Non-invasive Approaches to Identify the Cause of Fatigue in Inflammatory Bowel Disease Patients.
Condition: Crohn Disease
MeSH terms: Crohn Disease; Inflammatory Bowel Diseases
Study type: Interventional

Summary: 
      Crohn's disease (CD) presents with severe symptoms, but fatigue is a very predominant symptom
      that negatively impacts upon quality of life. Fatigue affects ~40% of patients when well and
      80% of patients when the disease is active. It is the second commonest symptom that an IBD
      patient gets throughout their life-time. The IBD priority-setting partnership between the
      James Lind Alliance and the British Society of Gastroenterology has recently identified
      fatigue as an area of unmet clinical need and a priority research field, in which diagnosis
      and therapeutic intervention are lacking.

      Based on other diseases that present with fatigue, the cause of fatigue may be divided into
      peripheral fatigue, mainly driven by anomalies in muscle mass and function and central
      fatigue, mainly driven through decreased blood supply to the brain during exercise probably
      due to decreased heart and lung fitness.

      Research in IBD fatigue until now has been patchy with no convincing evidence that any
      treatment helps. There has been no research aimed at studying whole body function. It is
      imperative to have a better understanding of the alterations in muscle, brain, heart and lung
      function seen in these patients before specific treatments are researched.

      In this study, the investigators aim to recruit 32 CD patients, half with fatigue and half
      without. Subjects with active disease or with other known reasons of fatigue will be
      excluded. Findings in this group will be compared to 16 other healthy control volunteers of a
      similar age, gender and Body Mass Index. The study aims to recruit all participants over 36
      months, and will target people aged from 16 to 60 years of age.

      Once recruited, the participants will be asked to provide their consent to take-part in 3
      experiments on two separate days. These experiments have been designed to carefully consider
      potential fatigue burden, experimental practicality, and participant availability.

      Objective 1: The investigators aim to measure muscle fitness and strength by asking subjects
      to exercise using a stepper, whilst body mass and composition will be measured using an
      X-ray. This session will take 2 hours and be undertaken on one day.

      Objective 2: Peripheral fatigue: The investigators aim to non-invasively measure the recovery
      of muscle physiology after exercise by using magnetic resonance imaging after 5 min of
      exercise undertaken with a limb cuff. This will take ~1 hour.

      Objective 3: Central fatigue: while in the scanner and performing exercise, the investigators
      aim to non-invasively measure heart and brain blood flow before and after a few minutes of
      exercise using magnetic resonance imaging. This will take 2 hours.

      Experimental work for Objectives 2 and 3 will be undertaken on the same day. There will be
      ample time for recovery in between and during the different studies. There will be no further
      commitment from the participants required after these 2 study visits.

      IBD fatigue has never been studied in such detail. This unique work will allow identification
      of fatigue mechanisms, which can then be targeted with exercise, nutritional, or medical
      treatments.
    

Detailed description: 
      Background information Inflammatory bowel disease (IBD) fatigue is, with diarrhoea, the most
      common medical symptom in patients with active Crohn's disease (CD) and the second commonest
      complaint after arthralgia in CD patients in remission. The IBD priority-setting partnership
      between the James Lind Alliance and the British Society of Gastroenterology has highlighted
      that IBD fatigue is a top 10 UK research priority.

      The prevalence of fatigue ranges from 41-48% when in remission, increasing up to 86% when the
      disease is active. Chronic fatigue is associated with an impaired health-related quality of
      life in IBD and a reduced physical activity, which in paediatric cohorts plays a major role
      in normal growth development. In the absence of reversible clinical causes such as anaemia,
      inflammatory burden or nutrient deficiency, it is as yet unclear what causes fatigue in these
      patients. Present approaches are limited in offering clues to potential therapeutic
      approaches or accurate clinical evaluation for CD patients. This is likely due to a lack of a
      multicomponent approach and poor methodological sensitivity and reliability when assessing
      fatigue. A multidimensional concept of physical, cognitive and affective components have been
      suggested for IBD fatigue. Yet, it remains unclear how to treat IBD fatigue. Exercise
      therapy, psychosocial interventions and solution-focused therapy, are all suggested as
      treatment options but none have been shown to be convincingly effective.

      Fatigue arises from peripheral and central processes, which are both equally important. While
      peripheral fatigue is ascribed to muscle aetiology, central fatigue is a progressive
      exercise-induced reduction in voluntary activation to the muscle due to failure of the
      central nervous system (CNS). Present approaches have been limited in failing to adequately
      quantify peripheral fatigue at a muscle level and central fatigue at the level of the CNS.

