Executive Functions and Pain. a Systematic Review

Review Article Executive Functions and Pain A Systematic Review

Stefanie Bunk1, Lukas Preis2, Sytse Zuidema1, Stefan Lautenbacher3, and Miriam Kunz1

1 Department of General Practice and Elderly Care Medicine, University Medical Center Groningen, The Netherlands 2 Clinical and Developmental Neuropsychology, University of Groningen, The Netherlands 3 Physiological Psychology, University of Bamberg, Germany

Abstract: A growing body of literature suggests that chronic-pain patients suffer from problems in various neuropsychological domains, including executive functioning. In order to better understand which components of executive functioning (inhibition, shifting and/or updating) might be especially affected by pain and which mechanisms might underlie this association, we conducted a systematic review, including both chronic-pain studies as well as experimental-pain studies. The chronic-pain studies (N = 57) show that pain is associated with poorer executive functioning. The ﬁ ndings of experimental-pain studies (N = 28) suggest that this might be a bidirectional relationship: Pain can disrupt executive functioning, but poorer executive functioning might also be a risk factor for higher vulnerability to pain.

Keywords: executive functioning, inhibition, shifting, updating, pain

Exekutivfunktionen und Schmerz, eine systematische Übersichtsarbeit

Zusammenfassung: Eine Vielzahl von Studien weist darauf hin, dass chronische Schmerzpatienten in ihren neuropsychologischen Leistungen, u. a. den Exekutivfunktionen, beeinträchtigt sind. Um besser zu verstehen, welche Komponenten der Exekutivfunktionen (Inhibition, kognitive Flexibilität und/oder Arbeitsgedächtnis) besonders betroffen sind und wie sich der Zusammenhang zwischen Schmerz und Exekutivfunktionen erklären lässt, haben wir die empirischen Befunde zu chronischen als auch zu experimentellen Schmerz in einer systematischen Übersichtsar- beit zusammengetragen. Studien zu chronischen Schmerzpatienten (N = 57) zeigen, dass chronischer Schmerz mit milden Einbußen in den Exekutivfunktionen einhergeht. Die Befunde aus experimentellen Schmerzstudien (N = 28) deuten darauf hin, dass der Zusammenhang zwischen Schmerz und Exekutivfunktionen sogar bidirektional ist, das heißt: Schmerz interferiert/stört die Exekutivfunktionen und beeinträchtig- te Exekutivfunktionen wiederum können ein Risikofaktor für eine erhöhte Schmerzvulnerabilität sein.

Schlüsselwörter: Exekutivfunktion, Inhibition, kognitive Flexibilität, Arbeitsgedächtnis, Schmerz

More than one-third of people worldwide suff er from chron- (“inhibition”). Whereas updating refers to on-going task ic pain (Fayaz et al., 2016; Tsang et al., 2008). It is widely monitoring and online adjustments, shifting is the ability to acknowledged that chronic pain not only leads to emotional switch attention between diff erent task demands. Inhibi- suff ering, but can also have a negative impact on neuropsy- tion relates to an individual’s ability to exert control over chological functioning (Hart et al., 2000; Moriarty et al., prepotent responses, which are refl exive and automatic re- 2011). One domain of cognition that has been repeatedly sponses that need conscious, top-down control in order to found to be aff ected by pain is executive functioning (Berry- be suppressed. Although additional executive functioning man et al., 2014; Moriarty et al., 2011). Executive functions components have been postulated (Fisk et al., 2004), these are described as higher-order skills that enable an individu- three components have been used most frequently (Jura- al to regulate actions and thoughts during goal-directed be- do & Rosselli, 2007). havior. They can be seen as an umbrella term to encompass First evidence for a link between pain and executive a variety of quite heterogeneous cognitive processes (Fried- functioning stems from clinical studies (Armstrong et al.,

${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233 man & Miyake, 2017). To break executive functions down 1997; Grace et al., 1999; Grisart & Plaghki, 1999). Here, into more homogeneous components, Miyake and col- the relationship between diff erent components of execu- leagues (2000) suggest three diff erent components: infor- tive functioning and pain is usually studied using two dif- mation updating and monitoring (“updating”), mental set ferent study designs, namely by (1) group comparisons of shifting (“shifting”), and inhibition of prepotent responses executive functioning performance between pain patients

and pain-free healthy controls and/or (2) correlational ap- to better understand whether poor executive functioning proaches between executive functioning performance might be linked to high pain responsiveness. and self-reported pain intensity within a group of chronic- In sum, this review provides a comprehensive overview pain patients. Using both designs, evidence has been of the fi ndings on the relationship between executive func- found in favor of as well as evidence against a link be- tioning and pain by taking both chronic-pain studies and tween chronic pain and executive functions. In order to experimental-pain studies using various study designs draw conclusions, all empirical evidence has to be gath- into consideration. Regarding executive functions, we ered in a systematic review or meta-analysis. So far, two have attempted to organize the results into the three do- meta-analyses by Berryman and colleagues (2013, 2014) mains proposed by Miyake and colleagues (2000): updat- have been conducted on this topic, which focused solely ing, shifting, and inhibition. Considering that pain is om- on group comparisons between patients and controls. It nipresent in the clinical fi eld, we hope to create a useful was reported that people with chronic pain show a small review not only for researchers, but also for people work- to moderate impairment in executive functioning perfor- ing in the clinic. mance compared to pain-free individuals. The question remains whether executive functioning problems worsen with higher pain intensity. Our systematic review serves to close this gap and in- Methods cludes the empirical evidence on correlational analyses as well as group comparisons. Moreover, we gather evidence Search Strategy on the potential directions of this association. Is pain causing the executive functioning problems or might poor ex- We conducted a systematic search of literature published ecutive functioning precede the development of chronic through July 2018 according to the Preferred Reporting pain – and even be a vulnerability factor for chronic pain? It Items for Systematic Reviews and Meta-Analyses (PRIS- is impossible to study the causal link using cross-sectional MA) Statement Guidelines (Moher et al., 2015). We scru- study designs in chronic-pain patients, though by experi- tinized the most appropriate electronic databases for this mentally inducing pain (e. g., using heat or pressure), it topic, namely, PSYCINFO and MEDLINE, via EBSCO- might be possible to study the direction of the association host with the following sensitive keywords relating to ex- between executive functions and pain. Therefore, we also ecutive functioning: “executive function*” or “cognitive include experimental-pain studies in the current system- inhibition” or “prepotent inhibition” or “response inhibi- atic review. tion” or “cognitive control” or “stroop” or “anti saccade” In experimental-pain studies, pain responsiveness is of- or “antisaccade” or “anti-saccade” or “stop-signal task” ten measured by asking the participants to rate the inten- or “stop signal task” or “set shifting” or “mental fl exibili- sity of the experimental pain stimulus or by measuring ty” or “attention switching” or “attention regulation” or when participants start to feel pain (pain threshold) or how “task switching” or “plus-minus task” or “plus minus much pain participants can tolerate (pain tolerance) task” or “number-letter task” or “number letter task” or (Bjekić et al., 2017). One additional experimental pain “local-global task” or “local global task” or updating or model of interest in the context of executive functioning is “working memory” or “N-back” or “keep track task” or the conditioned pain modulation paradigm, an experi- “letter memory task” or “tone monitoring task.” The mental pain model to measure endogenous pain inhibition above keywords were paired with the keyword pain. The (Ickmans et al., 2015; Yarnitsky, 2010). The relationship search was further narrowed down to journal articles between these diff erent responses to experimental pain written in English that made use of a human adult popu- and executive functions is studied mostly using three dif- lation. Access to the search log can be granted on inquiry. ferent designs: (1) an interference design in which participants perform an executive task twice, once with and once without painful stimulation; (2) an interference design in Study Selection which participants receive painful stimulation twice, once with and once without simultaneously performing an ex- Only those articles were considered to be part of this sys- ecutive function task; and/or (3) a correlational approach tematic review if all relevant methods and measures (i. e.,

${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233 in which executive functioning performance and pain re- executive functioning tests, measures of pain responses, sponsiveness are assessed in two separate blocks. Whereas and/or pain induction methods) had previously been vali- interference designs allow to draw more causational con- dated (e. g., tested for construct, criterion, or content va- clusions about interference eff ects of pain on executive lidity). Moreover, studies had to provide a clear descrip- functioning (or vice versa), correlational approaches help tion of statistics. For chronic-pain studies, two types of

