A Scoping Review Exploring Psychological Resilience in Relation to Various Biomolecular variables

Psychological Relation to Various variables. Abstract Objective: This scoping review aimed to explore the research investigating the relationship between psychological resilience and biomolecular variables, especially those related to cancer. The goal was to obtain a knowledge base that could advise further studies of the interaction between these aspects. Method: A systematic literature search of psychological resilience and various biomarkers initially resulted in 252 possible studies, of which 63 were read in full and 16 fulfilled the inclusion criteria. Result: The most used measure for psychological resilience was the CD-RISC

Furthermore, the definitions of adaptation in the resilience literature may vary, depending, for example, on the nature of the adversity. Adaptation to severe adversity may be defined in terms of an absence of psychiatric diagnoses, whereas adaptation to mild adversity could be defined as maintaining psychological health and achieving goals [2,4]. Personal factors such as self-efficacy, spirituality, and adaptability, as well as systemic microenvironmental (e.g. social support from family and friends) and macroenvironmental (e.g. health care services) factors, may increase psychological resilience [3]. There has also been a growing interest in the interaction between biological and genetic factors and psychological resilience. Genetically informative research is important for understanding the processes underlying individual variability in response to stress and, consequently, for providing a scientific basis for interventions to support psychological resilience [5]. Genetic research has enhanced the knowledge of resilience through studies of complex gene x environment (G x E) interaction processes, in which the health effects that arise from exposure to risk factors are moderated by certain genetic variations.
For example, studies of the genetic etiology of psychopathology have identified individuals with the low-activity allele of the monoamine oxidase-A (MAO-A) gene as being at increased risk of developing behavioral problems if they have experienced childhood maltreatment. However, without maltreatment, this genetic variation does not exacerbate the risk of behavioral problems [6,7]. There are repeated reports that having two copies of the 5-hydroxytryptamine-linked polymorphic region polymorphism (5-HTTLPR) short allele (S) seems to be linked to emotional problems. 5-HTTLPR is the promoter region of the serotonin transporter (5-HTT) gene. The 5-HTTLPR genetic variation increases vulnerability to depression and anxiety in contexts of high-stress childhood environments; otherwise it does not. Studies have shown that individuals carrying 5-HTTLPR S alleles function better than carriers of long alleles (L) when not exposed to stressors (see for example ref. Kim-Cohen, et al. [8], Belsky and Pluess [9]).
Hence, early life experiences may cause lasting epigenetic changes that modify gene expression which, subsequently, can affect the individual response to environmental stressors during adulthood.
In addition, these genetic variations increase plasticity and susceptibility to environmental effects [9]. Kim-Cohen and Gold [7] argue that these genes might predict psychological resilience to adversity, as well as predict psychopathology.
In medicine, there is a growing understanding of the role of psychosocial factors in disease incidence and progression. Cal and coworkers [10] identified negative correlations between psychological resilience and symptom activity for diseases, such as diabetes and Parkinson's disease. High resilience was associated with health-promoting behaviors and treatment adherence.
Additionally, some studies have described a link between stressful experiences and later cancer initiation [11]. Cancer patients are at a heightened risk for depression, which are, in turn, associated with poorer survival potentially due to an increased metastatic activity. Pinquart and Duberstein [12,13] describe the importance of social support in cancer survival. Lutgendorf and Andersen [14] outline how psychological and behavioral processes can affect biological variables involved in tumor progression. Studies show that stress peaks at the time of diagnosis (both initial diagnosis and recurrence). If stress levels are continuously high, there is a heightened risk for diminished cellular immunity and poorer cellular response to specific antigens [14]. Interestingly, Creed and coworkers [15] showed that stressed induced neural signaling affected the migration pattern of tumor cells, indicating an increased metastasizing ability. It is therefore obvious that the ability to regain psychological stability when facing such a risk is crucial. Clinically, it is important to identify those least able to manage the stressor of cancer and who, thus, are at increased risk of having a poor outcome and lower quality of life. Lutgendorf and Andersen [14] identify the need for a more nuanced understanding of the role of psychosocial factors during the cancer trajectory.

