ORIGINAL RESEARCH published: 25 October 2021 doi: 10.3389/fpsyg.2021.752623 Cognitive Reserve as a Protective Factor of Mental Health in Middle-Aged Adults Affected by Chronic Pain Selma Delgado-Gallén 1,2,3*, M. Dolors Soler 1,3,4 , Sergiu Albu 1,3,4 , Catherine Pachón-García 1,2,3 , Vanessa Alviárez-Schulze 1,2,3 , Javier Solana-Sánchez 1,3,4 , David Bartrés-Faz 1,5,6 , Josep M. Tormos 1,3,4 , Alvaro Pascual-Leone 1,7,8 and Gabriele Cattaneo 1,4 1 Institut Guttmann, Institut Universitari de Neurorehabilitació adscrit a la Universitat Autònoma de Barcelona (UAB), Badalona, Spain, 2 Departament de Medicina, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain, 3 Fundació Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Barcelona, Spain, 4 Universitat Autònoma de Barcelona, Bellaterra, Spain, 5 Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain, 6 Departament de Medicina, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Barcelona, Spain, 7 Hinda and Arthur Marcus Edited by: Institute for Aging Research and Center for Memory Health, Hebrew SeniorLife, Boston, MA, United States, 8 Department of Barbara Colombo, Neurology, Harvard Medical School, Boston, MA, United States Champlain College Neuroscience Lab, United States Reviewed by: Chronic pain is associated with worse mental health and cognitive impairment, which Dorina Cadar, can be a cause or a consequence of brain structure and function alterations, e.g., University College London, United Kingdom maladaptive plasticity, antinociceptive system dysregulation. Cognitive reserve reflects Panayiotis Patrikelis, the effectiveness of the internal connections of the brain and it has been shown to National and Kapodistrian University be a protective factor in brain damage, slowing cognitive aging or reducing the risk of Athens, Greece of mental health disorders. The current study explored the impact of chronic pain on *Correspondence: Selma Delgado-Gallén psychosocial factors, mental health, and cognition. Furthermore, we aimed to examine selmadelgado@guttmann.com the role of cognitive reserve in the relationship between mental health and chronic pain clinical characteristics in middle-aged adults. The study group consisted of 477 Specialty section: This article was submitted to volunteers from the Barcelona Brain Health Initiative who completed online surveys on Psychology for Clinical Settings, pain, mental health, cognitive reserve, and psychosocial factors (sleep and quality of life). a section of the journal Frontiers in Psychology We described the differences in sociodemographic data, psychosocial factors, mental Received: 10 August 2021 health, and self-perceived cognitive impairment, and neuropsychological assessment, Accepted: 16 September 2021 between participants reporting pain compared with those without pain, as well as the Published: 25 October 2021 main characteristics of the chronic pain group. Finally, to study the role of cognitive Citation: reserve in the modulation of the relationship between chronic pain and mental health, Delgado-Gallén S, Soler MD, Albu S, Pachón-García C, Alviárez-Schulze V, we compared variables between subgroups of participants with high/low pain intensity Solana-Sánchez J, Bartrés-Faz D, and cognitive reserve. The results showed that chronic pain was reported by 45.5% Tormos JM, Pascual-Leone A and Cattaneo G (2021) Cognitive Reserve of middle-aged adults. Our results revealed that participants with chronic pain were as a Protective Factor of Mental older and had worse health status than people without pain. The presence of chronic Health in Middle-Aged Adults Affected pain affected working memory, mental health, and daily life activities. Moreover, cognitive by Chronic Pain. Front. Psychol. 12:752623. reserve moderated the influence of pain intensity on mental health, resulting in less mental doi: 10.3389/fpsyg.2021.752623 health affection in people suffering from high pain intensity with high cognitive reserve. In Frontiers in Psychology | www.frontiersin.org 1 October 2021 | Volume 12 | Article 752623 Delgado-Gallén et al. Cognitive Reserve and Chronic Pain conclusion, the construct of the cognitive reserve could explain differential susceptibility between chronic pain and its mental health association and be a powerful tool in chronic pain assessment and treatment, principally due to its modifiable nature. Keywords: cognition, disease susceptibility, middle-aged, healthy lifestyle, brain reserve, psychological distress INTRODUCTION MATERIALS AND METHODS Chronic pain, a pain persisting beyond 3 months, has been Participants and Study Design linked with altered mood and mental health disorders (Baliki and This study involved 477 healthy voluntaries from the Barcelona Apkarian, 2015; Baker et al., 2016; Kawai et al., 2017), cognitive Brain Health Initiative (BBHI) (Cattaneo et al., 2018, 2020), who impairments (refer to Moriarty et al., 2011 for a review), sleep answered online questionnaires (Phase I) and performed an in- disturbances (Karaman et al., 2014; Generaal et al., 2017), and person neuropsychological assessment (Phase II). BBHI is an decreased quality of life (Leadley et al., 2014; Kawai et al., 2017; ongoing prospective longitudinal study that started in 2017 to Senba and Kami, 2017). identify lifestyle factors and biological mechanisms underlying These factors can influence the experience of pain and good brain health in healthy middle-aged adults (between 40 help the transition from acute to chronic pain (CP) (Apkarian and 65). The main BBHI aim was to study healthy participants et al., 2013). Furthermore, pain is strongly influenced by the in a pre-clinical stage of possible age-related pathologies, like cognitive context (Kucyi and Davis, 2015), altering the response dementia or Parkinson’s disease. Due to this, the inclusion to subsequent noxious stimuli, which potentially contribute to criterion was to be aged between 40 and 65 years (middle- CP development. aged adults) and to recruit only healthy participants. Exclusion A complete model for understanding pain must include not criteria were if they had a history or current diagnosis of only risk factors, which have been widely studied but also neurological disease, traumatic brain injury associated with post- protective ones. In this regard, Cognitive Reserve (CR) could traumatic sequelae, or current or recent diagnosis (<2 years) potentially play a role. CR is intended as the adaptability of of psychiatric conditions, e.g., major depression, post-traumatic cognitive processes that explain differential susceptibility to brain stress disorders, substance abuse/dependence. aging, pathology, or insult (Stern et al., 2020). People with higher Participants were divided into two groups based on CP CR have more efficient brain networks that allow them to actively presence/absence (as shown in Figure 1), i.e., if they had been cope with pathology using compensatory mechanisms (Stern, having pain for the last 3 months. 2002, 2009; Barulli et al., 2013). Previous studies suggested the The protocol was approved by the “Comité d’Ètica i role of CR as a protective factor in dementia and traumatic Investigació Clínica de la Unió Catalana d’Hospitals” and was brain injury (Reynoso-Alcántara et al., 2018) or its moderator carried out following the Declaration of Helsinki (World Medical effect in psychiatric diseases (Pertl et al., 2017; Opdebeeck Association, 2013). Written informed consent was obtained from et al., 2018), but only a few studies explored CR associations all participants before inclusion in the study. with CP and emotional factors. The study of Gómez-Beldarrain et al. found that high levels of CR in migraine patients, could Online Assessment facilitate pain control and reduce the tendency to migraine In Phase I, 4,686 participants underwent an online self- chronification (Gomez-Beldarrain et al., 2016). On the other assessment between July and December 2017 through the BBHI hand, low CR estimates decreased quality of life, increased web-based platform about sociodemographic characteristics, anxiety and depression, and increased risk for drug dependence MH, CR, and psychosocial factors (sleep, quality of life, and self- and medication overuse (Gómez-Beldarrain et al., 2015). perceived cognitive impairment), as well as a detailed screening Given these results and considering the importance of for CP or other chronic conditions. cognitive processes in pain chronification reported in previous literature (Bushnell et al., 2013; Landrø et al., 2013; Attal et al., In-person Assessment 2014; Moriarty and Finn, 2014; Brucki and Brucki, 2016), we In Phase II, from May 2018 to February 2020, 634 hypothesized that CR could modulate cognitive processes which participants selected from 1,000 performed an in-person can vary its impact on mental health (MH) in the presence assessment, including a medical and physical exam and a of CP. cognitive assessment. The aims of the current study were: (1) to investigate the The same evaluation protocol was applied to all participants. presence of CP, its clinical characteristics, and their impact on First, participants underwent a medical visit with a physician measured and self-perceived cognition and general psychological (SA), which included a clinical interview to assess previous and aspects (sleep and quality of life), (2) to explore its putative present medical conditions, body mass index (BMI), presence interference with specific psychological aspects related with MH, of CP and medication intake, tobacco, alcohol (Alcohol Use and (3) to examine the hypothesized CR protective role, expected Disorder Identification Test; AUDIT) (Carretero et al., 2016), and to weaken the relation between pain and MH in a healthy middle- use of other substances. A neuropsychological assessment session aged sample. was conducted by two expert clinical neuropsychologists (CPG Frontiers in Psychology | www.frontiersin.org 2 October 2021 | Volume 12 | Article 752623 Delgado-Gallén et al. Cognitive Reserve and Chronic Pain FIGURE 1 | Flowchart of the selection and distribution of patients in this study. BBHI, Barcelona Brain Health Initiative; NP, Neuropsychological; CP, Chronic Pain. *Volunteers were selected by BBHI methodology. For more detail information refer to Cattaneo et al. (2018, 2020). For this study, we selected participants enrolled in the project until February 2020. and VAS). The neuropsychological tests (as shown below) were and medical in-person assessment). Thus, our sample underwent administered in the same order for all participants. completely both the online (surveys) and the in-person assessments (neuropsychological testing). Inclusion and Exclusion Criteria The main exclusion criteria, as explained above, was to At the time of this analysis, between the 4,686 participants have a diagnosis of neurological disease, traumatic brain who completed the baseline set of Phase I questionnaires injury associated with post-traumatic sequelae, or current (sociodemographic, psychological aspects, psychosocial factors, or recent diagnosis (<2 years) of psychiatric conditions, pain-related questionnaires, etc.), we selected 477 subjects who e.g., major depression, post-traumatic stress disorders, also participated and completed Phase II (neuropsychological substance abuse/dependence. Moreover, participants currently Frontiers in Psychology | www.frontiersin.org 3 October 2021 | Volume 12 | Article 752623 Delgado-Gallén et al. Cognitive Reserve and Chronic Pain consuming opioids or anti-epileptics drugs, which can affect (Bartrés-Faz et al., 2018). This questionnaire has been previously cognitive performance, and participants with incomplete or validated in the Spanish population (Rami et al., 2011). The neuropsychological assessment biases, e.g., interruption during complete questionnaire can be seen in Supplementary Material. the assessment, previous knowledge about tests, or cultural background, were excluded from the analyses. Psychosocial Factors Sleep quality was assessed with The Jenkins Sleep Evaluation Assessments Questionnaire (JSEQ) (Jenkins et al., 1988). Each item was rated Online Surveys on a 6-point Likert scale, where 1 indicated no sleep problems Pain and 6 indicated frequent sleep problems. This questionnaire Participants were screened online for CP, which was considered scored from 4 to 24, where higher scores reflect low sleep the pain that persists or recurs for >3 months according to the quality. The published Spanish translation has also shown International Association for the Study of Pain (IASP) criteria good psychometric properties in a validation study (Pallarés- (Treede et al., 2015). Only those participants who answered to Sanmartín et al., 2019). have recurring or persisting pain underwent the posterior pain To assess the quality of life, we used WHO-QoL-AGE, a assessment explained below. 13-item questionnaire scored on a 5-point Likert scale. This The Brief Pain Inventory-Short form (BPI-SF) (Keller et al., questionnaire attempts to assess satisfaction with one’s life, 2004) was used to assess the intensity and severity of pain living place, general health, i.e., hearing, vision, daily activities, and pain onset. Validation studies among CP patients, and the personal relationships, goal achievements, or economic status published Spanish translation demonstrated good psychometric (The Whoqol Group, 1998). The published Spanish translation properties (Badia et al., 2003). has good psychometric data in a validation study (Lucas- Individuals referring presence of CP were asked to indicate Carrasco, 2012). the location of pain on the body map that was modified to adapt We used PROMIS R Cognitive Abilities and Cognitive to online administration. To answer pain-related questionnaires, Concerns (Fieo et al., 2016) scales to assess self-perceived participants were asked to identify the most prevalent/disturbing cognitive impairment. This scale consisted of 12-item, extracted pain, i.e., participants with more than one pain site selected the from the PROMIS R item bank, measuring self-reported main pain location. In addition, they were told to answer how cognitive deficits in memory (e.g., my memory is as good as many sites or kind of pain/location they had (one or more than usual), working memory (WM, e.g., I had trouble remembering one site). The pain location categories included: headache, facial what I was doing if I was interrupted), attention (e.g., I have had pain, neck, low back, visceral or pelvic pain, joint pain, e.g., knees, to work hard to pay attention and not make mistakes), processing shoulders, and chronic widespread pain. speed (e.g., my thinking has been slower), or cognitive flexibility. Each item asked participants to answer “within the last 7 days” Depression and Anxiety (MH) using five response options: never, rarely (once), sometimes (two We employed the ultra-brief self-reported Patient Health or three times), often (about once a day), very often (several times Questionnaire-4 (PHQ-4). It is a screener for anxiety and a day). depression, which combines the Patient Health Questionnaire- 2 (PHQ-2) and the Generalized Anxiety Disorder-2 (GAD-2). In-person Neuropsychological Assessment The PHQ-4 had four items asking mood disorder symptoms (two Neuropsychological in-person testing was administered in a items for depression and the other two items for anxiety) in the single session. Cognitive tests were administered to all subjects past 2 weeks. All items were rated on a 4-point scale ranging from in the following fixed order: direct and inverse digit span (Peña- 0 (not at all) to 3 (nearly every day). Given that the depressive Casanova et al., 2012), Trail Making Test part A and B (TMT-A and anxiety symptoms were highly correlated (r = 0.71), a and TMT-B, respectively; Peña-Casanova et al., 2012), Reasoning sum score of all four items was used to represent psychological Matrix subtest from Wechsler Adult Intelligence Scale- Fourth distress. In addition, we divided responses into four psychological Edition (WAIS-IV; Wechsler, 2012), Rey Auditory-Verbal distress levels, i.e., normal (0–2), mild (3–5), moderate (6–8), Learning Test (RAVLT; Bowler, 2013); Block Design subtest and severe (9–12) according to the diagnosis guideline suggested from WAIS-IV (Wechsler, 2012). Letter-Number Sequencing by Kroenke et al. (2009). The published Spanish translation also (Peña-Casanova et al., 2012), Digit-Symbol Substitution Test and demonstrated good psychometric properties in a validation study Cancellation subtests from WAIS-IV, and Corsi block-tapping (Kocalevent et al., 2014). test (Peña-Casanova et al., 2012). The cognitive assessment session was conducted by two expert neuropsychologists (CPG Cognitive Reserve and VAS) and lasted ∼90 min (for details refer to Cattaneo et al., Cognitive reserve was assessed using a short questionnaire 2018). (Cognitive Reserve Questionnaire; Rami et al., 2011) evaluating classical proxies of CR like the attained level of education, Data and Statistical Analysis occupation, musical formation, language skills, reading activity, Differences in sociodemographic status, drug use, and pain- and intellectual games. Two last questions explored if these related comorbidities characteristics between participants activities were being carried at present. The total score (from 0 affected by CP and pain-free participants were explored using to 34) was obtained by directly adding the single response scores one-way ANOVAs and chi-square statistics. Frontiers in Psychology | www.frontiersin.org 4 October 2021 | Volume 12 | Article 752623 Delgado-Gallén et al. Cognitive Reserve and Chronic Pain Within people affected by CP we used descriptive statistics to TABLE 1 | Sociodemographic data of participants. characterize pain location, the number of pain sites, and average No pain CP intensity over the last week, and pain onset. N = 260 N = 217 Then, we explored group differences between people Mean (SD) Mean (SD) p-value affected by CP and healthy controls in psychosocial factors, which were sleep and quality of life (The Jenkins Sleep Age (Years) 52.5 (6.8) 53.7 (6.7) 0.045* Evaluation Questionnaire and the WHO-QoL-AGE), self- Education (Years) 17.3 (3.5) 16.8 (3.9) 0.145 perceived cognitive impairment (PROMIS Cognitive abilities Frequency Frequency p-value and cognitive concerns scale), CR (CR questionnaire), MH (%) (%) (PHQ-4), and cognitive performance (measured by in-person Gender (Women) 44.2 51.6 0.108 neuropsychological assessment) running one-way ANOVAs, Professional status 0.304 correcting for age, educational level, and BMI. In these analyses, Unemployed 3.8 6.0 the variable “Group” (CP, no pain) was used as between the factor Retired 5.4 6.9 of subjects, while psychosocial aspects, such as self-perceived Part-time contract 8.8 6.9 cognitive impairment, CR, MH, and cognitive performance, Full-time contract 81.9 80.2 were used as dependent variables. Professional category 0.059 In the analyses, to compare CP with healthy controls in Unskilled manual 3.8 3.7 cognitive performance, we used scores normalized for age and labor educational level were possible (Peña-Casanova et al., 2012; Qualified manual 26.2 32.3 labor Wechsler, 2012), and raw scores when normative data were not Professional (with 27.3 31.3 available. Statistical tests were performed separately for each test university studies) and, to explore the possible influence of MH affliction in group Manager or director 42.7 32.7 differences in cognition we re-ran significant tests using MH as (with university a covariate. studies) Within the CP group, the relationship between MH and pain Civil status 0.209 was assessed with multiple regression models. We used MH as a Single 60.0 17.5 dependent variable, demographic data (age and gender), and CP Separated/Divorced 15.4 15.7 characteristics (pain intensity in the last week, duration, and the Married 22.7 65.4 number of pain sites). Widower 1.9 1.4 In a second step, we added CR to explore its contribution to Monthly incomes 0.613 <1,000e 3.5 3.7 CP and MH relationship, correcting for possible confounders like Between 1,000 and 18.1 15.2 sleep quality and BMI. 2,000 e Finally, to study the role of CR in modulating the relation Between 2,000 and 54.2 62.7 between pain and MH, we divided CP participants into two 5,000 e pain intensity (higher pain intensity/lower pain intensity) and More than 5,000 e 24.2 18.4 two CR groups (higher CR/lower CR), based on a percentile Medication <0.001** 50 of the distribution. Finally, we ran an ANOVA using None 65.0 47.5 the variable MH as the dependent variable, and the created Analgesics (NSAIDs, 2.3 6.5 groups as between-subject factors, correcting for possible aspirine…) sociodemographic confounders (age, gender, and BMI) and Antimigraine 0.4 1.4 sleep quality. Other drugs (no 31.2 34.6 pain-related) Statistical analyses were performed using SPSS version 20 Mixed medications 1.2 10.1 (Statistical Package for Social Sciences, Chicago, IL, USA). (no pain and pain) BMI <0.001** Underweight 1.5 0.5 RESULTS Normal 60.8 46.1 Differences Between CP and No Pain Overweight 29.6 39.2 Obese 8.1 14.3 Groups Mean (SD) Mean (SD) p-value Sociodemographic Characteristics of the Participants Audit 2.6 (1.5) 2.9 (2.4) 0.103 Sociodemographic data of participants are reported in Table 1. Frequency Frequency p-value Among the 477 individuals included in this study (47.60% (%) (%) women; mean age 53.5 ± 6.7 years), 217 individuals Cannabis 0.221 referred pain for more than 3 months (51.6% women, No 98.5 96.8 mean age 53.7 ± 6.7 years) and 260 individuals reported Yes 1.5 3.2 no pain (44.2% women, mean age 52.5 ± 6.8 years). There was a significant difference in age between groups. (Continued) Frontiers in Psychology | www.frontiersin.org 5 October 2021 | Volume 12 | Article 752623 Delgado-Gallén et al. Cognitive Reserve and Chronic Pain TABLE 1 | Continued TABLE 2 | Mental health, cognitive reserve and psychosocial factors in no pain and chronic pain group. Frequency Frequency p-value (%) (%) No pain Chronic pain Nicotine 0.968 Freq. (%) Freq. (%) p-value No 85.4 85.3 Mental health (PHQ-4) 0.004* Yes 14.6 14.7 (levels) Comorbidities 12.3 16.1 0.237 Low 77.7 65.9 Hypertension Mild 20.4 26.3 Cardiovascular 5.8 5.5 0.911 Moderate 1.5 6.9 diseases Severe 0.4 0.9 Cholesterol 20.4 25.3 0.201 Mean (SD) Mean (SD) p-value Diabetes 4.2 4.6 0.842 Arthritis 2.3 3.2 0.541 Mental health (PHQ-4) 1.4 (1.7) 2.3 (2.2) <0.001** (mean) Thyroid disease 8.5 12.4 0.161 Cognitive reserve 24.8 (4.8) 24.1 (4.9) 0.121 Prothesis 1.5 2.3 0.541 Psychosocial factors Gastric ulcer 2.3 4.6 0.178 Self-perceived 52.9 (7) 49.1 (9.5) <0.001** Post-hoc comparisons revealed that differences were statistically significant between cognitive impairment participants without pain and those with CP (p = 0.02); **p < 0.05; *p < 0.01. (PROMIS) SD, standard deviation; NSAIDs, Non-steroidal anti-inflammatory drugs; BMI, body mass Sleep (JSEQ) 7.1 (3.1) 9 (4.2) <0.001** index; AUDIT, Alcohol Use Disorders Identification Test. Quality of Life 31.5 (6.5) 28.7 (6.4) <0.001** (WHOQoL-AGE) Post-hoc comparisons revealed that differences were statistically significant between Professional category, professional status and marital status, participants without pain and those with CP (p = 0.02); **p < 0.05; *p < 0.01. SD, standard deviation; PHQ-4, Patient Health questionnaire; JSEQ, Jenkins Sleep monthly incomes, and educational level were not different Evaluation Questionnaire. between groups. Participants with CP had significantly higher BMI compared the digit span backward (p = 0.032), a WM test, which was worst with people without pain. Moreover, there was a high use of performed by participants with CP. drugs not related to pain in participants with CP. No differences To explore the possible influence of MH in cognitive were found between groups on alcohol, nicotine, cannabis use, or functioning differences between groups, we ran a one-way other comorbidities. ANOVA using the result of the digit span backward as the dependent variable and the variable “group” (pain, no pain) Online Questionnaires: Mental Health, Cognitive as between-subject factors. The difference between groups was Reserve, and Psychosocial Factors still significant, and the marginal significant effect of MH on People affected by CP presented a higher number of emotional cognition (F = 3.085, p = 0.080), suggests an independent role complaints (PHQ-4) (M = 2.3, SD = 2.2; p < 0.001) compared of pain in WM (F = 6.142, p = 0.014). with the no pain group (M = 1.4, SD = 1.7). Using the psychological distress level diagnosis guideline suggested by Differences Within CP Group Kroenke et al. (2009), 65.9% of CP participants experienced a Chronic pain was more frequently located at the back (36.9%), normal level of distress, 26.3% reported mild distress, 6.9% had followed by the lower limbs (29.5%) and upper limbs (19.8%), moderate distress, and severe distress was present in 0.9% of our head/face (6.5%), widespread (4.6%), and visceral/pelvic (2.8%) pain sample (Table 2; Figure 2). (Figure 2). The cognitive reserve score was not significantly different The average pain intensity was 3.75 (SD = 1.8) on a scale from between pain groups (p = 0.121). However, an increased level 0 to 10. From all the subjects who reported having CP pain, only of subjective cognitive impairment in the PROMIS R Cognitive one person rated 0/10 of pain intensity during the last week. Abilities and Cognitive Concerns survey was observed in the CP From our sample, 37.8% had a single site pain, while 62.2% group (p < 0.001). reported two or more pain sites. A relatively small proportion People affected by CP reported poorer sleep quality than the of participants experienced pain for the last 3–6 (12.9%) and 6– no pain group (p < 0.001) and lower quality of life (p < 0.001). 12 months (18.4%), while most participants suffered from CP for more than 12 months (68.7%) (Figure 3). In-person Assessment: Cognitive Performance Results of cognitive tests are summarized in Table 3. All tests Pain Intensity, Cognitive Reserve Interaction, and were interpreted as mean values in normalized scores, except for Mental Health in CP the results of the Rey Auditory Verbal Learning Test and Trail Multiple regression in CP sample analysis revealed that age Making Test B-A that did not have Spanish normative values. (β = −0.212; p = 0.001) and pain intensity (β = 0.167, There were no statistical differences between groups, except for p = 0.016) were significantly associated with MH. No significant Frontiers in Psychology | www.frontiersin.org 6 October 2021 | Volume 12 | Article 752623 Delgado-Gallén et al. Cognitive Reserve and Chronic Pain FIGURE 2 | Descriptive distribution of participants with and without CP according to their distress level: low (0–2), mild (3–5), moderate (6–8), and severe (9–12). TABLE 3 | Mean normalized and raw scores in neuropsychological assessment. (F = 5.767; p = 0.017) indicated that people with high CR showed lower MH affliction. Crucially, we found a significant Cognitive test Score No CP (mean) CP (mean) p-value pain intensity and reserve interaction (F = 6.956; p = 0.009; WAIS-IV Matrices Normalized 13.2 (2.6) 13.2 (2.5) 0.981 Figure 4). Block design Normalized 12.2 (2.9) 11.9 (3.1) 0.414 Trail making Test A Normalized 11.5 (2.6) 11.3 (2.8) 0.580 Trail making Test B Normalized 8.9 (2.1) 8.6 (2.1) 0.083 DISCUSSION Trail making test B-A Raw 48.9 (22.4) 51.2 (23.7) 0.698 The current study explored the impact of CP on psychosocial Digit symbol substitution Normalized 14 (2.6) 14.7 (2.4) 0.873 factors, MH, and cognition. Furthermore, we aimed to examine Cancellation WAIS-IV Normalized 11.3 (2.7) 11.6 (2.8) 0.241 the role of CR in the relationship between MH and CP clinical Letter-number sequencing Normalized 14.5 (2.4) 13.9 (2.5) 0.320 characteristics in middle-aged adults. Digit span backward Normalized 11.1 (2.6) 11.6 (2.7) 0.032* Our main results suggested that: (1) CP participants showed Corsi cubes Normalized 14 (2.5) 14.2 (2.5) 0.269 worst levels of WM and MH, and (2) the presence of high/low Digit span forward Normalized 10.9 (2.5) 11.1 (2.7) 0.529 CR modifies the interaction between pain intensity and MH. RAVLT immediat recall Raw 51.9 (8.8) 52.3 (8.4) 0.117 We found a high prevalence of CP (45.5%, 217 participants) RAVLT delayed recall Raw 11.4 (2.8) 11.4 (2.5) 0.324 in our cohort, in line with previous reports of a peak prevalence Mean normalized scores corrected for age and education, except for RAVLT and Trail in late middle-aged adults (50–65 years), affecting up to 20–80% Making test B-A (raw scores). *p < 0.05. of people (Gibson and Lussier, 2012). CP at multiple pain sites was the most prevalent pain condition (62.2%; Brady et al., 2015; Suvinen et al., 2016; Finney et al., 2017), CP in the back and joints associations were found for gender (β = 0.008; p = 907), pain in the lower limbs were the most prevalent pain sites (Ligthart duration (β = 0.079, p = 0.238), or the number of pain sites et al., 2014; Maixner et al., 2016), and 40% of people affected by (β = 0.102, p = 0.138). CP referred the presence of pain for more than 3 years. When we included into the regression model CR and Our CP group showed a higher presence of overweight psychosocial variables, we found that MH was still significantly compared with people without pain. There may be a bidirectional associated with age (β = −0.173, p = 0.005) and pain intensity causality, wherein CP may result in weight gain by reducing (β = 0.131, p = 0.048), but in addition, it resulted related to sleep physical activity (Verbunt et al., 2003), and individuals could quality (β = 0.332, p < 0.001) and CR (β = − 0.260, p < 0.001) have structural body changes causing pain (Lake et al., 2000). The (as shown in Table 4). fact that the CP group consumed significantly more medication, The evaluation of the interaction between CR and pain which is associated with higher BMI, suggested that this group intensity using pain intensity groups (higher, lower) and CR has worse general health. Finally, overweight has been related groups (higher, lower) as between-subject factors, revealed an previously with other domains referred to in our study, as well intensity main effect (F = 8.639; p = 0.004), indicating worse as sleep quality (Hargens et al., 2013) or cognitive impairment MH in people with higher pain intensity. The CR main effect (Nilsson and Nilsson, 2009). Frontiers in Psychology | www.frontiersin.org 7 October 2021 | Volume 12 | Article 752623 Delgado-Gallén et al. Cognitive Reserve and Chronic Pain FIGURE 3 | (A) Number of participants (in %) in each pain location; (B) Percentage of participants according to their last week pain intensity perception in an NRS (Numerical Rating Scale). Ratings have been classified into three main groups: from 0 to 2; 3–5; 6–10; (C) Population (in %) with one pain site (or one kind of pain) and more than one site; (D) Participants’ pain onset, classified in 3–6 months; 6–12 months; 1–3 years; 3–6 years; 6–9 years, and more than 10 years. TABLE 4 | Multiple regressions: the influence of chronic pain and psychosocial A further finding of our study prolonged experience of factors on mental health. pain was associated with significantly lower quality of life, Domain β p-value cognitive and mood consequences, such as mild depressive symptoms (PHQ-4), and self-perceived cognitive impairment Age −0.173 0.005** (PROMIS). Unquestionably, feeling pain may evolve from typical Gender 0.008 0.895 reactive emotional symptoms related to stress (Hammen, 2005) Pain duration 0.062 0.308 to clinically relevant depression (DeVeaugh-Geiss et al., 2010). Pain intensity 0.131 0.048* This close relationship between emotions and pain is a complex Multisite pain 0.041 0.525 experience that is perceived differently across people and varies BMI −0.041 0.523 even within individuals depending on context (Bushnell et al., Sleep 0.332 < 0.001** 2013). As for other adaptive affective responses, such as fear CR −0.260 < 0.001** and anxiety, the level of emotional facilitation of pain when it comes to some individuals can be maladaptive, leading to long- **p < 0.05; *p < 0.01. Table reports β-standardized scores and p-values. BMI, body mass index; CR, Cognitive Reserve. term suffering (Gandhi et al., 2020). Additionally, people with CP reported more subjective cognitive complaints. On one hand, pain acts through the consumption of attentional resources, and, Our findings were consistent with previous research, reporting on the other, through psychological and emotional aspects. This an association between CP with sleep, mood, and psychosocial can give rise to feelings of discomfort, leading some individuals alterations (Edwards et al., 2016). Pain and sleep have a to overestimate their difficulties, including subjective emotional reciprocal, interdependent relationship, wherein poor sleep can and cognitive impairment, which can be ultimately transferred in predict pain in certain conditions and compounds the pain everyday behavior. experience (Turk et al., 2016). Furthermore, sleep deprivation Concerning the cognitive performance in our sample, almost can lower the pain threshold, affecting the cognitive ability to all domains were not affected when we compared CP with no cope with pain, increasing ratings of pain intensity, which in turn pain group. This is coherent with the fact that we are describing exacerbates poor sleep (Okifuji and Hare, 2011). a healthy and young sample, and exclusion criteria were specially Frontiers in Psychology | www.frontiersin.org 8 October 2021 | Volume 12 | Article 752623 Delgado-Gallén et al. Cognitive Reserve and Chronic Pain FIGURE 4 | Distribution of CP participants (Higher pain intensity/Lower pain intensity; Higher CR/Lower CR) according to the percentile 50. Participants with higher CR showed less impact on mental health in the higher pain-intensity group. *p < 0.05. chosen to avoid other variables that could affect cognition (use processing and WM has been demonstrated (Davis et al., 2008). of psychiatric or neurologic disorders or opioids). In addition, For instance, patients with back pain, fibromyalgia, or CRPS we also analyzed possible cofounders as age, educational level, have shown deficits in emotional decision-making when they or BMI. Notwithstanding, our results indicated that people were tested with the Iowa gambling task (Apkarian et al., 2004; with CP showed lower WM performance, in the digit span Tamburin et al., 2014). Thus, the anatomical changes observed backward test, and this was consistent with several previous in patients with CP may well be an underlying factor in their studies (Sjøgren et al., 2005; Veldhuijzen et al., 2006; Buhle altered performance in cognitive tasks. It is important to point and Wager, 2010). WM has been related to a better capacity out that when we explored if the cognitive function was primarily to choose cognitive strategies when facing a situation or task due to pain or to MH results showed that, although MH had a (Hilbert et al., 2015), and it is considered as one of several partial contribution, the pain has an independent effect in WM, functions within the executive control domain strongly related as previously seen by Bunk et al. in their review (Bunk et al., to attentional processes (McCabe et al., 2010). Indeed, evidence 2019). suggested that selective attention facilitates working memory In this sense, it has been also demonstrated that persistent processing, by preventing inference from unrelated distractions, and CP is associated with alteration in the activity of the while maintaining attention to the relevant targets (Legrain Default Mode Network (DMN) and the connectivity between its et al., 2011). Thus, painful stimuli or emotional discomfort nodes (medial prefrontal cortex, lateral parietal cortex/angular could act as distractors in our pain participants, causing an gyrus, and posterior cingulate cortex/precuneus) (Baliki et al., abnormal allocation of attentional resources to pain stimuli and 2008; Tessitore et al., 2013), consistently related with WM consequently impact WM capacity. dysfunctions (Mazoyer et al., 2001; Sambataro et al., 2010), At a neurobiological level, two main regions in the frontal coping strategies (Santarnecchi et al., 2018) and several MH cortex, related with both WM and pain processing, could pathological conditions (refer to Broyd et al., 2009 for a review) represent the substrate of this relation. The dorsolateral (Broyd et al., 2009). Recent evidence from non-invasive brain prefrontal cortex (DLPFC) and orbitofrontal cortex were stimulation (NIBS) indicates that stimulation of nodes of the evidently both involved in the ability to cope with pain and DMN is associated with WM performance in healthy adults to inhibit pain, respectively (Bunk et al., 2019). Several studies (Pupíková et al., 2021) or could be a promising therapeutic not only have shown decreased gray matter in left DLPFC approach to reduce cognitive and mood disorders in different and orbitofrontal cortex in CP patient but also how these pathologies (Alexoudi et al., 2019, 2020; Chou et al., 2020). abnormalities can be reversed with CP resolution (Davis and Finally, it has been recently shown that transcranial direct current Moayedi, 2013; Seminowicz and Moayedi, 2017; Ong et al., 2019). stimulation (tDCS) modulates pain perception, but depending Furthermore, an association between these areas and attentional on the age, the brain target should be M1 (for older adults) or Frontiers in Psychology | www.frontiersin.org 9 October 2021 | Volume 12 | Article 752623 Delgado-Gallén et al. Cognitive Reserve and Chronic Pain DLPFC (for younger adults), although both sides increased WM concept of a dynamic “pain connectome,” in which differences ability (Saldanha et al., 2020). These gains are related to different in mind wandering from pain and attention to pain stimuli are connections of these structures with pain processing, but it has associated with cognitive performance and brain functioning. also an impact on cognitive and emotional features related to Increased activations of the above-mentioned DMN, were seen pain perception. when the minds of people wander away from pain. Moreover, What we considered as one of the most relevant findings strong interactions between the DMN and periaqueductal gray, was that the relationship between MH and pain intensity was an opiate-rich region mediating pain suppression (Pessoa, modulated by CR, wherein only in the high pain intensity group, 2008), resulting in weaker anatomical connections and the participants with higher CR showed less MH affliction, compared antinociceptive system were found in subjects with difficulty with lower CR participants. Under certain assumptions, this tuning out pain. could be interpreted as individuals with higher levels of CR This tuning out pain difficulty is often explained in terms can handle and manage pain and attentional resources more of the specific construct of a “hyper-vigilance” to pain, i.e., efficiently (with lower suffering) than people with low CR. a tendency to increase attentional allocation to pain-related In this line previous studies have seen a CR moderator effect information, related to habits to attend to bodily sensations or the between mood and cognition (Pertl et al., 2017; Opdebeeck et al., persistent search for pain relief in patients (Crombez et al., 2005). 2018; Huang et al., 2019), wherein higher CR may increase Individuals who expect somatosensory stimuli to be painful (fear the ability to manage difficulties, employing the best strategy and catastrophic thoughts) show more attentional interruption for performing a task and better allocating cognitive resources by non-painful somatosensory stimuli that are delivered at the (Barulli et al., 2013). This then allows some individuals to be less same location (Crombez et al., 2005) and this is associated prone to attend to pain or depressive symptoms and more capable with greater activity in operculo-insular and mid-cingulate to easily “tune out” it. cortex (Seminowicz and Davis, 2006). Further, individuals with Cognitive reserve did not prevent the pre-determinate constitutively limited attentional resources or cognitive flexibility biological factors from spurring the pathology, as it acted as are at greater risk of more difficulties to cope with pain, partly due a complementary mechanism, which modified how the brain to a decision-making ability or may be linked to the mechanisms responds to that factors once they were present (Barulli and Stern, of pain chronicity (Attal et al., 2014). 2013, 2018). In this sense, it is important to note that the CR levels From this perspective, the construct of CR could be used of our sample were similar in both groups. Once pathology was in the prevention or treatment of CP, as it has already been present, as said before, CR could be associated with the ability of seen in Alzheimer’s disease (Scarmeas and Stern, 2003; Arenaza- an individual to resolve difficulties and use optimally cognitive Urquijo et al., 2015). CP approaches based on cognition have resources and alternative processes and strategies (Barulli et al., been showing to be effective. As Kucyi et al. (2016) stated in their 2013). study, CP treatment should be addressed to change the cognitive This role of CR in modulating the relation between CP and context in which pain occurs, maladaptive neuroplastic changes MH, via better allocation of cognitive and attentional resources, occurring in response to spontaneous neuronal pain-related could potentially be extended to other consequences of CP. activity should be modified. In their study about cognitive- In this line, one can speculate a more general model of the behavioral therapy, they found changes in fMRI, like increased moderator role of CR in CP, considering that CR could exert, intrinsic connectivity between the ventrolateral prefrontal cortex through the same mechanisms, a similar protective effect also and DMN (Kucyi et al., 2016). Cognitive training has also been for the development of pain-related comorbidities or cognitive shown to be effective in improving cognitive skills and decrease dysfunctions like the WM impairment we found in our sample. pain intensity (Baker et al., 2018). In the absence of an effective In this sense, since pain is also actively determined by pharmacological treatment for CP, we can consider that the expectations and learned experiences, more general-domain potential role of lifestyles factors (for example, training cognitive functional descending top-down modulatory effects orchestrated skills in daily life), understanding the neural mechanisms by prefrontal structures linked with CR may buff the ability underlying expectations, emotional state, or focus attention on to manage the bottom-up and involuntary capture of attention pain, seems crucial. by pain (Legrain et al., 2009a,b; Wiech, 2016), affecting the processing of nociceptive stimuli at early levels by biasing Limitations somatosensory brain activity (Legrain et al., 2002). From The main limitation of this study was that our sample was a pathophysiological point of view, the study of Villemure non-homogenous, with a high prevalence of individuals with and Schweinhardt (2010) suggested that supraspinal pain high education, which may lead to results that may not be processing, and specifically, increased activity in the lateral representative of the general population. Moreover, the sample of orbitofrontal cortex [closely related to CR; refer to Gomez- the study is relatively small, and most measures are self-reported. Beldarrain et al. (2016)] induced by negative emotions, could lead Another limitation was that our participants were healthy, that to descending facilitatory pathways by increasing nociceptive is, not patients in a pain unit, and they did not have high signals transmitted from the spinal cord to the brain. levels of pain in intensity or pain-related impairments (cognition, Regarding descending modulation networks in fMRI studies pain interference, or affective disorders). Future research should (also known as antinociceptive system) in fMRI studies, Kucyi consider the potential effects of cognition and emotion in et al. (2013) and Kucyi and Davis (2015) introduced the pain modulation more carefully, for example focusing on pain Frontiers in Psychology | www.frontiersin.org 10 October 2021 | Volume 12 | Article 752623 Delgado-Gallén et al. Cognitive Reserve and Chronic Pain catastrophizing and coping strategies, their relationship with CR, JS-S contributed to revising it critically for important intellectual and their influence on pain. content. MDS, GC, and SD-G participated in drafting the Finally, this study has some disadvantages derived from the manuscript, made substantial contributions to analysis, and cross-sectional design, where the principal flaw is that we cannot interpretation of data. SA, VA-S, CP-G, JS-S, and SD-G had made determine if the relationship explained above between pain and substantial contribution to acquisition of data. All authors have mental health is cause or effect. given final approval of the version to be submitted. CONCLUSIONS FUNDING In summary, CR may play a determinant protective role in CP, MDS was supported by ERANET fund from the Instituto de reducing its impact on psychological and MH well-being, and Salud Carlos III of Spain. AP-L is a co-founder of Linus Health buff endogenous control mechanisms. Persistent pain can be and TI Solutions AG, serves on the scientific advisory boards detrimental to the brain, decreasing the ability of an individual for Starlab Neuroscience, Neuroelectrics, Magstim Inc., and to endogenously control it and lead to many comorbidities, MedRhythms, and is listed as an inventor on several issued and concluding with the idea that “no pain, healthy brain.” pending patents on the real-time integration of non-invasive Understanding the dynamic relationship between CP, MH, brain stimulation with electroencephalography and magnetic and CR, and that higher CR in healthy adults was associated resonance imaging. DB-F was funded by a Spanish Ministry of with better emotional decision-making and strategies selection Science, Innovation and Universities (MICIU/FEDER; RTI2018- to cope with pain and MH, resulting in relevant implications for 095181-B-C21) and an ICREA Academia 2019 research grants, developing new spots on CP and treatment approaches. and also supported by an ICREA Academia 2019 grand award, JT This provided a good starting point for further research. was partly supported Fundació Joan Ribas (Araquistain_FJRA), Longitudinal assessments with appropriate control conditions AGAUR, Agència de Gestió d’Ajuts Universitaris i de Recerca. are needed to determine how CR and changes in pain Convocatòria 2018 d’Indústria del Coneixement (modalitat connectome dynamics mediate the effects in middle-aged adults PRODUCTE) and FEDER, Fons Europeu de Desenvolupament with CP. Regional (2018 PROD 00172), Fundació La Marató De TV3 (201735.10), and European Commission - H2020/Call H2020- DATA AVAILABILITY STATEMENT SC1-2016-2017 (RIA) (Grant Agreement No. 777107). The raw data supporting the conclusions of this article will be ACKNOWLEDGMENTS made available by the authors, without undue reservation. A special thanks is extended to all participants, the project ETHICS STATEMENT team and research assistants, and other partners (Ad-Salutem Institute, Sodexo, I.C.A. Informàtica y Comunicaciones The studies involving human participants were reviewed and Avanzadas, Neuroelectrics, Corporació Catalana de Mitjans approved by Comité d’Ètica i Investigació Clínica de la Unió Audiovisuals, Club Metropolitan, Casa Ametller, and Agència de Catalana d’Hospitals. The patients/participants provided their Qualitat i Avaluació Sanitàries de Catalunya-AQuAS) for their written informed consent to participate in this study. invaluable collaboration. AUTHOR CONTRIBUTIONS SUPPLEMENTARY MATERIAL MDS, GC, SA, VA-S, CP-G, JS-S, AP-L, DB-F, JT, and SD-G The Supplementary Material for this article can be found had made substantial contributions to conception, design, and online at: https://www.frontiersin.org/articles/10.3389/fpsyg. interpretation of data. AP-L, DB-F, JT, SA, VA-S, CP-G, and 2021.752623/full#supplementary-material REFERENCES Apkarian, A. V., Sosa, Y., Krauss, B. R., Thomas, P. S., Fredrickson, B. E., Levy, R. E., et al. (2004). Chronic pain patients are impaired on an emotional Alexoudi, A., Patrikelis, P., Deftereos, S., Fasilis, T., Karakalos, D., Verentzioti, decision-making task. Pain 108, 129–136. doi: 10.1016/j.pain.2003.12.015 A., et al. (2019). Effects of anodal transcranial direct current stimulation Arenaza-Urquijo, E. M., Wirth, M., and Chételat, G. (2015). Cognitive reserve and on cognitive dysfunction in patients with progressive supranuclear palsy. lifestyle: moving towards preclinical Alzheimer’s disease. Front. Aging Neurosci. Psychiatriki 30, 320–328. doi: 10.22365/jpsych.2019.304.320 7:134. doi: 10.3389/fnagi.2015.00134 Alexoudi, A., Patrikelis, P., Fasilis, T., Deftereos, S., Sakas, D., and Gatzonis, Attal, N., Masselin-Dubois, A., Martinez, V., Jayr, C., Albi, A., Fermanian, J., S. (2020). Effects of anodal tDCS on motor and cognitive function in et al. (2014). Does cognitive functioning predict chronic pain? Results from a a patient with multiple system atrophy. Disabil. Rehabil. 42, 887–891. prospective surgical cohort. Brain 137, 904–917. doi: 10.1093/brain/awt354 doi: 10.1080/09638288.2018.1510043 Badia, X., Muriel, C., Gracia, A., Manuel Núñez-Olarte, J., Perulero, N., Apkarian, A. V., Baliki, M. N., and Farmer, M. A. (2013). Predicting Gálvez, R., et al. (2003). Validación española del cuestionario Brief Pain transition to chronic pain. Curr. Opin. Neurol. 26, 360–367. Inventory en pacientes con dolor de causa neoplásica. Med. Clín. 120, 52–59. doi: 10.1097/WCO.0b013e32836336ad doi: 10.1016/S0025-7753(03)73601-X Frontiers in Psychology | www.frontiersin.org 11 October 2021 | Volume 12 | Article 752623 Delgado-Gallén et al. Cognitive Reserve and Chronic Pain Baker, K. S., Georgiou-Karistianis, N., Lampit, A., Valenzuela, M., Gibson, Davis, K. D., and Moayedi, M. (2013). Central mechanisms of pain revealed S. J., and Giummarra, M. J. (2018). Computerised training improves through functional and structural MRI. J. Neuroimm. Pharmacol. 8, 518–534. cognitive performance in chronic pain: a participant-blinded randomised doi: 10.1007/s11481-012-9386-8 active-controlled trial with remote supervision. Pain 159, 644–655. Davis, K. D., Pope, G., Chen, J., Kwan, C. L., Crawley, A. P., and doi: 10.1097/j.pain.0000000000001150 Diamant, N. E. (2008). Cortical thinning in ibs: implications for Baker, T. A., Krok-Schoen, J. L., O’Connor, M. L., and Brooks, A. K. homeostatic, attention, and pain processing. Neurology 70, 153–154. (2016). The influence of pain severity and interference on satisfaction with doi: 10.1212/01.wnl.0000295509.30630.10 pain management among middle-aged and older adults. Pain Res. Manag. DeVeaugh-Geiss, A. M., West, S. L., Miller, W. C., Sleath, B., Gaynes, B. N., 2016:9561024. doi: 10.1155/2016/9561024 and Kroenke, K. (2010). The adverse effects of comorbid pain on depression Baliki, M. N., and Apkarian, A. V. (2015). Nociception, pain, negative moods, and outcomes in primary care patients: results from the ARTIST trial. Pain Med. 11, behavior selection. Neuron 87, 474–491. doi: 10.1016/j.neuron.2015.06.005 732–741. doi: 10.1111/j.1526-4637.2010.00830.x Baliki, M. N., Geha, P. Y., Apkarian, A. V., and Chialvo, D. R. (2008). Beyond Edwards, R. R., Dworkin, R. H., Sullivan, M. D., Turk, D. C., and Wasan, A. D. feeling: chronic pain hurts the brain, disrupting the default-mode network (2016). The role of psychosocial processes in the development and maintenance dynamics. J. Neurosci. 28, 1398–1403. doi: 10.1523/JNEUROSCI.4123-07.2008 of chronic pain. J. Pain 17, T70–92. doi: 10.1016/j.jpain.2016.01.001 Bartrés-Faz, D., Cattaneo, G., Solana, J., Tormos, J. M., and Pascual-Leone, A. Fieo, R., Ocepek-Welikson, K., Kleinman, M., Eimicke, J. P., Crane, P. K., Cella, (2018). Meaning in life: resilience beyond reserve. Alzheimers Res. Ther. 10:47. D., et al. (2016). Measurement equivalence of the patient reported outcomes doi: 10.1186/s13195-018-0381-z measurement information system R (PROMIS R ) applied cognition - general Barulli, D., and Stern, Y. (2013). Efficiency, capacity, compensation, maintenance, concerns, short forms in ethnically diverse groups. Psychol. Test Assess. Model. plasticity: emerging concepts in cognitive reserve. Trends Cogn. Sci. 17, 58, 255–307. Available online at: https://psycnet.apa.org/record/2016-42060- 502–509. doi: 10.1016/j.tics.2013.08.012 002 Barulli, D., and Stern, Y. (2018). “Cognitive reserve: theory, measurement, and Finney, A., Dziedzic, K. S., Lewis, M., and Healey, E. (2017). Multisite peripheral evidence,” in APA Handbook of Dementia APA Handbooks in Psychology R , joint pain: a cross-sectional study of prevalence and impact on general health, eds G. E. Smith and S. T. Farias (Washington, DC: American Psychological quality of life, pain intensity and consultation behaviour. BMC Musculoskelet Association), 357–368. Disord. 18:535. doi: 10.1186/s12891-017-1896-3 Barulli, D. J., Rakitin, B. C., Lemaire, P., and Stern, Y. (2013). The influence of Gandhi, W., Rosenek, N. R., Harrison, R., and Salomons, T. V. (2020). Functional cognitive reserve on strategy selection in normal aging. J. Int. Neuropsychol. connectivity of the amygdala is linked to individual differences in emotional Soc. 19, 841–844. doi: 10.1017/S1355617713000593 pain facilitation. Pain 161, 300–307. doi: 10.1097/j.pain.0000000000001714 Bowler, D. (2013). “Rey auditory verbal learning test (rey AVLT),” in Encyclopedia Generaal, E., Vogelzangs, N., Penninx, B. W. J. H., and Dekker, J. (2017). Insomnia, of Autism Spectrum Disorders, ed. F. R. Volkmar (New York, NY: Springer), sleep duration, depressive symptoms, and the onset of chronic multisite 2591–2595. musculoskeletal pain. Sleep 40. doi: 10.1093/sleep/zsw030 Brady, S. R. E., Mamuaya, B. B., Cicuttini, F., Wluka, A. E., Wang, Y., Hussain, Gibson, S. J., and Lussier, D. (2012). Prevalence and relevance of pain in older S. M., et al. (2015). Body composition is associated with multisite lower persons. Pain Med. 13, S23–S26. doi: 10.1111/j.1526-4637.2012.01349.x body musculoskeletal pain in a community-based study. J. Pain 16, 700–706. Gómez-Beldarrain, M., Anton-Ladislao, A., Aguirre-Larracoechea, U., Oroz, I., doi: 10.1016/j.jpain.2015.04.006 and García-Moncó, J. C. (2015). Low cognitive reserve is associated with Broyd, S. J., Demanuele, C., Debener, S., Helps, S. K., James, C. J., and chronic migraine with medication overuse and poor quality of life. Cephalalgia Sonuga-Barke, E. J. S. (2009). Default-mode brain dysfunction in mental 35, 683–691. doi: 10.1177/0333102414553822 disorders: a systematic review. Neurosci. Biobehav. Rev. 33, 279–296. Gomez-Beldarrain, M., Oroz, I., Zapirain, B. G., Ruanova, B. F., Fernandez, doi: 10.1016/j.neubiorev.2008.09.002 Y. G., Cabrera, A., et al. (2016). Right fronto-insular white matter tracts Brucki, S. M., and Brucki, S. M. (2016). Chronic pain and cognition. Arquivos link cognitive reserve and pain in migraine patients. J. Head. Pain 17:4. Neuro-Psiquiatr. 74, 359–360. doi: 10.1590/0004-282X20160062 doi: 10.1186/s10194-016-0593-1 Buhle, J., and Wager, T. D. (2010). Performance-dependent inhibition Hammen, C. (2005). Stress and depression. Annu. Rev. Clin. Psychol. 1, 293–319. of pain by an executive working memory task. Pain 149, 19–26. doi: 10.1146/annurev.clinpsy.1.102803.143938 doi: 10.1016/j.pain.2009.10.027 Hargens, T. A., Kaleth, A. S., Edwards, E. S., and Butner, K. L. (2013). Association Bunk, S., Preis, L., Zuidema, S., Lautenbacher, S., and Kunz, M. (2019). Executive between sleep disorders, obesity, and exercise: a review. Nat. Sci. Sleep 5, 27–35. functions and pain A systematic review. Zeitschrift Neuropsychol. 30, 169–196. doi: 10.2147/NSS.S34838 doi: 10.1024/1016-264X/a000264 Hilbert, S., Nakagawa, T. T., Puci, P., Zech, A., and Bühner, M. (2015). Bushnell, M. C., Ceko, M., and Low, L. A. (2013). Cognitive and emotional control The digit span backwards task: verbal and visual cognitive strategies of pain and its disruption in chronic pain. Nat. Rev. Neurosci. 14, 502–511. in working memory assessment. Eur. J. Psychol. Assess. 31, 174–180. doi: 10.1038/nrn3516 doi: 10.1027/1015-5759/a000223 Carretero, M. Á. G., Ruiz, J. P. N., Delgado, J. M. M., and González, C. O. (2016). Huang, C.-M., Fan, Y.-T., Lee, S.-H., Liu, H.-L., Chen, Y.-L., Lin, C., et al. Validación del test para la identificación de trastornos por uso de alcohol (2019). Cognitive reserve-mediated neural modulation of emotional control en población universitaria: AUDIT y AUDIT-C. Adicciones 28, 194–204. and regulation in people with late-life depression. Soc. Cogn. Affect. Neurosci. doi: 10.20882/adicciones.775 14, 849–860. doi: 10.1093/scan/nsz054 Cattaneo, G., Bartrés-Faz, D., Morris, T. P., Sánchez, J. S., Macià, D., Tarrero, C., Jenkins, C. D., Stanton, B. A., Niemcryk, S. J., and Rose, R. M. (1988). A scale et al. (2018). The barcelona brain health initiative: a cohort study to define for the estimation of sleep problems in clinical research. J. Clin. Epidemiol. 41, and promote determinants of brain health. Front. Aging Neurosci. 10:321. 313–321. doi: 10.1016/0895-4356(88)90138-2 doi: 10.3389/fnagi.2018.00321 Karaman, S., Karaman, T., Dogru, S., Onder, Y., Citil, R., Bulut, Y. E., et al. (2014). Cattaneo, G., Bartrés-Faz, D., Morris, T. P., Sánchez, J. S., Macià, D., Tormos, Prevalence of sleep disturbance in chronic pain. Eur. Rev. Med. Pharmacol. Sci. J. M., et al. (2020). The barcelona brain health initiative: cohort description 18, 2475–2481. Available online at: https://www.europeanreview.org/article/ and first follow-up. PLoS ONE 15:e0228754. doi: 10.1371/journal.pone. 7760 0228754 Kawai, K., Kawai, A. T., Wollan, P., and Yawn, B. P. (2017). Adverse Chou, T., Hooley, J. M., and Camprodon, J. A. (2020). Transcranial direct impacts of chronic pain on health-related quality of life, work productivity, current stimulation of default mode network parietal nodes decreases depression and anxiety in a community-based study. Fam. Pract. 34, 656–661. negative mind-wandering about the past. Cogn. Ther. Res. 44, 10–20. doi: 10.1093/fampra/cmx034 doi: 10.1007/s10608-019-10044-9 Keller, S., Bann, C. M., Dodd, S. L., Schein, J., Mendoza, T. R., and Cleeland, Crombez, G., Van Damme, S., and Eccleston, C. (2005). Hypervigilance C. S. (2004). Validity of the brief pain inventory for use in documenting to pain: an experimental and clinical analysis. Pain 116, 4–7. the outcomes of patients with noncancer pain. Clin. J. Pain 20, 309–318. doi: 10.1016/j.pain.2005.03.035 doi: 10.1097/00002508-200409000-00005 Frontiers in Psychology | www.frontiersin.org 12 October 2021 | Volume 12 | Article 752623 Delgado-Gallén et al. Cognitive Reserve and Chronic Pain Kocalevent, R.-D., Finck, C., Jimenez-Leal, W., Sautier, L., and Hinz, A. (2014). Ong, W.-Y., Stohler, C. S., and Herr, D. R. (2019). Role of the Standardization of the Colombian version of the PHQ-4 in the general prefrontal cortex in pain processing. Mol. Neurobiol. 56, 1137–1166. population. BMC Psychiatry 14:205. doi: 10.1186/1471-244X-14-205 doi: 10.1007/s12035-018-1130-9 Kroenke, K., Spitzer, R. L., Williams, J. B. W., and Löwe, B. (2009). An ultra- Opdebeeck, C., Matthews, F. E., Wu, Y.-T., Woods, R. T., Brayne, C., and brief screening scale for anxiety and depression: the PHQ-4. Psychosomatics 50, Clare, L. (2018). Cognitive reserve as a moderator of the negative association 613–621. doi: 10.1016/S0033-3182(09)70864-3 between mood and cognition: evidence from a population-representative Kucyi, A., and Davis, K. D. (2015). The dynamic pain connectome. Trends cohort. Psychol. Med. 48, 61–71. doi: 10.1017/S003329171700126X Neurosci. 38, 86–95. doi: 10.1016/j.tins.2014.11.006 Pallarés-Sanmartín, A., Gonzalez, F. J. C., Fiorentino, F., and Crespo, M. G. Kucyi, A., Salomons, T. V., and Davis, K. D. (2013). Mind wandering away from (2019). Validation of the sleep Jenkins questionnaire (SJQ) into Spanish: pain dynamically engages antinociceptive and default mode brain networks. assessment of quality of sleep in patients with asthma. Chest 156:A1715. Proc. Natl. Acad. Sci. USA. 110, 18692–18697. doi: 10.1073/pnas.1312902110 doi: 10.1016/j.chest.2019.08.1501 Kucyi, A., Salomons, T. V., and Davis, K. D. (2016). Cognitive behavioral training Peña-Casanova, J., Casals-Coll, M., Quintana, M., Sánchez-Benavides, G., reverses the effect of pain exposure on brain network activity. Pain 157, Rognoni, T., Calvo, L., et al. (2012). Spanish normative studies in a 1895–1904. doi: 10.1097/j.pain.0000000000000592 young adult population (NEURONORMA young adults project): methods Lake, J. K., Power, C., and Cole, T. J. (2000). Back pain and obesity in the and characteristics of the sample. Neurología (Eng. Ed.) 27, 253–260. 1958 British birth cohort cause or effect? J. Clin. Epidemiol. 53, 245–250. doi: 10.1016/j.nrleng.2011.12.008 doi: 10.1016/S0895-4356(99)00155-9 Pertl, M. M., Hannigan, C., Brennan, S., Robertson, I. H., and Lawlor, B. A. (2017). Landrø, N. I., Fors, E. A., Våpenstad, L. L., Holthe, Ø., Stiles, T. C., and Cognitive reserve and self-efficacy as moderators of the relationship between Borchgrevink, P. C. (2013). The extent of neurocognitive dysfunction in stress exposure and executive functioning among spousal dementia caregivers. a multidisciplinary pain centre population. Is there a relation between Int. Psychogeriatr. 29, 615–625. doi: 10.1017/S1041610216002337 reported and tested neuropsychological functioning? Pain 154, 972–977. Pessoa, L. (2008). On the relationship between emotion and cognition. Nat. Rev. doi: 10.1016/j.pain.2013.01.013 Neurosci. 9, 148–158. doi: 10.1038/nrn2317 Leadley, R. M., Armstrong, N., Reid, K. J., Allen, A., Misso, K. V., and Kleijnen, J. Pupíková, M., Šimko, P., Gajdoš, M., and Rektorová, I. (2021). Modulation of (2014). Healthy aging in relation to chronic pain and quality of life in Europe. working memory and resting-state fMRI by tDCS of the right frontoparietal Pain Pract. 14, 547–558. doi: 10.1111/papr.12125 network. Neural Plast. 2021:5594305. doi: 10.1155/2021/5594305 Legrain, V., Crombez, G., Verhoeven, K., and Mouraux, A. (2011). The role Rami, L., Valls-Pedret, C., Bartrés-Faz, D., Caprile, C., Solé-Padullés, C., Castellvi, of working memory in the attentional control of pain. Pain 152, 453–459. M., et al. (2011). Cognitive reserve questionnaire. Scores obtained in a healthy doi: 10.1016/j.pain.2010.11.024 elderly population and in one with Alzheimer’s disease. Rev. Neurol. 52, Legrain, V., Damme, S. V., Eccleston, C., Davis, K. D., Seminowicz, D. A., and 195–201. doi: 10.33588/rn.5204.2010478 Crombez, G. (2009a). A neurocognitive model of attention to pain: behavioral Reynoso-Alcántara, V., Silva-Pereyra, J., Fernández-Harmony, T., and and neuroimaging evidence. Pain 144, 230–232. doi: 10.1016/j.pain.2009. Mondragón-Maya, A. (2018). Principales efectos de la reserva cognitiva 03.020 sobre diversas enfermedades: una revisión sistemática. Psiquiatr. Biol. 25, Legrain, V., Guérit, J.-M., Bruyer, R., and Plaghki, L. (2002). Attentional 53–67. doi: 10.1016/j.psiq.2018.02.005 modulation of the nociceptive processing into the human brain: selective Saldanha, J. S., Zortea, M., Deliberali, C. B., Nitsche, M. A., Kuo, M.-F., Torres, I. spatial attention, probability of stimulus occurrence, and target detection L., et al. (2020). Impact of age on tDCS effects on pain threshold and working effects on laser evoked potentials. Pain 99, 21–39. doi: 10.1016/S0304-3959(02) memory: results of a proof of concept cross-over randomized controlled study. 00051-9 Front. Aging Neurosci. 12:189. doi: 10.3389/fnagi.2020.00189 Legrain, V., Perchet, C., and García-Larrea, L. (2009b). Involuntary orienting Sambataro, F., Murty, V. P., Callicott, J. H., Tan, H.-Y., Das, S., Weinberger, of attention to nociceptive events: neural and behavioral signatures. J. D. R., et al. (2010). Age-related alterations in default mode network: Neurophysiol. 102, 2423–2434. doi: 10.1152/jn.00372.2009 impact on working memory performance. Neurobiol. Aging 31, 839–852. Ligthart, L., Visscher, C. M., van Houtem, C. M. H. H., Geels, L. M., Vink, J. doi: 10.1016/j.neurobiolaging.2008.05.022 M., de Jongh, A., et al. (2014). Comorbidity among multiple pain symptoms Santarnecchi, E., Sprugnoli, G., Tatti, E., Mencarelli, L., Neri, F., Momi, D., et al. and anxious depression in a Dutch population sample. J. Pain 15, 945–955. (2018). Brain functional connectivity correlates of coping styles. Cogn. Affect doi: 10.1016/j.jpain.2014.06.007 Behav. Neurosci. 18, 495–508. doi: 10.3758/s13415-018-0583-7 Lucas-Carrasco, R. (2012). The WHO quality of life (WHOQOL) questionnaire: Scarmeas, N., and Stern, Y. (2003). Cognitive reserve and lifestyle. J. Clin. Exp. Spanish development and validation studies. Qual. Life Res. 21, 161–165. Neuropsychol. 25, 625–633. doi: 10.1076/jcen.25.5.625.14576 doi: 10.1007/s11136-011-9926-3 Seminowicz, D. A., and Davis, K. D. (2006). Cortical responses to pain in Maixner, W., Fillingim, R. B., Williams, D. A., Smith, S. B., and Slade, G. D. healthy individuals depends on pain catastrophizing. Pain 120, 297–306. (2016). Overlapping chronic pain conditions: implications for diagnosis and doi: 10.1016/j.pain.2005.11.008 classification. J. Pain 17, T93–T107. doi: 10.1016/j.jpain.2016.06.002 Seminowicz, D. A., and Moayedi, M. (2017). The dorsolateral prefrontal cortex in Mazoyer, B., Zago, L., Mellet, E., Bricogne, S., Etard, O., Houdé, O., et al. acute and chronic pain. J. Pain 18, 1027–1035. doi: 10.1016/j.jpain.2017.03.008 (2001). Cortical networks for working memory and executive functions Senba, E., and Kami, K. (2017). A new aspect of chronic pain as a lifestyle-related sustain the conscious resting state in man. Brain Res. Bull. 54, 287–298. disease. Neurobiol. Pain 1, 6–15. doi: 10.1016/j.ynpai.2017.04.003 doi: 10.1016/S0361-9230(00)00437-8 Sjøgren, P., Christrup, L. L., Petersen, M. A., and Højsted, J. (2005). McCabe, D. P., Roediger, H. L., McDaniel, M. A., Balota, D. A., and Hambrick, Neuropsychological assessment of chronic non-malignant pain patients D. Z. (2010). The relationship between working memory capacity and treated in a multidisciplinary pain centre. Eur. J. Pain 9, 453–462. executive functioning: evidence for a common executive attention construct. doi: 10.1016/j.ejpain.2004.10.005 Neuropsychology 24, 222–243. doi: 10.1037/a0017619 Stern, Y. (2002). What is cognitive reserve? Theory and research Moriarty, O., and Finn, D. P. (2014). Cognition and pain. Curr. Opin. Supp. Palliat. application of the reserve concept. J. Int. Neuropsychol. Soc. 8, 448–460. Care 8, 130–136. doi: 10.1097/SPC.0000000000000054 doi: 10.1017/S1355617702813248 Moriarty, O., McGuire, B. E., and Finn, D. P. (2011). The effect of pain on cognitive Stern, Y. (2009). Cognitive reserve. Neuropsychologia 47, 2015–2028. function: a review of clinical and preclinical research. Prog. Neurobiol. 93, doi: 10.1016/j.neuropsychologia.2009.03.004 385–404. doi: 10.1016/j.pneurobio.2011.01.002 Stern, Y., Arenaza-Urquijo, E. M., Bartrés-Faz, D., Belleville, S., Cantilon, M., Nilsson, L.-G., and Nilsson, E. (2009). Overweight and cognition. Scand. J. Psychol. Chetelat, G., et al. (2020). Whitepaper: defining and investigating cognitive 50, 660–667. doi: 10.1111/j.1467-9450.2009.00777.x reserve, brain reserve, and brain maintenance. Alzheimers Dement 16, Okifuji, A., and Hare, B. D. (2011). Do sleep disorders contribute 1305–1311. doi: 10.1016/j.jalz.2018.07.219 to pain sensitivity? Curr. Rheumatol. Rep. 13, 528–534. Suvinen, T. I., Kemppainen, P., Le Bell, Y., Kauko, T., and Forssell, H. (2016). doi: 10.1007/s11926-011-0204-8 Assessment of pain drawings and self-reported comorbid pains as part of the Frontiers in Psychology | www.frontiersin.org 13 October 2021 | Volume 12 | Article 752623 Delgado-Gallén et al. Cognitive Reserve and Chronic Pain biopsychosocial profiling of temporomandibular disorder pain patients. J. Oral Wiech, K. (2016). Deconstructing the sensation of pain: the influence Facial Pain Head. 30, 287–295. doi: 10.11607/ofph.1589 of cognitive processes on pain perception. Science 354, 584–587. Tamburin, S., Maier, A., Schiff, S., Lauriola, M. F., Di Rosa, E., Zanette, G., doi: 10.1126/science.aaf8934 et al. (2014). Cognition and emotional decision-making in chronic low back World Medical Association (2013). World medical association declaration of pain: an ERPs study during Iowa gambling task. Front. Psychol. 5:e01350. Helsinki: ethical principles for medical research involving human subjects. doi: 10.3389/fpsyg.2014.01350 JAMA 310, 2191–2194. doi: 10.1001/jama.2013.281053 Tessitore, A., Russo, A., Giordano, A., Conte, F., Corbo, D., De Stefano, M., et al. (2013). Disrupted default mode network connectivity in migraine without aura. Conflict of Interest: AP-L received funding from MagStim Inc. The funder was J. Head. Pain 14:89. doi: 10.1186/1129-2377-14-89 not involved in the study design, collection, analysis, interpretation of data, the The Whoqol Group (1998). The World Health Organization quality of life writing of this article or the decision to submit it for publication. assessment (WHOQOL): development and general psychometric properties. Soc. Sci. Med. 46, 1569–1585. doi: 10.1016/S0277-9536(98)00009-4 The remaining authors declare that the research was conducted in the absence of Treede, R.-D., Rief, W., Barke, A., Aziz, Q., Bennett, M. I., Benoliel, R., et al. any commercial or financial relationships that could be construed as a potential (2015). A classification of chronic pain for ICD-11. Pain 156, 1003–1007. conflict of interest. doi: 10.1097/j.pain.0000000000000160 Turk, D. C., Fillingim, R. B., Ohrbach, R., and Patel, K. V. (2016). Assessment Publisher’s Note: All claims expressed in this article are solely those of the authors of psychosocial and functional impact of chronic pain. J. Pain 17, T21–49. and do not necessarily represent those of their affiliated organizations, or those of doi: 10.1016/j.jpain.2016.02.006 the publisher, the editors and the reviewers. Any product that may be evaluated in Veldhuijzen, D. S., Kenemans, J. L., van Wijck, A. J. M., Olivier, B., Kalkman, C. J., this article, or claim that may be made by its manufacturer, is not guaranteed or and Volkerts, E. R. (2006). Processing capacity in chronic pain patients: a visual event-related potentials study. Pain 121, 60–68. doi: 10.1016/j.pain.2005.12.004 endorsed by the publisher. Verbunt, J. A., Seelen, H. A., Vlaeyen, J. W., van de Heijden, G. J., Heuts, P. H., Pons, K., et al. (2003). Disuse and deconditioning in chronic low back pain: Copyright © 2021 Delgado-Gallén, Soler, Albu, Pachón-García, Alviárez-Schulze, concepts and hypotheses on contributing mechanisms. Eur. J. Pain 7, 9–21. Solana-Sánchez, Bartrés-Faz, Tormos, Pascual-Leone and Cattaneo. This is an open- doi: 10.1016/S1090-3801(02)00071-X access article distributed under the terms of the Creative Commons Attribution Villemure, C., and Schweinhardt, P. (2010). Supraspinal pain processing: License (CC BY). The use, distribution or reproduction in other forums is permitted, distinct roles of emotion and attention. Neuroscientist 16, 276–284. provided the original author(s) and the copyright owner(s) are credited and that the doi: 10.1177/1073858409359200 original publication in this journal is cited, in accordance with accepted academic Wechsler, D. (2012). WAIS-IV. Escala de inteligencia de Wechsler para adultos-IV. practice. No use, distribution or reproduction is permitted which does not comply Manual de aplicación y corrección. Madrid: NCS Pearson, Inc. with these terms. Frontiers in Psychology | www.frontiersin.org 14 October 2021 | Volume 12 | Article 752623