study designs were considered relevant: (1) a group com- the selection procedure, two systematic reviews by Berry- parison of executive function performance between man and colleagues (2014) and Moriarty and colleagues chronic-pain patients and a healthy control group and (2) a (2011) as well as the literature summary by Buhle and Wa- correlational approach that assesses the correlation be- ger (2010) were searched for additional articles relevant tween executive functioning performance and self-report- for the present review. Figure 1 shows the selection proce- ed pain intensity within a group of chronic-pain patients. dure with a PRISMA fl owchart. For the experimental-pain studies, three types of study designs were considered relevant: (1) an interference design in which participants perform an executive task twice, Information Extraction once with and once without receiving painful stimulation, (2) an interference design in which participants receive We extracted the following information from each in- painful stimulation twice, once with and once without si- cluded study: type of pain (chronic pain and/or experi- multaneously performing an executive function task and mental pain), sample information (patients and/or (3) a correlational approach in which executive function- healthy participants, mean age, number of participants), ing performance and pain sensitivity are assessed in two name of executive function test, cognitive domain re- separate blocks and later correlated. The fi rst interference fl ected by the executive function test, type of study de- design is conducted to investigate whether painful stimu- sign (group comparison, correlational approach or inter- lation reduces executive function performance (pain → ex- ference design), and the outcome of the study (which ecutive functioning), while the second interference design executive tests showed signifi cant associations with ei- is conducted to investigate whether performing an execu- ther chronic or experimental pain, the direction of this tive functioning task reduces responsiveness to painful association and, if available, eff ect sizes [for group com- stimulation (executive functioning → pain). parisons: mean values and standard deviation for the computation of the Glass’ Δ eff ect size; for correlations: correlation coeffi cients]). For chronic-pain studies, we Exclusion Criteria also extracted the mean pain intensity rating and the disease duration of the patient group. For experimental-pain Studies that measured executive functioning based solely studies, we also extracted the type of pain stimulus (e. g., on subjective self-report or observer ratings were exclud- heat, pressure) and the type of pain measure (e. g., inten- ed. Studies were also excluded when the executive func- sity rating, threshold, tolerance, conditioned pain modu- tioning task was confounded by other tasks that had to be lation, temporal summation). The information was ex- performed simultaneously (e. g., a distraction task) – with tracted by one reviewer (LP) and independently the exception of a simultaneous application of pain. If a counterchecked by a second reviewer (SB). neuropsychological test could not be assigned to one of the three domains proposed by Miyake (2000), or if test scores were compiled across diff erent domains of execu- Risk of Bias Assessment tive functioning without reporting outcomes for the dif- ferent domains separately, these studies were also ex- To assess the quality of the studies and the risk of bias, we cluded. For chronic-pain studies, we included only graded the studies based on the following criteria (adopt- studies in which the patient group was suff ering from dis- ed from the Newcastle Ottowa criteria; Wells et al., n. d.), eases whose symptoms are strongly pain-related (e. g., fi - (1) information about the sex distribution and age of the bromyalgia, migraine). Whiplash and chronic fatigue participants, (2) a study population that represents the syndrome were excluded because these diseases have a true population, (3) a screening for psychiatric disorders, weaker link to pain. (4) specifi cation of executive function tests, (5) specifi cation of type of pain stimulus in case of experimental pain and a diagnosis according to the accepted criteria in case Study Selection Protocol of chronic pain, (6) in case of chronic pain, control for age and education in the between-group comparison, and (7) The results were exported to the citation management in case of chronic pain, report of analgesic medication

${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233 software Refworks (Proquest, Ann Arbor, Michigan, USA) use. Each criterion was judged as either successfully ful- and title screened for eligibility by one author (LP). Fol- fi lled (1), partially fulfi lled (0.5), or not fulfi lled (0). The lowing the title screening, the abstracts were independent- maximum score for experimental-pain studies was 5. For ly investigated by two authors (LP, SB). If there was disa- chronic-pain studies, the maximum was 6 (correlational greement, a group discussion was held (LP, SB, MK). After design) or 7 (group comparisons).

Records identifi ed through database Additional records identifi ed searching through other sources cation (n = 807) (n = 15) Identifi

Records after duplicates removed (n = 612)

Records screened Records excluded (n = 612) (n = 514) Screening

Full-text articles assessed for eligibi- Full-text articles excluded lity (n = 17) (n = 98) – Executive function criteria not fulﬁ lled (n = 6) – Confounding by other task (n = 2) – Study design not according to criteria (n = 5) – Effect of drugs (n = 1) Studies included – Pain measure not relevant (n = 3) in qualitative synthesis (n = 81)

Chronic-pain studies Combination of chronic Experimental-pain studies (n = 53) and experimental pain (n = 24) (n = 4) Included Eligibility

Figure 1. PRISMA (preferred reporting items for systematic review and meta-analysis) ﬂ ow diagram.

Results the average eff ect sizes extracted from the studies. The results are discussed below separately for the chronic-pain The initial literature search identifi ed 807 studies with 15 studies and the experimental-pain studies and organized additional studies found through manual searching of in terms of the three executive function domains proposed reference lists (see Figure 1). After excluding duplicates by Miyake and colleagues (2000). and screening the remaining titles and abstracts, 98 studies remained. Seventeen articles were excluded after re- viewing the full text articles (the reasons for exclusion are Chronic-Pain Studies listed in Figure 1). Thus, altogether 81 articles were re- tained for analysis, with 53 chronic-pain studies, 24 ex- Fifty-seven studies investigating the association between perimental-pain studies and 4 studies investigating both executive functioning and chronic pain were included in experimental and chronic pain. The average quality this review (see Table 3). The most commonly studied score, based on the risk of bias criteria, was 5.5 (out of 6 chronic pain condition was fi bromyalgia, which was investi- or 7, depending on the design) for the chronic-pain stud- gated in 21 studies. Other common studied pain conditions ies and 4.4 (out of 5) for the experimental-pain studies were migraine/headache (10 studies), rheumatoid arthri- (see Tables S1 and S2 in the supplemental material for the tis/arthrosis (7 studies), and chronic back pain (5 studies). risk of bias data of each study). Thus, we are confi dent Less commonly studied conditions include eosinophilia- that the reported outcomes are not biased by a lack of myalgia, chronic pancreatitis, complex regional pain syn-

${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233 quality of the included studies. drome, temporomandibular disorder and chronic neuro- Table 1 and Table 2 summarize the number of signifi - pathic/radicular pain. Sixteen studies did not investigate a cant fi ndings for chronic pain and experimental pain, re- specifi c pain condition but studied a group of patients under spectively. In Table 3 and Table 4, the fi ndings of each the name “various chronic pain conditions,” “musculoskel- study are presented in detail. In addition, Figure 2 displays etal pain,” or “multiple functional somatic symptoms.”

Table 1. Percentage of tests that show a signiﬁ cant association between chronic pain and executive functioning

Correlational approach Group comparison Total Chronic pain is negatively correlated with Chronic pain patients show reduced exe cutive task executive functioning performance performance compared to controls

Inhibition 16.7 % 41.5 % 33.9 % (3 out of 18 tests) (17 out of 41 tests) (20 out of 59 tests)

Updating 19.4 % 33.3 % 28.2 % (6 out of 31 tests) (18 out of 54 tests) (24 out of 85 tests)

Shifting 21.7 % 32.4 % 28.3 % (5 out of 23 tests) (12 out of 37 test) (17 out of 60 tests)

Total 19.4 % 33.3 % (14 out of 72 tests) (44 out of 132 tests)

Table 2. Percentage of tests showing a signiﬁ cant association between experimental pain responses and executive functioning

Correlational approach Interference design Interference design Total Executive functioning performance Executive task demand reduces Pain reduces executive is negatively correlated with pain pain responsiveness functioning performance responsiveness (executive functioning → pain) (pain → executive functioning)

Inhibition 33.3 % 50.0 % 0 % 33.3 % (16 out of 48 tests) (3 out of 6 tests) (0 out of 3 tests) (19 out of 57 tests)

Updating 4.44 % 100 % 50 % 17.5 % (2 out of 45 tests) (3 out of 3 tests) (4 out of 8 tests) (10 out of 57 tests)

Shifting 15.4 % – 66.7 % 25.0 % (2 out of 13 tests) (2 out of 3 test) (4 out of 16 tests)

Total 19.6 % 66.7 % 42.9 % (21 out of 107 tests) (6 out of 9 tests) (6 out of 14 tests)

Table 3. Summary of papers investigating the association between chronic pain and executive functioning.

Participants Pain intensity Disease Executive Cognitive Study Signiﬁ cance of Reference patients duration functioning domain design ﬁ ndings and tests effect sizes

Rheumatoid Self-report 11.5 years Stroop, Letter Inhibition, Correlation Stroop/Letter Abeare et al. arthritis patients, (0–100 VAS): Number updating Number Sequenc- (2010) 54 years, N=157 36.4 Sequencing ing & pain intensity: p<0.05 (Δ=0.17/0.24)

Rheumatoid ar- 7.3 years Stroop Inhibition Group Stroop perfor- Akdoğan thritis patients, comparison mance patients < et al. (2013) 37.3 years, N=28; controls: p<0.05 pain-free individuals, 33.7 years, N=30

${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233 Fibromyalgia Self-report 3.1 years Group Stroop perfor- patients, 36.2 (0–10 VAS): 8 comparison, mance patients < years, N=40; correlation controls: p<0.05 same control Stroop & pain group intensity: ns

Table 3. continuation

Participants Pain intensity Disease Executive Cognitive Study Signiﬁ cance of Reference patients duration functioning domain design ﬁ ndings and tests effect sizes

Chronic back pain 8.6 years Stroop, Digit Inhibition, Group Stroop/Digit Span Apkarian patients, 21–71 Span Back- updating, comparison Backward/WCST et al. (2004) years, N=6; pain- ward, WCST shifting performance free individuals, patients < con- 25–64 years, trols: ns N=10 (Δ=1/0.5/–0.3)

Eosinophilia-my- PASAT, WCST Updating, Group PASAT/WCST per- Armstrong algia patients, shifting comparison, formance patients et al. (1997) 46.7 years, N=23; correlation < controls: p<0.05 pain-free indi- (Δ=1.57) viduals, 47.6 years, N=18 WCST/PASAT & pain intensity: ns

Frequent Self-report Flanker test, Inhibition, Group Cued Task Switch- Attridge et al. headache (0–100 VAS): N-back, Cued Updating, comparison ing performance (2017) patients, 30.4 52.8 during Task Switching shifting during headache < years, N=59 headache during no headache: p<0.05 (Δ=0.4) Flanker/N-back task performance during headache < during no headache: ns (only women: p<0.05)

Patients with MPQ-SF: >3 months Digit Span Updating, Group Digit Span Back- Buckalew chronic low back 30.75 Backward, shifting comparison ward/Letter Num- et al. (2008) pain, 74.5 years, Letter Number ber Sequencing/ N=8; pain-free Sequencing, TMT (B) perfor- individuals, 69.9 TMT (B) mance patients < years, N=8 controls: ns (Δ=1/0.5/0.91)

Fibromyalgia pa- Self-report: Stroop, Digit Inhibition, Group Stroop perfor- Cherry et al. tients, 63.0 years, 6.3 Span Back- updating, comparison mance patients < (2014) N=43; pain-free (0–10 VAS) ward, Verbal shifting controls: p<0.05 individuals, 64.8 Fluency task, (Δ=0.51) years, N=44 TMT (B) Digit Span Back- ward/Verbal Fluency task TMT (B) performance patients < controls: ns (Δ=0.45/– 0.23/0.13)

Fibromyalgia pa- 96.3 months Stroop, OSPAN Inhibition, Group Stroop/OSPAN Coppieters tients, 44.5 years, updating comparison performance pa- et al. (2015) N=21; Pain-free tients < controls: individuals, 38.0 p<0.05 years, N=22

Fibromyalgia pa- MPQ: 7.61 4 years Go-/No-go Inhibition Group Go-/No-go task Correa et al.

