Fatigue in Chronic Pain - Cognition, Emotional Aspects, Biomarkers, and Neuronal Correlates
Condition: Pain; Fatigue; Cognitive Impairment
MeSH terms: Fatigue; Chronic Pain
Study type: Observational

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. 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. What is the relationship between cognitive impairments, mental fatigue, or fatigability
           and

             1. the duration of pain

             2. generalization of pain and are they affected by covariates, such as sleep disorders
                and degree of depression/anxiety?

        3. Is there an association between immunological biomarkers and cognitive functions/mental
           fatigue/cognitive fatigability?

        4. 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?

        5. Is there an association between connectivity in the brain and

             1. immunological biomarkers

             2. fatigability and

             3. 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.
    

Intervention name(s): Neuropsychological (NPA); Imaging; Inflammatory biomarkers
Intervention type(s): Diagnostic Test; Other; Diagnostic Test
Intervention description(s): 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; 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).; Blood samples from inflammatory biomarkers will be taken on 36 patients and 36 controls. Everyone who undergoes imaging will undergo blood tests.
Other intervention name(s): fMRI
Observational model: Case-Control
Time perspective: Cross-Sectional
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.
      
Biospecimen description: 
      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.
    
Keywords: Fatigue; Cognition; Pain; Imaging; Inflammatory markers; Executive functions; Attention; Processing speed