E2 Journal of Neuroscience Nursing

Biobehavioral Framework of Symptom and

Health Outcomes of Uncertainty and
Psychological Stress in Parkinson Disease
Kim W. Austin, Suzanne W. Ameringer, Angela R. Starkweather, Leslie J. Cloud,
Jamie L. Sturgill, Ronald K. Elswick Jr.
LITERATURE REVIEW

ABSTRACT
Parkinson disease (PD) is a debilitating, progressive neurodegenerative disorder characterized by
complex motor and nonmotor symptoms that fluctuate in onset, severity, level of disability, and
responsiveness to treatment. The unpredictable nature of PD and the inability to halt or slow disease
progression may result in uncertainty and psychological stress. Uncertainty and psychological stress have
important implications for symptom and health outcomes in PD. Uncertainty and psychological stress
have been shown to worsen symptoms, functional capacity, and quality of life in chronic illnesses;
however, the causal mechanisms have yet to be elucidated. We propose a biobehavioral framework for
examining uncertainty and psychological stress in PD. The framework considers factors that may
contribute to uncertainty and neuroendocrineYimmune mechanisms of uncertainty and psychological
stress that may influence symptom and health outcomes in PD, for the ultimate purpose of improving
symptom and disease progression, functional capacity, and quality of life.

Keywords: biobehavioral outcomes, fatigue, motor symptoms, pain, Parkinson disease, psychological
stress, uncertainty in illness

P
Questions or comments about this article may be directed to
arkinson disease (PD) is a chronic, neurodegen-
Kim W. Austin, MSN RN, at kim@kwaustin.net. She is a PhD erative disorder with no known cure that is
Candidate, School of Nursing, Virginia Commonwealth Uni- characterized by the progressive loss of dopami-
versity, Richmond, VA. nergic and nondopaminergic neurons within the central,
Suzanne W. Ameringer, PhD RN, Associate Professor, Depart- autonomic, and peripheral nervous systems (Dexter &
ment of Family and Community Health Nursing, School of Jenner, 2013). As the second most prevalent neurode-
Nursing, Virginia Commonwealth University, Richmond, VA.
generative disorder, PD affects an estimated four million
Angela R. Starkweather, PhD ACNP-BC, Professor and Director, individuals worldwide (Dorsey et al., 2007). Although
Center for Advancements in Managing Pain, School of Nursing,
University of Connecticut, Storrs, CT.
PD can occur in individuals as early as 21 years old,
prevalence rates increase significantly after the age of
Leslie J. Cloud, MD MSc, Assistant Professor of Neurology, School
of Medicine, Virginia Commonwealth University, Richmond, VA.
65 years. Population estimates suggest that the prevalence
of PD will double by 2030. The progressive nature of PD
Jamie L. Sturgill, PhD, Assistant Professor, Department of Family
and Community Health Nursing, School of Nursing; Director,
combined with the inability to halt or slow disease
Behavioral Laboratory Services, Virginia Commonwealth Uni- progression results in significant societal and patient
versity, Richmond, VA. burdens. In 2010, national economic costs associated
Ronald K. Elswick, Jr., PhD, Professor, Department of Family with PD exceeded $14.4 billion (Kowal, Dall, Chakrabarti,
and Community Health Nursing, School of Nursing; Director Storm, & Jain, 2013). PD also places enormous burdens
of Biostatistics and Data Services, Virginia Commonwealth on individuals attempting to cope with and adapt to
University, Richmond, VA.
complex symptom patterns that fluctuate in onset,
The authors declare no conflicts of interest.
severity, associated level of disability, and responsive-
Supplemental digital content is available for this article. Direct
URL citations appear in the printed text and are provided in
ness to treatment. Further obscuring the illness experience,
the HTML and PDF versions of this article on the journal’s a considerable number of individuals also experience
Web site (www.jnnonline.com). debilitating pain and fatigue and unpredictable
Copyright B 2016 American Association of Neuroscience Nurses medication-induced motor complications, which signifi-
DOI: 10.1097/JNN.0000000000000244 cantly contribute to poorer quality of life and increased

Copyright © 2016 American Association of Neuroscience Nurses. Unauthorized reproduction of this article is prohibited.
 Volume 48 & Number 6 & December 2016 E3