${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233 tients, 48.0 years, task comparison performance pa- (2011) N=18; pain-free tients < controls: individuals, 42.0 p<0.05 (Δ=0.29) years, N=19

Table 3. continuation

Participants Pain intensity Disease Executive Cognitive Study Signiﬁ cance of Reference patients duration functioning domain design ﬁ ndings and tests effect sizes

Fibromyalgia pa- FIQ: 7 6.47 years Tower of Inhibition, Group Tower of London/ Di Tella et al. tients, 41.29 (0–10 NRS) London, Digit- updating, comparison Digit-Span Back- (2015) years, N=40; Span Back- shifting ward/Verbal Flu- Pain-free indi- ward, Verbal ency task/TMT (B) viduals, 40.72 Fluency task, performance pa- years, N=41 TMT (B) tients < controls: p<0.05 (Δ=0.56/ 0.88/0.80/n/a)

Fibromyalgia Self-report: 11.0 years Test of Every- Updating, Group Updating perfor- Dick et al. patients, 48.0 4.6 day Attention: shifting comparison, mance patients < (2002) years, N=20; Pain- (0–10 VAS) updating and correlation controls: p<0.05 free individuals, shifting (Δ=0.98) 60.0 years, N=20 Shifting performance patients < controls: ns (Δ=0.10) Updating/shifting & pain intensity: ns

Rheumatoid ar- Self-report: 18.9 years Updating perfor- thritis patients, 4.5 mance patients < 62.9 years, N=20; (0–10 VAS) controls: p<0.05 same control (Δ=1.64) group Shifting performance patients < controls: ns (Δ=0.68) Updating/shifting & pain intensity: ns

Musculoskeletal Self-report: 10.2 years Updating/shifting disorder patients, 4.7 performance 52.3 years, N=20; (0–10 VAS) patients < controls: same control ns (Δ=0.84/0.61) group Updating/shifting & pain intensity: ns

Patients with mi- Self-report: Stroop Inhibition Correlation Stroop/Flanker Galioto et al. graine and obe- 5.9 (0–10) test performance & (2018) sity, 38.3 years, pain intensity: ns N=124 (interictal assessment)

Patients with vari- Stroop Inhibition Correlation Stroop perfor- Gijsen et al. ous chronic pain mance & pain (2011) conditions, 51.9 intensity: p<0.05 years, N=1399 (Δ=0.12)

Migraine patients, Self-report: 19.30 years Stroop, Digit Inhibition, Group Stroop/Digit Span Gil-Gouveia 38.0 years, N=24 5.7 (0–10 Span Back- updating, comparison Backward/Verbal et al. (2015) VAS) during ward, Verbal shifting Fluency task/TMT migraine Fluency task, (B) performance attack TMT (B) during attack < during no headache: ns (Δ=0.19/

${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233 0.35/0.35/0.11)

Table 3. continuation

Participants Pain intensity Disease Executive Cognitive Study Signiﬁ cance of Reference patients duration functioning domain design ﬁ ndings and tests effect sizes

Fibromyalgia PED: 55.4 Go-/No-Go Inhibition Group Go-/No-Go Task Glass et al. patients, 43.6 (0–100) Task comparison, performance (2011) years, N=18; pain- correlation patients < con- free individuals, trols: ns (Δ=0.11) 41.1 years, N=14 Go-/No-Go Task performance & pain intensity: ns

Fibromyalgia Self-report: N-back Updating Group N-back task González- patients, 48.9 6.5 comparison performance Villar et al. years, N=32; pain- (0–10 VAS) patients < con- (2017) free individuals, trols: ns (Δ=0.20) 48.4 years, N=30

Fibromyalgia pa- Self-report: PASAT Updating Group PASAT performance Grace et al. tients, 45.9 years, 4.2 comparison, patients < controls: (1999) N=29 (+7 for cor- (0–10 VAS) correlation p<0.05 (Δ=0.61) relation analysis); PASAT performance pain-free & pain intensity: individuals, 44.7 p<0.05 (r=0.36) years, N=29

Patients with vari- Low-pain >1 year Modiﬁ ed Inhibition, Group Inhibition/shifting Grisart & ous chronic pain patients: 31.0 Stroop: inhibi- shifting comparison performance Plaghki conditions, 45.0 (0–100 VAS) tion and high-pain patients (1999) years, N=33; pain- shifting < controls: p<0.05 free individuals, High-pain 45.0 years, N=20 patients: 73.0

Multiple function- Self-report: 10.5 years Digit Span Updating, Group Digit Span Back- Hall et al. al somatic symp- 2.63 Backward, shifting comparison, ward/COWAT/TMT (2011) toms patients, (0–10 VAS) COWAT, TMT correlation (B) performance 36.6 years, N=22; (B) patients < controls: pain-free indi- p<0.05 (Δ=0.69/ viduals, 35.6 0.74/0.85) years, N=27 Digit Span Back- ward/TMT (B) performance & pain intensity: p<0.05 (r=0.71/0.49) COWAT performance & pain intensity: ns (r=0.34)

Fibromyalgia with Self-report: 11.3 years Stroop, OSPAN Inhibition, Group Stroop perfor- Ickmans comorbid chronic 39.9 updating comparison, mance patients < et al. (2015) fatigue syndrome (0–100 SF-36) correlation controls: p<0.05 patients, 40.2 (Δ=1.41) year, N=30; pain- OSPAN perfor- free individuals, mance patients < 37.3 years, N=30 controls: ns (Δ=0.44) Stroop/OSPAN & pain intensity: ns

Chronic pancrea- 6.1 years Verbal Inter- Inhibition, Group Go-/No-Go Task/ Jongsma

${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233 titis patients, 49.5 ference, Go-/ shifting comparison Verbal Interference et al. (2011) years, N=16; pain- No-Go Task, Switching of Atten- free individuals, Switching of tion test perfor- 48.0 years, N=16 Attention test mance patients < controls: p<0.05 (Δ=0.72/0.94/0.68)

Table 3. continuation

Participants Pain intensity Disease Executive Cognitive Study Signiﬁ cance of Reference patients duration functioning domain design ﬁ ndings and tests effect sizes

Fibromyalgia Self-report: Domain execu- Inhibition Group Stroop/Go-/No- Kalfon et al. patients, 42.2 5.8 tive function- comparison Go Task perfor- (2016) years, N=50 (0–10 VAS) ing: Go-/No-Go (to norma- mance patients < Task, Stroop tive data), controls: ns correlation Executive functioning domain performance & pain intensity: p<0.05 (r=0.32)

Patients with vari- Self-report: TMT (B) Shifting Correlation TMT (B) perfor- Karp et al. ous chronic pain 58.1 (0–100 mance & pain in- (2006) conditions, 76.1 VAS) tensity: p<0.05 years, N = 56 (r=0.42)

Migraine patients, Stroop Inhibition Group Stroop perfor- Kröner- 38.8 years, N=24; comparison mance patients < Herwig et al. pain-free indi- controls: ns (2005) viduals, 43.1 (Δ=0.11) years, N=24

Tension-type Stroop perfor- headache mance patients < patients, 42.8 controls: ns years, N=18; same (Δ=0.41) control group

Chronic low back Self-report: 7–15 years Stroop Inhibition Group Stroop perfor- Lamoth et al. pain patients, 25-48 (0–100 comparison mance patients < (2008) 45.0 years, N=12; VAS) controls: p<0.05 pain-free individuals, 44.0 years, N=14

Complex regional 2.8 years Stop-signal Inhibition, Group Stop-signal task/ Lee et al. pain syndrome task, WCST shifting comparison WCST perfor- (2015) patients, 36.1 mance patients < years, N=25; pain- controls: p<0.05 free individuals, (Δ=1.36/0.97) 31.7 years, N=25

Patients with MPQ: 21.4 10.7 years Stroop, COWAT, Inhibition, Correlation Stroop/COWAT/ Legaretta various chronic TMT (B) updating, TMT (B) perfor- et al. (2016) pain conditions, shifting mance & pain 37.7 years, N = 38 intensity: ns (r=0.02/0.10/0.02)

Fibromyalgia MPQ: 63.5 14.4 years Digit Span Updating, Group Corsi Block Span Luerding patients, 53.6 Backward, shifting comparison performance pa- et al. (2008) years, N = 20 Corsi Block (to norma- tients < controls: Span, TMT (B) tive data), p<0.05 correlation Digit Span Back- ward/TMT (B) performance patients < controls: ns Digit Span Back- ward/Corsi Block ${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233 Span/TMT (B) & pain intensity: ns

Table 3. continuation

Participants Pain intensity Disease Executive Cognitive Study Signiﬁ cance of Reference patients duration functioning domain design ﬁ ndings and tests effect sizes

Migraine patients, Stroop, Digit Inhibition, Group Stroop/Digit Span Martins et al. 61.9 years, N=61; Span Back- updating, comparison Backward/Verbal (2012) pain-free indi- ward, Verbal shifting Fluency task/TMT viduals, 66.8 Fluency task, (B) performance years, N=367 TMT (B) patients < controls: ns (Interictal assessment)

Non migraine Stroop/Digit Span headache pa- Backward/Verbal tients, 69.3 years, Fluency task/TMT N=50; same con- (B) performance trol group patients < controls: ns

Fibromyalgia pa- Self-report: 8.9 years Stroop Inhibition Group Stroop perfor- Martinsen tients, 49.8 years, 45.3 comparison mance patients < et al. (2014) N=29; pain-free (0–100 VAS) controls: p<0.05 individuals, 46.3 (Δ=0.89) years, N=31