Aim
The main objective of this report is to provide a scoping review of the relationship between psychological resilience and biomolecular processes, particularly the relationship in a cancer context.

Methods
The review procedure used in this work is based on the methodological framework described by Arksey and O'Malley [16].
Scoping reviews are suitable when the current knowledge base is sparse and thus it is expected to need a broad approach. The procedure occurs in five stages:

Study Selection
Articles were included in the review if they met the following criteria:  Figure 1). After duplicates were removed, the abstracts of 252 references were screened. The rationale for exclusion was primarily based on study subjects (animal subjects) and study cohorts (specific clinical cohorts such as patients suffering from diabetes, severe psychiatric illnesses or various addictions). Sixtythree references were selected for full-text readings (Appendix 1), and 47 were excluded for the following reasons: 1.
Twenty-one did not present primary research but were reviews, editorials, articles with theoretical approaches or book chapters.

2.
Eleven did not include psychological resilience as a variable but focused on post-traumatic responses or chronic stress or maltreatment.

3.
Ten focused on specific clinical cohorts.

4.
Two did not include interpretable biological markers.

5.
Two did not focus on psychological resilience but on secure attachment or traits such as sociability.

6.
One did not include a complete methodological description.

Charting the Data
Key pieces of information from the included studies were extracted and charted to facilitate data comparison (Appendix 2). Out of the 252 references included for abstract review, 16 references are included in this scoping review. These 16 references investigate the influence of psychological parameters, such as resilience, depression and stress, in persons exposed to a variety of potentially traumatic or disturbing events and if and how those psychological parameters are coupled to biomolecular markers.
Only three references investigated a cancer indication: ovarian cancer [17,18] and radical prostatectomy or radiation therapy [19].

A range of biomolecular markers and bio-behavioral conditions
were analyzed in the included articles ( Table 1). Regardless of the type of trauma, only a few biomolecular markers were investigated in relation to psychologic resilience.

Promoter Region of the Serotonin Transporter Gene:
Genetic variants of the promoter region (5-HTTLPR) of the serotonin transporter (5-HTT) gene were investigated in five of the studies included [20,22,23,30,32]. Compared to individuals who were homozygous for the L allele, carrying one or two copies of the S allele of the promotor gene was found to be associated with, (i) more symptoms of Posttraumatic Stress Disease PTSD and depression in soldiers exposed to war zone stressors [23], (ii) worse cognition and self-reported ratings of successful aging [30], and (iii) lower psychological resilience in college students [32]. Interestingly, Graham et al. [22] showed that carrying the L allele was associated with lower resilience and more perceived limitations related to community participation in war veterans.
Graham et al. and Carli et al. [20,22] showed that men that had been subjected to severe childhood adversities and that had the L allele had lower psychological resilience and higher depressive severity than men with homozygous S/S copies of the gene. In addition, there was no correlation between carrying the S gene and psychological resilience in older adults (> 55 years) [30].

Inflammatory Markers:
In four studies, inflammatory and anti-inflammatory markers were shown to correlate with biobehavioral conditions [18,19,25,27], (i) Individuals with high social support had lower levels of the inflammatory marker matrix metalloproteinase-9 (MMP-9) in tumor-associated macrophages (TAMs) [18]; (ii) Individuals who were more depressed and reported higher levels of stress had higher levels of MMP-9 expressing TAMs [18]; (iii) Lower levels of the inflammatory markers IL-6 and CRP were correlated with higher level of health-related quality of life (HRQOL) [25]; (iv) Lower levels of the inflammatory markers IL-6, sTNF-RII and CRP were correlated with higher emotion processing ability [19]; and (v) Lower levels of the inflammatory marker IL-12 and increased levels of the anti-inflammatory markers IL-4 and IL-10 were correlated with individuals who were more stress reactive [27]. Combined, these results suggest an association between a more balanced psychological profile and lower levels of inflammatory markers, however the study by Sandvik et al. [27] showed the opposite effect.

