Thermal Psychophysics and Associated Brain Activation Patterns
Along a Continuum of Healthy Aging
Paul A. Beach , DO, PhD,* Ronald L. Cowan, MD, PhD,
Mary S. Dietrich, PhD,
Stephen P. Bruehl,
Sebastian W. Atalla,
and Todd B. Monroe, PhD, RN
*Department of Neurology, Emory University School of Medicine, Atlanta, Georgia;
Department of Psychiatry and Behavioral Sciences, Vanderbilt
University Medical Center, Nashville, Tennessee;
Biostatistics, School of Medicine and School of Nursing, Vanderbilt University, Nashville, Tennessee;
Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee; ¶Center of Healthy Aging, The Ohio State University
College of Nursing, Columbus, Ohio, USA
Correspondence to: Paul A. Beach, DO, PhD, Department of Neurology, Emory University School of Medicine, 12 Executive Park Drive NE,
Atlanta, GA 30329, USA. Tel: 404-778-3444; Fax: 404-778-5150; E-mail: firstname.lastname@example.org.
Funding sources: This work was supported by the following grants: National Institutes of Health/National Institute on Aging K23 AG046379-01A1.
National Center for Research Resources, UL1 RR024975-01 National Center for Advancing Translational Sciences, UL1 TR000445-06.
Conﬂicts of interest: The authors report no conﬂicts of interest pertaining to this work.
Objective. To examine psychophysical and brain activation patterns to innocuous and painful thermal stimulation
along a continuum of healthy older adults. Design. Single center, cross-sectional, within-subjects design. Methods.
Thermal perceptual psychophysics (warmth, mild, and moderate pain) were tested in 37 healthy older adults (65–
97 years, median ¼73 years). Percept thresholds (
C) and unpleasantness ratings (0–20 scale) were obtained and
then applied during functional magnetic resonance imaging scanning. General linear modeling assessed effects of
age on psychophysical results. Multiple linear regressions were used to test the main and interaction effects of brain
activation against age and psychophysical reports. Speciﬁcally, differential age effects were examined by comparing
percent-signal change slopes between those above/below age 73 (a median split). Results. Advancing age was asso-
ciated with greater thresholds for thermal perception (z¼2.09, P¼0.037), which was driven by age and warmth de-
tection correlation (r¼0.33, P¼0.048). Greater warmth detection thresholds were associated with reduced hippo-
campal activation in “older” vs “younger” individuals (>/<73 years; beta <0.40, P<0.01). Advancing age, in
general, was correlated with greater activation of the middle cingulate gyrus (beta >0.44, P<0.01) during mild pain.
Differential age effects were found for prefrontal activation during moderate pain. In “older” individuals, higher
moderate pain thresholds and greater degrees of moderate pain unpleasantness correlated with lesser prefrontal ac-
tivation (anterolateral prefrontal cortex and middle–frontal operculum; beta <–0.39, P<0.009); the opposite pattern
was found in “younger” individuals. Conclusions. Advancing age may lead to altered thermal sensation and (in some
circumstances) altered pain perception secondary to age-related changes in attention/novelty detection and cogni-
Key Words: Magnetic Resonance Imaging (MRI); Geriatric; Older Adults; Perception
Pain in aging is a growing problem, with painful condi-
tions increasingly prevalent in older populations [1–3].
Seventy percent of older adults have some level of pain,
and 38% have pain that interferes with daily living .
Untreated pain has significant effects on quality of life
(e.g., sleep disturbances, anxiety, depression, decreased
socialization) . Unfortunately, up to 60% of those in
the community and 80% of institutionalized older adults
experience untreated pain (reviewed in Herr and Garand
). Whether this high clinical pain prevalence in older
adults is related to age-related changes in central nervous
system pain processing pathways remains unclear. The
effects of aging on pain processing in the context of ex-
perimental evoked pain stimuli seem to be
C2019 American Academy of Pain Medicine.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License(http://creativecommons.org/licenses/by-nc/4.0/),
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Pain Medicine, 0(0), 2019, 1–14
Original Research Article
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psychophysically (e.g., threshold, suprathreshold, toler-
ance) and modality (e.g., pressure, thermal, electrical) de-
pendent . However, a recent meta-analysis concluded
that the best evidence for altered pain perception with ag-
ing relates to increased thresholds for low-level pain in
the setting of thermal modalities . Focused examina-
tion of associated neural correlates of altered pain proc-
essing in aging has been minimally explored and merits
Dampening of somatosensation and low-level pain
thresholds has been proposed to signify a kind of
“presbyalgos,” akin to visual (“presbyopia”) and audi-
tory (“presbycusis”) deficits associated with older age
. Although many of the changes leading to dampen-
ing of other sensations have a predominantly periph-
eral pathophysiology [10,11], this does not appear to
be the case for altered pain in aging. Indeed, although
older age is associated with reduced thinly myelinated
Adfiber activity, there is no parallel reduction in un-
myelinated C-fibers, the nociceptive fibers underlying
thermal evoked pain responses and most clinical
chronic pain conditions [12–16]. It is thus likely that
central processes are involved in age-related changes of
thermal pain perception. A supraspinal etiology in par-
ticular seems feasible given findings of reduced cold
pressor modulation of heat pain in older adults, sug-
gesting reduced endogenous pain modulation as age
increases [17,18]. The latter could suggest a deficit in
frontal, top-down pain modulation. However, placebo
analgesia, which is thought to be mediated by frontal
mechanisms, appears to remain intact in comparisons
of young and old individuals [19,20].