Chronic lower Self-report: 7.58 years Stroop, TMT (B) Inhibition, Group Stroop/TMT (B) Masiliūnas back pain 56 shifting comparison, performance pa- et al. (2017) patients, 59.6 (0–100 VAS) correlation tients < controls: years, N=29; pain- ns (Δ=0.07/0.29) free individuals, Stroop/TMT (B) & 60.7 years, N=30 pain intensity: ns

Fibromyalgia MPQ: 20.92 4.27 years ANT-I (atten- Inhibition Group ANT-I perfor- Miró et al. patients, 46.6 tional network comparison, mance patients < (2011) years, N=33; pain- test-interac- correlation controls: p<0.05 free individuals, tions) (Δ=0.79) 42.9 years, N=28 ANT-I performance & pain intensity: ns (r=0.03)

Fibromyalgia ANT-I (atten- Inhibition Group ANT-I perfor- Miró et al. patients, 45.9 tional network comparison, mance patients < (2015) years, N=77; pain- test-interac- correlation controls: p<0.05 free individuals, tions) ANT-I perfor- 44.7 years, N=48 mance & pain intensity: ns

Headache N-back task, Updating, Group N-back task/At- Moore et al. patients, 24.9, Attentional shifting comparison, tentional Switch- (2013A) N=75 Switching task correlation ing task performance during headache < during no headache: p<0.05 (Δ=0.57/0.12) N-back task/ Attentional Switching task

${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233 performance & pain intensity: ns

Table 3. continuation

Participants Pain intensity Disease Executive Cognitive Study Signiﬁ cance of Reference patients duration functioning domain design ﬁ ndings and tests effect sizes

Patients with CPG: 73.2 8.5 years WCST Shifting Group WCST perfor- Moriarty chronic neuro- comparison, mance patients < et al. (2017) pathic or radicular correlation controls: ns pain, 45.6 years, (Δ=0.35) N=38; pain-free WCST perfor- individuals, 44.2 mance & pain years, N=38 intensity: ns

Knee osteoarthri- MPQ-SF: 14.7 >3 months Tracking test Shifting Correlation Tracking test per- Morone et al. tis patients, 70.0 formance & pain (2014) years, N=79 intensity: ns

Chronic musculo- >4 (0–10 NRS) >3 months Letter and Updating, Group Category Verbal Murata et al. skeletal pain Category Ver- shifting comparison Fluency task per- (2017) patients, 74.6 bal Fluency formance patients years, N=44; pain- task, TMT (B) < controls: p<0.05 free individuals, (Δ=0.42) 72.2 years, N=190 Letter Verbal Flu- ency task/TMT (B) performance patients < controls: ns (Δ=-0.12/0.17)

Patients with vari- Self-report: A Quick Test, Inhibition, Group A Quick Test per- Nadar et al. ous chronic pain 6.35 Digit Span updating, comparison formance patients (2016) conditions, 39.9 (0–10 VAS) Backward, shifting < controls: p<0.05 years, N=40; pain- TMT (B) (Δ=0.86) free individuals, Digit Span Back- 35.0 years, N=29 ward/TMT (B) performance patients < controls: ns (Δ=0.47/0.86)

Patients with vari- Self-report: 11.7 years Digit Span Updating Group Digit Span Back- Oosterman ous chronic pain 34.9 Backward comparison, ward performance et al. (2011) conditions, 51.5 (0–100 VAS) correlation patients < con- years, N=34; pain- trols: p<0.05 free individuals, (Δ=0.44) 55.4 years, N=32 Digit Span Back- ward performance & pain intensity: p<0.05 (r=0.38)

Patients with vari- Self-report: 11.7 years Stroop, Zoo Inhibition, Group TMT (B) perfor- Oosterman ous chronic pain 34.9 Map test, TMT updating, comparison, mance patients < et al. (2012) conditions, 51.5 (0–100 VAS) (B), shifting correlation controls: p<0.05 years, N=34; pain- (Δ=0.76) free individuals, Stroop/Zoo Map 55.4 years, N=32 test performance patients < controls: ns (Δ=0.07/0.16) Stroop/Zoo Map test/TMT (B) performance & pain intensity: ns ${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233

Table 3. continuation

Participants Pain intensity Disease Executive Cognitive Study Signiﬁ cance of Reference patients duration functioning domain design ﬁ ndings and tests effect sizes

Patients with vari- 9.8 years Stroop, Verbal Inhibition, Correlation TMT (B) perfor- Oosterman ous chronic pain Fluency task, updating, mance & pain et al. (2013) conditions, 28.8 TMT (B) shifting intensity: p<0.1 years, N=22 Stroop/Verbal Fluency task performance & pain intensity: ns

Patients with vari- 10.6 years TMT (B) perfor- ous chronic pain mance & pain conditions, 65.0 intensity: p<0.05* years, N=24 Stroop/Verbal Fluency task performance & pain intensity: ns

Fibromyalgia MPQ: 33.8 Reading and Updating Group Working memory Park et al. patients, 47.83 computational comparison, performance pa- (2001) years, N=23; pain- Span task correlation tients < controls: free individuals, (working p<0.05 (Δ=2.44) 47.83 years, N=23 memory do- Verbal Fluency main), Verbal task performance Fluency task patients < controls: ns (Δ=0.40) Working memory performance & pain intensity: p<0.05 (r=0.61) Verbal Fluency task performance & pain intensity: ns

Migraine patients 18.4 years Stroop, COWAT, Inhibition, Group COWAT perfor- Le Pira et al. without aura, 36.7 TMT (B), updating, comparison mance patients < (2014) years, N=32; pain- shifting controls: p<0.05 free individuals, (Δ=1.11) 35.8 years, N=16 Stroop/TMT (B) performance patients < controls: ns (Δ=0.47/0.87) (Interictal assessment)

Migraine with 16.3 years Stroop/COWAT/ aura, 42.1 years, TMT (B) perfor- N=12; same con- mance patients < trol group controls: ns (Interictal assessment) (Δ=0.33/ 1.03/0.55)

Patients with vari- Self-report: 7 years Stroop, Verbal Inhibition, Correlation Stroop/Verbal Pulles & ous chronic pain 43 Fluency task, updating, Fluency task/TMT Oosterman conditions, 48.5 (0–100 VAS) TMT (B) shifting (B) performance & (2011) years, N=30 pain intensity: ns (r=0.08/0.12/0.21)

${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233 Fibromyalgia 1.1 years Stroop, Digit Inhibition, Group Stroop/Digit Span Roldán-Tapia patients, 48.5 Span Back- updating comparison Backward perfor- et al. (2007) years, N=15; pain- ward mance patients < free individuals, Stroop/Digit Span 44.3 years, N=15 Backward performance controls: ns

Table 3. continuation

Participants Pain intensity Disease Executive Cognitive Study Signiﬁ cance of Reference patients duration functioning domain design ﬁ ndings and tests effect sizes

Rheumatoid 1.6 years Stroop/Digit Span arthritis patients, Backward perfor- 41.9 years, N=15; mance patients < same control Stroop/Digit Span group Backward performance controls: ns

Patients with Self-report: Executive Updating Correlation Executive func- Scherder arthrosis/arthri- 50.85 functioning tioning perfor- et al. (2008) tis, 85.7 years, (0–100 CAS) domain: Digit mance & pain N=20 Span Back- intensity: ns ward, Category (r=0.17) Fluency, Knox’s Patients with Self-report: Cube Imitation Executive func- arthrosis/arthritis 21.55 Test, Incom- tioning perfor- and Alzheimer’s (0–100 CAS), plete ﬁ gures mance & pain disease, 86.4 0.56 (0–6 intensity: p<0.05* years, N=19 FPS) (r=–0.675)

Patients with vari- 7 years PASAT Updating Group PASAT perfor- Sjøgren et al. ous chronic pain comparison, mance patients < (2005) conditions, 44.4 correlation controls: ns years, N=91; pain- (Δ=0.20) free individuals, PASAT perfor- 47.6 years, N=64 mance & pain intensity: p<0.05

Fibromyalgia pa- MPQ: 38.0 Stroop, Letter Inhibition, Group Stroop/Letter Num- Suhr (2003) tients, 48.1 years, Number updating, comparison, ber /COWAT/PASAT/ N=23; pain-free Sequencing, shifting correlation WCST/TMT (B) per- individuals, 45.9 COWAT, PASAT, formance patients < years, N=21 TMT (B), WCST controls: ns (Δ=0.51/0.70/ 0.33/0.62/ –0.03/1.48) Stroop/WCST/ Let- ter Number /COW- AT/PASAT/TMT (B) performance & pain intensity: ns

Patients with vari- MPQ: 20.9 Stroop/Letter Num- ous chronic pain ber /COWAT/PASAT/ conditions, 49.5 WCST/TMT (B) per- years, N=22; formance patients < same control controls: ns (Δ=– group 0.02/0.67/ 0.25/0.20/ 0.49/1.76) Stroop/WCST/ Let- ter Number /COW- AT/PASAT/TMT (B) performance & pain intensity: ns

Chronic musculo- Self-report Emotional Inhibition Group Stroop perfor- Taylor et al.