      Peripheral fatigue: the need of muscle activity

      Physical fatigue is linked to reduced muscle mass and quality (sarcopenia) and consequently
      reduced muscle function. Drivers of muscle mass loss include physical inactivity and anabolic
      resistance, which to a large extent blunt the stimulatory effect of protein nutrition on
      muscle protein synthesis. In keeping with this, patients with active CD show a significant
      decrease in expression of hypertrophy skeletal muscle signalling pathways, but no changes in
      the expression of atrophy signals.

      Poor muscle quality is an important driver of metabolic dysfunction that is often overlooked
      as a driver of peripheral fatigue. In preliminary unpublished data, the investigators have
      shown for the first time that skeletal muscle of patients with active CD exhibits blunted
      glucose uptake in response to glucose feeding, suggesting diminished muscle metabolic quality
      in CD patients.

      In fatigued IBD subjects, medium-to-large effect sizes for impaired aerobic fitness (VO2max),
      muscle strength and physical activity are seen in subjects with fatigue when compared to
      subjects with no reported history of fatigue and the normal population. Physical inactivity
      in quiescent CD disease could be an explanation underpinning these observations, pointing to
      inactivity secondary to disease burden being the aetiology of fatigue in CD, much as in
      chronic obstructive pulmonary disease (COPD). Physical inactivity has already been shown in
      CD in both paediatric and adult cohorts and has been significantly correlated to disease
      activity but is still prevalent in remission. Although this might imply circularity in the
      aetiology of fatigue in the context of physical inactivity, it is unlikely that these two
      factors have a simple direct cause and effect relationship. Indeed, when habitual physical
      activity is matched between volunteers, skeletal muscle fatigue is still most prevalent in
      CD, and predominantly in those subjects who complain of fatigue. Collectively, these data are
      indicative that both reduced cardio-respiratory fitness and peripheral muscle deconditioning
      (possibly linked to reduced muscle mitochondrial density) are contributing to early fatigue
      development in IBD patients who report symptoms of fatigue.

      Central fatigue: the need of cardio-respiratory regulation

      Skeletal muscle, the cardio-respiratory system and the CNS are interlinked. In preliminary
      data, it has been shown for the first time that it is possible to assess change of brain
      perfusion (or cerebral blood flow; CBF), an indirect measurement of haemodynamic measurement
      of brain neuronal activity, using functional MRI techniques, in relation to decreased
      cardiovascular fitness with age. These data have demonstrated that CBF measured directly
      using arterial spin labelling (ASL) or indirectly using blood-oxygen-level-dependent (BOLD)
      was reduced in older people with reduced cardiorespiratory fitness, and who are likely more
      fatigable than young volunteers. This suggests that the coupling between CBF and brain
      activity can be modulated by cardiac output, and thus be manipulated to improve brain
      function linked to central fatigue in CD patients.

      This highlights the potential of non-invasive functional brain MRI techniques to determine
      the effect of brain perfusion during exercise on central fatigue in CD patients. Furthermore,
      these quantitative approaches could be used to determine whether improvements in
      cardiovascular fitness and appropriate downstream exercise or pharmacological interventions
      can alter central fatigue.

      1.Aims and purpose of the proposed investigation

      Hypothesis: The investigators hypothesize that the aetiology of IBD fatigue lies collectively
      with peripheral muscle deconditioning and brain central fatigue, the latter being secondary
      to a reduction in cardio-respiratory fitness and/or cardiac output, such that both central
      and peripheral fatigue contribute to fatigue development in IBD.

      Aims:

      To address this hypothesis, the investigators aim to recruit a cohort of fatigued and
      non-fatigued CD patients in remission and age-, gender- muscle mass-, and physical
      activity-matched healthy volunteers. Fatigue symptoms will be defined through relevant
      questionnaires at screening. The investigators will subsequently objectively quantify muscle
      strength of the knee extensors during a maximal voluntary isometric contraction, and fatigue
      development in the quadriceps muscle group. The latter will be defined as the loss in muscle
      peak-torque development over 20 consecutive isokinetic knee-extensions. Peripheral (muscle)
      and central (CNS) roles in fatigue aetiology will be investigated. Peripheral muscle
      deconditioning will be investigated by quantifying muscle phosphocreatine (PCr) re-synthesis
      during recovery from exercise using 31phosphorous MRS, while the potential of central fatigue
      will be examined through various measures of CNS perfusion and fractional brain oxygen
      extraction using MRI.

