Pain Severity and Interference in Different Parkinson’s Disease Cognitive Phenotypes

Abstract

Introduction
Chronic pain is prevalent in idiopathic Parkinson’s disease (PD) with many individuals also experiencing cognitive deficits negatively impacting everyday life.

Methods
In this study, we examine differences in pain severity and interference between 113 nondemented individuals with idiopathic PD who were statistically classified as having low executive function (n=24), low memory function (n=35), no cognitive deficits (n=54). The individuals with PD were also compared to matched non-PD controls (n=64).

Results
PD participants with low executive function reported significantly higher pain interference (p<0.05), despite reporting similar pain severity levels compared to other phenotypes. These differences remained statistically significant, even after accounting for important confounders such as anxiety and depression (p<0.05).

Discussion
Pain interference in those with lower executive function may represent a target for psychosocial interventions for individuals with pain and PD.

Full text

ORIGINAL RESEARCH
Pain Severity and Interference in Different
Parkinson’s Disease Cognitive Phenotypes
This article was published in the following Dove Press journal:
Journal of Pain Research
Yenisel Cruz-Almeida
1
Samuel J Crowley
2
Jared Tanner
2
Catherine C Price
2,3
1
Pain Research & Intervention Center of
Excellence, University of Florida,
Gainesville, FL, USA;
2
Department of
Clinical and Health Psychology, University
of Florida, Gainesville, FL, USA;
3
Norman
Fixel Institute for Neurological Diseases,
University of Florida, Gainesville, FL, USA
Introduction: Chronic pain is prevalent in idiopathic Parkinson’s disease (PD) with many
individuals also experiencing cognitive decits negatively impacting everyday life.
Methods: In this study, we examine differences in pain severity and interference between
113 nondemented individuals with idiopathic PD who were statistically classied as having
low executive function (n=24), low memory function (n=35), no cognitive decits (n=54).
The individuals with PD were also compared to matched non-PD controls (n=64).
Results: PD participants with low executive function reported signicantly higher pain
interference (p<0.05), despite reporting similar pain severity levels compared to other
phenotypes. These differences remained statistically signicant, even after accounting for
important confounders such as anxiety and depression (p<0.05).
Discussion: Pain interference in those with lower executive function may represent a target
for psychosocial interventions for individuals with pain and PD.
Keywords: Parkinson’s disease, pain, cognitive function, proles, phenotypes
Introduction
Idiopathic Parkinson’s Disease (PD) affects at least 1.5 million people in the United
States leading to disabling motor and non-motor impairments. Cognitive decits are
common in PD with patients experiencing problems across several domains.
1–5
Chronic pain is also commonly reported by this population compared to age-
matched non-PD peers
6–9
with pain being a signicant source of disability that
often precedes motor symptoms.
10
Pain is a multidimensional experience made up of interacting sensory, motor,
cognitive and emotional components. In regards to cognition, chronic pain sufferers
often present with executive function decits (see
11
for a meta-analysis) and acute
experimental pain reduces executive function abilities in healthy, pain-free
individuals.
12,13
Pain inhibition and modulation is associated with prefrontal cor-
tical regions,
14
while executive dysfunction in PD is caused in part by dysfunction
in cortico-striatal loops involving frontal regions.
15
These similarities suggest that
individuals with PD and executive difculties may also experience more interfer-
ence in their daily activities due to pain because of decreased function in prefrontal
brain regions needed for pain inhibition.
The aim of this brief report was to compare self-reported pain severity and
interference among individuals with PD shown in separate studies to have reduced
executive or episodic memory function relative to cognitively healthy individuals
with PD and non-PD peers.
16,17
We compared pain severity and interference across
Correspondence: Catherine C Price
ABPP/Cn
Tel +1 352-273-5929
Email cep23@phhp.u.edu
submit your manuscript | www.dovepress.com Journal of Pain Research 2020:13 3493–3497 3493
http://doi.org/10.2147/JPR.S270669
DovePress © 2020 Cruz-Almeida et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/
terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing
the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
Journal of Pain Research Dovepress
open access to scientific and medical research
Open Access Full Text Article