Pain is conceptualized as a multidimensional phenom-
enon consisting of an unpleasant sensory (intensity) and
affective (unpleasantness) experience that may or may
not be associated with actual tissue damage [21,22].
Although many brain regions appear to work in concert
to facilitate the neural signature of pain , the pain lit-
erature frequently refers to a core set of pathways and
regions collectively deemed the “pain matrix.” The lat-
eral pathway is associated with perceiving the location,
intensity, and quality of pain; it includes the primary (S1)
and secondary somatosensory (S2) cortices and posterior
insular cortex (pINS) [24–26]. The medial pathway,
which includes anterior insula (aINS), anterior/mid cin-
gulate cortex (A/MCC), and lateral prefrontal cortices
(PFC), is associated with pain-related affect and motiva-
tion [27–29]. The prefrontal components of the medial
pathway in particular are active in the cognitive–evalua-
tive aspects of pain [30–32], leading to top-down pain
modulation [33,34]. Pain-related affective states, such as
anxiety, and novelty detection, are mediated via limbic
activity in the amygdala (AMY) and hippocampus
Experimental work examining neural correlates of al-
tered pain processing in aging has implicated age-related
structural changes in multiple central pain processing
regions [38,39]; these include generalized atrophy
[19,40,41] and more focal volume loss of the insula 
and somatosensory regions . Data on pain-relevant,
age-related functional changes are more limited. A pilot
study by Quinton and colleagues  found that, in com-
parison with young adults, older adults demonstrate re-
duced activation to thermal pain in the aINS, S1, and
supplementary motor regions. A more recent thermal
pain study  found that decreased pain intensity and
“sharpness” in older subjects was associated with re-
duced activation in the contralateral mid-INS and S1.
These two studies’ results argue for a decrement of lat-
eral/sensory pain-related function with increased age and
provide a logical correlate for psychophysical results sug-
gesting reduced somatosensation and low-level pain in-
tensity. However, it is unclear how to reconcile
behavioral findings of reduced pain processing with in-
creased age with some studies indicating increased pain
unpleasantness with advancing age. For example, Cole
and colleagues , using mechanical stimuli, found that
more intensely rated pressure pain in older subjects was
associated with reduced activation of the contralateral
striatum; they posited that these results reflected age-
induced impairment of striatum-mediated pain modula-
tion. It thus remains possible that multiple supraspinal
mechanisms may also be involved in altered pain process-
ing in the elderly.
Age-associated alterations in the structure and func-
tion of various pain systems may lead to reduced ability
to manage pain effectively, perhaps by reduced percep-
tion of early, less intense, nociceptive signals that limit
early intervention. For example, if one is less sensitive to
lower levels of a noxious stimulus, then one is less likely
to seek care for painful conditions associated with pro-
gressive tissue damage (e.g., osteoarthritis) or conditions
in which ongoing activity may potentially further damage
tissue (e.g., after injury). In concert with possibly reduced
integrity of pain modulation, these changes could lead to
increased pain-related disability and suffering. Given the
paucity of combined psychophysical and neuroimaging
studies, drawing definitive conclusions about pain in ag-
ing is not yet possible. The primary aim of this study was
to examine thermal pain psychophysics and associated
functional magnetic resonance imaging (fMRI) brain ac-
tivation patterns along a continuum of healthy, pain-free
older adults (age range ¼65–97 years). We hypothesized
that the aging process leads to increased thermal pain
thresholds through reduced overall pain matrix activa-
tion, namely in sensory structures. Our first prediction
(psychophysics) was that increasing age would be associ-
ated with decreased pain sensitivity (increased thermal
thresholds) but no changes in reports of pain unpleasant-
ness. Our second prediction (fMRI) was that increasing
age would be associated with reduced activation patterns
primarily in sensory pain structures (e.g., S1, S2, and
pINS). However, given some prior findings of reduced
pain tolerance and impaired pain modulation in older
2Thermal Psychophysics and fMRI in Aging
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individuals, we posited that altered activation in addi-
tional medial/pain modulatory regions may also be seen.
The current study was a single-center cross-sectional in-
vestigation of only healthy aged subjects participating in
multiple prior studies; detailed recruitment, psychophysi-
cal, and fMRI methodology may be found elsewhere
[47–49]. The Vanderbilt University Institutional Review
Board approved all experimental procedures, and each
participant provided written informed consent before en-
rollment. We implemented the STROBE guidelines for
reporting cross-sectional data. As specific methodological
details are published elsewhere, a brief summary is pro-
The 37 subjects included in this study resided in metro-
politan Nashville, Tennessee. General study inclusion cri-
teria were age >64 years and generally healthy status.
Exclusion criteria were claustrophobia, inability to pass
MRI screening, chronic pain or daily use of analgesic
medications, or cognitive impairment (Mini-Mental State
Exam [MMSE] score 27). Extended exclusion criteria
included history of stroke, cancer, neuropathy,
Raynaud’s disease, diabetes, or current major depression.