      Detailed plan of investigation and scientific procedures/methodology

      The investigators aim to recruit 32 patients with CD in remission, with and without a history
      of IBD fatigue (n=16 for IBD fatigue cohort and n=16 for no IBD fatigue cohort) within 36
      months. These cohorts will be compared to 16 age-, gender- muscle mass-, and physical
      activity-matched healthy controls (from our existing Nottingham Digestive Diseases Biomedical
      Research Unit and MRC/ARUK databases) to undergo the experimental protocol outlined below.
      The investigators will specifically match for physical activity to investigate its potential
      primary effect on fatigue.

      Objective 1 (Day 1): To determine muscle strength, fatigue and cardiorespiratory fitness.

      Following consent, CD and healthy matched controls volunteers will perform 3 maximal
      isometric knee extensions of the quadriceps muscle group (each separated by 30s) to determine
      muscle strength. Following this, volunteers will perform 20 maximal single leg knee
      extensions on a Cybex isokinetic dynomometer (Cybex Norm, USA) at a constant angular velocity
      of 90 degrees per second to determine muscle torque development. Each maximal voluntary
      contraction will be initiated from a position of 90 degrees knee flexion and continued
      through to the point of full knee extension. After each contraction, the leg will be returned
      passively to the start position (approximately 1.1s) from which the next contraction will be
      immediately initiated. The outcome measure and the gold-standard definition of fatigue in
      this objective will be defined as the decline in peak torque generation for each contraction
      over the 20 knee extensions. Maximal voluntary contractions at this velocity has previously
      been shown to result in recruitment of both type I and type II muscle fibres of the
      quadriceps muscle group. Thirty minutes later, volunteers will undergo a continuous,
      incremental, supine exercise test using an MR compatible step ergometer (Ergospect diagnostic
      pedal). Exercise will commence at a low workload, which will increase every 3 min to
      determine peak VO2 during supine exercise using on-line expired gas analysis (Cosmed, Rome,
      Italy). Carbon dioxide (CO2) production and oxygen (O2) consumption will be measured
      throughout the test and used to measure peak oxygen uptake and respiratory exchange ratio
      (RER). These data will be normalized to body composition as measured by dual-energy X-ray
      absorptiometry (DEXA; Lunar Prodigy, GE Medical Systems, Bucks, UK) and will provide a
      gold-standard measure of cardiorespiratory (or aerobic) fitness.

      Objective 2 (Day 2): To determine brain perfusion and central fatigue.

      Recently, in collaboration with researchers at the Sir Peter Mansfield Imaging Centre at the
      University of Nottingham, the investigators have developed a protocol to quantify the
      cortical vascular response to exercise in volunteers and its modulation in ageing and
      cardiorespiratory fitness. Here, the same approach will be used to assess cortical vascular
      response to exercise in the brain regions associated with central fatigue of CD patients.

      To study this mechanism in CD patients, the investigators propose to measure cardiac output
      and, cerebral and regional perfusion using Blood-Oxygen-level-dependent (BOLD) measures and
      arterial spin-labelling (ASL)-MRI as well as fractional oxygen extraction using TRUST-MRI
      respectively during supine exercise of the quadriceps with the MR compatible ergometer
      (Ergospect diagnostic pedal) at given values of relative VO2max (as measured in Objective 1).

      This multimodal approach will determine a potential uncoupling between brain perfusion and
      neuronal activity and the role of central hypoxemia in central fatigue of IBD patients
      compared to healthy controls. Furthermore, these data will be correlated to cardiorespiratory
      fitness, muscle strength and fatigue, and will determine the predominant role of central
      processes in fatigue of IBD patients. If these brain vascular measures are associated with
      fatigue development, then this index of neurovascular coupling could benefit from exercise
      training in a similar way to muscle tissue.

      Objective 3 (Day 2): To determine muscle deconditioning.

      To maintain energy (ATP) during exercise, skeletal muscle regulates oxidative (mitochondrial)
      and non-mitochondrial production of ATP. In healthy individuals, the relative contribution of
      non-mitochondrial ATP production to total energy production is generally dictated by the
      exercise intensity, which determines the magnitude of accumulation of metabolic by-products
      that are directly linked to muscle discomfort and fatigue. In disease states, exacerbated
      fatigue and muscle pain has been attributed to reduced muscle blood flow and/or reduced
      mitochondrial mass.

