PainNCT05452915
Fatigue in Chronic Pain - Cognition, Emotional Aspects, Biomarkers, and Neuronal Correlates
An observational study of Pain and Fatigue, run by Danderyd Hospital at 3 sites in Sweden.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 50 yearsHealthy volunteers can take part
- Conditions the study is for
- Pain, Fatigue, Cognitive Impairment
- What is being tested?
- Neuropsychological (NPA), Imaging and Inflammatory biomarkers
- Type of treatment
- Injection or infusion
- How many people
- 72 participants
- Where
- 3 sitesSweden
- Study dates
- 1 Jan 2018to 31 Dec 2022
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- All sexes
- Healthy volunteers accepted
- Adult
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.
Who may be able to join
- Chronic pain
Who cannot join
- 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
Show all 14Show fewer
- Use of drugs with a strong sedative effect
- Pregnancy
- Additional exclusion for Imaging:
- 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
Trial locations and contacts
3 sites in 1 country.
Sweden3 sites
Pain and Rehabilitation Centre
Linköping
Department of Rehabilitation Medicine, Danderyd Hospital
Stockholm, 18288
Department of Community Medicine and Rehabilitation
Umeå
About this study
Official title: Fatigue in Chronic Pain - Cognitive Functions, Emotional Aspects, Biomarkers and Neuronal Correlates - a Descriptive Comparative Study
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:
- 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?
- What is the relationship between cognitive impairments, mental fatigue, or fatigability and
- the duration of pain
- generalization of pain and are they affected by covariates, such as sleep disorders and degree of depression/anxiety?
- Is there an association between immunological biomarkers and cognitive functions/mental fatigue/cognitive fatigability?
- 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?
- Is there an association between connectivity in the brain and
- immunological biomarkers
- fatigability and
- results on neuropsychological tests?
Read the detailed description
Many patients with chronic pain (CP) suffer from mental fatigue (fatigue) and cognitive dysfunction, which to a large extent contributes to difficulties returning to work and high sick leave rates. Previous research has primarily relied on subjective estimates, but then the results are affected by depression and sleep disorders. The general attitude has therefore been that fatigue is due to sleep disorders and depression.
However, fatigue is not only a subjective experience but can also be associated with impaired cognitive functioning. In patients with acquired brain injuries, fatigue has been linked to impaired attention, slower process speed and fatigue. Since objective measures have not been used in previous studies in chronic pain, it cannot be ruled out that fatigue and cognitive impairments may have similar underlying mechanisms.
To enable effective treatment, one needs to find markers that can distinguish different causes of fatigue (depression vs. impaired cognitive functions) from each other. Fatigue in cognitively demanding tasks can be such a marker, which has been shown in patients with mild traumatic brain injury and hormonal conditions. One theory is that the same mechanisms may play a role in CP.
In chronic pain the central nervous system is affected by an imbalance in the brain's pathway system, which leads to plastic changes in the brain. In particular, pain activates areas of the brain that are important for attention functions, which may explain why many patients with pain experience attention deficit disorders. Only a few studies have used objective tests to study the type and extent of cognitive problems and cognitive fatigue has not been studied before in patients with CP.
Functional MRI (fMRI) may reflect increased or decreased neuronal activity in the brain as changes in neuronal activity are linked to changes in regional blood flow (rCBF) and blood oxygenation levels (BOLD). Fatigue in mild traumatic brain injury is related to altered connectivity in the brain and that there are different neural networks that are related to subjective compared to objective measures of fatigue. Also in chronic pain, connectivity changes have been seen and that low back pain and rheumatic pain give different connectivity changes. These studies did not include fatigue and fatigue and did not link them to activity during the fMRI study itself.
Chronic low-grade systemic inflammation is also thought to play a major role in the onset of CP. Studies have shown that patients with generalized pain / fibromyalgia have elevated levels of immunological biomarkers. Similar results have been demonstrated in patients with neuropathic pain. It is unclear whether patients with other types of pain also have elevated levels of these proteins. It is also unknown if there is any relationship between immunological biomarkers and other variables such as fatigue and cognition.