These criteria resulted in a healthy sample of older
adults. As experimental pain thresholds have been shown
to be associated with hormone replacement therapy
(HRT) , we collected HRT status in females.
All participants were instructed to avoid caffeine for at
least four hours before scanning and to not use any pain
medication (opioid or nonopioid) for at least 24 hours
before all data collection procedures. Participants were
reimbursed $100.00 (USD) for their time. Data collection
occurred over two days. Day 1 procedures took place at
the subject’s residence and included screening and enroll-
ment procedures including review of current medica-
tions, assessment of socioeconomic status (SES) using the
Hollingshead four-factor socioeconomic status test ,
MRI safety clearance, and cognitive screening using the
MMSE . Day 2 procedures were conducted at the
Vanderbilt University School of Nursing and Vanderbilt
University Institute of Imaging Science; they consisted of
administering various assessment scales, psychophysical
testing, and functional neuroimaging. MRI safety screen-
ing was confirmed before multiple other assessments in-
cluding the Brief Pain Inventory Short-Form (BPI-SF)
, Geriatric Depression Scale Short-Form (GDS-SF)
, and Spielberger State-Trait Anxiety Inventory
(STAI) . Subjects then participated in psychophysical
and MRI procedures.
Thermal Stimulation Protocol (Psychophysics)
In an experiment room adjacent to the scanner, pain psy-
chophysics were assessed using the Medoc Pathway Pain
and Sensory Evaluation System . The Medoc ther-
mode (3030 cm) was attached to the palm of the right
hand and programmed to deliver heat increasing at a rate
of 1C/second for each of the individually defined per-
cepts (warmth, mild pain, moderate pain). The baseline
temperature was set at 30C, which was previously iden-
tified as a neutral temperature . Participants were
asked to stop the heat stimulus by clicking a mouse but-
ton when the perception of warmth, mild pain, and mod-
erate pain occurred. Immediately after threshold
detection, participants were asked to rate the unpleasant-
ness associated with each percept using a 0–20 unpleas-
antness scale (0 ¼neutral, 20 ¼extremely intolerable)
. Each trial was completed three times, with average
temperature and unpleasantness ratings subsequently
After basic psychophysical testing, the Medoc was pro-
grammed with each individual’s average temperature
eliciting percepts of warmth, mild pain, and moderate
pain. Using a standard block design, participants com-
pleted four functional runs consisting of six thermal stim-
ulation periods (two at each intensity, duration
16 seconds per stimulus, ramp rate 8C/sec), followed by
a 24-second baseline with no stimuli. During each func-
tional run, lights remained on and participants were
instructed to stay awake with eyes open.
Brain Imaging Acquisition: Structural and
Imaging was performed with a Philips 3T Achieva MRI
scanner (Philips Healthcare Inc., Best, the Netherlands).
Briefly, a standard whole-brain 3D anatomical T1-
weighted/TFE (with SENSE coil) scan was acquired for
alignment and display of fMRI activation maps. In each
264-second-duration functional run, 28-field echo EPI
scans were acquired (132 dynamics, 4.40-mm slice thick-
ness with 0.45-mm gap, two seconds of TR, 35-ms TE,
79flip angle, FOV ¼240, matrix ¼128128).
Slice timing correction and motion correction were con-
ducted using standard SPM8 approaches. Intrascan fMRI
volumes were co-registered using standard rigid body
registration in SPM8. Using the first image volume from
each scan, volumes were co-registered to structural T1-
weighted volumes. Images were spatially smoothed with
an 8-mm full-width half-maximum (FWHM) Gaussian
kernel. Structural data were registered to Montreal
Neuroimaging (MNI) space, and the resulting transfor-
mation matrix was applied to the fMRI data.
Beach et al. 3
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Analysis of Head Motion
To address the potential confound of head motion during
pain delivery and throughout scanning procedures, the
robust weighted least squares approach  was used to
motion-correct during standard preprocessing with
SPM8. Outliers were defined as any subject with mean
motion >1 mm across the x, y, z, pitch, roll, yaw
General and Psychophysical Analyses
Demographic standardized measure scores and all key
study variables were summarized using median and 25th
to 75th percentile interquartile ranges (IQRs; continuous
data) and numbers (percentages; categorical data).
Continuous data were transformed as necessary to meet
statistical assumptions of modeling approaches used in
the analyses and to generate appropriately centered inter-
action variables. General linear modeling that adjusted
the standard errors for the clustered (repeated) nature of
the data was used to assess the main and interaction
effects of age and thermal percept level (warmth, mild,
and moderate pain) on psychophysical data (temperature
thresholds and unpleasantness). Unless otherwise noted,
an unadjusted P<0.05 was used for determining statisti-
cal significance. STATA, version 14, and SPSS, version
24, were used for these analyses.