      To separate these two processes in CD patients, limb blood flow will be occluded with a cuff,
      whilst participants perform repeated plantar flexion exercise in a MRI scanner. This will
      drive PCr, (the available reserve of ATP) to zero. Specifically, participants with a lower
      limb cuff will perform 30 contractions over a 5-minute period using a MR compatible
      ergometer. Once the cuff is removed, they will undergo non-invasive and well-established in
      vivo 31P magnetic resonance (31P MRS) measurements on the gastrocnemius to determine PCr
      re-synthesis rate during resting recovery. 31P MRS data will be averaged, processed and
      quantified using in-house methods.

      Since the rate of PCr re-synthesis is directly proportional to mitochondrial mass and oxygen
      delivery is not limiting during exercise recovery, this will allow us to measure muscle
      metabolic deconditioning in vivo.

      Sample size

        1. Cardiorespiratory fitness: The investigators have previously shown that the VO2max of a
           healthy volunteer is 3.65 (0.5) L/min, whilst the VO2max of a fatigued IBD patient is
           1.99 (0.44) L/min and a non-fatigued patient is 2.43 (0.75) L/min. Assuming a power of
           80% and α=0.05, 6 subjects in each group are needed to show a significant difference
           between the healthy volunteers and the non-fatigued cohort, and 13 patients in each
           group are needed to show a difference between the 2 CD cohorts.

        2. Muscle Fatigue: Peak muscle Torque extension 180⁰/s (Nm) is lower in fatigued IBD vs
           non-fatigued IBD patients (60.73 vs 73.5, SD 12.3 respectively). Assuming a power of 90%
           and α=0.05, 16 CD subjects in each group are needed to show a difference between
           fatigued and non-fatigued CD cohorts. Importantly, the rate of muscle fatigue (defined
           as the gradient of force decrease from repetition 2 to 30 of an exercise protocol) is
           significantly greater in CD than healthy volunteers (5.2 Nm/min vs 1.3 Nm/min, SD 3. In
           this instance, assuming a power of 90% and α=0.05, 11 subjects in each group are needed
           to show a difference between CD and healthy volunteers.

        3. Muscle conditioning: recent studies have shown that Pcr re-synthesis rate is 27.9 ± 0.6
           s in lean sedentary subjects, whilst being 36.5 ± 2.4 s in Type 2 diabetes mellitus
           patients (T2DM). Thus, assuming a power of 100% and α=0.05, 3 subjects in each group are
           needed to show a difference between healthy volunteers and potentially fatigued cohort
           such as T2DM patients.

        4. Anabolic resistance: Furthermore, our recent work on anabolic resistance has already
           shown significant differences in muscle quality between CD and healthy volunteers
           (significant difference observed n=5 patients). Percentage forearm fatigue in the
           dominant arm is 26.75%±11.1 and 18.3±7.8 in CD and controls respectively. Assuming a
           power of 80% and α=0.05, 11 subjects are needed in each arm.

        5. MRI: It is not possible to power this exact MRI study as pilot data in these IBD cohorts
           has not been collected. However, the investigators have previously shown that brain
           perfusion in the young increases by 18±6% for 30% VO2max during a cardiorespiratory
           fitness test. Whilst in the elderly, it increases by only 3±4 %. Assuming a power of
           100% and α=0.05, 10 subjects in each group are needed to show a significant difference
           between healthy volunteers (young) and a potentially fatigued cohort (elderly). Further,
           for fMRI BOLD analysis it is generally considered that a minimum of 12 subjects is
           needed in each cohort, with improved sensitivity of MR scanners (and thus higher
           temporal signal-to-noise ratio (SNR) now allowing improved individual subject analyses.

      For the above reasons, the investigators feel that 16 subjects in each group (fatigued CD,
      non-fatigued CD and healthy volunteers) will suffice to show a difference in our chosen
      objective endpoints.

      Data analysis Fatigue will be measured as the decline in peak torque development over 20
      isokinetic knee extensions as described above. PCr re-synthesis rate and fractional brain
      oxygen extraction will be the primary endpoints in objectives 2 and 3.

