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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Fatigue in Chronic Pain - Cognitive Functions, Emotional Aspects, Biomarkers and Neuronal Correlates - a Descriptive Comparative Study

Conditions
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Pain, Fatigue, Cognitive Impairment

Intervention / Treatment
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* Diagnostic Test: Neuropsychological (NPA)
* Other: Imaging
* Diagnostic Test: Inflammatory biomarkers


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic pain Exclusion Criteria: 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 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Chronic Pain<br>Patients with chronic pain, aged 18 - 50 years for the neuropsychological assessment and 18-45 years for the fMRI examination | Diagnostic Test: Neuropsychological (NPA)<br>* 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<br>Other: Imaging<br>* 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).<br>* Other names: fMRI;Diagnostic Test: Inflammatory biomarkers<br>* Blood samples from inflammatory biomarkers will be taken on 36 patients and 36 controls. Everyone who undergoes imaging will undergo blood tests.<br>|
| Healthy Controls<br>Healthy controls matched on group level in terms of gender, age, and educational level | Diagnostic Test: Neuropsychological (NPA)<br>* 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<br>Other: Imaging<br>* 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).<br>* Other names: fMRI;Diagnostic Test: Inflammatory biomarkers<br>* Blood samples from inflammatory biomarkers will be taken on 36 patients and 36 controls. Everyone who undergoes imaging will undergo blood tests.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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). | 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. | 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. | baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fatigue, Cognition, Pain, Imaging, Inflammatory markers, Executive functions, Attention, Processing speed