fMRI Activation, Head Motion, Multiple
Whole-brain fMRI activation at the single-subject level
was modeled as the contrast of warmth >baseline, mild
pain >baseline, moderate pain >baseline. As each sub-
ject’s individual temperatures were used in the collection
of fMRI data, ramp upward and ramp downward times
were controlled in the general linear model (GLM) as
covariates of no interest. These resulting subject-specific
contrast maps were used in higher-level analyses for
within-group analysis in SPM8 to compare warmth and
pain (mild and moderate) with baseline. These analyses
generated an activation map of T-statistics that were
used to identify brain regions indicating statistically sig-
nificant activation. Analysis of head motion found that
no subjects exceeded the predetermined movement >1-
mm artifact criterion. Before group analysis, differences
in brain volume were controlled using a standardized re-
sidual of total gray matter volume to total intracranial
volume, calculated from the T1 images (in the same space
as the BOLD images). This residual was used a control
variable in the group-level analysis. To account for
voxelwise-multiple comparisons, statistical thresholds for
these higher-level analyses were corrected using the in-
trinsic smoothness of the data  and Monte Carlo sim-
ulations in 3dClustSim (http://afni.nimh.nih.gov/pub/
dist/doc/program_help/3dClustSim.html) at 10,000 itera-
tions to produce family-wise error-corrected data
(P0.05) based on whole-brain analysis with a cluster
size of 2,568 voxels for significance. After generating
whole-brain statistically significant clusters for each con-
trast using Marsbar , 5-mm spherical Region of
Interest (ROI)s were created around the peak MNI coor-
dinates in each cluster. Next, the average percent signal
change (PSC) was extracted to test for the association of
brain signal changes and psychophysical measures and
those clusters demonstrating significant associations with
age, psychophysics, or an age*psychophysics interaction
based on comparing “young” old individuals (<73 years)
with “older” old individuals (>73). Multiple linear
regressions were used to test the main and interaction
effects of age and psychophysical reports on brain activa-
tion data from each of the specific ROI contrasts.
Interaction effects were illustrated by displaying fit lines
for the upper and lower portions of the age distributions
(above and below the centered value, 73 years). These
results were then subjected to Bonferroni correction for
multiple comparisons based on the number of unique
regressions per region (five total: age, sensory threshold,
affective rating, age*temperature interaction, and age-
*affect interaction) for a final significance threshold of
P0.01. Primary findings of interest in this analysis per-
tained to answering the following question: What
changes in brain function underlie differences in psycho-
physical responses seen with aging?
The median age of the sample (N ¼37) was 68.0 years
(min ¼65, max ¼97), with similar proportions of
females and males (51.4% and 48.6%, respectively).
Most had at least a high school education (N ¼34,
92%), and many (N ¼14, 38%) had an advanced degree.
The sample had normative MMSE scores (IQR ¼29–30,
min ¼27), and most were not experiencing any pain at
the time of the fMRI acquisition (Table 1). State anxiety
and depression-related scores were minimal.
Summaries of the temperature at which warmth, mild
pain, and moderate pain thresholds were reported are
shown in Table 2, as are the unpleasantness ratings at
each respective percept level. Statistically significant
increases in both temperature intensity and unpleasant-
ness were reported at each of the increasing threshold lev-
A statistically significant interaction effect of age on
thermal percept threshold was found (z ¼2.09,
P¼0.037). As shown in Table 2, increasing age was sig-
nificantly correlated with an increase in temperature
threshold (i.e., decreased sensitivity) for the perception of
warmth (r¼0.33, P¼0.048). Age was not significantly
associated with sensation at the other thresholds or with
4Thermal Psychophysics and fMRI in Aging
reports of unpleasantness of the sensation at any thresh-
old (r 60.22).
Results from the one-sample T-test maps showing brain
regions activated during each level of thermal stimulation—
warmth >baseline, mild pain >baseline, and moderate
pain >baseline—are shown in Figure 1. Results reflect a
GLM with age included as a covariate of interest in order
to examine how increasing age was associated with activa-
tion patters across each thermal contrast. Significant clus-
ters labeled in Figure 1 (P<0.05) are further visualized in
the Supplementary Data. These were subjected to further
analyses examining the association between, activation,
age, and psychophysical responses (discussed below).
Age, Psychophysics, and fMRI
Table 3 displays summaries of the significant associations
between psychophysical reports with peak cluster PSC
that met Bonferroni correction for multiple comparisons
(P0.01). In Table 3, PSC across significant clusters were
placed in two separate GLMs with regressors including
subject age, psychophysical response (sensory perceptual
thresholds or affective ratings), and age*psychophysical
response. Each column thus represents the effect of an in-
dividual covariate of interest (e.g., age) on activation, ad-
justed for the effect of the other variables in the model
(e.g., percept threshold temperature). An age*psychophy-
sics interaction effect was indicative of a scenario in which
the correlation of a psychophysical response (i.e., percept
threshold temperature or affect) with thermal activation
significantly differed based on the age of the respondent.
In our study, participant age was mean-centered at
73 years. Therefore, an interaction effect indicated a statis-
tically significant difference for the correlation between
psychophysical responses with PSC for participants below
vs above 73years. Peak regions in Table 3 are organized
by the main effect of age on activation, as seen in Figure 1.
Significant effects were considered based on a Bonferroni-
corrected threshold of P0.01 (arrived at via the total
number of unique response effects tested, five total).
Warmth >Baseline Contrast
Warmth-induced activation in the HIPPO was negatively
associated with age (T ¼–3.54) (Figure 1) and remained
so after adjustment for effects of affective warmth ratings
but not sensory percept thresholds (affective: beta ¼
–0.44, P¼0.008; sensory: beta¼–0.37, P¼0.018).
There was a significant interaction effect of age*temp for
warmth detection threshold (beta ¼–0.40, P¼0.01).
Figure 2 illustrates this interaction effect: Specifically in
“older” subjects (73 years), as temperature thresholds
eliciting a sensation of warmth increased, there was a
Table 1. Demographic and clinical summaries (N ¼37)
Demographics Median [IQR] or No. (%)
Age 68.0 [66–81]
Caucasian 32 (86.5)
African American 4 (10.8)
Asian 1 (2.7)
Female 19 (51.4)
Male 18 (48.6)
Married 22 (59.5)
Not married 15 (40.5)
Marital occupational status
One spouse gainfully employed 21 (56.8)
Both spouses gainfully employed 16 (43.2)
Level of school completed (N ¼36)
<High school 3 (8.3)
High school graduate 2 (5.6)
Technical/some college 7 (19.4)
College graduate 10 (27.8)
Advanced degree 14 (37.9)
BMI 25.6 [23–29]
Total SES score* 58.0 [44–65]
BPI-SF average pain
BPI-SF pain right now
STAI state score
STAI trait score
BMI ¼body mass index; BPI-SF ¼Brief Pain Inventory Short-Form; IQR
¼interquartile range; MMSE ¼Mini-Mental State Examination; SES ¼
socioeconomic status; STAI ¼State or Trait Anxiety Inventory.
*Hollingshead Four-Factor Measure of Socioeconomic Status (range ¼8–
66; 8 ¼lowest SES, 66 ¼highest SES). This scale takes into account prior em-
ployment status of retired persons.
MMSE-Folstein Mini-Mental State Examination (range ¼0–30;
0¼completely cognitively impaired, 30 ¼completely cognitively intact).
BPI-SF-Brief Pain Inventory Short Form (range ¼0–10; 0 ¼no pain,
10 ¼most pain);ˆMax value was 3.
GDS-SF-Geriatric Depression Scale Short Form (range ¼0–15; 0 ¼no in-
dication of depress ion, 15 ¼high possibility of depression).
STAI-Spielberger State or Trait Anxiety Inventory (range ¼20–80;
20 ¼indicates increased anxiety, 80 ¼indicates least amount of anxiety).
Table 2. Summary of psychophysical results for sensory
thresholds and affective ratings (N ¼37)
Variables Min Max Median IQR r(Age)
Warmth 31 38 32.0 32–34 0.33*
Mild pain 33 47 36.0 34–39 0.12
Moderate pain 34 48 40.0 38–45 –0.06
Unpleasantness (0–20 scale)
Warmth 0 6 0.0 0–2 –0.06
Mild pain 0 16 3.0 0–5 –0.16
Moderate pain 0 19 6.0 5–9 –0.22
Sensory threshold (C) ¼temperature in which the percept variable was
obtained. Unpleasantness determined via 0–20 rating scale for each percept
(0 ¼neural, 20 ¼extremely intolerable). Statistically signiﬁcant increases in
both sensory and affective thresholds were reported at each of the increasing
threshold levels (P<0.001). A statistically signiﬁcant age*threshold interac-
tion effect was found for sensory thresholds (z¼2.09, P¼0.037) but not for
affective ratings (z¼1.70, P¼0.089).
IQR ¼interquartile range.
*Statistically signiﬁcant correlation between age and warmth detection
Beach et al. 5
Figure 1. Regression results examining the association of age with brain activation during thermal stimulation (N ¼37, df ¼30).
Signiﬁcant clusters were deﬁned as those having a voxel level of P<0.05, cluster volume of 2,568 voxels, familywise error cor-
rected (FWE) P<0.05. The upper and middle sections of the ﬁgure display brain activation (positive association with age) and deac-
tivation (negative association with age) to the contrasts of [warmth baseline] and [mild pain baseline], respectively. The bottom
portion of the ﬁgure displays deactivation only to the contrast of [moderate pain baseline]. Numbers next to the ﬁrst image in each
row indicate slice position relative to the AC/PC midline. Axial spacing ¼4 mm. The color bar represents the T-score intensity for
6Thermal Psychophysics and fMRI in Aging
corresponding decrease in activation in the HIPPO (beta
¼–0.60, P¼0.041). This effect was not borne out in
younger subjects (beta ¼0.22, P¼0.298).