LITERATURE REVIEW
functional disability (Antonini et al., 2012; Soh, Morris, neuroinflammation and oxidative stress because of the
& McGinley, 2011). high rate of oxygen consumption associated with dopa-
mine metabolism, limited antioxidant defenses within the
central nervous system, and an abundance of the
Purpose substrates needed for oxidation (see Text, available as
The ability to elucidate biobehavioral factors that may Supplemental Digital Content 1 at http://links.lww.
contribute to symptom outcomes of motor symptoms com/JNN/A75, number 30 shows content reference).
(tremors, rigidity, bradykinesia, and postural instability), As such, biological mechanisms of uncertainty and
pain, and fatigue has implications for improving health psychological stress may perpetuate neuroinflammation,
outcomes including disease progression, quality of life, oxidative stress, and loss of dopaminergic neurons
and functional capacity. One such factor, uncertainty in within the central nervous system and lead to poorer
illness, is a key component of the lived experience of symptom and health outcomes in PD.
PD (Habermann, 1996; Hermanns, 2011). Uncertainty, The purpose of this article is to propose a biobehav-
or the inability to accurately interpret illness-related ioral framework for examining the effects of uncertainty
events or predict outcomes, occurs in illness trajectories and psychological stress on symptom and health out-
that lack predictable or consistent symptom patterns comes in PD (Fig 1). Ensuing is an overview of major
and have complicated or ineffective treatment regimens symptoms of PD followed by presentation of the bio-
or ambiguous prognoses (Anema, Johnson, Zeller, Fogg, behavioral framework.
& Zetterlund, 2009; Cleanthous, Newman, Shipley,
Isenberg, & Cano, 2012; Mishel, 1981, 1988). The ap- Symptom Outcomes of Motor Symptoms,
praisal of uncertainty as either a threat or an opportunity Pain, and Fatigue in PD
results in the mobilization of coping strategies designed PD is characterized by complicated motor and non-
to promote adaptation (Mishel, 1988). The inability to motor symptom patterns that increase in frequency and
cope with and/or adapt to uncertainty has been shown severity as the disease progresses, resulting in progres-
to worsen psychological stress (Mishel, 1988; Shannon sive loss of functional capacity (Dexter & Jenner, 2013).
& Lee, 2008; Sorenson, 2002). Diagnostic motor symptoms include tremors, rigidity,
Uncertainty and psychological stress may contrib- bradykinesia, and postural instability. Because of
ute to poorer symptom and health outcomes in PD. dramatic heterogeneity in the expression of these
For example, uncertainty has been shown to increase cardinal motor features, patients are often subcategorized
pain, fatigue, and functional disability and worsen based on the most prominent features of their motor
quality of life. The causal mechanisms responsible for examination (see Text, available as Supplemental
these relationships have yet to be elucidated (Detprapon, Digital Content 1 at http://links.lww.com/JNN/A75,
Sirapo-ngam, Mishel, Sitthimongkol, & Vorapongsathorn, number 31 shows content reference). Well-recognized
2009; Dexter & Jenner, 2013; Johnson Wright, Afari, & motor phenotypes include tremor-predominant,
Zautra, 2009; Lasker, Sogolow, Olenik, Sass, & Weinrieb, akinetic-rigid, postural instability gait disorder PD,
2010; McCormick, Naimark, & Tate, 2006; Padilla, and mixed. Common nonmotor symptoms include but
Mishel, & Grant, 1992; Parker et al., 2013; Shannon & are not limited to pain, fatigue, cognitive impairments,
Lee, 2008; Suzuki, 2012). Furthermore, a considerable neuropsychiatric problems, sleep disturbances, and
body of research exists that links psychological stress symptoms of autonomic dysfunction (Dexter & Jenner,
to neuroinflammation, oxidative stress, and neuronal 2013). Pain and fatigue represent two of the most common
loss within the central nervous system, mechanisms nonmotor symptoms. Together, motor symptoms, pain,
that are believed to contribute to symptom and dis- and fatigue are recognized as major determinants of
ease progression in PD (Dexter & Jenner, 2013; see poorer quality of life and loss of functional capacity in
Text, available as Supplemental Digital Content 1 at PD; thus, they are important to address over the course
http://links.lww.com/JNN/A75, numbers 21Y28 show of the disease (see Text, available as Supplemental
content references). Pathogenic processes that have Digital Content 1 at http://links.lww.com/JNN/A75,
been implicated in these mechanisms in PD include numbers 32Y34 show content references). As such, these
exaggerated microglial activation, increased expression symptoms were chosen as symptom outcomes in the
of proinflammatory mediators, and imbalances in the proposed framework and are further described below.
production of reactive oxygen species and antioxidants
because of dopamine metabolism, mitochondrial dys- Motor Symptoms
function, and neuroinflammation (see Text, available The diagnostic motor symptoms of PD are believed to
as Supplemental Digital Content 1 at http://links.lww. result from the progressive loss of dopaminergic neurons
com/JNN/A75, number 29 shows content reference). within the substantia nigra pars compacta projecting into
Dopaminergic neurons are particularly vulnerable to the striatum of the nigrostriatal system (Dexter & Jenner,

Copyright © 2016 American Association of Neuroscience Nurses. Unauthorized reproduction of this article is prohibited.
E4 Journal of Neuroscience Nursing

FIGURE 1 Biobehavioral Framework of Uncertainty in Illness and Psychological Stress

LITERATURE REVIEW
in Parkinson Disease (PD)

Note. The framework proposes co-factors that may contribute to uncertainty and biobehavioral mechanisms of uncertainty and
psychological stress that may affect symptom and health outcomes in PD. Demographic and disease-specific co-factors may contribute
to uncertainty by affecting symptom pattern variability and/or the ability to cognitively processes illnesses-related events. Once
uncertainty occurs, bidirectional relationships exist between the appraisal of uncertainty as either a threat or an opportunity and the
mobilization of coping strategies designed to promote adaptation. The inability to adequately cope with or adapt to the appraisal of
uncertainty may lead to the development of additional uncertainty as well as psychological stress. Psychological stress is defined as
complex biobehavioral responses triggered by the inability to alleviate uncertainty perceived as a threat or maintain uncertainty
perceived as an opportunity. Neuroendocrine mediators and immunological indicators play a key role in mounting effective
biobehavioral responses to psychological stress. Dysregulation of bidirectional relationships between the neuroendocrine and immune
systems because of uncertainty and psychological stress may worsen neuroinflammation, oxidative stress, and neuronal loss within the
central nervous system. Given similarities in the underlying pathogenic features of PD, factors that perpetuate neuroinflammation,
oxidative stress, and neuronal loss may lead to poorer symptom and health outcomes. Informed by ‘‘Uncertainty in Illness’’ by Mishel, M. H.,
1988, Journal of Nursing Scholarship, 40, 167Y171, and ‘‘Implementing a Comprehensive Approach to the Study of Health Dynamics Using the
Psychoneuroimmunology Paradigm ’’ by McCain, N. L., Gray, D. P., Walter, J. M., & Robins, J., 2005, Advances in Nursing Science, 28, 321.

2013). Although the exact cause remains unknown, (see Text, available as Supplemental Digital Content 1
mechanisms that have been implicated in neuronal loss at http://links.lww.com/JNN/A75, number 40 shows
in PD include but are not limited to increased expression content reference). To lessen the severity of these
of proinflammatory cytokines (interleukin-1 beta, medication-induced motor complications, dosing re-
interleukin-6, tumor necrosis factor alpha, and interfer- ductions are needed, thereby leading to breakthrough
on gamma), transcription factors, and isoenzymes such motor symptoms. Further complicating the illness
as cyclooxygenase-2 and increased oxidative stress experience, onYoff phenomena, or the sudden loss of
within the central nervous system (Dexter & Jenner, medication efficacy leading to unpredictable motor
2013; see Text, available as Supplemental Digital symptom exacerbations and periods of immobility, are
Content 1 at http://links.lww.com/JNN/A75Vnumbers common with prolonged or high-dose treatment with
24, 26Y28, and 35Y39 show content references). dopamine replacement therapy. The ability to lessen the
Dopamine replacement therapy, the gold standard occurrence of medication-induced motor complications
treatment for PD, typically improves motor symptoms and onYoff phenomena while still achieving motor
early in the course of the disease. However, as the disease symptom improvements becomes more difficult as the
progresses, higher medication doses become neces- disease progresses, leading to poorer quality of life and
sary to achieve motor symptom benefits, leading to increased functional disability (see Text, available as
the development of debilitating medication-induced Supplemental Digital Content 1 at http://links.lww.
motor complications of dystonias and dyskinesias com/JNN/A75, number 40 shows content reference).

Copyright © 2016 American Association of Neuroscience Nurses. Unauthorized reproduction of this article is prohibited.
 Volume 48 & Number 6 & December 2016 E5

Pain

LITERATURE REVIEW
related fatigue is critical to address because it has been
Pain is a complex phenomenon in PD thought to be associated with decreased functional capacity and poorer
caused by: musculoskeletal pain from rigidity and quality of life (Antonini et al., 2012; Soh et al., 2011).
akinesia; neuropathic pain; dystonia-related pain as a Biobehavioral mechanisms of fatigue remain poorly
complication of dopamine replacement therapy; primary understood and insufficiently studied in PD. However,
pain as a direct result of neuronal injury; and restless leg significant relationships have been shown between
syndrome (see Text, available as Supplemental Digital fatigue severity and select cytokines in PD, suggesting
Content 1 at http://links.lww.com/JNN/A75, number 41 that the immune system may play an important role in
shows content reference). PD-related pain is important to fatigue (see Text, available as Supplemental Digital
understand and manage because it is often more Content 1 at http://links.lww.com/JNN/A75Vnumbers
disabling than the diagnostic motor symptoms of the 25, 27, and 50 show content references).
disease and has been associated with greater motor
complications and impaired functional abilities (see Biobehavioral Framework
Text, available as Supplemental Digital Content 1 at The proposed framework is informed by Mishel’s un-
http://links.lww.com/JNN/A75, numbers 42Y43 show certainty in illness theory (Mishel, 1988) and a psycho-
content references). The prevalence of PD-related pain neuroimmunology framework for the purpose of
is high, ranging from 40% to 85% (see Text, available examining the biobehavioral effects of uncertainty and
as Supplemental Digital Content 1 at http://links.lww. psychological stress on symptom and health outcomes
com/JNN/A75, number 44 shows content reference), in PD (see Text, available as Supplemental Digital Con-
yet pain remains underrecognized and undertreated in tent 1 at http://links.lww.com/JNN/A75, number 51 shows
PD. It is not uncommon for individuals with PD to content reference). Uncertainty in illness theory seeks
experience multiple types of pain concurrently. In one to explain how individuals cognitively process illness-
study, 30% of individuals reported two or more dif- related events. Uncertainty occurs when individuals are
ferent types of pain concurrently, with the most frequent unable to assign meaning to illness-related events or
being musculoskeletal pain (70%), dystonic pain predict outcomes and can be influenced by co-factors
(40%), and neuropathic pain (30%; see Text, available that affect symptom pattern variability and cognitive
as Supplemental Digital Content 1 at http://links.lww. capacity (Mishel, 1981, 1988). The appraisal of uncer-
com/JNN/A75, number 45 shows content reference). tainty as a threat or opportunity results in the mobiliza-
In the same study, average pain scores in the preceding tion of coping strategies designed to promote adaptation.
24 hours for individuals with PD-related pain were In situations in which meaning or predictable outcomes
3.39 (0Y10 range), with most individuals reporting con- cannot be achieved, uncertainty causes psychological
stant pain for more than 6 months. Further complicating stress. Psychoneuroimmunology provides a framework
pain in PD, treatment with dopamine replacement therapies for examining plausible psychoYneuroendocrineY
often fail to alleviate pain. Although the underlying bio- immune mechanisms of uncertainty and psychological
logical mechanisms responsible for pain remain poorly stress that may contribute to symptom and health out-
understood in PD, evidence suggests that increased pro- comes (see Text, available as Supplemental Digital Con-
duction of proinflammatory cytokines, oxidative stress, tent 1 at http://links.lww.com/JNN/A75, number 51 shows
and decreased striatal dopamine D2 receptors may con- content reference). As described in detail below, we
tribute to abnormal nociceptive input in PD (see Text, propose that salient demographic and disease-specific
available as Supplemental Digital Content 1 at http:// co-factors may contribute to the development of uncertainty
links.lww.com/JNN/A75Vnumbers 41, 46, and 47 show in PD. We further propose that uncertainty may cause
content references). psychological stress in PD and worsen motor symp-
toms, pain, and fatigue, thereby contributing to disease
Fatigue progression, poorer quality of life, and loss of functional
Fatigue is considered one of the most debilitating non- capacity through biological mechanisms and interactions
motor manifestations of PD, with prevalence rates ranging of the neuroendocrine and immune system.
from 58% to 77.6% (see Text, available as Supplemental
Digital Content 1 at http://links.lww.com/JNN/A75, num- Co-Factors of Uncertainty in PD
bers 48Y49 show content references). PD-related fatigue Demographic and disease-specific co-factors that may
includes physical fatigue, or an overwhelming, subjective contribute to uncertainty in PD include age; gender; age
sense of physical exhaustion and lack of energy, and at the time of diagnosis; length of time since diagnosis; con-
mental fatigue, or a subjective sense of impaired concen- current treatment regimens for motor symptoms, pain,
tration and decreased memory (see Text, available as and fatigue; cognitive impairment; disease severity;
Supplemental Digital Content 1 at http://links.lww.com/ medication-induced motor complications; and motor
JNN/A75, number 49 shows content reference). PD- phenotypes. The effect of these co-factors on uncertainty

Copyright © 2016 American Association of Neuroscience Nurses. Unauthorized reproduction of this article is prohibited.
E6 Journal of Neuroscience Nursing

LITERATURE REVIEW in PD remains unknown, highlighting the need for rance in individuals with chronic illnesses and cancer
future research. However, many of these co-factors (Johnson Wright et al., 2009; Lasker et al., 2010; see
have been associated with key differences in clinical Text, available as Supplemental Digital Content 1 at
and/or disease progression in PD. For instance, studies http://links.lww.com/JNN/A75, numbers 61Y63 show
of motor phenotypes in PD have shown that individuals content references). Although uncertainty is a key com-
with akinetic/rigid or postural instability gait-dominant ponent of PD (Habermann, 1996; Hermanns, 2011), no
phenotypes often experience more rapid progression of known studies have examined biobehavioral symptom
motor symptoms and cognitive impairments and in- and health outcomes of uncertainty in PD.
creased medication-induced motor complications when
compared with those with tremor-dominant phenotypes
(see Text, available as Supplemental Digital Content 1 Appraisal and Coping
at http://links.lww.com/JNN/A75, numbers 52Y53 show Appraisal and use of coping strategies are intricately
content references). Gender-based studies in PD have linked to uncertainty. Uncertainty is considered a neu-
shown that men often report greater motor and non- tral state until appraised by the individual as either a
motor symptom burdens whereas women often per- threat or an opportunity (Mishel, 1988). In instances in
ceive symptoms as more distressing (see Text, available which uncertainty is appraised as a threat, coping
as Supplemental Digital Content 1 at http://links.lww. strategies are mobilized to lessen uncertainty. When
com/JNN/A75, numbers 54Y55 show content refer- uncertainty is appraised as an opportunity, coping
ences). Age-based studies have shown that individuals strategies are mobilized to maintain uncertainty. Adap-
with younger-onset PD are more likely to experience tation occurs when coping strategies successfully lessen
medication-induced motor complications and slower uncertainty that is perceived as a threat or maintain
disease progression whereas those with older-onset PD uncertainty that is perceived as an opportunity. Psycho-
are at greater risk for more rapid disease progression logical stress occurs when coping strategies fail to
and significant cognitive impairments (see Text, avail- achieve these outcomes.
able as Supplemental Digital Content 1 at http://links. The importance of the appraisal of uncertainty and
lww.com/JNN/A75, numbers 56Y58 show content use of coping strategies has been shown in a number of
references). Finally, medication-induced motor compli- studies. The appraisal of uncertainty as a threat has been
cations are recognized as important contributors to un- shown to result in greater uncertainty and emotional
predictable symptom exacerbations and periods of distress as well as increased use of emotional-focused
immobility in PD (see Text, available as Supplemental coping strategies (see Text, available as Supplemental
Digital Content 1 at http://links.lww.com/JNN/A75, num- Digital Content 1 at http://links.lww.com/JNN/A75,
ber 40 shows content reference). As such, we propose numbers 64Y68 show content references). Conversely,
that these co-factors may affect symptom pattern variabil- the appraisal of uncertainty as an opportunity has been
ity and/or the ability to accurately process illness-related associated with greater use of problem-focused coping
events or predict outcomes in PD, factors that result in strategies (see Text, available as Supplemental Digital
greater uncertainty (Mishel, 1988; see Text, available as Content 1 at http://links.lww.com/JNN/A75, number
Supplemental Digital Content 1 at http://links.lww.com/ 68 shows content reference). The use of emotional-
JNN/A75, numbers 59Y60 show content references). focused coping strategies in PD has been associated
with poorer emotional, mobility, and cognitive domains
Uncertainty of health-related quality of life, whereas the use of
Evidence exists in support of the importance of un- problem-focused coping strategies resulted in less
certainty to symptom outcomes. In a longitudinal, case- psychological stress (see Text, available as Supplemen-
control study of individuals with multiple sclerosis, tal Digital Content 1 at http://links.lww.com/JNN/A75,
most of which reported relapsing-remitting or chronic number 69 shows content reference). However, in another
progressive subtypes (73.8%), greater uncertainty was study, the use of problem-focused coping strategies by
associated with higher stress levels and more severe individuals with more severe PD resulted in greater
symptoms (Sorenson, 2002). This study further showed perceived stress and poorer quality of life (see Text,
significant differences in the cytokines interleukin-6 and available as Supplemental Digital Content 1 at http://
interleukin-10 in individuals with high and low stress links.lww.com/JNN/A75, number 70 shows content ref-
and in interleukin-6 in individuals with high and low erence). These conflicting findings suggest that factors
uncertainty, providing preliminary evidence that uncer- such as disease severity may play a role in the ef-
tainty may influence underlying immune mechanisms fectiveness of coping strategies in PD; for example,
indirectly through stress. Significant relationships have problem-focused coping strategies may become inef-
also been shown between greater uncertainty and in- fective when individuals are faced with outcomes that
creased fatigue, pain sensitivity, and reduced pain tole- cannot be changed.

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 Volume 48 & Number 6 & December 2016 E7

Psychological Stress

LITERATURE REVIEW
PD and often include asymmetrical diaphoresis. The
Individuals with PD are often faced with psychological results of this study revealed no significant relation-
stress resulting from an uncertain illness trajectory ship between psychological stress and sympathetic skin
characterized by unpredictable symptom patterns, responses. However, subjects with PD-related auto-
medication-induced motor complications, and levels nomic dysfunction were excluded from this study,
of disability as well as complicated and/or ineffective potentially explaining the lack of significant results.
treatment regimens (Habermann, 1996; see Text, avail- The biobehavioral effects of psychological stress on
able as Supplemental Digital Content 1 at http://links. PD-related pain and fatigue have yet to be examined;
lww.com/JNN/A75, numbers 70Y71 show content ref- however, significant relationships have been shown in
erences). Psychological stress is defined as complex other chronic illnesses. In multiple sclerosis, significant
biobehavioral responses triggered by the inability to relationships have been shown between psychological
alleviate uncertainty perceived as a threat or maintain stress and increased motor and sensory disturbances,
uncertainty perceived as an opportunity (Mishel, 1988). fatigue, and select cytokines (interleukin-6, interleukin-
Evidence suggests that psychological stress has dele- 10; see Text, available as Supplemental Digital Content 1
terious effects on symptom outcomes in PD. In animal at http://links.lww.com/JNN/A75, number 81 shows con-
models of PD, significant relationships have been shown tent reference). In fibromyalgia, psychological stress
between psychological stress and motor symptom has been shown to significantly correlate with increased
severity as mediated by increased striatal dopamine pain and fatigue (see Text, available as Supplemental
deficiencies and loss of dopaminergic neurons within Digital Content 1 at http://links.lww.com/JNN/A75,
the substantia nigra pars compacta (see Text, available number 82 shows content reference). In rheumatoid
as Supplemental Digital Content 1 at http://links.lww. arthritis, predictive relationships have been shown
com/JNN/A75, numbers 72Y76 show content references). between psychological stress and increased fatigue
However, the use of animal models may not adequately and pain as well as between select proinflammatory
reflect the multidimensional and dynamic effects of cytokines (interleukin-1 beta, interferon gamma) and
psychological stress on symptom and health outcomes future fatigue severity (see Text, available as Supple-
in human populations. mental Digital Content 1 at http://links.lww.com/JNN/
The research regarding the effects of psychological A75, number 83 shows content reference).
stress on symptom outcomes in individuals with PD is
minimal, with only four such studies published. In a
study conducted by Macht, Schwarz, and Ellgring (2005), Neuroendocrine Mediators and
approximately two thirds of individuals with PD who Immunological Indicators
had increased levels of psychological stress reported Biological mechanisms and interactions of the neuro-
greater frequencies of depressive mood, sleep distur- endocrine and immune systems may further our under-
bances, anxiety, sexual problems, and communication standing of the effects of uncertainty and psychological
difficulties (see Text, available as Supplemental Digital stress on symptom and health outcomes in PD. Un-
Content 1 at http://links.lww.com/JNN/A75, number certainty and psychological stress are complex phe-
77 shows content reference). Rahman, Griffin, Quinn, nomena that involve cognitive, emotional, behavioral,
and Fahanshahi (2008) showed significant relationships and biological responses (Mishel, 1988; see Text, available
between psychological stress and increased incidents of as Supplemental Digital Content 1 at http://links.lww.
freezing of gait, a common motor manifestation in PD com/JNN/A75, number 84 shows content reference).
(see Text, available as Supplemental Digital Content 1 Complex bidirectional links between the neuroendocrine
at http://links.lww.com/JNN/A75, number 78 shows and immune systems are responsible for mounting ef-
content reference). In a study by Macht, Brandsteter, fective biobehavioral responses to psychological stress.
and Ellgring (2007), psychological stress was associ- These responses are coordinated by the hypothalamicY
ated with decreased pleasure but had no significant pituitaryYadrenal axis, which plays an important role in
effect on reachingYgrasping movements in individuals mediating immunological responses (see Text, avail-
with PD (see Text, available as Supplemental Digital able as Supplemental Digital Content 1 at http://links.
Content 1 at http://links.lww.com/JNN/A75, number lww.com/JNN/A75, numbers 51 and 85 show content
79 shows content reference). Giza, Katsarou, Georgiadis, references). Dysregulation of these relationships, as seen
and Bostantjopoulou (2012) examined the effects of with prolonged, intense, or repetitive psychological stress,
psychological stress on sympathetic skin responses, a has been associated with neuroinflammation, oxidative
marker of autonomic dysfunction (see Text, available as stress, and loss of dopamine-producing neurons within
Supplemental Digital Content 1 at http://links.lww. the central nervous system (Dexter & Jenner, 2013; see
com/JNN/A75, number 80 shows content reference). Text, available as Supplemental Digital Content 1 at
Symptoms of autonomic dysfunction are common in http://links.lww.com/JNN/A75, numbers 21Y28 show

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E8 Journal of Neuroscience Nursing

LITERATURE REVIEW content references). As such, biological mechanisms remain poorly understood, studies have shown signif-
of uncertainty and psychological stress may exacerbate icant relationships between uncertainty, psychological
underlying pathogenic processes in PD and contribute stress, and increased motor symptom, pain, and fatigue
to motor symptom, pain, and fatigue severity, thereby severity. Neuroinflammation, oxidative stress, and loss
leading to disease progression, poorer quality of life, of dopaminergic neurons within the central nervous
and decreased functional capacity. system represent plausible biological mechanisms to
Neuroendocrine mediators and immunological indi- explain uncertainty-induced and psychological-stress-
cators represent measureable biological markers of neuro- induced symptom and health outcomes in PD. Given
endocrine and immune system stress responses (see Text, the contribution of motor symptoms, pain, and fatigue
available as Supplemental Digital Content 1 at http://links. to health outcomes in PD, the need for research fo-
lww.com/JNN/A75, number 51 shows content refer- cusing on underlying biobehavioral mechanisms of un-
ence). As described, psychological stress resulting from certainty and psychological stress that may exacerbate
uncertainty may influence these biological mechanisms. these symptoms is great.
Biological markers that may be significant to symptom Initial steps to increase understanding of these com-
and health outcomes of uncertainty and psychological plex relationships include conducting descriptive stud-
stress in PD include but are not limited to cortisol, ies designed to examine factors that may contribute to
neuropeptide Y, cytokines (interleukin-1 beta, interleukin-2, uncertainty and relationships between uncertainty, psy-
interleukin-4, interleukin-6, interleukin-10, tumor ne- chological stress, neuroendocrine and immune biolog-
crosis factor alpha, interferon gamma), nuclear factor ical mechanisms, and motor symptom, pain, and fatigue
kappa beta, cyclooxygenase-2, and biomarkers of oxi- severity in PD. Additional studies are needed to elu-
dative stress (plasma F2 -isoprostanes, 7 beta- and cidate predictive relationships between uncertainty- and
27-hydroxycholesterol, 7-ketocholesterol, neuropro- stress-induced mechanisms of neuroinflammation, ox-
stanes). A substantial body of research exists linking idative stress, and neuronal loss that may be associated
these biological markers to neuroendocrine- and immune- with symptom and health outcomes in PD. Prospective,
mediated stress responses as well as stress-induced longitudinal studies are needed to examine the effects of
neuroinflammation, oxidative stress, and neurodegen- uncertainty and psychological stress on disease pro-
eration within the central nervous system (see Text, gression over time. There will also be a need for bio-
available as Supplemental Digital Content 1 at http:// behavioral interventional research specifically targeted
links.lww.com/JNN/A75Vnumbers 24, 28, 74, and to uncertainty and psychological stress.
86Y99 show content references). Evidence in animal Preliminary evidence suggests that interventions
models and chronic illnesses also supports relationships targeted to uncertainty and psychological stress may be
between many of these biological markers and motor beneficial to biobehavioral symptom and health out-
function, pain, and fatigue (see Text, available as Sup- comes in PD. Interventions aimed at uncertainty have
plemental Digital Content 1 at http://links.lww.com/ been effective at significantly decreasing uncertainty as
JNN/A75Vnumbers 81, 83, and 100Y104 show content well as improving coping strategies, quality of life,
references). Specific to PD, significant relationships psychosocial adjustment, and self-care in individuals
have been shown between elevated glucocorticoid levels with incurable, chronic illnesses (see Text, available as
and more severe gait and motor deficits. Significant Supplemental Digital Content 1 at http://links.lww.com/
relationships have also been shown between select JNN/A75, numbers 107Y108 show content references).
cytokines (interleukin-6, tumor necrosis factor alpha) Evidence exists to suggest that complementary alternative
and more severe motor and nonmotor symptoms and therapies, such as acupuncture and Japanese massage
increased disability in PD (see Text, available as Supple- therapy, result in improvements in PD-related pain and
mental Digital Content 1 at http://links.lww.com/JNN/ fatigue, respectively (see Text, available as Supplemen-
A75Vnumbers 25, 27, 74, and 105Y106 show content tal Digital Content 1 at http://links.lww.com/JNN/A75,
references). This evidence suggests that neuroendocrine numbers 109Y110 show content references). In animal
mediators and immunological indicators may explain models of PD, acupuncture has been shown to decrease
underlying mechanisms of uncertainty and psychological production of reactive oxygen species, increase expres-
stress that affect symptom and health outcomes in PD. sion of antioxidants, and attenuate oxidative stress in
dopaminergic neurons within the substantia nigra pars
Implications for Future Research and compacta (see Text, available as Supplemental Digital
Clinical Practice Content 1 at http://links.lww.com/JNN/A75, numbers
Uncertainty and psychological stress may contribute to 111Y112 show content references).
symptom and health outcomes in PD through underly- Cumulatively, this research, as well as future studies
ing biological mechanisms of the neuroendocrine and that expand on these results, represents an exciting
immune systems. Although the causal mechanisms opportunity to improve symptom and health outcomes

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 Volume 48 & Number 6 & December 2016 E9

Projected number of people with Parkinson disease in the most

LITERATURE REVIEW
in PD. The knowledge gained from the biobehavioral in-
populous nations, 2005 through 2030. Neurology, 68, 384Y386.
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symptoms, pain, and fatigue severity. This knowledge will Western Journal of Nursing Research, 18, 397Y413.
also promote the development of new clinical approaches Hermanns, M. (2011). Weathering the storm: Living with
Parkinson’s disease. Journal of Christian Nursing, 28,
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of life, and functional capacity in individuals with PD. illness uncertainty concept: A review. Current Pain and
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transplant. Women and Health, 50, 359Y375. doi:10.1080/
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and psychological stress that may explain symptom and Uncertainty, symptom distress, anxiety, and functional
health outcomes in individuals with PD. In doing so, this status in patients awaiting coronary artery bypass surgery.
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