Pain Medicine 2012; 13: S37–S43
Wiley Periodicals, Inc.
Age-Related Changes in the Structure
and Function of Brain Regions Involved
in Pain Processing
pme_1287
37..43
Michael J. Farrell, PhD
Florey Neuroscience Institutes, University of
Melbourne, Parkville, Victoria, Australia
Reprint requests to: Michael J. Farrell, PhD, Florey
Neuroscience Institutes, University of Melbourne,
Level 2, 161 Barry Street, Parkville, Vic. 3010,
Australia. Tel: +61-3-8344-1941; Fax:
+61-3-9347-0446; E-mail: michael.farrell@florey.
edu.au.
Disclosure/Conflict of interest: Dr. Farrell has received
support from the Derek Denton Foundation and the
National Health and Medical Research Council of
Australia.
Abstract
Objective. This review summarizes the scientific
literature addressing the effects of aging on pain
processing in the brain.
Design. A literature search was undertaken using
PubMed and search terms including pain, aging, and
brain.
Settings and Patients. Studies including healthy
older people and older people with painful disorders
were reviewed.
Measures. Publications reporting the outcomes of
neuroimaging techniques including positron emission tomography, structural and functional magnetic
resonance imaging, and electroencephalography in
samples incorporating older people were reviewed.
Results. Age-related decreases in regional brain
volume occur in structures implicated in pain processing, and are most pronounced in the prefrontal
cortex and hippocampus, whereas age-related
atrophy in brainstem regions involved in pain modulation is less pronounced. Functional brain imaging
has revealed decreased pain activation in the
putamen and insula among older people during
extrinsic stimuli, but any effects of aging on the
processing of clinical pain are yet to be reported.
Conclusions. The network of brain regions involved
in pain processing are subject to age-related
changes in structure, but that the functional implications of these changes are yet to be determined.
Key Words. Older Adults; Magnetic Resonance
Imaging (MRI)
Introduction
This review will examine the proposition that age-related
changes in the brain are likely to impact on pain processing by briefly discussing the neuroanatomy of pain processing, by summarizing the literature of aging effects on
brain structure and function, and through reference to
applied studies of pain, aging, and brain structure and
function.
The effect of aging on the pain experience cannot be
encapsulated simply as an increase, a decrease, or no
change in sensitivity because all three situations have
been identified in cross-sectional studies of pain and
aging. Psychophysical tests have shown that older age is
generally associated with an increase in pain threshold, a
decrease in pain tolerance, and an increase in the duration
of hyperalgesia after tissue injury [1]. Persistent pain is
more common in older people, reflecting the epidemiology
of many painful chronic disorders such as arthritis and
neuropathic pain states [2], although age-related differences in pain processing could provide a partial explanation for the increased vulnerability of older people to
ongoing pain. However, some clinical conditions are associated with a decreased risk of pain with increasing age,
most notably disorders of the viscera [2]. The variability of
aging effects on pain clearly reflects a processing system
incorporating multiple components that do not age uniformly. Pain is a function of the brain and the brain is
subject to age-related change so it is likely that interactions between brain aging and pain processing contribute
to the experience of pain in older people. The focus of this
review will be on the extent to which brain aging could
provide an explanation for the range of age-related
changes in pain experience.
Pain Processing in the Brain
Age-related changes in structure and function occur differentially across brain regions and so it is likely that aging
impacts on different pain processing regions to greater or
lesser degrees. Understanding the likely impact of aging on
pain processing would be facilitated by first apprehending
the functional roles of the brain regions in the pain network.
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Farrell
The functional roles of regions within the pain network
have been inferred from existing knowledge of functional
neuroanatomy and tested with functional brain imaging
techniques such as electroencephalography (EEG),
positron emission tomography, and functional magnetic
resonance imaging (fMRI). The literature of functional brain
imaging of pain is dominated by studies involving extrinsic
stimuli applied to healthy people. Experimental pain in
healthy people is represented in a distributed brain
network that reflects the multidimensional nature of the
experience [3]. Regional brain activation during experimental pain is influenced by many factors that are known
to shape the experience of pain, including stimulus
attributes [4,5], concurrent mood state [6], and thoughts
about pain as well as distracting thoughts [7,8]. Irrespective of the circumstances that shape the experience, there
are core brain regions that are commonly activated during
experimental pain. These regions include the primary and
secondary somatosensory cortices, the insula, anterior
cingulate cortex, thalamus, prefrontal cortex, and posterior parietal cortex [9].
gray show activation when painful stimuli occur concurrently with placebo analgesia or distracting cognitive
tasks [7,21–23]. Recent studies indicate that these cortical and midbrain regions are likely to exert effects on
dorsal horn responses via projections from the rostroventral medulla [24,25].