Mild Pain >Baseline Contrast
Increasing age was associated with greater left MCC acti-
vation during the perception of mild thermal pain
(T ¼5.0) (Figure 1). This effect of age on MCC activation
during mild pain remained after adjusting the perception
of mild pain sensory threshold and affective ratings (sen-
sory: beta ¼0.44, P¼0.006; affective: beta ¼0.48,
Moderate Pain >Baseline Contrast
Moderate pain–induced activation of two anterolateral
prefrontal cortex (alPFC) clusters in BA 10 (cluster 1
and 2) decreased as a function of age (T ¼–3.43 and
3.27) (Figure 1 bottom). This relationship persisted
with adjustment for sensory percept thresholds and af-
fective ratings for cluster 1 (sensory: beta ¼–0.39,
P¼0.007; affective: beta –0.51, P¼0.001), whereas
cluster 2 showed this pattern only for affective ratings
correction (beta ¼–0.45, P¼0.004). There were also
significant interaction effects for each cluster with re-
spect to age*sensory percept of moderate pain for cluster
1 (age*sensory: beta ¼–0.44, P¼0.002). Cluster 2
Table 3. Thermal brain activations (percent signal change) with signiﬁcant age and psychophysical response effects
[X, Y, Z] T Sensory Threshold Affect Rating
(L) HIPPO –32, –30, –14 3.54 –0.37 (0.018) –0.11 (0.454) –0.40 (0.010) –0.44 (0.008) –0.03 (0.827) –0.13 (0.416)
(L) MCC (BA 24) –9, –12, þ34 5.00 0.44 (0.006) –0.18 (0.203) 0.29 (0.060) 0.48 (0.003) –0.21 (0.155) 0.05 (0.752)
(R) alPFC (BA 10) –
þ30, þ42, þ12 3.43 –0.39 (0.007) 0.12 (0.394) –0.44 (0.002) –0.51 (0.001) –0.01 (0.939) –0.37 (0.013)
(R) alPFC (BA 10) –
þ32, þ46, þ22 3.27 –0.31 (0.035) 0.23 (0.113) –0.41 (0.006) –0.45 (0.004) –0.03 (0.849) –0.43 (0.005)
(R) mFO (BA 44) þ60, þ10, þ4 3.19 –0.12 (0.395) 0.17 (0.213) –0.58 (<0.001) –0.28 (0.083) –0.03 (0.843) –0.43 (0.009)
Sensory threshold refers to temperature (temp, C) in which the percept variable (warmth, mild and moderate pain) was obtained. Affect rating refers to percept
unpleasantness as rated by a 0–20 scale. Bold indicates meeting Bonferroni correction for multiple comparisons (P0.01).
alPFC ¼anterolateral prefrontal cortex; BA ¼Brodmann Area; HIPPO ¼hippocampus; L ¼left; MCC ¼middle cingulate cortex; MNI ¼Montreal
Neurologic Institute; mFO ¼middle frontal operculum; R ¼right; T ¼T-statistic.
Figure 2. Qualitative view of signiﬁcant interaction effect between age*temperature of warmth detection for warmth-associated
hippocampal (HIPPO) activation. This interaction was driven by individuals >73 years of age (red line), who showed a signiﬁcant
tendency for reduced activation with higher warmth detection thresholds. The opposite pattern tended to occur in those <73 years
Beach et al. 7
additionally had interaction effects for age*sensory per-
cept and age*affective ratings of moderate pain
(age*sensory: beta ¼–0.41, P¼0.006;age*affective rat-
ings: beta ¼–0.43, P¼0.005). The significant interaction
effect for the sensory domain at alPFC cluster 1 was
driven by “younger” old subjects (<73 years old:
age*sensory beta ¼0.50, P¼0.013; >73 years old:
age*sensory beta ¼–0.36, P¼0.227) (Figure 3). In con-
trast to “older” subjects, “younger” individuals showed
increased activation associated with the perception of
moderate pain sensory thresholds. “Older” subjects addi-
tionally drove interactions for cluster 2 (sensory inter-
action: <73 years old: age*sensory beta ¼0.60,
P¼0.002; >73 years old: age*sensory beta ¼–0.24,
P¼0.427; affective interaction: <73 years old: age-
*affective rating beta ¼0.39, P¼0.058; >73 years old:
age*affective rating beta ¼–0.48, P¼0.096).
Moderate pain–induced right middle frontal opercu-
lum (mFO, BA 44) activation was also reduced with in-
creasing age (T ¼–3.19) (Figure 1 bottom). Here, while
adjustments for psychophysical responses led to loss of
main effects of age, there were significant interaction
effects for age*sensory percept threshold (beta ¼–0.58,
P<0.001) and age*affective ratings of moderate pain
(beta ¼–0.43, P<0.009). Although the age*sensory in-
teraction effect was driven primarily by increased activa-
tion in “younger” old (<73 years) subjects (beta ¼0.55,
P¼0.005) (Figure 4A), the age*affective rating interac-
tion was seemingly driven by general slope differences be-
tween “younger” and “older” individuals (P>0.05 for
both groups) (Figure 4B).
The increasing prevalence of older individuals makes an
understanding of age-associated changes in pain percep-
tion crucial. Here, in a sample of healthy older persons,
we examined psychophysical and fMRI-associated
responses to innocuous and painful thermal stimuli. We
predicted that increasing age would be associated with
decreased pain sensitivity (increased thermal thresholds)
but no change in pain unpleasantness. This prediction
was partly supported. We found a significant
age*sensory threshold interaction driven by greater
warmth detection threshold temperatures as age ad-
vanced. There were no significant correlations specifi-
cally for age and pain-related percept thresholds, nor
between age and affective ratings of warmth and thermal
A number of prior psychophysical studies comparing
younger and older subjects have found evidence of age-
related effects on sensory detection , pain thresholds,
mild/moderate pain intensity ratings, and pain tolerance
for thermal [45,63,64], mechanical [46,65], and electri-
cal or laser pain stimulus modalities [17,66]. Here we
found a general sensory threshold and age interaction ef-
fect driven by increased warmth detection thresholds in
relatively older individuals. It is possible that a lack of
“pain-specific” age effects was secondary to examining
psychophysics in the setting of a continuum of older age,
rather than comparing young and old adults. We also did
not collect pain intensity ratings related to the percept-
driven nature of our sensory stimuli in our study design;
doing so may have added to the pain-specific findings.