In order to improve and diagnostic and prognostic models as well as develop the treatment pharmacologically and / or with cognitive training, the connection between pain and underlying pathophysiological mechanisms needs to be studied further with objective markers.
Pain rehabilitation clinics at the Department of Rehabilitation Medicine, Danderyd University Hospital and at the Department of Pain Rehabilitation, Pain Center, Umeå University Hospital offer assessment and evidence-based team-based multimodal rehabilitation for patients with complex chronic pain.
To receive rehabilitation at the clinics, a referral is required. Information about the study is sent to the referred patients at the same time as the call for initial assessment.
At time for the team assessment, the patient is asked orally by the team nurse if the testing psychologist may contact the patient to inform about the study.
All participants are provided oral and written information and will give informed consent to participate in the study. The patient's consent is recorded and a log is made of the number who accept to participate and the number and gender of those who decline and why they chose to decline. No personal data other than gender will be registered on those who say no. The purpose of the log is only to be able to assess generalizability based on the proportion who have agreed to participate in the study.
The testing psychologist then calls the patient and inform them about the study and if the patient agrees, an appointment is made for the neuropsychological investigation, which takes about an hour.
In connection with the assessment, the psychologist ensures that the patients have understood the information, inquire about whether they have further questions and collect the consent form.
In connection with the patient being asked to participate in the study, patients investigated at the Department of Pain Rehabilitation at Umeå University Hospital are asked if they also want to participate in the fMRI study.
Healthy controls will be recruited through advertising among hospital staff. Matching at group level will take place regarding age, gender and level of education.
The patients are assessed by an independent psychologist, who does not see the patients clinically. In the statistical processing, the participants will be coded. Code key is stored separately.
Background information is received from the Swedish Quality Register for Pain Rehabilitation (SQRP) as well as information about medication. Possible trauma and background information from the time of the injury and degree of sick leave will be obtained from the medical record.
Immunological markers will be taken from a total of 36 patients and 36 controls. Everyone participating in the fMRI examination will take blood samples.
Analysis of fMRI data will be done with special software for MRI analysis, developed at Oxford University (http://www.fmrib.ox.ac.uk/fsl/). Statistical comparison of gray matter volume, white matter damage and blood flow at rest and in cognitive activation is done in specific analysis modules where MRI data from the different groups are compared at pixel level (voxels) with methodology specifically developed for the different MRI modalities.
Data from omics and targeted analysis will be analyzed using advanced multivariate data analysis using SIMCA-P+, that is recommended method in omics where it account for multicollinearity problems and missing data and when the numbers of variable exceed the number of observations. This technology is well established at PAINOMICS lab in Linköping, Sweden.
- Conditions
- Pain, Fatigue, Cognitive Impairment
- Being tested
- Neuropsychological (NPA), Imaging, Inflammatory biomarkers
- Keywords
- Fatigue, Cognition, Pain, Imaging, Inflammatory markers, Executive functions, Attention, Processing speed
- Medical subject headings
- Pain, Fatigue, Cognitive Dysfunction
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
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
ImagingOther
Also called fMRI
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:
- High-resolution T1-weighted.
- High-resolution T2-weighted Scan (FLAIR).
Inflammatory biomarkersDiagnostic test
Blood samples from inflammatory biomarkers will be taken on 36 patients and 36 controls. Everyone who undergoes imaging will undergo blood tests.
| Study group | Role | What they receive |
|---|---|---|
| Chronic Pain | Patients with chronic pain, aged 18 - 50 years for the neuropsychological assessment and 18-45 years for the fMRI examination Receives: 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 Receives: Diagnostic Test: Neuropsychological (NPA); Other: Imaging; Diagnostic Test: Inflammatory biomarkers |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
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.
Measured: baseline
Task-fMRI
BOLD signal changes during fatiguing attention task (PVT)
Measured: baseline
Resting state fMRI
Changes in functional connectivity after performance of fatiguing attention task (PVT)
Measured: 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.