The ventral posterior thalamus receives input from the
spinothalamic tract and projects to the primary and secondary somatosensory cortices. These regions have
been ascribed with sensory/discriminative functions such
as pain localization and intensity coding [3,4,10]. The
anterior cingulate cortex receives inputs from the medial
dorsal thalamus and shows levels of activation that are
closely related to ratings of pain unpleasantness [11,12].
The insula cortex also has a role in the affective dimension of pain [13], although pain-related function varies
between regions within the insula that are also distinguished by differences in cytoarchitecture [14]. Accumulating evidence suggests that the granular, posterior
insula is particularly important for the representation
of attributes that distinguish pain from other somatic
sensations [15–17]. Pain activations in the prefrontal
and posterior parietal cortices are likely to represent cognitive processes. Irrespective of the side of painful stimulation, both these regions show right hemisphere
predominance [18], which is also observed in studies of
brain responses associated with attention to novel
stimuli [19].
Extrinsic stimuli have been used in clinical pain groups to
identify brain activation associated with experimental
pain. Generally, clinical pain patients show similar brain
responses to experimental pain when compared with
healthy people [9]. However, differences can be apparent
when extrinsic stimuli are clinically relevant, such as
the application of mechanical stimuli to allodynic
skin, although these differences can vary considerably
between clinical groups and experimental protocols [26].
What remains to be established is the brain representation of ongoing clinical pain that occurs in the absence
of extrinsic stimulation. Progress in clinical pain imaging
has been slow because clinical pain does not usually
change with a frequency or predictability that is compatible with the standard methods used to measure human
brain function. The recent application of a perfusionbased fMRI technique called arterial spin labeling has
provided insights into the likely representation of one
form of ongoing clinical pain [27]. Contrasts of regional
cerebral blood flow between the pre- and postoperative
stages of tooth extraction revealed activation in the core
components of the pain network and other brain
regions. Included among the brain regions activated by
ongoing mouth pain were the amygdala, hippocampus,
and posterior cingulate cortex, which are rarely activated
during experimental pain. The identification of these
additional regions is consistent with speculation that
clinical pain is likely to involve phylogenetically older pain
pathways that project from brainstem nuclei to cortical
targets without relay through the thalamus and is consistent with observations made with chronic pain models
in animals [28]. Activation in the amydala and hippocampus during clinical pain could reflect processes
involved in emotional responses, memory formation,
and the regulation of the hypothalamic pituitary adrenal
axis that would evolve as pain persists for longer
periods.
Activation during experimental pain includes brain
regions that are reported less frequently than the core
components of the network. These activations can occur
in regions that have roles in motor function, including the
primary motor cortex, premotor cortex, basal ganglia,
and cerebellum. Participants in functional brain imaging
experiments are required to remain still during scanning
and would consequently need to counteract reflex withdraw responses and override any conscious desire to
escape from painful stimuli, both of which could involve
motor responses [20]. Experimental paradigms that
involve modulation of pain responses are notable for
activation in brain regions that are likely to be involved in
the recruitment of descending pathways that modify
dorsal horn responses. For instance, the pregenual
region of the cingulate cortex and the periaqueductal
In summary, pain in humans is represented in a distributed
brain network that incorporates core regions ascribed
with sensory/discriminative, affective/motivational, and
cognitive/evaluative functions during the application of
relatively brief, novel, noxious stimuli. Expansion of the
core pain network can include brain regions involved in
motor responses and the recruitment of modulating circuits. The representation of clinical pain states in the brain
is an outstanding question, but preliminary findings
suggest that brain regions receiving spinobulbar projections are likely to further expand the network of responses
when pain persists. The distributed nature of pain in the
brain means that aging could interact differentially with
functional processing depending on the extent to which
constituent brain regions are subject to age-related
change.
