Structural White and Gray Matter Correlates of Impaired Muscle Control and Deficient Pain Processing

Although the cause of persistent non-specific low back pain (LBP) remains unknown, structural and functional alterations of the brain, alterations in the lumbar muscles and dysfunction of the central nervous system have been proposed as underlying mechanisms. In this case-control study, 1) brain structure/function, 2) lumbar muscle function and 3) central pain processing are compared across four groups: 1) healthy participants, 2) recurrent LBP (both during pain flare and during pain remission), 3) chronic LBP and 4) fibromyalgia. According to previous research, healthy participants and fibromyalgia patients are two extremes of a "musculoskeletal pain continuum". Healthy participants representing one extreme of the continuum with no pain and fibromyalgia representing the other extreme of the continuum with chronic widespread pain. It is thought that different LBP populations (i.e. (sub)acute, recurrent, chronic LBP) float between the aforementioned extremes. Past studies already highlighted the need for studies comparing the pathophysiological mechanisms for different pain syndromes to identify common underlying mechanisms across pain syndromes. For this reason, the goal of the current study is to compare alterations in brain structure/function, alterations in lumbar muscle function and alterations in central pain processing across the aforementioned "musculoskeletal pain continuum". It is hypothesized that longer duration of pain (recurrent vs chronic) and the extensiveness of the pain (one location vs widespread pain) are associated with more pronounced alterations in 1) brain structure/function, 2) lumbar muscle function and 3) central pain processing.

Introduction: Chronic pain is one of the most disabling symptoms in several medical conditions, including LBP and fibromyalgia. A crucial factor for the persistence of recurrent/chronic pain are alterations in lumbar muscle structure and function in patients experiencing recurrent/chronic LBP. Previous studies revealed that these alterations in lumbar muscle structure and function do not resolve when patients with recurrent LBP experience a pain-free episode. According to other recent studies, dysfunction of the central nervous system is another crucial factor to the maintenance of chronic pain. The aforementioned alterations in lumbar muscle structure and function could constitute constant nociceptive input leading to the development of central sensitization (i.e. heightened sensitivity or hyperexcitability of central nervous system). Although it is plausible that central sensitization and disturbed pain processing do exist in patients experiencing chronic LBP, previous studies investigating these mechanisms are scant and results are inconsistent. These inconsistent results might be explained by the fact that previous studies used mixed back pain populations (i.e. different types of back pain are included in one study). In contrast to the inconsistent evidence for the presence of central sensitization in chronic LBP, previous studies in fibromyalgia populations have shown convincing evidence for central sensitization and disturbed pain processing in fibromyalgia. It could be possible that the long-term presence of pain and nociceptive input not only influence pain processing, but also motor control. To support this hypothesis, past studies have revealed altered organization of brain areas involved in trunk and lumbar motor control in patients experiencing recurrent LBP. In addition to alterations in brain function, changes in brain structure are also probable in patients experiencing persistent pain and nociceptive input. Previous studies in fibromyalgia already confirmed the presence of structural brain alterations. To date, only two studies investigated the presence of structural brain alterations in gray matter in patients experiencing LBP and the results are contradicting. Whether structural brain alterations in white matter exist in patients experiencing LBP has not yet explored in previous studies. Past studies in fibromyalgia do confirm that white matter structural changes exist. It is still unclear which specific properties of white matter change in patients with fibromyalgia, because more advanced imaging techniques are necessary to answer this question. In our current study we want to elaborate on the aforementioned results obtained in fibromyalgia patients to investigate whether the same alterations in central mechanisms (i.e. altered pain processing and alterations in brain structure/function) occur in patients experiencing recurrent/chronic LBP. Past studies already highlighted the need for studies comparing similarities and differences in the pathophysiological mechanisms for different pain syndromes to identify similarities in underlying mechanisms across different pain syndromes (e.g. fibromyalgia and LBP). For this reason, the current study will include both patients with fibromyalgia and patients experiencing recurrent/chronic LBP to allow for comparison of the pathophysiological mechanisms.