Measured: Baseline
Secondary outcomes (4)
MFI-20
The MFI-20 consists of five scales, based on different modes of expressing fatigue. Each scale contains four items for which the person have to indicate on a seven-point scale to what extent the particular statement applies to him or her. 'General fatigue' includes general statements concerning a person's functioning. 'Physical fatigue' refers to the physical sensation related to the feeling of tiredness. 'Reduced activities' measures reduction in activities and 'Reduced motivation' lack of motivation. 'Mental fatigue' measures cognitive symptoms related to fatigue. Some sentences are inverted and need to be rescored. On each scales the higher values the higher fatigue.
Measured: baseline
Visual Analog Scale of Fatigue
Measurement of self-rated current fatigue level. Ranges from 0 (corresponding to no fatigue) to 10 (corresponding to the worst possible fatigue).
Measured: baseline
D-KEFS - Word Fluency Test
The test measures expressive language skills, initiative and working memory and consists of three different conditions: verbal phonological flow (1) where the test person for 60 seconds produces as many unique words as possible.
begins with a given letter., category flow (2) where the test person for 60 seconds per category produce as many unique words as possible in two given semantic categories and category change (3) where the test person in 60 seconds produce so many unique words and switch between two specified semantic categories every other time. The more words, the better the performance. The number of perseverations and category errors are also measured.
Measured: baseline
Working memory from WAIS-IV - Digit Symbol subtest - backward repetition
The test person must repeat numbers that the test leader reads out the leader reads out. The number of digits is increased by one unit every two times). The test person repeats the numbers in the same order (forward repetition) or reverse order (backward repetition). Backward repetition measures auditory working memory. Both the total number of digits and the difference between forward and backward repetition are measured.
Measured: baseline
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Jul 2022
- Study start1 Jan 2018
- Primary completion31 Dec 2022
- Study completion31 Dec 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (18)Papers the sponsor has linked to this study.
- Other trials for PainStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Enrolment
- 72 participants (actual)
Sponsor and investigators
- Lead sponsor
- Danderyd Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- University Hospital, Umeå, Karolinska Institutet, Umeå University, Linkoeping University
- Responsible party
- Principal investigator, Marika Moller, Danderyd Hospital
- Investigators
- Marika C Möller, PhD, Principal investigator, Department of Rehabilitation Medicine, Danderyd Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05452915
- Sponsor's protocol ID
- 2018.424-31 Fatigue in pain
- Status last verified
- Jul 2023
- First submitted
- 4 Jul 2022
- Last updated
- 13 Jul 2023
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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/
PubMed 21882455Backryd 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.
PubMed 28930774DeLuca, 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.
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.
PubMed 31584875Hasselstrom 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.
PubMed 12160512Hysing 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.
PubMed 30893060Johansson 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.
PubMed 19909051Kluger 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.
PubMed 23339207Kurtze 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.
PubMed 11780799Moller 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.
PubMed 28983280Moriarty 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.
PubMed 21216272Möller, 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
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.
PubMed 24965830Moller 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.
PubMed 23095007Ng 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.
PubMed 28719509
Study at a glance
From the registry record, last updated by the sponsor on 13 Jul 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Fatigue in Chronic Pain - Cognitive Functions, Emotional Aspects, Biomarkers and Neuronal Correlates - a Descriptive Comparative Study
- ClinicalTrials.gov ID
- NCT05452915
- Acronym / sponsor ID
- 2018.424-31 Fatigue in pain
- Conditions
- Pain, Fatigue, Cognitive Impairment
- Keywords
- Fatigue, Cognition, Pain, Imaging, Inflammatory markers, Executive functions, Attention, Processing speed
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 72 participants (actual)
- Lead sponsor
- Danderyd HospitalUniversity, hospital or other
- Collaborators
- University Hospital, Umeå, Karolinska Institutet, Umeå University, Linkoeping University
- Study start
- 1 Jan 2018 (actual)
- Primary completion
- 31 Dec 2022 (actual)
- Study completion
- 31 Dec 2022 (actual)
- First posted
- 11 Jul 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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?