three statistically derived clusters of PD cognitive pheno-
types (PD Executive, PD Memory, and PD Cognitively
Well). Based on known shared neural substrates of pain
modulation and PD pathophysiology, we hypothesized
individuals with PD and low performance in executive
function tasks would experience signicantly greater pain
severity and pain interference compared to other patterns
of cognitive functioning after controlling for relevant PD
and pain-related variables.
Methods
Participants
This study was part of a federally funded investigation
focused on cognitive function and PD, in cooperation with
the University of Florida’s Center for Movement Disorder
and Neurorestoration, with approval of the University of
Florida’s Institutional Review Board, and in compliance
with the Declaration of Helsinki. Participants with PD
were recruited through movement disorder clinic referrals
and advertisements to local MDC support groups afliated
with the movement disorder clinic. Idiopathic PD was con-
rmed by a fellowship-level movement disorder specialist,
using UK Parkinson’s Disease Society Brain Bank Clinical
Diagnostic Criteria.
18
Individuals with early, mild to mod-
erate PD with a Hoehn and Yahr scale
19
score between
1 and 3 were included. The predominant motor PD pheno-
type; ie, tremor dominant vs postural instability-gait dif-
culty was assessed clinically based on the rst presenting
symptom or predominant symptomatology on initial and
subsequent exams (and also of primary concern to the
patient). Non-PD participants were recruited through 1)
mailings to demographically similar individuals in two
counties, 2) community iers, and 3) free community mem-
ory screenings. Exclusion criteria included other neurode-
generative disorders, signicant disease that could limit
lifespan, major psychiatric disorder, or dementia deter-
mined from structured telephone interview and medical
record review. Depression and apathy were not exclusion
criteria due to high prevalence in PD.
20,21
Participants in the
current study provided informed consent and are a subset of
participants also reported in a separate manuscript investi-
gating PD cognitive phenotypes and brain structure.
16
Clinical Measures
Measures were administered using standardized and vali-
dated methods as previously reported by our group and
others.
5,16
While on-medication, participants completed
neuropsychological testing, as well as measures of 1) PD
symptom severity (ie, Unied Parkinson’s Disease Rating
Scale (UPDRS
22
); 2) pain severity and interference (ie, the
Brief Pain Inventory (BPI)
23
); 3) disease comorbidity (ie,
Charlson Comorbidity Scale
24
); and 4) depression (ie, the
Geriatric Depression Scale; GDS
25
). Medications were
reverted to a common metric and compared for dopami-
nergic (Levodopa Equivalency Dose; LED
26
), and antic-
holinergic levels.
27
Raters blinded to diagnosis double
scored and double entered all data.
Cognitive Measures and Cognitive
Phenotypes
The methods for deriving the cognitive phenotypes is
described elsewhere.
16
Cognitive phenotypes were derived
from executive function and episodic memory measures
including WAIS-III Letter-Number Sequencing and Digit
Symbol tests,
28
Stroop Color-Word Test color-word trial,
29
Trail Making Test Part B,
30
Hopkins Verbal Learning Test,
Revised delay and recognition discrimination measures,
31
and WMS-III Logical Memory delay recall.
32
The cluster
analysis yielded three distinct cognitive phenotypes: 1)
participants with the lowest performance across processing
speed and executive tasks (PD Executive); 2) participants
with the lowest performance in learning and memory tasks
(PD Memory); and 3) participants with relatively normal
performance across all measures (Cognitively Well). The
nal cluster solution underwent internal and external vali-
dation procedures.
16,17
Statistical Analyses
The empirically derived clusters were reconrmed relative
to a previous report
16
and compared across demographic
and health-related measures using a one-way analysis of
variance (ANOVA) for normally distributed, Kruskal–
Wallis ANOVAs for non-normally distributed continuous
variables, and chi-square tests for nominal variables.
Demographic and disease-related characteristics signi-
cantly different across clusters at a p<0.100 were included
as covariates in subsequent analyses. First, an ANCOVA
compared pain severity between cognitive phenotypes and
non-PD peers with age, sex, and years of education as
covariates. PD phenotypes were also considered for differ-
ences in disease duration and motor severity. A second
ANCOVA compared pain interference between cognitive
phenotypes and non-PD peers, but with pain severity added
as a covariate. Where the omnibus analysis was signicant,
submit your manuscript | www.dovepress.com
DovePress
Journal of Pain Research 2020:13
3494
Cruz-Almeida et al Dovepress