This case-control study has multiple goals: 1) investigate whether central sensitization and disturbed central pain processing are present in patients experiencing recurrent and chronic LBP. 2) investigate whether structural alterations in gray and white matter exist in patients experiencing recurrent and chronic LBP. 3) investigate whether alterations in white matter microstructure exist in patients experiencing recurrent and chronic LBP and if these alterations are comparable to alterations in white matter structure in fibromyalgia reported in previous studies. 4) investigate whether there is an association between alterations in brain structure/functional connectivity and the degree of disturbances in pain processing. 5) investigate whether there is an association between alterations in brain structure/functional connectivity and lumbar muscle dysfunction. 6) investigate to what extent the duration of pain (i.e. (sub)acute, recurrent, chronic) and the extensiveness of pain (i.e. one location vs widespread pain) influences lumbar motor control, pain processing and brain structure/function.

Method: In this case-control study, 80 female participants will be divided over 4 groups: 1) healthy participants (N=20), 2) recurrent non-specific LBP patients, both during pain remission and during pain flare pain (N = 20), 3) chronic non-specific LBP (N = 20) and 4) fibromyalgia patients (N = 20). The test protocol consists of three parts: 1) participants complete a series of questionnaires measuring several clinical characteristics, including: sociodemographic variables, pain intensity, functional disability, central sensitization and psychosocial factors (i.e. coping, catastrophizing, kinesiophobia, hypervigilance and anxiety/depression). 2) magnetic resonance imaging (MRI) will be used to measure brain structure. Functional MRI (fMRI) and diffusion tensor imaging (DTI) will be used to measure brain function (i.e. resting state and functional connectivity respectively). 3) a series of clinical tests will be performed to measure lumbar muscle function and central pain processing. Lumbar muscle function will be evaluated by using surface electromyography (EMG) for testing anticipatory postural adjustments (APA) in a rapid arm movement (RAM) task and compensatory postural adjustments (CPA) in a quick force release test (QFRT). Central pain processing will be assessed by using 1) pressure algometry for determining pain pressure thresholds (PPT), 2) measuring PPT after a conditioned pain modulation paradigm (CPM) and 3) by determining the nociceptive flexion reflex (NFR) threshold by using repetitive transcutaneous electrical nerve stimulation (TENS) of the n. suralis.

Eligibility Criteria:
Inclusion Criteria:

1. Dutch speaking female participants (age between 18 and 45 years).
2. Non-specific recurrent LBP patients experiencing a period of remission at the moment of testing. Patients have to meet the criteria for recurrent LBP (in remission) as described by De Vet et al. (2002) and D'Hooge et al. (2013).
3. Non-specific recurrent LBP patients experiencing a pain flare at the moment of testing. Patients have to meet the criteria for recurrent LBP (during pain flare) as described by De Vet et al. (2002) and D'Hooge et al. (2013).
4. Participants experiencing non-specific chronic LBP (meeting the International Association for the Study of Pain \[IASP\] criteria)
5. Participants diagnosed with fibromyalgia according to the American College of Rheumatology (ACR) criteria (2010)
6. Healthy volunteers with no history of serious respiratory, orthopedic, neurologic or circulatory conditions. No history of low back pain (i.e. low back pain in this case is defined as a period of symptoms lasting a minimum of 2 consecutive days and for which a paramedic is consulted). Participants with a history of spinal surgery, spinal trauma or spinal deformities are also excluded. Healthy participants will be matched for age and BMI with included participants experiencing chronic/recurrent LBP or fibromyalgia.

Exclusion Criteria:

1. Pregnancy or breastfeeding in the past year
2. Contraindications for MRI (e.g. electrical/mechanical implants or electrodes in de body, eye/skin injury by metal fragments in the past, etc)
3. BMI lower than 18 or higher than 30
4. Participant performed specific trunk muscle training in the past year.
5. Participating in sports at a professional level