Methods used to Analyze the Psychological Parameters:
The majority of the included articles used self-report questionnaires ( PTSD symptoms either by self-report [22,23] or by clinical interview [24]. Resilience was then defined as a lack of PTSD symptoms after trauma exposure. In contrast, self-reports of optimism, selfefficacy, or well-being despite stressful experiences (e.g., being diagnosed with cancer) indicate high resilience. Ten articles included measures of hardships [18,[20][21][22][23]25,28,[30][31][32]. Four articles used retrospective self-reports to assess negative childhood experiences due to their known impact on adult psychopathology and resilience [20,21,31,32], three studies measured present life changes [18,25,28], and three studies measured experiences of specific stressors, such as concussion, combat or returning home after military service [22,23,30] (Table 2). Two studies investigated neurophysiological responses to stress or trauma [24,28].

Neuro-physiological Measures
The Trier Social Stress Task TSST Aschbacher et al. [28] Psychological Resilience and Biomolecular Markers

Related to Specific Types of Trauma:
A. Cancer: Lutgendorf et al. [18] showed that ovarian cancer patients who are more depressed and who report higher levels of stress have higher levels of MMP-9 expressing TAMs.
They also showed that patients who perceived that they had access to supportive social relationships had lower levels of Hoyt et al. [19] showed that a person's ability to cope with and regulate emotion affects inflammatory markers. Men who underwent radical treatment for prostate cancer and who had the ability to process their emotions (i.e. understand, make meaning of and work through these emotions) had lower expression levels of the inflammatory markers IL-6, sTNF-RII and CRP. Men (from the same patient group) who were prone to emotional expression but who were less able to process their emotional experiences had elevated levels of sTNF-RII. Thus, emotional regulation via emotional processing appeared to modulate inflammatory processes.

B. Childhood Adversity:
Carli et al. [20] analyzed the correlation between the 5-HTTLPR genotype and psychological resilience and depressive symptoms in a high-risk group (male prisoners). As described above, 5-HTTLPR is the promoter region of the serotonin transporter (5-HTT) gene. The 5-HTTLPR polymorphism results in either L or S alleles. The low functional allele (S) is associated with less efficient transcription of the 5-HTT gene [35]. Carli el al. [20] concluded that men who have been subjected to severe childhood adversities and who have the L allele had lower psychological resilience and increased depressive severity than men who have the S/S homozygous gene. Das et al. [21] showed that a higher number of reported childhood adversities correlated with a lower resilience score. In addition, they also showed that a person who had the 7-repeat allele of the dopamine D4 receptor (DRD4) appeared to be protected against the decrease in psychological resilience associated with an increased number of childhood adversities because this decrease was only evident in persons without the 7-repeat allele.

C.
War: Graham et al. [22] investigated the relationship between the 5-HTTLPR genotype and psychological resilience.
This study compared resilience and the perception of community participation in war veterans that had or had not been diagnosed with traumatic brain injury. It was concluded that both, (i) the presence of traumatic brain injury and (ii) carrying the L allele were associated with lower resilience and more perceived limitations related to community participation, which is similar to the results by Carli et al. [20]. Telch et al. [23] investigated soldiers exposed to war zone stressors to identify any correlation between developing PTSD, depression or anxiety and the 5-HTTLPR genotype. Their study showed that individuals carrying one or two of the low functional alleles (S) had more symptoms of PTSD, depression and anxiety than individuals who were homozygous for the high functioning allele, L. This result was contradictory to the results of Carli and Graham, et al. [20,22].