${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233 skeletal pain median: 60 counting comparison mance patients < (2016) patients, 57.9 (0–100 NRS) Stroop Stroop perfor- years, N=15; pain- mance controls: free individuals, p<0.05 25-83 years, N=14

Table 3. continuation

Participants Pain intensity Disease Executive Cognitive Study Signiﬁ cance of Reference patients duration functioning domain design ﬁ ndings and tests effect sizes

Patients with Attack self- 11.0 years Verbal Fluency Updating, Group Verbal Fluency Tessitore migraine with report: 8.0 task, TMT (B), shifting comparison task/TMT (B)/ et al. (2015) aura, 30.1 years, (0–10 VAS) WCST WCST perfor- N=20; pain-free mance patients < individuals, 29.2 controls: ns years, N=20 (Δ=0.87/0.60/ 0.14) (Interictal assessment)

Patients with Attack self- 11.2 years Verbal Fluency migraine without report: 8.6 task/TMT (B)/ aura, 30.1 years, (0–10 VAS) WCST perfor- N=20; same con- mance patients < trol group controls: ns (Δ=0.38/0.68/– 0.14) (Interictal assessment)

Episodic cluster 10.8 years Stroop, Verbal Inhibition, Group Digit Span/TMT (B) Torkamani headache Fluency task, Updating, comparison performance pa- et al. (2015) patients, 40.8 Digit Span, shifting tients < controls: years, N=11; pain- Letter-number p<0.05 free individuals, Sequencing, (Δ=1.65/2.44) 53.2 years, N=12 TMT (B) Stroop/Letter-number Sequencing Verbal Fluency task performance patients < controls: ns (Δ=1.10/1.31/0.47) (Assessment during headache episode)

Chronic cluster 14.6 years Digit Span/Letter- headache number Sequencing patients, 49.2 performance years, N=11; same patients < controls: control group p<0.05 (Δ=1.63/1.39) Stroop/Verbal Fluency task/TMT (B) performance patients < controls: ns (Δ=1.34/1.21/ 1.71) (Interictal assessment)

Elderly with vari- Clock-in-the- Updating, Correlation Clock-in-the-box van der ous chronic pain box Test, Letter shifting Test/Letter Flu- Leeuw et al. conditions, 78.1 Fluency task, ency task/TMT (B) (2016) years, N=765 TMT (B) performance & pain intensity: ns

Fibromyalgia pa- Self-report: Stroop, Multi- Inhibition Group Stroop/Multi- Veldhuijzen tients, 30.4 years, 49 source Inter- comparison source Interfer- et al. (2012)

Table 3. continuation

Participants Pain intensity Disease Executive Cognitive Study Signiﬁ cance of Reference patients duration functioning domain design ﬁ ndings and tests effect sizes

Fibromyalgia pa- WHYMPI: 4.62 11.5 years WCST Shifting Group WCST perfor- Verdejo- tients, 45.9 years, (0–6 NRS) comparison, mance patients < García et al. N=36; pain-free correlation controls: p<0.05 (2009) individuals, 45.0 (Δ=0.75) years, N=36 WCST performance & pain intensity: p<0.05 (r=0.23)

Fibromyalgia pa- Self-report: >6 months Stroop, Digit Inhibition, Group Stroop/Digit Span Walteros tients, 50.4 years, 4.5 Span updating comparison performance pa- et al. (2011) N=15; pain-free (0–10 VAS) tients < controls: individuals, 49.0 ns (Δ=0.64/0.09) years, N=15

Chronic low back MPQ: 12.2 14.2 years TMT (B) Shifting Group TMT (B) perfor- Weiner et al. pain patients, comparison, mance patients < (2006) 73.6 years, correlation controls: p<0.05 N=163; pain-free (Δ=0.25) individuals, 73.5 TMT (B) perfor- years, N=160 mance & pain intensity: p<0.05

Temporomandib- Self-report: 9.3 years Counting Inhibition Group Stroop perfor- Weissman- ular disorder pa- 4.2 Stroop comparison mance patients < Fogel et al. tients, 35.2 years, (0–10 NRS) controls: ns (2011) N=17; pain-free (Δ=0.63) individuals, 34.0 years, N=17

*Positive association Abbreviations: VAS = Visual Analogue Scale; WCST = Wisconsin Card Sorting Test; PASAT = Paced Auditory Serial Addition Test; TMT = Trail Making Test; OSPAN = Operation Span Task; FIQ = Fibromyalgia Impact Questionnaire; CPG = Chronic Pain Grade; PED = Patient Experience Diary; NRS = Numerical Rating Scale; COWAT = Controlled Oral Word Association Test; MPI = Multidimensional Pain Inventory; WAIS-R = Wechsler Adult Intelligence Scale Revised; MPQ(-SF) = McGill Pain Questionnaire (Short Form); SF-36 = Short Form (36) health survey (higher scores represent less pain); CAS = Colored Analogue Scale; FPS = Faces Pain Scale; WHYMPI = West Haven-Yale Multidimensional Pain Inventory; n/a = not available; r = correlation coefﬁ cient, Δ = Glass’ Δ effect size, ns = nonsigniﬁ cant.

Most studies (46 studies) compared executive function- patients compared to pain-free individuals. In line with ing performance between chronic-pain patients and pain- this, the computation of eff ect sizes for the group com- free individuals (group-comparison design). Thirty stud- parisons revealed medium eff ects. Interestingly, this re- ies correlated self-reported pain intensity of chronic-pain duced ability to inhibit (on a group-level) does not seem patients with executive functioning performance (correla- to be closely linked to the intensity of the chronic pain tional approach). Three studies assessed executive func- (correlational approach), given that only a small percent- tioning performance with and without headache attack age of tests (16.7 %) showed that a high pain intensity is (Attridge et al., 2017; Gil-Gouveia et al., 2015; Moore et al., signifi cantly correlated with reduced inhibition perfor- 2013A). We decided to label these three studies as group mance. These meager results were also refl ected in a very comparison designs, given that they follow a similar logic. small averaged eff ect size (correlation coeffi cients, see Figure 2). Inhibition – Chronic-Pain Studies The most commonly used task to measure inhibition was Updating – Chronic-Pain Studies

${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233 the Stroop task (29 studies). In total, 33.9 % of all 59 tests The most commonly used task to measure information confi rmed that there is a signifi cant association between updating and monitoring was the digit span backwards inhibition and chronic pain (Table 1). Most of these tests task (15 studies). Other commonly reported tasks includ- were group comparisons, 41.5 % of which showed that the ed verbal fl uency tasks, the Operation Span Task, and the ability to inhibit is signifi cantly reduced in chronic-pain Paced Auditory Serial Addition Test (see Table 3). In total,

Table 4. Summary of papers investigating the association between experimental pain and executive functioning.

Sample Pain Pain Executive Cognitive Study Signiﬁ cance of ﬁ nd- Reference stimulus measure functioning tests domain design ings and effect sizes

Pain-free indi- Heat Intensity Stroop Inhibition Interference Pain intensity during Bantick viduals, 30.0 Stroop interference < et al. (2012) years, N=8 during Stroop neutral: p<0.05

Pain-free indi- Infrared Intensity N-back Updating Interference Pain intensity during Bingel et al. viduals, 26.0 laser 2-back task < during (2007) years, N=16 1-back task: p<0.05 2-Back task performance during pain < during no pain: p<0.05

Pain-free indi- Cold pres- Threshold Stroop, Stop-sig- Inhibition, Correlation Stroop & threshold/ Bjekić et al. viduals, 22.6 sor test and tolerance nal, Left-right, updating, tolerance: p<0.05 (2017) years, N=54 Keep-track, Let- shifting (r=0.28/0.40) ter-memory, N- Stop-signal/Left-right/ back, Plus-mi- Keep-track/Letter- nus, memory/N-back/Plus- Number-letter, minus/Number-letter/ Local-global Local-global & threshold: ns (r= –0.10.03–0.13/0.04/ 0.01/0.016/–0.01) Stop-signal/Left-right/ Keep-track/ Letter- memory/N-back/Plus- minus/Number-letter/ Local-global & tolerance: ns (r=– 0.16/0.08/–0.01/– 0.02/–0.01/ –0.06/–0.04)

Pain-free indi- Heat Task-shifting Shifting Interference Task-shifting perfor- Boselie viduals, 21.5 mance during pain < et al. (2017) years, N=61 during no pain: p<0.05

Pain-free indi- Heat Intensity N-Back task Updating Interference Pain intensity during Buhle and viduals, 25.0 3-back task < during Wager years, N = 24 neutral task: p<0.05 (2010) 3-back task performance during pain < 3-back task performance during no pain: p<0.05

Pain-free indi- Esophageal Intensity N-back task Updating Interference Pain intensity during Coen et al. viduals, 26.0 pressure 1-back task < during (2008) years, N=12 neutral task: p<0.05 1-Back task performance during pain < during no pain: ns

Pain-free indi- Pressure Threshold Stroop, OSPAN Inhibition, Correlation Stroop & CPM shoul- Coppieters viduals, 38.0 cuff, CPM updating der: p<0.05 (r=0.45) et al. (2015)

${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233 years, N=22 fi nger and Stroop & threshold shoulder, TS cuff/CPM fi nger/TS fi nger and fi nger/TS shoulder: shoulder ns (r=–0.01/0.30/ 0.33/0.08)

Table 4. continuation

Sample Pain Pain Executive Cognitive Study Signiﬁ cance of ﬁ nd- Reference stimulus measure functioning tests domain design ings and effect sizes

OSPAN & threshold cuff/CPM ﬁ nger/CPM shoulder/TS ﬁ nger/ TS shoulder: ns (r=0.31/0.29/0.18/ 0.09/–0.16)

Fibromyalgia OSPAN & TS shoul- patients, 44.5 der: p<0.05 (r=0.53) years, N=21 OSPAN & threshold cuff/CPM fi nger/CPM shoulder/TS fi nger: ns (r=0.19/–0.07/– 0.19/0.43) Stroop & threshold cuff/CPM fi nger/CPM shoulder/TS fi nger/ TS shoulder: ns (r=– 0.09/–0.17/0.33/ 0.30/0.17)

Pain-free indi- Pressure Threshold, Stroop, OSPAN Inhibition, Correlation Stroop/OSPAN & Ickmans viduals, 37.3 CPM, TS; all updating threshold fi nger/ et al. (2015) years, N=30 on fi nger threshold shoulder/ and CPM fi nger/CPM shoulder shoulder/TS fi nger/ TS shoulder: ns

Chronic fatigue Stroop/OSPAN & syndrome with CPM fi nger: p<0.05 comorbid fi bro- (r=0.41/0.55) myalgia patients, Stroop/OSPAN & 40.2 year, N=30 threshold fi nger/ threshold shoulder/ CPM shoulder/TS fi n- ger/TS shoulder: ns

Pain-free indi- Heat Intensity Stroop, Inhibition Correlation Anti-saccade & facial Karmann viduals, 22.2 year, measured anti-saccade expression: p<0.05 et al. (2015) N=49 by facial task (r=0.31) expression Stroop & facial expression: ns (r=-0.17)

Pain-free indi- Cold pres- Tolerance Stop-signal Inhibition Correlation Stop-signal & Karsdorp viduals, 21.8 year, sor test tolerance: p<0.05 et al. (2014) N=57

Pain-free indi- Finger- Tolerance Stop-signal Inhibition Correlation Stop-signal & Karsdorp viduals, 20.6 pressing tolerance: p<0.05 et al. 2016 years, N=70 task

Pain-free indi- Heat Word Generation Updating Interference Word generation task Keogh viduals, 25.0 task performance during et al. (2013) years, N=62 pain < during no pain: ns

Pain-free indi- Electrical Nociceptive SIDAM (domain Shifting Correlation SIDAM & nociceptive Kunz et al. viduals (dementia, stimuli fl exion intellectual abili- fl exion refl ex thresh- (2015) ${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233 mild cognitive refl ex ties/executive old/facial expression: impairments, 75.6 threshold function) p<0.05 years, N=70 and facial expression

Table 4. continuation

Sample Pain Pain Executive Cognitive Study Signiﬁ cance of ﬁ nd- Reference stimulus measure functioning tests domain design ings and effect sizes

Pain-free indi- Infrared N-back Updating Interference Performance 1-back Legrain viduals, 30.0 laser task during pain < et al. (2011) years, N=10 during no pain: ns

Pain-free indi- Infrared N-back Updating Interference Performance 1-back Legrain viduals, 25.0 year, laser task during pain < et al. (2013) N=16 during no pain: ns

Pain-free indi- Electrical CPM Stroop Inhibition Correlation Stroop & CPM: p<0.05 Marouf viduals, ~45.9 stimulation (r=0.34) et al. (2014) years, N=44

Pain-free women, Pressure Threshold Stroop Inhibition Interference Threshold during Martinsen 46.3 years, N=31 Stroop interference > et al. (2014) during control condition: ns

Fibromyalgia Threshold during patients, 49.8 Stroop interference > years, N=29 during control condition: ns

Pain-free indi- Pressure Threshold, Stroop, OSPAN Inhibition, Correlation Stroop & CPM fi nger/ Meeus et al. viduals, 40.9 CPM; both updating CPM shoulder: p<0.05 (2015) years, N=16 on fi nger (r=0.61/0.60) and Stroop & threshold fi n- shoulder ger/threshold shoulder: ns (r=–0.26/–0.29) OSPAN & CPM fi nger/ CPM shoulder/threshold fi nger/threshold shoulder: ns (r=–0.33/ –0.32/–0.4/0.03)

Pain-free indi- Heat N-back task, Updating, Interference N-back/Attentional Moore et al. viduals, 22.06 Attentional shifting switching perfor- (2013B) years, N=50 Switching task mance during pain < during no pain: p<0.05

Pain-free indi- Heat N-back task Updating Interference N-back performance Moore et al. viduals, 30.0 during pain < during (2017) years, N=20 no pain: p<0.05

Pain-free indi- Attentional Shifting Attentional switching viduals, 31.0 Switching task performance during years, N=20 pain < during no pain: ns

Pain-free indi- Cold pressor Tolerance, Stroop, Letter Inhibition, Correlation Stroop & tolerance: Oosterman viduals, 59.1 test intensity fl uency test, Digit updating, p<0.05 (r=0.42) et al. (2010) years, N=31 Span Backward, shifting Letter fl uency test/ Zoo Map Test, TMT (B)/Zoo Map TMT (B) Test/Digit Span Back- ward & tolerance: ns (r=0.04/–0.29/ –0.26/–0.35) Stroop/Letter fl uency

Table 4. continuation

Sample Pain Pain Executive Cognitive Study Signiﬁ cance of ﬁ nd- Reference stimulus measure functioning tests domain design ings and effect sizes

Pain-free indi- Pressure Intensity Stroop, Digit Inhibition, Correlation Stroop & pain inten- Oosterman viduals, 66.7 measured Span Backward, updating sity/facial expres- et al. (2016) years, N=51 by rating Zoo Map Test sion: p<0.05 and facial Digit Span Backward/ expression Zoo Map Test & pain intensity/facial expression: ns

Pain-free indi- Electrical Counting Stroop Inhibition Interference Counting Stroop per- Seminowicz viduals, 26.4 nerve formance during pain et al. (2004) years, N=16 stimulation < during no pain: ns

Pain-free indi- Electrical Intensity Multisource in- Inhibition Interference Pain intensity during Seminowicz viduals, 25.6 nerve terference task multisource infer- and Davis years, N=23 stimulation ence test difﬁ cult < (2007) during multisource easy: ns Multisource interference test performance during pain < during pain: ns

Pain-free indi- Cold pressor Tolerance Stroop Inhibition Interference Stroop performance Terrighena viduals, 24.0 test during pain < during et al. (2017) years, N=36 no pain: ns Pain tolerance during Stroop > during Stroop neutral: p<0.05

Pain-free indi- Heat Intensity Stroop Inhibition Interference Pain intensity during Valet et al. viduals, 32.1 Stroop task < during (2004) years, N=7 Stroop neutral: p<0.05

Pain-free women, Pressure Threshold Stroop, Multi- Inhibition Correlation Stroop/multisource Veldhuijzen 29.3 years, N=35 source Interfer- interference test & et al. (2012) ence Test threshold: ns (r=0.2/0.34)

Fibromyalgia pa- Stroop/multisource tients, 30.4 years, interference test & N=35 threshold: p<0.05 (r=0.41/0.37)

Pain-free indi- Cold pressor Threshold, Stroop, Letter Inhibition, Correlation Stroop & pain inten- Zhou et al. viduals, 67.5 test tolerance, Fluency test, TMT updating, sity: p<0.05 (r=0.48) (2015) years, N=26 intensity (B) shifting Stroop & threshold/ tolerance: ns (r=–0.2/–0.2) TMT (B) & threshold/ tolerance/pain intensity: ns (r=0.09/0.09/–0.1) Letter Fluency test & threshold/tolerance/ pain intensity: ns (r=0.26/0.26/–0.31)

Abbreviations. CPM=Conditioned Pain Modulation; TS=Temporal Summation; OSPAN=Operation Span Task; SIDAM=Structured Interview for the Diagnosis of dementias of the Alzheimer type and Multi-infarct dementia and dementias of other aetiology; TMT=Trail Making Test; r=correlation coefﬁ cient, Δ=Glass’ ${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233 Δ effect size.

fl ected in moderate-to-large eff ect sizes (see Figure 2). A !% +, $% smaller proportion (21.7 %) found that reduced shifting performance is signifi cantly correlated to a higher pain in- ( )

)( tensity in patients. One study (4.3 % of all tests using a correlational approach) found that higher pain intensity was * "# ) )* "# correlated with better shifting performance, namely, in a group of elderly with various chronic pain conditions ) #%% (Oosterman et al., 2013). On average, correlation coeffi - #%% ) cients point to a very small association between pain intensity and shifting performance (see Figure 2). -"# %" % "% !" # $% % $% %

$ &' # % Summary – Chronic-Pain Studies

Figure 2. Average effect sizes for the association between pain (chron- There is medium to strong evidence that executive func- ic and experimental pain) and the three executive functioning domains tioning performance is reduced in chronic-pain patients (inhibition, shifting, and updating). Glass’ Δ effect size was computed compared to pain-free controls, with all three domains of for group differences (chronic-pain patients vs. controls). The correla- executive functioning being similarly aff ected. In contrast, tion coefﬁ cient indicates the strength of association between executive functioning performance and pain (intensity in chronic pain or re- the evidence for a signifi cant correlation between the in- sponsiveness to experimental pain, respectively). The number of tests tensity of chronic pain and executive functioning perfor- included in the calculation are shown in the ﬁ gure because effect sizes mance is much weaker. were not available for every study. The effect sizes of the experimental- pain studies using interference designs could not be calculated, given the lack of descriptive data reported in the original studies. The inter- pretation of the strength of the effect sizes is based on Cohen (1988) Experimental-Pain Studies and Mukaka et al. (2012). Twenty-eight studies investigated the association between executive functioning and experimental pain responses (see Table 4). The most commonly used methods 28.2 % of all 85 tests confi rmed that there is a signifi cant of inducing pain were thermal heat pain and pressure association between updating and pain (Table 1). Again, pain, both used in eight studies. Other methods were the stronger fi ndings were found for group comparisons. One- cold pressor test, electrical stimulation, and infrared laser third of these studies showed that updating performance stimulation. is signifi cantly reduced in chronic-pain patients compared Thirteen studies investigated whether responsiveness to pain-free individuals. In line with this, there was a me- to painful stimulation is correlated with executive func- dium-to-large eff ect size for group diff erences between tioning performance (correlational approach). Twelve patients and controls. The correlations between pain in- studies investigated whether painful stimulation reduces tensity and updating performance show that only 19.4 % executive functioning performance (pain → executive of the tests demonstrated that higher pain intensity in pa- functioning) by letting the participants perform an execu- tients is signifi cantly correlated with reduced updating tive task twice, once while receiving painful stimulation performance. Only one study (3.2 % of all tests using a and once without receiving painful stimulation (6 stud- correlational approach) reported a signifi cant correlation ies) or with nonpainful stimulation (6 studies). In seven in the opposite direction, namely, within a group of Alz- studies participants received painful stimulation twice, heimer patients with arthrosis or arthritis (Scherder et al., once while performing an executive function task and 2008). The averaged correlation coeffi cients point to very once while performing a neutral task, to investigate small eff ects (see Figure 2). whether executive task demand reduces responsiveness to painful stimulation (executive functioning → pain). Shifting – Chronic-Pain Studies The Trail Making Test B was used most often to assess Inhibition – Experimental-Pain Studies shifting performance (23 studies). The Wisconsin Card Similar to the chronic-pain studies, the most commonly Sorting task was also used frequently (see Table 3). In to- used task to measure inhibition was the Stroop task (15