      31P MRS data will be analysis using standard NMR software (jMRUI Software for the clinical
      and biomedical MRS). Precisely, all spectra from the time series will be apodized (15-20 Hz
      Lorentzian shape). From these spectra, the signal intensities of 5 peaks will be determined
      after lineshaping. The pH will be determined prior to and at the end of the exercise protocol
      by measuring the frequency shift between the PCr and Pi, whilst in-house written code in
      MATLAB (MathWorks Inc., Matrix House, Cambridge, UK) will be used for further calculations of
      the PCr recovery rate. In this case, peak area intensities of the PCr peak from jMRUI will be
      used as input in the script to fit the data time courses using a mono-exponential function:
      PCr (t) = PCr (t0) + C (1 - e-t/τ); with PCr being the intensity level of the PCr peak, C a
      constant, τ [s] the rate constant for PCr recovery, and t [s] time, starting at the end of
      the exercise protocol (t0). The Reproducibility of 31P MRS measures of muscle energetics has
      been recently evaluated in trained human and show that coefficient of variation during
      exercise (27%) and at rest (8%) was relatively low, and difference were detectable with 15
      volunteers. This confirms that 31P MRS approach provides reproducible and experimentally
      useful measures of PCr re-synthesis rate in human skeletal muscle.

      BOLD MRI data will be analysed using standard neuroimaging packages (Statistical Parametric
      Mapping (SPM); Wellcome Department of Imaging Neuroscience and FMRIB Software Library
      software. Images will be motion-corrected, normalized to a standard Montreal Neurological
      Institute template to facilitate inter-participants averaging. For all data acquisitions, the
      investigators will record the vectocardiogram (VCG) and respiratory motion to allow data to
      be corrected for physiological noise. Contrast vectors will be formed to identify the CNS
      response to the exercise stimulus. The investigators will form statistical maps of those
      brain regions which show a decrease/increase in BOLD signal following the exercise
      intervention. These statistic maps will be used in contrasts by intervention and between
      participant groups. Results will be pooled in a second level, random effects group analysis
      (RFX) and active brain areas displayed at a false discovery rate corrected probability P <
      0.05, k > 5. These analyses have been previously carried out and published by our group. ASL
      data will be motion corrected and modelled to quantify perfusion in ml/100g/min, and global
      and regional perfusion measures compared before and during the exercise intervention. TRUST
      data will be used to compute fractional oxygen extraction before and during exercise
      intervention. Data will be presented as mean +/- standard error of the mean (SEM). Binary
      comparisons will be carried out by t-tests while multiple comparisons will be carried out
      with an analysis of variance with a post-hoc Bonferroni correction in between the 3 groups.
      The effects of cytokines, vitamin D and disease duration will be investigated through a
      correlation co-efficient and post-hoc multivariate analysis.

      The investigators will stratify subjects based on the quantitative outcome measures: PCr
      re-synthesis rate, cardiorespiratory fitness as measured through VO2max, decline in muscle
      output and change in regional perfusion and fractional brain oxygen extraction irrespective
      of their fatigue status. This will aid our understanding regarding which alterations in
      physiology and metabolism are best associated with specific fatigue symptoms. Doing this will
      allow objective quantification of a subjective cut-off for the IBD Fatigue scale, thereby
      better defining fatigue.
    

Intervention name(s): Muscle strength and fatigue assessment; Dual-energy X-ray absorptiometry (DEXA scan); Supine cardiorespiratory fitness assessment; fMRI Exercise assessment; Muscle deconditioning assessment
Intervention type(s): Diagnostic Test; Diagnostic Test; Diagnostic Test; Diagnostic Test; Diagnostic Test
Intervention description(s): Measurement of maximum voluntary isometric contraction of the quadricep muscle on a cybex isokinetic dynomometer. This will be followed by a fatigue assessment where the torque decrement over 20 isokinetic knee extensions at a fixed angular velocity will be quantified to assess muscle fatigue; Body composition will be assessed via DEXA scan (Lunar Prodigy, GE Medical Systems, Bucks, UK); VO2 peak will be quantified during completion of a continuous, incremental exercise test performed in the supine position on an MR adapted stepper machine (Ergospect, Innsbruck Austria); Measurement of cardiac output and, cerebral and regional perfusion using Blood-Oxygen-level-dependent (BOLD) measures and arterial spin-labelling (ASL)-MRI as well as fractional oxygen extraction using TRUST-MRI during supine exercise of the quadriceps with the MR compatible cardiostepper (Ergospect, Innsbruck, Austria) at 50% of relative VO2 peak as measured during the supine cardiorespiratory fitness assessment.; Limb blood flow will be occluded with a cuff, whilst participants perform repeated plantar flexion exercise in a MRI scanner. This will drive PCr, (the available reserve of ATP) to zero. Once the cuff is removed, they will undergo non-invasive and well-established in vivo 31P magnetic resonance (31P MRS) measurements on the gastrocnemius to determine PCr re-synthesis rate during resting recovery.
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic