Fatigue in Chronic Pain - Cognition, Emotional Aspects, Biomarkers, and Neuronal Correlates

NCT05452915 | Completed

• 1 other identifier: 2018.424-31 Fatigue in pain
• Study Type: observational
• Target: 72
• Locations: 1 country
• Sites: 3

Brief Summary

The investigators will examine mental/cognitive as well as cognitive functions (executive functions, attention functions, processing speed, learning and memory) in 200 patients with chronic pain and 36 healthy controls. Mental fatigue will be measured with questionnaires and cognitive fatigue and cognitive functions with neuropsychological tests. As studies on patients with mild traumatic brain injury has shown that fatigue is associated with altered communication (connectivity) in the brain's attention-related networks, brain connectivity will be measure in 24 patients (women only) and 22 healthy female controls using functional magnetic resonance imaging (fMRI) technology. During the fMRI examination, participants will also perform a 20-minute vigilance task in a scanner. Studies have also shown that inflammatory biomarkers may be related to chronic pain, but inflammatory biomarkers has not been studied in relation to objective measures regarding cognition, fatigue and connectivity changes. Therefore, the patients and controls performing fMRI will also be examined with immunological biomarkers. In addition to this, a further 14 patients and 14 controls carrying out the neuropsychological testing alone will also be examined for immunological biomarkers. The main objectives are:

1. 1.Do patients with chronic pain show more pronounced self-rated mental fatigue and cognitive fatigue compared to healthy controls and are fatigue measures related to cognitive functions such as process speed and attention functions?
2. 2.What is the relationship between cognitive impairments, mental fatigue, or fatigability and
3. 3.the duration of pain
4. 4.generalization of pain and are they affected by covariates, such as sleep disorders and degree of depression/anxiety?
5. 5.Is there an association between immunological biomarkers and cognitive functions/mental fatigue/cognitive fatigability?
6. 6.Does the connectivity in the brain of patients with chronic pain differ from healthy controls at rest as well as during activity while performing a vigilance task?
7. 7.Is there an association between connectivity in the brain and
8. 8.immunological biomarkers
9. 9.fatigability and
10. 10.results on neuropsychological tests?

Conditions

Pain; Fatigue; Cognitive Impairment

Keywords

Fatigue; Cognition; Pain; Imaging; Inflammatory markers; Executive functions; Attention; Processing speed

Outcome Measures

Primary Outcomes (6)

• Fatigability from WAIS-III - Coding

  The subject must fill in the blank spaces with the symbol which is paired to the number during 120 seconds. Cognitive fatigue was assessed by subtracting the number of digits produced in the first 30 seconds from the number of digits produced in the last 30 seconds during the full 120-second period. A non ascending score (\< 0) is considered an indicator of cognitive fatigue. Both the total value in the difference between the production between 0-30 seconds and 91-120 seconds are measured and a dichotomized variable (non-ascending value) will be used.

  baseline

• D-KEFS - Color Word Test

  Inhibition of over-learned verbal responses. The test has four conditions: 1) naming colors (red, blue or green, 2) reading color words printed in black, 3) naming the color of the color words red, blue or green write in a different color than what is written, which means inhibition of an over-learned function of reading the word; 4) repeatedly switching between naming colors and reading out the printed words as quickly as possible, while at the same time the person needs to keep track of clues that indicate rule change. Contrast scores are used to examine the performance of the more complex tasks 3 and 4 and the basic tasks 1 and 2. The faster the time, the better. The number of errors is also measured

  baseline

• Fatigability on e-prime vigilance (reaction time) task in the fMRI scanner

  The participants are instructed to push a button as quick as they can when a set of four zeroes appears in a red rectangle, and do nothing if other numbers appeared. After each response visual feedback of the reaction time is displayed. If the participant reacts at a false stimulus or if the response time of more than 1 sec. the feedback "false answer" or "no answer" is displayed respectively. The stimuli are presented at random intervals. The results are divided into quintiles and the mean reaction time is calculated for each quintile.

  baseline

• Task-fMRI

  BOLD signal changes during fatiguing attention task (PVT)

  baseline

• Resting state fMRI

  Changes in functional connectivity after performance of fatiguing attention task (PVT)

  baseline

• Inflammatory markers

  he analyzes that will be used in this study are mainly exploratory, i.e., which proteins, metabolites and lipoproteins are identified cannot be determined in advance. Exploratory analyzes using panels for inflammation, cytokines \& chemokines and neuroinflammation comprising many proteins (72-92 substances.

  Baseline

Secondary Outcomes (4)

• MFI-20

  baseline

• Visual Analog Scale of Fatigue

  baseline

• D-KEFS - Word Fluency Test

  baseline

• Working memory from WAIS-IV - Digit Symbol subtest - backward repetition

  baseline

Study Arms (2)

Chronic Pain

Patients with chronic pain, aged 18 - 50 years for the neuropsychological assessment and 18-45 years for the fMRI examination

Diagnostic Test: Neuropsychological (NPA); Other: Imaging; Diagnostic Test: Inflammatory biomarkers

Healthy Controls

Healthy controls matched on group level in terms of gender, age, and educational level

Diagnostic Test: Neuropsychological (NPA); Other: Imaging; Diagnostic Test: Inflammatory biomarkers

Interventions

Neuropsychological (NPA) DIAGNOSTIC_TEST

The neuropsychological assessment consists of following tests and questionnaires: * Wechsler Adult Intelligence Scale (WAIS)-III: Digit-Symbol-Coding (Coding) * WAIS-IV: Digit Span, Matrix reasoning * Delis-Kaplan Executive Function Scale (D-KEFS): Color-Word Test, Word Fluency Test * Ruff 2 \& 7 * MapCog Spectra Questionnaires: * EuroQoL five dimensions questionnaire (EQ5D) * Hospital Anxiety and Depression Scale (HADS) * Insomnia Severity Index (ISI) * Multidimensional Fatigue Inventory-20 (MFI-20) * Multidimensional Pain Inventory (MPI) * Screening questions on physical activity * Visual analogue scale on fatigue (VAS-f) before and after NPA * Visual analogue scale on fatigue (VAS-f) and pain before and after the fMRI scanning. * Pain level, experienced during the NPA, will be rated (0-10) at the end of the session

Chronic Pain; Healthy Controls

Imaging OTHER

Imaging (24 patients + 22 controls): BOLD resting-state before and after 20-min vigilance task (e-prime). During the vigilance task, fMRI is performed. Clinical protocol: 1. High-resolution T1-weighted. 2. High-resolution T2-weighted Scan (FLAIR).

Also known as: fMRI

Chronic Pain; Healthy Controls

Inflammatory biomarkers DIAGNOSTIC_TEST

Blood samples from inflammatory biomarkers will be taken on 36 patients and 36 controls. Everyone who undergoes imaging will undergo blood tests.

Chronic Pain; Healthy Controls

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)
• Sampling Method: Probability Sample

Study Population

Consecutive outpatients with chronic pain referred to the Department of Rehabilitation Medicine at Danderyd University Hospital, Stockholm, Sweden or to the Department of Pain Rehabilitation, Pain Center at University Hospital, Umeå, Sweden.

You may qualify if:

• Chronic pain

You may not qualify if:

• Traumatic brain injury (including concussion and mild traumatic brain injury)
• Extensive psychiatric problems or substance abuse
• Congenital or acquired brain injury and / or does not live in their own home and who needs support in everyday life
• Not sufficient knowledge of the Swedish language
• Progressive disease
• Abuse
• Use of drugs with a strong sedative effect
• Pregnancy
• Over 45 years of age
• Male subjects
• Metal objects implanted in the body or metal chips in body parts
• Afraid of cramped spaces
• Left-handedness

Sponsors & Collaborators

• Danderyd Hospital: lead
• University Hospital, Umeå: collaborator
• Karolinska Institutet: collaborator
• Umeå University: collaborator
• Linkoeping University: collaborator

Study Sites (3)

Pain and Rehabilitation Centre

Linköping, Sweden

Location

Department of Rehabilitation Medicine, Danderyd Hospital

Stockholm, 18288, Sweden

Location

Department of Community Medicine and Rehabilitation

Umeå, Sweden

Location

Related Publications (18)

• Apkarian AV. Human Brain Imaging Studies of Chronic Pain: Translational Opportunities. In: Kruger L, Light AR, editors. Translational Pain Research: From Mouse to Man. Boca Raton (FL): CRC Press/Taylor & Francis; 2010. Chapter 15. Available from http://www.ncbi.nlm.nih.gov/books/NBK57254/

  PMID: 21882455 BACKGROUND

• Backryd E, Lind AL, Thulin M, Larsson A, Gerdle B, Gordh T. High levels of cerebrospinal fluid chemokines point to the presence of neuroinflammation in peripheral neuropathic pain: a cross-sectional study of 2 cohorts of patients compared with healthy controls. Pain. 2017 Dec;158(12):2487-2495. doi: 10.1097/j.pain.0000000000001061.

  PMID: 28930774 BACKGROUND

• DeLuca, J. (2005). Fatigue: Its Definition, Its Study and Its Future. In J. DeLuca (Ed.), Fatigue as a window to the brain (pp. 319-325). MIT Press.

  BACKGROUND

• Gerdle B, Backryd E, Falkenberg T, Lundstrom E, Ghafouri B. Changes in inflammatory plasma proteins from patients with chronic pain associated with treatment in an interdisciplinary multimodal rehabilitation program - an explorative multivariate pilot study. Scand J Pain. 2019 Dec 18;20(1):125-138. doi: 10.1515/sjpain-2019-0088.

  PMID: 31584875 BACKGROUND

• Hasselstrom J, Liu-Palmgren J, Rasjo-Wraak G. Prevalence of pain in general practice. Eur J Pain. 2002;6(5):375-85. doi: 10.1016/s1090-3801(02)00025-3.

  PMID: 12160512 BACKGROUND

• Hysing EB, Smith L, Thulin M, Karlsten R, Bothelius K, Gordh T. Detection of systemic inflammation in severely impaired chronic pain patients and effects of a multimodal pain rehabilitation program. Scand J Pain. 2019 Apr 24;19(2):235-244. doi: 10.1515/sjpain-2018-0340.

  PMID: 30893060 BACKGROUND

• Johansson B, Berglund P, Ronnback L. Mental fatigue and impaired information processing after mild and moderate traumatic brain injury. Brain Inj. 2009 Dec;23(13-14):1027-40. doi: 10.3109/02699050903421099.

  PMID: 19909051 BACKGROUND

• Kluger BM, Krupp LB, Enoka RM. Fatigue and fatigability in neurologic illnesses: proposal for a unified taxonomy. Neurology. 2013 Jan 22;80(4):409-16. doi: 10.1212/WNL.0b013e31827f07be.

  PMID: 23339207 BACKGROUND

• Kurtze N, Svebak S. Fatigue and patterns of pain in fibromyalgia: correlations with anxiety, depression and co-morbidity in a female county sample. Br J Med Psychol. 2001 Dec;74(Pt 4):523-37. doi: 10.1348/000711201161163.

  PMID: 11780799 BACKGROUND

• Moller MC, Nordin LE, Bartfai A, Julin P, Li TQ. Fatigue and Cognitive Fatigability in Mild Traumatic Brain Injury are Correlated with Altered Neural Activity during Vigilance Test Performance. Front Neurol. 2017 Sep 21;8:496. doi: 10.3389/fneur.2017.00496. eCollection 2017.

  PMID: 28983280 BACKGROUND

• Moriarty O, McGuire BE, Finn DP. The effect of pain on cognitive function: a review of clinical and preclinical research. Prog Neurobiol. 2011 Mar;93(3):385-404. doi: 10.1016/j.pneurobio.2011.01.002. Epub 2011 Jan 7.