D. High-Impact Trauma:
Two studies investigated persons that, (i) had developed PTSD (the low-resilience group) or (ii) had not developed or had recovered from PTSD (high-resilience group) after being exposed to high-impact trauma (e.g., sexual assault or rape, nonsexual assault, childhood physical/sexual abuse, adult physical abuse, lifethreating accident, witnessing violent death, domestic violence, etc.). Cowdin et al. [24] showed that persons in the high-resilience group had right frontal theta activity during REM sleep. In contrast, persons in the low-resilience group lacked this activity. This result suggests that right frontal theta activity during REM sleep is a biomarker for the capacity to adaptively process emotional memory among trauma-exposed individuals. Gill et al. [25] compared women in two groups, similar to the groups above, as well as a healthy control group (women not exposed to trauma and no PTSD diagnosis). They found that the recovered group and the control group had similarly high levels of HRQOL and similarly low levels of the inflammatory markers CRP and IL-6 compared to the women who currently had PTSD. Thus, psychological recovery from PTSD was found to be associated with normal levels of both inflammatory biomarkers and HRQoL [25].

E.
Stress: Three studies have analyzed the relationship between biological markers and psychological hardiness (later termed resilience), socioenvironmental conditions and oxidative damage in individuals exposed to different kinds of stress, e.g., acutely stressful situations [26,27] and chronic stress [28].
Psychological hardiness refers to three interrelated personality characteristics [36,37]: commitment (the tendency to involve oneself in, rather than experience alienation from, whatever one encounters in life), control (the tendency to think, feel and act as if one is influential, rather than helpless, in the face of the varied challenges of life) and challenge (the tendency to believe that change rather than stability is normal in life and that changes are interesting incentives to growth rather than threats to security).
Sandvik et al. [27] studied navy cadets in a highly stressful military field exercise. All cadets scored high on hardiness, but some However, interpersonal stress later in adulthood affected this IL-6 x SE interaction and was related to inflammatory processes. Cole et al. [26] concluded that the polymorphism in the IL-6 promoter was related to psychological resilience but also conferred a genetic vulnerability, depending on the somatic environment. Oxidative damage seems to be an important mediator of this process.
Aschbacher et al. [28] showed that women under chronic stress (i.e., who had spouses with dementia) had higher levels of 8-oxoG, reflecting oxidative damage to RNA, than the control group. These results support the emerging model that chronic psychological stress exposure promotes oxidative damage through the frequent and sustained activation of the hypothalamic-pituitary-adrenal axis.

F. Psychological Resilience in a Non-Trauma Setting:
One's level of psychological resilience is thought to be an important This is in line with findings by Telch et al. [23] but is contradictory to the results by Carli, Graham et al. [20,22]

Discussion
The main objective of this report was to provide a scoping review of the relationship between psychological resilience and biomolecular processes in a cancer context to advise research on the interaction between psychological resilience and biomolecular variables during demanding life situations such as cancer [38].
However, only few references were identified to fit those criteria; thus, the scope was broadened to include threats other than cancer, resulting in a total of 16 peer reviewed articles. This lack of cancerrelated research shows that there is a gap in the current literature connecting the body and mind in a cancer context. In addition, a spectrum of biomolecular parameters was assessed throughout the studies, and there is no systematic method for the setup of a study coupling psychological resilience to biomolecular processes.
However, there are indications that psychological resilience relates to the outcome of various diseases and that it might influence cancer diagnosis and treatment outcomes [17][18][19]. This result is also shown by the enhanced effect that stress, which is related to psychological resilience, has on the metastatic potential of tumor cells [15]. Taken together, these results show a prerequisite for more research to pave the way for a novel avenue of therapeutic interventions, both medical and psychosocial, for cancer patients.
Biomolecular variables related to inflammation and to plasticity genes has got attention.

Inflammation
Some studies Table 1  and IL-10) is more stress reactive [27], (ii) a less inflammatory microenvironment (e.g., a decreased levels of TNF-RII, IL-6 and CRP) correlated with a better ability to process emotions [19], and (iii) persons that either recovered from PTSD or never developed PTSD after experiencing trauma have a lower inflammatory signature (lower levels of CRP and IL-6) than persons with PTSD and, in addition, reported higher levels of HRQOL [25]. Thus this finding indicates a connection between psychological behaviors and inflammation, cancer progression and prognosis. Understanding, assigning meaning to and working through emotional experiences may be a promising target of intervention to reduce inflammation with potential effects on psychological resilience and cancer outcomes.

Plasticity Genes
Another finding was that the G x E interaction may relate to psychological resilience. Belsky and Pluess [9] proposed that genes that had earlier been described as vulnerability genes may be more accurately described as plasticity genes, meaning that individuals -due to their genetic make-up -can be more (or less) susceptible to environmental influences. This susceptibility goes both ways. A certain genetic variation can be associated with beneficial effects in nurturing environments, while the same variation can be associated with negative effects in poor environments. A biomarker that has been investigated in several of the included studies is the genetic variant of the promoter region (5-HTTLPR) of the serotonin transporter (5-HTT) gene. However, the results are contradictory.
Three studies [23,30,32] showed that carrying the S allele in the promotor gene is associated with a more vulnerable profile.
However, two studies [20,22] showed that the L allele is associated with a more vulnerable psychological profile. Carli et al. [20] showed that the genotype alone did not influence resilience and depression severity; however, among individuals exposed to high levels of childhood trauma, carriers of the L-allele had lower resilience scores and more severe depressive symptoms than those who were s/s homozygous. This contrasts with evidence supporting the S allele as conferring a higher risk for psychopathology in subjects exposed to recent stressful events, again demonstrating the complexed relation between biomarkers and resilience. Another biomarker of interest is the dopamine receptor gene D4. Das et al. [21] found that the 7-repeat allele of DRD4 was associated with higher resilience scores in adults. Individuals without the 7-repeat allele showed lower resilience levels. The protective effect of the 7-repeat allele was only present in individuals who had experienced negative events during childhood. Hence, their findings are coherent with findings by Carli, et al. [20].  [39] argue that these genes might predict psychological resilience to adversity, as well as psychopathology.
Sexspecific effects; differences in the type, time and duration of stressors; and the specific composition of the sample may explain the discrepancies.

Psychological Resilience Construct
The two core concepts adversity and positive adaptation showed great variation ( varied in terms of when in time participants had been exposed to adversity. In studies investigating childhood trauma exposure, adversity had occurred years before the biomolecular data were collected [24,25]. In other studies, the data were collected closer in time to the stressful event. For example, Sandvik et al. [27] collected blood samples five days after a demanding military exercise.
Previous reviews [2,4] have emphasized that the definition of positive adaptation must be appropriate for the type of adversity.
In the context of serious life-threatening events, adaptation may be defined as fewer psychopathological symptoms and/or not meeting the criteria for a major depression or PTSD. Several articles included in the present review took this approach to adaptation, e.g. Cowdin et al. [24]. Regarding everyday stressors, adaptation may instead be defined as continued optimism and/or sustained HRQOL [29,31]. Some articles combined these approaches, hence using both psychiatric illnesses (i.e., the absence of symptoms) and sustained life quality as signs of positive adaptation. Several studies measured psychological resilience directly, in most cases using the CD-RISC instrument. Instead of measuring symptoms of psychopathology or particular personal factors such as self-efficacy or optimism, the CD-RISC more comprehensively measures both intrapsychic and contextual factors. It rests on the conceptualization of psychological resilience as a protective process to employ in response to adverse conditions. In comparison, articles screening for psychopathologies investigate the "result" of psychological resilience, using methods such as depression or PTSD inventories.

Conclusion
In conclusion, this scoping review demonstrates that only very few reports have explored an association between psychological resilience and biomarkers in cancer, hence no firm conclusion can be drawn. Furthermore, the associations reported is only based on a few single biomarkers involved in inflammation or variations in a promotor region, where also the results are partly contradictory.
Since individual protein/genetic biomarkers contains too little information to form the basis for any clinical conclusions, there is a need to focus on connection macroscopic events, such as metastatic ability [15] with massive screening of biomarkers. Also the approach to assessing psychological resilience needs to be stringent in terms of adversity and adaptation. Such approaches will allow, for the first time, to analyze massive amount of biological data and then to start building biomarker networks, genetic maps and signaling pathways that will advance the knowledge of the association between psychological resilience and biomolecular variables.