- What is the relationship between cognitive impairments, mental fatigue, or fatigability and
- the duration of pain
- generalization of pain and are they affected by covariates, such as sleep disorders and degree of depression/anxiety?
- Is there an association between immunological biomarkers and cognitive functions/mental fatigue/cognitive fatigability?
- 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?
- Is there an association between connectivity in the brain and
- immunological biomarkers
- fatigability and
- results on neuropsychological tests?
Detailed description
Many patients with chronic pain (CP) suffer from mental fatigue (fatigue) and cognitive dysfunction, which to a large extent contributes to difficulties returning to work and high sick leave rates. Previous research has primarily relied on subjective estimates, but then the results are affected by depression and sleep disorders. The general attitude has therefore been that fatigue is due to sleep disorders and depression.
However, fatigue is not only a subjective experience but can also be associated with impaired cognitive functioning. In patients with acquired brain injuries, fatigue has been linked to impaired attention, slower process speed and fatigue. Since objective measures have not been used in previous studies in chronic pain, it cannot be ruled out that fatigue and cognitive impairments may have similar underlying mechanisms.
To enable effective treatment, one needs to find markers that can distinguish different causes of fatigue (depression vs. impaired cognitive functions) from each other. Fatigue in cognitively demanding tasks can be such a marker, which has been shown in patients with mild traumatic brain injury and hormonal conditions. One theory is that the same mechanisms may play a role in CP.
In chronic pain the central nervous system is affected by an imbalance in the brain's pathway system, which leads to plastic changes in the brain. In particular, pain activates areas of the brain that are important for attention functions, which may explain why many patients with pain experience attention deficit disorders. Only a few studies have used objective tests to study the type and extent of cognitive problems and cognitive fatigue has not been studied before in patients with CP.
Functional MRI (fMRI) may reflect increased or decreased neuronal activity in the brain as changes in neuronal activity are linked to changes in regional blood flow (rCBF) and blood oxygenation levels (BOLD). Fatigue in mild traumatic brain injury is related to altered connectivity in the brain and that there are different neural networks that are related to subjective compared to objective measures of fatigue. Also in chronic pain, connectivity changes have been seen and that low back pain and rheumatic pain give different connectivity changes. These studies did not include fatigue and fatigue and did not link them to activity during the fMRI study itself.
Chronic low-grade systemic inflammation is also thought to play a major role in the onset of CP. Studies have shown that patients with generalized pain / fibromyalgia have elevated levels of immunological biomarkers. Similar results have been demonstrated in patients with neuropathic pain. It is unclear whether patients with other types of pain also have elevated levels of these proteins. It is also unknown if there is any relationship between immunological biomarkers and other variables such as fatigue and cognition.
In order to improve and diagnostic and prognostic models as well as develop the treatment pharmacologically and / or with cognitive training, the connection between pain and underlying pathophysiological mechanisms needs to be studied further with objective markers.
Pain rehabilitation clinics at the Department of Rehabilitation Medicine, Danderyd University Hospital and at the Department of Pain Rehabilitation, Pain Center, Umeå University Hospital offer assessment and evidence-based team-based multimodal rehabilitation for patients with complex chronic pain.
To receive rehabilitation at the clinics, a referral is required. Information about the study is sent to the referred patients at the same time as the call for initial assessment.
At time for the team assessment, the patient is asked orally by the team nurse if the testing psychologist may contact the patient to inform about the study.
All participants are provided oral and written information and will give informed consent to participate in the study. The patient's consent is recorded and a log is made of the number who accept to participate and the number and gender of those who decline and why they chose to decline. No personal data other than gender will be registered on those who say no. The purpose of the log is only to be able to assess generalizability based on the proportion who have agreed to participate in the study.
The testing psychologist then calls the patient and inform them about the study and if the patient agrees, an appointment is made for the neuropsychological investigation, which takes about an hour.
In connection with the assessment, the psychologist ensures that the patients have understood the information, inquire about whether they have further questions and collect the consent form.
In connection with the patient being asked to participate in the study, patients investigated at the Department of Pain Rehabilitation at Umeå University Hospital are asked if they also want to participate in the fMRI study.
Healthy controls will be recruited through advertising among hospital staff. Matching at group level will take place regarding age, gender and level of education.
The patients are assessed by an independent psychologist, who does not see the patients clinically. In the statistical processing, the participants will be coded. Code key is stored separately.
Background information is received from the Swedish Quality Register for Pain Rehabilitation (SQRP) as well as information about medication. Possible trauma and background information from the time of the injury and degree of sick leave will be obtained from the medical record.
Immunological markers will be taken from a total of 36 patients and 36 controls. Everyone participating in the fMRI examination will take blood samples.
Analysis of fMRI data will be done with special software for MRI analysis, developed at Oxford University (http://www.fmrib.ox.ac.uk/fsl/). Statistical comparison of gray matter volume, white matter damage and blood flow at rest and in cognitive activation is done in specific analysis modules where MRI data from the different groups are compared at pixel level (voxels) with methodology specifically developed for the different MRI modalities.
Data from omics and targeted analysis will be analyzed using advanced multivariate data analysis using SIMCA-P+, that is recommended method in omics where it account for multicollinearity problems and missing data and when the numbers of variable exceed the number of observations. This technology is well established at PAINOMICS lab in Linköping, Sweden.
Study design
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Chronic Pain | – | Diagnostic Test: Neuropsychological (NPA), Other: Imaging, Diagnostic Test: Inflammatory biomarkersPatients with chronic pain, aged 18 - 50 years for the neuropsychological assessment and 18-45 years for the fMRI examination |
| Healthy Controls | – | Diagnostic Test: Neuropsychological (NPA), Other: Imaging, Diagnostic Test: Inflammatory biomarkersHealthy controls matched on group level in terms of gender, age, and educational level |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
- 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.
Key inclusion criteria (1 listed)
- Chronic pain
Key exclusion criteria (14 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Neuropsychological (NPA)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 | Diagnostic test | Chronic Pain, Healthy Controls |
| ImagingAlso: fMRIImaging (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). | Other | Chronic Pain, Healthy Controls |
| Inflammatory biomarkersBlood samples from inflammatory biomarkers will be taken on 36 patients and 36 controls. Everyone who undergoes imaging will undergo blood tests. | Diagnostic test | Chronic Pain, Healthy Controls |
Primary outcome
Fatigability from WAIS-III - Coding
Time frame: baseline
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.
D-KEFS - Color Word Test
Time frame: baseline
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
Fatigability on e-prime vigilance (reaction time) task in the fMRI scanner
Time frame: baseline
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.
Task-fMRI
Time frame: baseline
BOLD signal changes during fatiguing attention task (PVT)
Resting state fMRI
Time frame: baseline
Changes in functional connectivity after performance of fatiguing attention task (PVT)
Inflammatory markers
Time frame: Baseline
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.
4 secondary outcomes
MFI-20
Time frame: baseline
Visual Analog Scale of Fatigue
Time frame: baseline
D-KEFS - Word Fluency Test
Time frame: baseline
Working memory from WAIS-IV - Digit Symbol subtest - backward repetition
Time frame: baseline
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Jul 2023.
- Background: PubMed 21882455Apkarian 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/
- Background: PubMed 28930774Backryd 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.
- BackgroundDeLuca, 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: PubMed 31584875Gerdle 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.
- Background: PubMed 12160512Hasselstrom 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.
- Background: PubMed 30893060Hysing 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.
- Background: PubMed 19909051Johansson 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.
- Background: PubMed 23339207Kluger 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.
- Background: PubMed 11780799Kurtze 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.
- Background: PubMed 28983280Moller 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.
- Background: PubMed 21216272Moriarty 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.
- BackgroundMöller, 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
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Marika C Möller, PhD principal investigator
Department of Rehabilitation Medicine, Danderyd Hospital
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Pain and Fatigue, run by Danderyd Hospital at 3 sites in Sweden.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Jul 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Sweden. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Fatigability from WAIS-III - Coding (time frame: baseline). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05452915, which also lists 18 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Jul 2023.