Figure 3. Qualitative view of signiﬁcant interaction effect between age*temperature of moderate heat pain for associated activation
of one cluster in the anterolateral prefrontal cortex (alPFC). This interaction was driven by individuals >73 years of age (red line),
who showed a signiﬁcant tendency for reduced activation with higher warmth detection thresholds. The opposite pattern tended to
occur in those <73 years (blue line).
8Thermal Psychophysics and fMRI in Aging
Nevertheless, our psychophysical results do fit well with
a recent systematic meta-analysis showing that the most
consistent age-related effect on pain pertains to low-
intensity stimuli using thermal modalities . A quarter
of our sample was >80 years of age (max ¼97); thus,
our results extend prior findings to the “oldest old,” who
have seldom been included in pain studies.
Based on prior psychophysical studies and our own
results, our second prediction (fMRI) was that increased
thermal sensory threshold temperatures, in conjunction
with advancing age, would be associated with reduced
activation among lateral pain pathway structures (S1, S2,
pINS). Given (albeit less frequent) prior findings sugges-
tive of reduced pain tolerance and pain modulation in
older age, we also posited that altered activation patterns
of medial pain-related regions might be found. These pre-
dictions were partly supported. Notably, no relationships
were found between activation in lateral pain structures
and age for any tested percept. We did, however, find a
number of medial pathway-related regions displaying
age-associated alterations of activation. First, activation
of the contralateral HIPPO during warmth perception
generally lessened as age increased, a pattern generally
independent of psychophysical responses. However,
there was a differential age effect between “younger”
(<73 years) and “older” (>73 years) individuals with re-
spect HIPPO activation during warmth perception. In
“younger” old individuals, contralateral HIPPO activa-
tion tended to be positively correlated with warmth per-
ception; the opposite pattern occurred in “older”
individuals. With respect to somatosensation and pain,
the HIPPO is implicated in novelty detection, pain-
related anxiety, and aversion [36,37], with deactivations
predominating during low-level pain, at least in younger
Figure 4. Qualitative view of signiﬁcant interaction effects between age*temperature (A) and age*affective ratings (B) of moderate
heat pain for associated activation in the medial frontal operculum (mFO). The age*temperature effect was driven primarily by in-
creased activation in “young” old (<73 years) subjects (beta ¼0.55, P¼0.005); the age*affective rating effect was seemingly driven
by general slope differences between “young” and “old” old individuals (P>0.05 for both groups).
Beach et al. 9
samples . Large cross-sectional studies suggest that
the HIPPO has pronounced volume loss and reduced
large-scale network connectivity with healthy aging
[39,68]. Similarly, aging is associated with reduced
novelty-related processing in the HIPPO . Reduced
functional and structural integrity of this region as part
of advanced aging may thus impair novelty-related soma-
tosensation detection, leading to greater innocuous
Our primary psychophysical finding was that of in-
creased warmth detection threshold with increased older
age; thus, we found no “pain-specific” age-related psy-
chophysical changes. Nevertheless, we did find altered
activation patterns as a function of age during pain. First,
we found that, in the contralateral (left) MCC, advancing
age (adjusted for psychophysical responses) was generally
associated with increased activation during mild thermal
pain. The MCC is a key hub within the medial pain sys-
tem, implicated in cognitive control and affect-related
visceral (e.g., cardiac) and somatomotor (e.g., facial ex-
pression) responses to salient stimuli [70,71]. Prior stud-
ies of pain in aging have found similar MCC activation
during pain perception in young and older individuals
[44–46]. Further, gray matter volume reductions are not
commonly reported in this region. Thus pain-related
structure and function in the MCC appears to be rela-
tively preserved even in advanced old age, at least for
mild thermal pain. This preservation may help explain a
lack of correlations between age and affective responses
to thermal stimuli here.
Moderate thermal pain was associated with age-
related activation changes in two prefrontal regions, the
mFO and alPFC. Activation in these regions during mod-
erate pain was generally correlated negatively with age.
Closer inspection of these results again revealed differen-
tial activation patterns between “younger” and “older”
old adults; activation in these frontal regions in
“younger” old tended to be positively correlated with
moderate pain threshold and affective ratings, whereas
“older” old adults tended to show the opposite pattern.