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Brain Aging and Pain
Aging and Brain Structure and Function
Advanced age is associated with decreased brain volume
and increased volume of the ventricles. Changes in brain
morphology across the lifespan follow varied trajectories.
Some brain regions increase in volume early in life and
some plateau in middle age, but almost all brain regions
show volume loss of varying degrees in the later years of
life. The notable exception is the preservation of brainstem
volumes into advanced age [29] because the brainstem
contains nuclei that are critical for top-down modulation of
dorsal horn responses to nociceptive inputs. The literature
of aging and brain morphology is yet to reach a firm
consensus on regional age-related volume loss but
reports of large cross-sectional and longitudinal studies
usually identify the hippocampus, prefrontal cortex, inferior
temporal cortex, cerebellum, and striatum as regions
showing the most pronounced decreases in volume with
increasing age in the later part of the lifespan [29,30].
Contrary to conventional wisdom, neuronal loss only contributes to a small degree to age-related changes in brain
morphology. Histological evidence has indicated that
other factors including shrinking of neurons, loss of synaptic spines, and reduction of synapses are the principle
drivers of decreased gray matter volumes in advanced
age [31]. Additionally, age-related changes in white matter
are likely to contribute substantially to decreased brain
volumes [32]. The neurochemistry of the brain is also
subject to differential age-related changes, with dopamine
[33,34] and serotonin showing substantial age-related
decreases [35,36].
Morphological and biochemical changes in the brain measured longitudinally or in different age groups explain variances in behavioral performance that are consistent with
knowledge of regional brain function. A growing literature
continues to identify age-related changes in brain measures including regional volumes, cortical thicknesses,
white matter integrity, and receptor dynamics that show
associations with measures of cognitive and behavioral
performance. Instances include increased levels of cortical
thickness in the inferior temporal lobe and posterior cingulate that are associated with increased performance on
tests of fluid intelligence in older people [37], and longitudinal changes in hippocampus volumes that predict episodic memory performance in older people [38]. Of
particular note are the observations that training can influence brain morphology and that increases in cortical
thickness during training are correlated with improvements in memory performance in older people [39], which
suggests that age-related changes in brain structure and
function are dynamic.
The dynamic nature of the brain during aging has been
amply demonstrated by functional brain imaging experiments. Comparisons between older and younger people
of regional patterns of brain activation during cognitive
tasks are notable for substantial differences that do not
simply conform to the decreases that would be expected
on the basis of age-related changes in cognitive perfor-
mance and brain morphology [40]. For instance, cognitive
paradigms that involve lateralized prefrontal cortex activations in younger people are frequently associated with
bilateral prefrontal activations in older people [41]. The
expansion and distinct nature of distributed networks in
older people is also observed for other experimental paradigms, such as motor tasks [42,43]. More importantly, the
extension of brain activity in older people would appear
to be adaptive because the levels of activation in these
additional regions show a positive correlation with task
performance [44].
In summary, aging is associated with a loss of brain volume
that exhibits regional variability. The ubiquitous nature of
age-related changes in brain morphology means that all the
regions in the hemispheres that activate during pain are
likely to be affected by aging. The components of the
broader pain network that show the most pronounced
age-related decreases in volume are the prefrontal cortex
and the hippocampus. In contradistinction, brainstem
regions that project to pain processing regions and that
are involved in descending modulation of dorsal horn
responses show preservation of volume with aging.
However, it is difficult to predict the impact of age-related
changes in brain structure on pain processing. This difficulty arises because the aging brain can undergo plastic
changes that seemingly compensate for decreases in functional capacity associated with morphological, histological,
and biochemical decrements. The dynamic interplay
between age-related structural and functional brain
changes means that empirical tests of pain and brain aging
must adopt a multimodal approach that integrates measures of behavior, brain morphology, and brain function.
Structure and Function of Brain Regions Involved
in Pain Processing in Older People
Experimental Pain
The literature of pain and aging is replete with psychophysical studies that generally report an increase in the
pain threshold for most stimulus modalities [1]. The
reasons for decreased pain sensitivity in older people are
likely to be multivariate, but brain processing is certainly a
candidate factor. Changes in peripheral neural elements
have been implicated in age-related increases of the pain
threshold, with evidence supporting an increased contribution of nociceptive C-fibers to pain responses in concert
with age-related decreases of Ad fibers [45]. This relative
deafferentation has implications for cortical processing
because clinical conditions involving loss of peripheral
nerves are associated with shrinking areas of the associated homunculi in the primary somatosensory cortex [46],
although this effect has not been examined in the context
of age-related change. The implication of peripheral fiber
loss in older people for processing of threshold levels of
pain has not been tested yet, and there are limited data
available for age-related changes in somatosensory
responses to innocuous stimuli and associated brain function. In one study of aging and two-point discrimination,
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Farrell
dipole analysis of EEG potentials associated with fingertip
stimulation showed an expansion of the representation of
the fingers in the primary somatosensory cortex in older
people that reflected age-related decrements in tactile
acuity [47]. If replicated for painful stimuli, this expansion of
the homunculus would be in direct contrast to the
expected changes on the basis of decreasing peripheral
inputs. However, speculation of this nature may be illadvised. Due to the lack of empirical data, it is impossible
to predict how aging actually impacts on the structure and
functions of the primary somatosensory cortex in the processing of painful stimuli. Furthermore, a recent experiment involving fMRI measures of brain responses during
stimuli at the pain threshold in young people indicated that
the posterior insula, and not the primary somatosensory
cortex, was the brain region that showed discrimination
for pain [17], which elevates the posterior insula for
focused attention in future investigations of age-related
changes in the pain threshold.
Age-related changes in brain responses during suprathreshold thermal pain stimuli have been reported for EEG
evoked potentials and fMRI measures. Brief laser stimuli at
twice the pain threshold evoke decreased potentials at
increased latency in older people compared with younger
people [48], suggesting that aging leads to a decrease
and slowing of brain activation during the experience of
moderate pain. The brain regions contributing to the
evoked potentials recorded in this study were not
reported, but were presumably cortical. Brain activation
during moderate levels of thermal pain measured with
fMRI has identified regional age-related decreases in the
anterior insula and supplementary motor area, albeit in a
small sample using a region of interest analysis [49]. Replication of this study in a larger sample and a voxelwise
analysis would be a welcome test of the veracity of this
preliminary outcome.
Pain responses to mechanical stimuli are notable for
showing a relationship to aging that is the inverse of other
stimulus modalities, in that older people tend to be more
sensitive to noxious pressure [1]. Age-related changes in
regional brain activation have been investigated during the
experience of pressure pain using fMRI and standard
whole-brain analyses [50]. The only regions with agerelated changes during moderately painful thumbnail pressure were the contralateral putamen and caudate, which
both showed a decreased level of activation in the older
group. Volumes of the putamen and caudate were
decreased in the older group, but this atrophy was in
proportion to global brain volumes, and individual levels of
atrophy did not account for age-related changes in pain
activation. The parsimonious explanation for the age difference in pressure pain activation is that motor responses
were altered in the older people, although this proposition
was not tested by the experimental design. Differences in
pain modulation between the age groups provide another
prospective explanation because there is evidence that
the basal ganglia is involved in the recruitment of descending pain-modulating circuits (see [51] for review) and aging
is associated with decreased efficiency of endogenous
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analgesia [52,53]. Supporting this interpretation is the
observation that the older group required lower levels of
stimulation than the younger participants to evoke moderate levels of pain during brain scanning.
Any summary of studies of aging and brain responses to
experimental pain must necessarily be circumscribed
given the lack of empirical data. The most substantive
study to date, involving pressure pain in two age groups
[50], reported decreased pain activation in the striatum,
but is possibly more notable for an absence of age differences in the core regions of the pain network. At time of
writing, there are no empirical data that address age
effects on brain responses during experimental pain at
levels near tolerance, nor the experience of pain in association with hyperalgesia.
Clinical Pain
Studies of brain structure and function in older people with
clinical pain have appeared in the literature, although the
majority of these studies do not expressly investigate agerelated changes through contrasts with younger people.