  PMID: 21216272 BACKGROUND

• Möller, M. C., Bartfai, A., Nygren de Boussard, C., Flöter Rådestad, A., & Calissendorff, J. (2014). High rates of fatigue in newly diagnosed Graves' disease. Fatigue: Biomedicine, Health & Behavior, 2(3), 153-162

  BACKGROUND

• Moller MC, Nygren de Boussard C, Oldenburg C, Bartfai A. An investigation of attention, executive, and psychomotor aspects of cognitive fatigability. J Clin Exp Neuropsychol. 2014;36(7):716-29. doi: 10.1080/13803395.2014.933779. Epub 2014 Jun 26.

  PMID: 24965830 BACKGROUND

• Moller MC, Radestad AF, von Schoultz B, Bartfai A. Effect of estrogen and testosterone replacement therapy on cognitive fatigue. Gynecol Endocrinol. 2013 Feb;29(2):173-6. doi: 10.3109/09513590.2012.730568. Epub 2012 Oct 25.

  PMID: 23095007 BACKGROUND

• Ng SK, Urquhart DM, Fitzgerald PB, Cicuttini FM, Hussain SM, Fitzgibbon BM. The Relationship Between Structural and Functional Brain Changes and Altered Emotion and Cognition in Chronic Low Back Pain Brain Changes: A Systematic Review of MRI and fMRI Studies. Clin J Pain. 2018 Mar;34(3):237-261. doi: 10.1097/AJP.0000000000000534.

  PMID: 28719509 BACKGROUND

• Nordin LE, Moller MC, Julin P, Bartfai A, Hashim F, Li TQ. Post mTBI fatigue is associated with abnormal brain functional connectivity. Sci Rep. 2016 Feb 16;6:21183. doi: 10.1038/srep21183.

  PMID: 26878885 BACKGROUND

• Ziino C, Ponsford J. Selective attention deficits and subjective fatigue following traumatic brain injury. Neuropsychology. 2006 May;20(3):383-90. doi: 10.1037/0894-4105.20.3.383.

  PMID: 16719631 BACKGROUND

• Moller MC, Berginstrom N, Ghafouri B, Holmqvist A, Lofgren M, Nordin L, Stalnacke BM. Cognitive and mental fatigue in chronic pain: cognitive functions, emotional aspects, biomarkers and neuronal correlates-protocol for a descriptive cross-sectional study. BMJ Open. 2023 Mar 29;13(3):e068011. doi: 10.1136/bmjopen-2022-068011.

  PMID: 36990481 DERIVED

Biospecimen

Retention: SAMPLES WITHOUT DNA

Venous blood samples are collected in P100 tubes from BD diagnostic, containing a protease inhibitor cocktail that prevents protein cleavage / degradation). The blood samples are centrifuged to remove red blood cells. The plasma fraction is transferred to a new tube, portioned and stored at -86 ° C until analysis at PAINOMICS lab. Plasma samples will be analyzed using antibody-based methods such as multiplex technology (Meso Scale Diagnostics, Rockville, MD). It is a multiplex instrument, that can analyze up to 92 different substances (cytokines, chemokines, growth factors and metabolic proteins) in one go. Omics analysis consisted of proteomics, metabolomics and lipoprotein profiling will be used to identify other inflammatory markers than those analyzed by the antibody-based method.

MeSH Terms

Conditions

Pain; Fatigue; Cognitive Dysfunction

Interventions

X-Rays

Condition Hierarchy (Ancestors)

Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Cognition Disorders; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Electromagnetic Radiation; Electromagnetic Phenomena; Magnetic Phenomena; Physical Phenomena; Radiation; Radiation, Ionizing

Study Officials

• Marika C Möller, PhD

  Department of Rehabilitation Medicine, Danderyd Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: July 4, 2022
• First Posted: July 11, 2022
• Study Start: January 1, 2018
• Primary Completion: December 31, 2022
• Study Completion: December 31, 2022
• Last Updated: July 13, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will not share

Locations

SE (3)