The mFO and neighboring aINS frequently co-activate
during salient internal and external stimuli, promoting
outward, goal-directed or inward, introspective process-
ing, respectively [72,73]. With respect to pain, the mFO
and alPFC are active during encoding and evaluation of
pain intensity . The mFO in particular is thought to
be involved in active attention and working memory re-
lated to a salient stimulus . Meanwhile, the alPFC is
implicated in cognitive reappraisal processes [76,77], in-
cluding the cognitive modulation of pain.Cognitive con-
trol and emotional regulation are known to be impaired
with older age , with associated reductions in pre-
frontal gray matter volume and activation of prefrontal
networks involving mFO and alPFC during reappraisal
tasks [45,79,80]. However, as our current findings and
other work show, older adults still recruit prefrontal and
cingulate activation in the context of affective stimuli, as
well as during deliberate emotion regulation .
Behavioral studies indicate that altered emotional regula-
tion in older age manifests through reduced attention to
negative affective stimuli ; the latter behavioral effect
may be secondary to, for example, reduced mFO activa-
tion in advancing age.
In contrast to more sensory-specific changes with age,
age-related changes in the pain-related affect have been
neither strong nor consistent among prior studies .
However, prior analyses have considered potential age-
related changes in pain affect secondary to impaired pain
modulation in the elderly [17,18]. An age-associated re-
duction in prefrontal activation fits well with prior work
suggesting impaired top-down pain modulation or in-
creased pain unpleasantness in elderly individuals
[17,18]. Intriguingly, expectation-based (placebo) anal-
gesia, which requires intact frontal function, is intact in
healthy older adults [19,20]. It may be that older adults
rely on compensatory, or context-dependent, affect regu-
lation pathways. Our data suggest that, at least with re-
spect to thermal pain, prefrontal activation processes are
altered in advanced age in a manner that may place these
individuals at higher risk for greater disability and
Several caveats must be kept in mind with respect to
this study. First, we examined pain psychophysics and ac-
tivation in the context of an older age continuum; this
may help explain, compared with prior work, our finding
fewer “pain-specific” changes in age-related psychophys-
ical responses and brain activation. Our results apply
only to comparisons of relatively “older” vs relatively
“younger” older individuals, a comparison rarely studied
in prior work. Further, use of suprathreshold pain stimuli
beyond moderate pain may have also led to alternative,
possibly more robust, psychophysical and activation-
based findings. With respect to imaging findings, we did
not perform partial volume corrections in processing ac-
tivation maps, which could have affected signal-to-noise
ratios and spatial extent of significant clusters .
However, use of more conservative multiple comparison
correction methods likely limited the extent of false-
positive results. Our use of a median split procedure to
examine differential aging effects is a somewhat arbi-
trary, though useful, means for examining these effects in
a single sample design. An additional limitation pertains
to our demographics, which reflected participants who
were predominantly Caucasian with relatively elevated
socioeconomic status. Finally, to better answer the ques-
tion of how age alone affects pain perception and proc-
essing, we took care to exclude any individuals with
frequent or chronic pain; it would thus be interesting in a
future study to perhaps see how age-related changes are
different in a population afflicted by daily pain.
Relative strengths of this study pertain to our analyses
of data from a relatively large number of “older old” sub-
jects (80–90 years), who are not frequently included in
pain studies. Our use of standardized psychophysical
10 Thermal Psychophysics and fMRI in Aging
methods and thermal stimuli was also beneficial; this mo-
dality has provided the most consistent behavioral results
across multiple studies . Future work in this regard
should be extended to examine both effective (pain-in-
duced) and resting-state functional connectivity in
healthy older adults to obtain a network-based perspec-
tive on pain-related changes. Examining neural correlates
of additional pain modalities, as well as quantitative sen-
sory testing, would also be useful.
This study examined patterns of altered psychophysi-
cal responses and associated brain activations along a
continuum of older adult aging. We found that advanc-
ing age was associated with greater thresholds for
warmth perception (i.e., decreased warmth perception),
possibly facilitated by less HIPPO-mediated novelty de-
tection. Thresholds for mild pain and associated affective
ratings were unaltered by increasingly older age, which
was, however, associated with intact cingulate (medial
pain) activation. Moderate thermal pain was associated
with less activation in “older” old adults in prefrontal
pain modulatory regions, which could relate to a trend
reported in prior studies toward greater pain-related un-
pleasantness in older individuals. Our understanding of
pain in the aged will benefit from future studies examin-
ing the effects of suprathreshold pain levels as well as
pain-related functional connectivity measures across the
All authors have read and agree with the contents of the
manuscript and take full responsibility for the data pre-
sented. PB synthesized data interpretation, helped pro-
duce figures and tables, and wrote the manuscript. RC
assisted with conceptualization of the project, planning/
design of MRI-related tasks, and manuscript drafting and
editing. MD conducted all statistical analyses outside
neuroimaging and produced initial drafts of tables and
graphical figures. SB designed psychophysical proce-
dures, trained subjects on procedures, and assisted in
manuscript drafting. SA analyzed imaging data and con-
tributed to manuscript drafting. JG assisted with concep-
tual MRI and associated task development. TM
conceptualized the project and assisted with all levels of
The authors thank all participants. The project described
was supported by the National Center for Research
Resources, Grant UL1 RR024975-01, and is now at the
National Center for Advancing Translational Sciences,
Grant 2 UL1 TR000445-06. The content is solely the re-
sponsibility of the authors and does not necessarily repre-
sent the ofﬁcial views of the NIH.
Supplementary data are available at Pain Medicine
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