What is your age? ______
2. How long has it been since you last had your blood pressure checked by your doctor?
___ 0 to 6 months ___ 6 to 12 month ___ 1 to 5 years ___ more than 5 years ___ never
3. If you know, what is your typical blood pressure now? ______systolic diastolic
4. Have you ever been told by a doctor that you had hypertension (high blood pressure)? Yes No Don't Know
If yes, how old were you when you received this diagnosis? ______If yes, was your high blood pressure related to pregnancy? ______
5. Has a doctor ever prescribed medication for you to treat hypertension (high blood pressure)? Yes No Don't Know
If yes, please list the medication(s):______
6. Do you suffer from diabetes or kidney disease? Yes No Don't Know
If yes, please describe: ______
7. Do you suffer from any other significant health problems? Yes No Don't Know
If yes, please describe: ______
8. From the list below, please circle any of your biological relatives who were told by a doctor that they had hypertension (high blood pressure) before age 55:
Your Mother Your Father Your Sister(s) Your Brother(s)