post-hoc analyses compared the groups with a Bonferroni
correction for multiple comparisons. Finally, these analyses
were repeated with GDS as an additional covariate due to
the established association between depression and both
chronic pain
33
and executive function.
34
A p<0.05 was
considered statistically signicant.
Results
Cognitive Phenotypes
The nal sample included 113 individuals with PD and 60
non-PD peers; of the original recruitment sample, eight
participants (3 PD, 5 non-PD) did not complete the BPI
and thus were not included here. The three cognitive phe-
notypes consisted of 1) participants with the lowest perfor-
mance across processing speed and executive tasks (PD
Executive, N=24); 2) participants with the lowest perfor-
mance in episodic memory tasks (PD Memory, N=35);
and 3) participants with normal performance across all
measures (PD Cognitively Well, N=54). Neuropsychology
scores are provided (Supplementary Table 1). Groups dif-
fered signicantly in years of education (Executive < Non-
PD), disease duration (Memory < Executive), UPDRS Part
II (Cognitively Well < Executive), depressive symptom
severity (Executive < Non-PD), and anticholinergic burden
(Non-PD < Cognitively Well; Supplementary Table 2).
Pain Differences - Cognitive Phenotypes
After controlling for age, sex, disease duration, and educa-
tion, there were no signicant cluster differences in the
BPI pain severity subscale with participants across all
clusters reporting mild pain ratings. However, clusters
differed signicantly in the BPI pain interference subscale
after controlling for these covariates. Post-hoc tests with
Bonferroni correction showed that the PD Executive clus-
ter reported signicantly higher pain interference than
Cognitively Well phenotype (p=0.01) and non-PD peers
(p<0.01, Supplementary Tables 3 and 4, Figure 1).
Findings did not change signicantly after controlling for
GDS score (Supplementary Table 5).
Discussion
Individuals with PD who showed more difculty on work-
ing memory and inhibitory function tests reported higher
levels of pain interference than individuals with PD and no
cognitive difculties, as well as higher interference than
non-PD peers. Yet, each PD group reported similar pain
severity even after accounting for important PD and pain-
related covariates including depression. These ndings are
consistent with the existing literature supporting an asso-
ciation between chronic pain and impaired executive func-
tion (see meta-analysis by Berryman et al, 2014
11
), with
greater levels of pain usually associated with greater levels
of executive impairment. The association between pain
and cognition in PD was also reported by Okada and
colleagues (2016), who found decreased amplitudes of
pain-related somatosensory evoked potentials and
impaired attention and memory in individuals with PD.
35
Some prior research, however, did not nd an association
between executive functioning and pain. Engels and col-
leagues (2016) reported that mood, and not any measured
cognitive construct, was a signicant predictor of pain in
individuals with PD. However, this study did not assess
pain interference directly,
36
and this is consistent with the
similar pain severity across the clusters in the present
study.
Associations between executive function and pain inter-
ference are theoretically consistent with neurophysiology.
Prefrontal brain regions are crucial for both executive func-
tion and pain inhibition and modulation, and the prefrontal
cortex changes in persons with PD.
14,37,38
Individuals with
PD show more activity in cingulate and precuneus regions
during painful stimulation compared to age-matched non-
PD peers,
39,40
and individuals with PD and persistent pain
have thinner prefrontal and frontal cortex than individuals
with PD and no persistent pain.
41
Alterations to frontal lobe
integrity (outside of atrophy alone) may account for our
observed differences in pain interference without signicant
Figure 1 Brief Pain Inventory pain severity and pain interference across the
cognitive phenotypes. *Statistically signicant differences across groups.
Journal of Pain Research 2020:13 submit your manuscript | www.dovepress.com
DovePress
3495
Dovepress Cruz-Almeida et al

differences in pain severity; there are known neuroanatomi-
cal differences in the processing of pain severity versus its
perception of interference.
14,42–44
Frontal regions are highly
interconnected with subcortical regions involved in pain
modulation
14
and emotional regulation for appropriately
directing behavior.
Study limitations include the sample size, homogeneous
sample from a diversity and geographic standpoint and
reliance upon self-report measures of pain versus experi-
mental measures of pain response. Additionally, all testing
was conducted on-dopaminergic medication in order to
achieve the best test performance. We encourage future
research examining off-medication pain and cognitive pro-
les, as well as interactions between pain, cognition, and
motor presentation. Strengths include the well-characterized
cohort of individuals and considerations of two common
cognitive complaints (reduced attention and memory) in
relation to pain. Our study provides initial evidence for the
association between frontal function (working memory, inhi-
bition) cognitive symptoms in PD and the self-report of pain
interference. Pain interference is a core component of
health-related quality of life in assessing pain treatments,
45
representing an important domain that should be targeted for
psychosocial interventions in persons with PD. Future long-
itudinal studies are needed to decipher the directionality of
these ndings and the neurobiological substrates accounting
for the high pain interference in individuals with PD and
executive function. Such multifactorial approach may also
lead to development of evidence-based pain treatments that
are tailored to individuals’ cognitive proles.
Acknowledgments
The authors would like to acknowledge Dr Andrew
Ahn for his initial ideas and early discussions of this
work, Katie Rodriguez for her excellent work as
a study coordinator, and colleagues within the
Norman Fixel Institute for Neurological Diseases who
help make work on PD possible at our institution. This
work was supported in part by funding from NIH/
NINDS (R01NS082386 to Dr Catherine Price) and
NIH/NIA (K01AG048259, R01AG059809,
R01AG067757 to Dr Cruz-Almeida supporting her
time).
Disclosure
All authors report no conict of interest.
References
1. Aarsland D, Bronnick K, Williams-Gray C, et al. Mild cognitive
impairment in Parkinson disease: a multicenter pooled analysis.
Neurology. 2010;75:1062–1069.
2. Goldman JG, Weis H, Stebbins G, Bernard B, Goetz CG. Clinical
differences among mild cognitive impairment subtypes in
Parkinson’s disease. Mov Disord. 2012;27:1129–1136.
3. Goldman JG, Aggarwal NT, Schroeder CD. Mild cognitive impair-
ment: an update in Parkinson’s disease and lessons learned from
Alzheimer’s disease. Neurodegener Dis Manag. 2015;5:425–443.
4. Tanner JJ, Mareci TH, Okun MS, Bowers D, Libon DJ, Price CC.
Temporal lobe and frontal-subcortical dissociations in non-demented
Parkinson’s disease with verbal memory impairment. PLoS One.
2015;10:e0133792.
5. Price CC, Tanner J, Nguyen PT, et al. Gray and white matter con-
tributions to cognitive frontostriatal decits in non-demented
Parkinson’s disease. PLoS One. 2016;11:e0147332.
6. Broen MP, Braaksma MM, Patijn J, Weber WE. Prevalence of pain in
Parkinson’s disease: a systematic review using the modied
QUADAS tool. Mov Disord. 2012;27:480–484.
7. Beiske AG, Loge JH, Ronningen A, Svensson E. Pain in Parkinson’s
disease: prevalence and characteristics. Pain. 2009;141:173–177.
8. Defazio G, Berardelli A, Fabbrini G, et al. Pain as a nonmotor
symptom of Parkinson disease: evidence from a case-control study.
Arch Neurol. 2008;65:1191–1194.
9. Negre-Pages L, Regragui W, Bouhassira D, Grandjean H, Rascol O.
Chronic pain in Parkinson’s disease: the cross-sectional French
DoPaMiP survey. Mov Disord. 2008;23:1361–1369.
10. Young Blood MR, Ferro MM, Munhoz RP, Teive HA, Camargo CH.
(2016) Classication and characteristics of pain associated with
Parkinson’s disease. Parkinsons Dis. 2016;6067132.
11. Berryman C, Stanton TR, Bowering KJ. Do people with chronic pain
have impaired executive function? A meta-analytical review. Clin
Psychol Rev. 2014;34:563–579.
12. Oosterman JM, Dijkerman HC, Kessels RP, Scherder EJ. A unique
association between cognitive inhibition and pain sensitivity in
healthy participants. Eur.J.Pain. 2010;14:1046–1050.
13. Bjekic J, Zivanovic M, Puric D, Oosterman JM, Filipovic SR. Pain
and executive functions: a unique relationship between Stroop task
and experimentally induced pain. Psychol Res. 2017;1:15.
14. Tracey I, Mantyh PW. The cerebral signature for pain perception and
its modulation. Neuron. 2007;55:377–391.
15. Alexander GE, DeLong MR, Strick PL. Parallel organization of
functionally segregated circuits linking basal ganglia and cortex.
Annu Rev Neurosci. 1986;9:357–381.
16. Crowley SJ, Banan G, Amin M. Statistically dened Parkinson’s
Disease executive and memory cognitive phenotypes: demographic,
behavioral, and structural neuroimaging comparisons. J Parkinson’s
Dis. 2015;2:1254
17. Crowley SJ, Hizel L, Tanner JJ, Cruz-Almeida Y, Price CC. In
International Neuropsychological Society. Washington, DC; 2018.
18. Hughes AJ, Ben-Shlomo Y, Daniel SE, Lees AJ. What features
improve the accuracy of clinical diagnosis in Parkinson’s disease:
a clinicopathologic study. Neurology. 1992;42:1142–1146.
19. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and
mortality. Neurology. 1967;17:427–442.
20. Reijnders JS, Ehrt U, Weber WE, Aarsland D, Leentjens AF.
A systematic review of prevalence studies of depression in
Parkinson’s disease. Mov Disord. 2008;23:183–189.
21. den Brok MG, van Dalen JW, van Gool WA. Apathy in Parkinson’s
disease: a systematic review and meta-analysis. Mov Disord.
2015;30:759–769.
22. Jankovic J, McDermott M, Carter J, et al. Variable expression of
Parkinson’s disease: a base-line analysis of the DATATOP cohort.
The Parkinson Study Group. Neurology. 1990;40:1529–1534.
submit your manuscript | www.dovepress.com
DovePress
Journal of Pain Research 2020:13
3496
Cruz-Almeida et al Dovepress