Musculoskeletal pain has been the most frequent clinical
problem among older people participating in studies of
pain and the brain, and osteoarthritis is the most common
diagnosis for pain in these samples.
Two studies from independent groups have examined the
effects of osteoarthritis of the hips on brain morphology
when symptoms are present and after the resolution of
pain following arthroplasty in patients with mean ages in
the mid- to late 60s [54,55]. One of these studies reported
a significant reduction in the volume of the contralateral
thalamus in the osteoarthritis patients compared with controls [54]. This observation is consistent with reports from
other clinical pain groups [56,57] and resonates with functional measures of the thalamus that indicate a decrease
of activation associated with duration of persistent pain
[58–60]. Thus, middle-aged people with persistent pain
show qualitative changes in the thalamus that match findings in younger people. It remains to be established if
aging leads to different quantitative effects on the thalamus during clinical pain compared with younger people.
The other major finding of the osteoarthritis study was that
the volume of the thalamus increased after arthroplasty
to the degree that differences between patients and controls were no longer apparent [54]. This effect is qualitatively similar to other longitudinal studies in older people
that have noted increases in regional brain volumes associated with changes in function, such as increased cortical
thickness following cognitive training. The implication of
reversed volume loss is that pain-related atrophy is not
driven by cell death and that other histological changes
are more likely to be in operation [55].
Reports of morphological change in older samples with
musculoskeletal pain are not confined to atrophy of the
thalamus. However, it is difficult to synthesize the outcomes across studies because results are inconsistent.
For instance, in addition to changes in the thalamus,
Brain Aging and Pain
Gwilym and colleagues [54] reported volume increases
among hip osteoarthritis patients compared with controls
in brain regions, including the orbitofrontal cortex,
amygdala, insula, and cerebellum that were reported by a
second group as showing the opposite effect of a
decreased volume in a very similar cohort of hip osteoarthritis patients. Another study of older people (mean age
75 years) with low back pain has shown decreases of
volume in the posterior parietal cortex [61], which did not
show changes in the two studies of hip osteoarthritis
[54,55]. In the oldest cohort reported to date (mean age
82 years), pain intensity and duration were inversely
related to hippocampal volumes [62]. To some extent, the
variance across studies in the older cohorts replicates a
similar diversity among morphological studies in younger
people with persistent pain. It is feasible that the diversity
reflects a highly variable effect of different pain pathologies
on brain morphology, although it is also possible that the
low sensitivity of measures of brain morphology necessitate sample sizes that are not typically enrolled into studies
of brain volumes in pain patients.
Functional brain imaging studies of ongoing clinical pains
have involved groups of knee osteoarthritis patients with
mean ages in the range of 56–59 years [63–65]. Unlike the
reports of brain morphology in pain patients, the activations associated with spontaneous osteoarthritis pain
have been consistent across studies. The major finding of
these studies is that ongoing osteoarthritis pain is primarily
represented in medial prefrontal and limbic regions,
including the orbitofrontal cortex, hippocampus and
amygdala [64,65]. Akin to the samples used to investigate
brain morphology in osteoarthritis patients, the functional
studies have not included younger participants as a point
of contrast, and so, commonalities and differences in clinical pain activation between older and younger cohorts are
unknown. However, the distinction between ongoing pain
and evoked pain is clearly important with respect to brain
processing and, consequently, future investigations of
pain and brain aging should avoid interpretations that
extrapolate the outcomes from experimental pain imaging
to the clinical situation.
Conclusion
The well-established effects of aging on pain experience
provide considerable impetus to explore the interaction
between brain aging and pain processing. It is very likely
that aspects of the pain experience in older people including acuity for noxious stimuli, tolerance, endogenous analgesia, and hyperalgesia are influenced by age-related
changes in the brain. Furthermore, processing of clinical
pain occurs in regions including the prefrontal cortex and
hippocampus that are particularly vulnerable to agerelated changes in structure and function, which may
provide future explanations for the manifestation of clinical
pain in older people. Despite a strong rationale for the
investigation of pain and brain aging, progress in this field
has been slow. Hopefully, the pace will accelerate in the
near future. There are powerful tools available for the
investigation of human brain structure and function, and a
rich literature of brain aging that will inform future efforts to
explore pain processing in older people.
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