${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233 tal, 28.3 % of all 60 tests confi rmed that there is a signifi - studies). In total, one-third of the 57 tests confi rmed that cant association between pain and shifting performance there is a signifi cant association between inhibition and (Table 1). Similar to updating, almost one-third of the responsiveness to painful stimulation (Table 2). Most of group comparisons showed that shifting ability is signifi - these tests used a correlational approach (48 tests), of cantly reduced in chronic-pain patients, which is also re- which again one-third showed that a reduced ability to in-

hibit is signifi cantly correlated with a higher responsive- Pain inhibition – experimental-pain studies ness to experimental pain (e. g., a higher pain intensity In the context of this review, one type of pain responsive- rating, a lower pain threshold, or a lower pain tolerance). ness might be especially interesting, namely, the ability The eff ect size for this correlation, however, was only to inhibit pain. The ability to inhibit pain may be closely small (Figure 2). Three out of six studies showed that pain linked to a general ability to inhibit cognitive and behav- responsiveness was signifi cantly reduced when perform- ioral responses (as assessed with neuropsychological ing an inhibition task (executive functioning → pain). tests). The ability to inhibit pain is most often measured None of the studies (3 out of 3) found evidence for a sig- using the conditioned pain modulation (CPM) paradigm, nifi cant reduction in inhibition performance when simul- which refers to the process whereby one painful stimulus taneously receiving painful stimulation (pain → executive inhibits the perception of a second painful stimulus. Our functioning). For the interference design, no eff ect sizes results show that this endogenous pain inhibition seems could be computed given the lack of reported data in the to be especially associated with cognitive inhibitory func- respective studies. tioning. In total, 45 % of all tests performed showed that poor pain inhibition is signifi cantly correlated with poor Updating – Experimental-Pain Studies cognitive inhibition (5 out of 11 tests), with an average Several tests were frequently used to measure updating, correlation coeffi cient of 0.36 (a small eff ect size). In including the N-back task, Digit Span backward, and the comparison, the correlation between pain inhibition and OSPAN task (see Table 4). In total, 17.5 % of all 57 tests updating performance was less strong, only 10 % of the confi rmed that there is a signifi cant association between tests performed showed signifi cant associations. The cor- updating and responsiveness to experimental pain (Table relation between shifting performance and pain inhibi- 2). Most of these tests used a correlational approach. How- tion has not been investigated. ever, only 4.4 % of these correlational tests showed that higher responsiveness to painful stimulation is signifi cant- Summary – Experimental-Pain Studies ly correlated with reduced updating performance (2 out 46 The fi ndings of studies using experimental pain stimula- tests). The eff ect size for this correlation was negligible tion partly confi rm the fi ndings of chronic-pain studies. (Figure 2). In contrast, all interference studies conducted The results of studies using an interference design indi- to investigate whether pain responsiveness changes when cate that there is moderate evidence that painful stimula- simultaneously performing an updating task (executive tion reduces executive functioning performance, and that functioning → pain), showed that pain responsiveness is responsiveness to experimental pain is reduced when per- signifi cantly reduced in this situation (3 out of 3 tests). forming an executive task. The results of studies using a Similarly, 4 out 8 interference studies demonstrated that correlational approach show that responsiveness to experi- updating performance is signifi cantly reduced when si- mental pain can be negatively correlated with executive multaneously receiving painful stimulation (pain → execu- functioning performance, although evidence for this is tive functioning). Again, eff ect sizes for the interference very weak. Inhibition shows the strongest association with designs could not be computed. pain compared to updating and shifting, especially when looking at one specifi c type of pain responsiveness, name- Shifting – Experimental-Pain Studies ly, the ability to inhibit pain. Shifting was assessed using a variety of diff erent tasks (e. g., Trail Making Task B, attentional switching task, Plus-minus) (see Table 4). In total, 4 of the 16 tests confi rmed that there is a signifi cant association between shift- Discussion ing and responsiveness to painful stimulation (Table 2). Only 15.4 % of the tests using a correlational approach Executive Functioning and Chronic Pain showed that higher responsiveness to experimental pain is signifi cantly correlated with reduced shifting performance With regard to the chronic-pain studies, this review reveals (2 out of 13 tests). The eff ect size was also negligible (Fig- ample evidence for a reduction in executive functioning in ure 2). Two out of three tests showed that painful stimula- chronic pain, despite the heterogeneous patient groups in- tion signifi cantly reduces shifting performance in an inter- vestigated and despite the various tests used to assess ex-

${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233 ference design (pain → executive functioning). No study ecutive functioning. On average, one-third of all group investigated whether performing a shifting task reduces comparisons performed showed that executive function- responsiveness to painful stimulation (executive functioning is signifi cantly reduced in chronic-pain patients, with ing → pain). Eff ect sizes for the interference designs could medium-to-large eff ect sizes. No study reported an in- not be computed. crease in executive functions in chronic-pain patients

compared to pain-free individuals, which corroborates the functioning via functional and anatomical changes in the notion that the demonstrated decline in executive func- brain caused by the chronic pain condition itself (Moriarty tioning is not simply a false-positive fi nding. Our fi ndings et al., 2011). Chronic pain has been found to be associated are in line with previous reviews (Berryman et al., 2013; with several structural changes in the brain, when gray Berryman et al., 2014; Moriarty et al., 2011), which also matter declines in the anterior cingulate cortex, the insu- found small to moderate impairments in inhibition, updat- lar cortex, the orbitofrontal cortex, and the dorsolateral ing and shifting ability in chronic-pain patients (Berryman prefrontal cortex (Rodriguez-Raecke et al., 2013). Two et al., 2013; Berryman et al., 2014). chronic-pain studies included in this review demonstrat- In contrast to previous reviews/meta-analyses, we not ed that these structural brain changes correlate with ex- only looked for diff erences between chronic-pain patients ecutive functioning performance. Gray matter volumes in and pain-free controls, we also included studies investi- the medial frontal cortex and the left middle frontal gyrus gating whether executive functioning performance is cor- were positively correlated with updating performance in related with the severity of chronic pain. We found that fi bromyalgia patients (Luerding et al., 2008). Similarly, executive functioning was negatively correlated with self- cortical thickness of the right dorsolateral prefrontal cor- reported pain intensity across several studies, with strong- tex was positively correlated with inhibition performance er pain being associated with worse executive function- in patients with complex regional pain syndrome (Lee et ing. However, the evidence for this negative correlation is al., 2015). much weaker (average correlation coeffi cients were negli- The above-mentioned theories act on the strong as- gible) than the evidence for the reduction in executive sumption that pain is the causal factor leading to a decline functions in patients compared to controls. Nevertheless, in executive functioning, either by limiting the cognitive almost all studies that found evidence for a signifi cant recourses and/or by causing structural changes in the correlation between pain intensity and executive func- brain. These are, however, only assumptions, given that tioning report a negative correlation. Only two studies cross-sectional chronic-pain studies do not allow investi- (2.8 % of all tests) report a positive correlation, with one of gation of the causal direction between executive functions these studies having been conducted on patients suff ering and pain. However, by manipulating pain using experi- from dementia-related cognitive impairment (Scherder et mental pain stimuli, we may be able to better determine al., 2008). Given that the ability to validly report pain de- the direction of the association between executive func- clines across the course of dementia (Achterberg & Laut- tions and pain. The fi ndings of these experimental-pain enbacher, 2017), the positive correlation between execu- studies are discussed in the next section. tive functioning and reported pain intensity could be because of the more severely impaired patients not being able to give a self-report of pain. Executive Functions and Experimental Pain: Taken together, the fi ndings of chronic-pain studies What Disrupts What? suggest that patients often have impairments in executive functions (moderate eff ect size), but that these im- Interference Design pairments do not increase linearly when pain intensity In an experimental setting, it is possible to investigate the increases. eff ect of simultaneously receiving painful stimulation while performing an executive functioning task. This condition is then compared with a control condition, in which Possible Mechanisms Mediating participants only perform an executive functioning task Executive Functioning Impairment and/or only receive painful stimulation. The results of the in Chronic-Pain Patients interference design studies included in this review suggest that pain does indeed interfere with executive functioning One hypothesis that may explain the executive function- and vice versa. By letting the participants perform an ex- ing problems occurring in chronic-pain patients is the the- ecutive task twice, once while receiving painful stimula- ory of limited cognitive resources (Eccleston & Crombez, tion and once without receiving painful stimulation, 1999), which states that the processing of pain demands roughly 40 % of the studies demonstrated that painful attention, similar to that demanded to perform an execu- stimulation reduces executive functioning performance

${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233 tive task. Because of the attention demanded by pain, (especially for the domains “updating” and “shifting”). there are thus less attentional resources available to per- This proves the causal direction of pain leading to a de- form executive functions (Eccleston, 1995). cline in executive functioning, which is assumed by the Another possibility, but not one excluding the theory of studies on chronic pain. At the same time, the fi ndings of limited resources, is that chronic pain aff ects executive the interference design studies also show that performing

an executive task can reduce pain responsiveness, though tive functioning being a risk factor for higher vulnerabili- this is not exclusively the case for executive tasks. Distrac- ty to pain. tion generally reduces pain, so that other cognitive tasks besides executive function tasks can also reduce pain responsiveness (Dowman, 2004; Frankenstein et al., 2001). The Frontal Cortex Interestingly, pain-related brain activation also declines as Underlying Mechanism signifi cantly when participants simultaneously perform an executive functioning task while receiving painful stimula- One candidate for the idea of a shared underlying mecha- tion (Bantick et al., 2012; Coen et al., 2008; Seminowicz et nism might be the frontal cortex. As discussed above, al., 2004; Seminowicz & Davis, 2007; Valet et al., 2004). chronic-pain patients can show structural brain changes in Thus, in clinical practice, chronic patients should be en- the frontal cortex which correlate with executive function- couraged to engage in cognitively stimulating and enter- ing performance (Lee et al., 2015; Luerding et al., 2008). taining tasks or activities, since these have the capacity to The role of the frontal cortex in pain is supported by fi nd- distract from the pain. ings of animal studies showing that pain can lead to changes in neuronal morphology (Metz et al., 2009) and a de- Correlational Design crease in neuronal activation (Ji et al., 2010) in the frontal In recent years, the association between executive func- cortex. Of course, the frontal cortex is a broad area that tioning and pain has been suggested to be even more com- can be divided into multiple subregions. Regarding the plex, because it has been suggested that declining execu- link between executive functions and pain, two regions tive functioning might be associated with a higher might be of particular interest: (1) the orbitofrontal cortex sensitivity to pain and a worse ability to cope with pain – and (2) the dorsolateral prefrontal cortex. and therefore be a risk factor for higher vulnerability to The orbitofrontal cortex is suggested as playing a sub- developing chronic pain. Evidence that reduced executive stantial role in the ability to inhibit pain. This notion is functioning might be a risk factor for a higher pain sensi- based on observations of increased activation of the orbit- tivity came from a recent longitudinal study investigating ofrontal cortex during diff erent pain inhibition tasks (Ban- whether executive functioning performance before the tick et al., 2012; Moont et al., 2011; Valet et al., 2004). Be- start of a surgery can predict the extent to which people sides being involved in pain inhibition, the orbitofrontal suff er from pain after surgery (Attal et al., 2014). The study cortex is also involved in executive functioning, especially showed that poorer executive functioning performance in inhibitory functioning (Collette et al., 2005). Thus, our predicts pain intensity up to a year after the surgery. Evi- fi nding of a signifi cant positive correlation between cogni- dence supporting this assumption of a link between pain tive inhibition and pain inhibition could be moderated by sensitivity and executive functioning stems from correla- the orbitofrontal cortex. tional analyses, usually conducted in pain-free individu- The dorsolateral prefrontal cortex is involved in the abil- als. This review shows that executive functioning can cor- ity to cope with pain (Gracely et al., 2004; Seminowicz & relate negatively with responsiveness to experimental Davis, 2006; Seminowicz et al., 2013). Pain-coping skills pain. However, the association is only weak, given very are important because maladaptive coping can increase small eff ect sizes and the low number of studies that found pain intensity and can be a risk factor for the development a signifi cant correlation (20 %). Nevertheless, all signifi - of chronic pain (Sullivan et al., 2001). Beyond being in- cant fi ndings were in the same direction of a negative cor- volved in pain coping, the dorsolateral prefrontal cortex is relation. Interestingly, the association becomes much also involved in various domains of executive functioning stronger in those studies that use a specifi c type of pain re- (Jurado & Rosselli, 2007). Thus, dorsolateral prefrontal sponse, namely, the pain inhibitory response (conditioned functioning can aff ect both the ability to cope with pain as pain modulation) and correlate it with cognitive inhibition well as executive performances. (e. g., Stroop task). Here, 45 % of the correlations per- In summary, poor functionality of the frontal cortex formed show that poor pain inhibition is correlated with can result in poor executive performances as well as in poor cognitive inhibition. Thus, it might not be the pain high responsiveness to pain, possibly because of (1) lim- responsiveness that is linked to executive functioning, but ited pain inhibition as a consequence of reduced orbito- rather certain aspects of the pain response system (e. g., frontal functioning and/or (2) limited pain-coping skills

${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233 the ability to inhibit pain). as a consequence of reduced dorsolateral prefrontal func- Together, the diff erent study designs used by experi- tioning. A clinical implication of this assumption is that mental-pain studies suggest that not only does pain dis- chronic-pain patients might benefi t from strengthening rupt executive functioning, there might also be a shared frontal capacities, for example, by executive functioning underlying mechanism (see below), with poorer execu- training, to strengthen the system’s ability to better in-

hibit pain as well as better cope with pain. It should be in a testing situation it should be taken into account that tested in future research whether this would make indi- cogniphobia might exist in certain types of pain, which can viduals less vulnerable to pain. decrease cognitive performance. Another limitation is that many studies failed to report in detail the analgesic medication use in the chronic-pain The Role of Depression patient group, which was revealed by the risk of bias assessment. This would have been important because opioid Given that depressive symptoms are prevalent in chronic- use can have an eff ect on cognition, including executive pain patients and have been shown to be associated with functions (Baldacchino et al., 2014). executive functioning defi cits (Rock et al., 2014), it possible that the link between pain and executive functioning might also be moderated by depressive symptoms. Being Conclusion aware that depression is associated both with pain as well as with defi cits in executive functioning, most chronic- In conclusion, this review shows that there is moderate to pain studies included in this review (approximately 65 %) strong evidence that executive functions are decreased in did assess the level of depressive symptoms. Upon testing chronic-pain patients, and that these executive dysfunc- whether depressive symptoms might explain the relation tions do not linearly increase with the pain intensity. The between chronic pain and executive functioning, three fi ndings of experimental-pain studies suggest that there studies found confi rming evidence (Gijsen et al., 2011; might be a bidirectional relation between pain and execu- Jongsma et al., 2011; van der Leeuw et al., 2016). Howev- tive functioning: Pain not only disrupts executive func- er, even more studies failed to show that depressive symp- tioning, but poorer executive functioning may be a (small) toms can explain the executive functioning defi cits in risk factor for higher vulnerability to pain. Changes in the chronic-pain patients (Abeare et al., 2010; Akdoğan et al., frontal cortex of the brain, especially in orbitofrontal and 2013; Armstrong et al., 1997; Dick et al., 2002; Glass et al., dorsolateral regions, might moderate this association. 2011; Grace et al., 1999; Grisart & Plaghki, 1999; Hall et al., 2011; Ickmans et al., 2015; Karp et al., 2006; Legaretta et al., 2016; Luerding et al., 2008; Miró et al., 2011; Mura- ta et al., 2017; Park et al., 2001; Weiner et al., 2006). Electronic supplementary material Therefore, depressive symptoms seem to play only a mi- nor role in the association between chronic pain and ex- The electronic supplementary material (ESM) is available ecutive functioning. with the online version of the article at https://doi.org/10.1024/1016/-264X/a000264 ESM 1. Table S1. Risk of bias assessment chronic pain Limitations studies ESM 2. Table S2. Risks of bias assessment experimental An important limitation of this systematic review is the pain studies heterogeneous patient group investigated. We decided to include many diff erent pain conditions, in order to give a comprehensive overview of the fi ndings on the relationship between executive functioning and pain. When com- References piling the outcomes, we did not diff erentiate between dif- ferent types of pain, although diff erent types of pain can be Abeare, C. A., Cohen, J. L., Axelrod, B. N., Leisen, J. C. C., Mosley- Williams, A., & Lumley, M. A. (2010). Pain, executive functioning, expected to have a diff erent impact on executive functions. and affect in patients with rheumatoid arthritis. The Clinical However, the limited number of studies and the diversity Journal of Pain, 26, 683–689. of executive functioning tests being used did not allow for Achterberg, W., & Lautenbacher, S. (2017). Pain in dementia: A dis- a more diff erentiated approach. Nevertheless, a distinc- tressing combination of several factors. Current Alzheimer Re- search, 14, 468–470. tion between diff erent pain types seems reasonable. An Akdoğan, S., Ayhan, F. F., Yıldırım, S., & Borman, P. (2013). Impact of interesting example for the need for diff erentiation be- fatigue on cognitive functioning among premenopausal women

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${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233 Seminowicz, D. A., Mikulis, D. J., & Davis, K. D. (2004). Cognitive The relationship between pain, neuropsychological perfor- modulation of pain-related brain responses depends on behav- mance, and physical function in community-dwelling older ioral strategy. Pain, 112, 48–58. adults with chronic low back pain. Pain Medicine, 7, 60–70. Silverberg, N. D., Iverson, G. L., & Panenka, W. (2017). Cogniphobia in Weissman-Fogel, I., Moayedi, M., Tenenbaum, H. C., Goldberg, M. B., mild traumatic brain injury. Journal of Neurotrauma, 34, Freeman, B. V., & Davis, K. D. (2011). Abnormal cortical activity in 2141–2146.

patients with temporomandibular disorder evoked by cognitive Zhou, S., Kemp, J., Després, O., Pebayle, T., & Dufour, A. (2015). The and emotional tasks. Pain, 152, 384–396. association between inhibition and pain tolerance in the elder- Wells, G. A., Shea, B., O’Connell, D., Peterson, J., Welch, V., Losos, M., ly: Evidence from event-related potentials. European Journal of & Tugwell, P. The Newcastle-Ottawa Scale (NOS) for assessing Pain, 19, 669–676. the quality if nonrandomized studies in meta-analyses. Re- treived from: http://www.ohri.ca/programs/clinical_epidemiol- ogy/oxford.asp. History/Historie Yarnitsky, D. (2010). Conditioned pain modulation (the diffuse nox- Received October 5, 2018 ious inhibitory control-like effect): Its relevance for acute and Revision received January 22, 2019 chronic pain states. Current Opinion in Anaesthesiology, 23, Accepted February 15, 2019 611–615. Conﬂ ict of interest/Interessenskonﬂ ikt None

Stefanie Bunk Department of General Practice and Elderly Care Medicine University Medical Center Groningen University of Groningen Hanzeplein 1 9713 GZ Groningen The Netherlands

s. [email protected] ${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/1016-264X/a000264 - Friday, September 20, 2019 7:14:17 AM Universitätsbibliothek Bamberg IP Address:141.13.70.233