23. Cleeland CS. Measurement of pain by subjective report. In: Cr C,
Jd L, editors. Advances in Pain Research and Therapy Vol. 12: Issues
in Pain Management. New York: Raven Press; 1989:391–403.
24. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of
classifying prognostic comorbidity in longitudinal studies: develop-
ment and validation. J Chronic Dis. 1987;40:373–383.
25. Sheikh JA, Yesavage JA. Geriatric Depression Scale (GDS): recent
evidence and development of a shorter version. Clin Gerontol. 1986.
26. Tomlinson CL, Stowe R, Patel S, Rick C, Gray R. Clarke CE
Systematic review of levodopa dose equivalency reporting in
Parkinson’s disease. Mov Disord. 2017;25:2649–2653.
27. Carnahan RM, Lund BC, Perry PJ, Pollock BG, Culp KR. The
Anticholinergic Drug Scale as a measure of drug-related anticholi-
nergic burden: associations with serum anticholinergic activity. J Clin
Pharmacol. 2006;46:1481–1486.
28. Wechsler D. WAIS-III Administration and Scoring Manual (3rd Ed).
San Antonio, TX: The Psychological Corporation; 1997.
29. Jensen AR, Rohwer WD. The Stroop color-word test: a review. Acta
Psychol (Amst). 1966;25:36–93.
30. Spreen O, Strauss E. A Compendium of Neuropsychological Tests:
Administration, Norms, and Commentary. New York: Oxford
University Press; 1991.
31. Benedict RHB, Schretlen D, Groninger L, Brandt J. Hopkins Verbal
Learning Test – revised: normative Data and Analysis of Inter-Form
and Test-Retest Reliability. Clin Neuropsychol. 1998;12:43–55.
32. Wechsler D. WAIS-III: Wechsler Adult Intelligence Scale.
Psychological Corporation; 1997.
33. Zis P, Daskalaki A, Bountouni I, Sykioti P, Varrassi G, Paladini A.
Depression and chronic pain in the elderly: links and management
challenges. Clin Interv Aging. 2017;12:709–720.
34. Rock PL, Roiser JP, Riedel WJ, Blackwell AD. Cognitive impairment
in depression: a systematic review and meta-analysis. Psychol Med.
2014;44:2029–2040.
35. Okada A, Nakamura T, Suzuki J, et al. Impaired pain processing
correlates with cognitive impairment in Parkinson’s disease. Intern
Med. 2016;55:3113–3118.
36. Engels G, Weeda WD, Vlaar AM, Weinstein HC, Scherder EJ.
Clinical pain and neuropsychological functioning in Parkinson’s dis-
ease: are they related? Parkinsons Dis. 2016;(2016):8675930.
37. Hanganu A, Bedetti C, Degroot C, et al. Mild cognitive impairment is
linked with faster rate of cortical thinning in patients with Parkinson’s
disease longitudinally. Brain. 2014;137:1120–1129.
38. Tinaz S, Courtney MG, Stern CE. Focal cortical and subcortical
atrophy in early Parkinson’s disease. Mov Disord. 2011;26:436–441.
39. Aschermann Z, Nagy F, Perlaki G, et al. ‘Wind-up’ in Parkinson’s
disease: a functional magnetic resonance imaging study. Eur J Pain.
2015;19:1288–1297.
40. Forkmann K, Grashorn W, Schmidt K, Frundt O, Buhmann C,
Bingel U. Altered neural responses to heat pain in drug-naive patients
with Parkinson disease. Pain. 2017;158:1408–1416.
41. Polli A, Weis L, Biundo R, et al. Anatomical and functional corre-
lates of persistent pain in Parkinson’s disease. Mov Disord.
2016;31:1854–1864.
42. Levesque J, Eugene F, Joanette Y, et al. Neural circuitry underlying
voluntary suppression of sadness. Biol Psychiatry. 2003;53:502–510.
43. Ohira H, Nomura M, Ichikawa N, et al. Association of neural and
physiological responses during voluntary emotion suppression.
Neuroimage. 2006;29:721–733.
44. Apkarian AV, Bushnell MC, Treede RD, Zubieta JK. Human brain
mechanisms of pain perception and regulation in health and disease.
Eur J Pain. 2005;9:463–484.
45. Dworkin RH, Turk DC, Wyrwich KW. Interpreting the clinical
importance of treatment outcomes in chronic pain clinical trials:
IMMPACT recommendations. J Pain. 2008;9:105–121.
Journal of Pain Research Dovepress
Publish your work in this journal
The Journal of Pain Research is an international, peer reviewed, open
access, online journal that welcomes laboratory and clinical ndings in
the elds of pain research and the prevention and management of pain.
Original research, reviews, symposium reports, hypothesis formation
and commentaries are all considered for publication. The manuscript
management system is completely online and includes a very quick
and fair peer-review system, which is all easy to use. Visit http://
www.dovepress.com/testimonials.php to read real quotes from pub-
lished authors.
Submit your manuscript here: https://www.dovepress.com/journal-of-pain-research-journal
Journal of Pain Research 2020:13 submit your manuscript | www.dovepress.com
DovePress
3497
Dovepress Cruz-Almeida et al