Brain Rhythms in Fibromyalgia: A Magnetoencephalography (MEG) Study
Condition: Fibromyalgia
MeSH terms: Fibromyalgia; Myofascial Pain Syndromes
Study type: Observational

Summary: 
      The long-term purpose of the investigator's research is to understand the pathophysiological
      basis of chronic pain. This will help provide a framework for the development of effective
      treatments. The purpose of this specific study is to find if there are abnormal brain rhythms
      in patients with fibromyalgia syndrome (FM) who are in pain since this will indicate
      particular types of treatments.

      FM is a disorder of the muscles and/or joints, and patients experience sever fatigue. FM
      occurs more often in women than in men (3.4% of women, 0.5% of men). The diseases can appear
      at any age, but in most of the cases it occurs in women of childbearing age. FM is considered
      a chronic pain condition since the pain is persistent. Pain and tenderness can be widespread
      throughout the body. FM patients are more sensitive to sound and pressure stimulation than
      healthy controls, indicating that there may be changes in the brain. Also, pain is made worse
      under conditions of stress.

      Treatments for FM pain include life style changes such as exercise, dietary changes,
      cognitive-behavioral therapy, medications and even surgery, but there is no accepted "best"
      treatment. This is partly because the underlying cause of the pain is not well understood.
      The design of this study is to record brain activity to find if there are abnormal brain
      rhythms in people with FM that are not present in healthy adults of the same age.

      Specifically, the investigators will test the hypothesis that constant low frequency
      oscillations will be present in patients with chronic pain due to FM. This has been found in
      people with other types of pain and is called Thalamocortical Dysrhythmia (TCD). The study
      has two parts. In the first part, a complete medical history will be obtained, including a
      description of the person's pain. In the second part the investigators will use
      magnetoencephalography (MEG) to non-invasively record brain activity. The MEG data will be
      analyzed in terms the presence of normal alpha rhythm and abnormal low and high frequency
      oscillations. Each person will have an MRI so the investigators can localize the rhythms
      recorded by the MEG in the person's brain using their MRI. The people who record and analyze
      the MEG recordings will not know if the person is a healthy control or a FM patient. The two
      parts will be joined to test the hypothesis and find if there is a correlation between the
      people with abnormal low frequency brain rhythms and the presence or degree of pain.
    

Detailed description: 
      The investigators will use magnetoencephalography (MEG) to non-invasively record brain
      activity in women with fibromyalgia (FM) pain and in healthy subjects. The MEG data will be
      analyzed in terms of the presence of normal alpha rhythm and abnormal low frequency and gamma
      oscillations and their source in the person's brain using their MRI. The investigators will
      use clinical evaluation, MEG recordings and MRI scans to achieve the following aims:

        1. Determine if abnormal brain rhythms in the delta (<4Hz) and theta (4-8Hz) frequency
           bands are present in patients with FM while they are in pain. The hypothesis predicts
           that such low frequency activity will be present in FM patients in pain, but not in
           healthy controls or patients not in pain.

        2. To determine if brain activity in the gamma (35-55Hz) frequency range is present in FM
           patients. The hypothesis predicts that, in FM patients, areas of low frequency activity
           will have an "edge" area of high frequency activity.

        3. To determine if brain activity in the alpha (8-12Hz) frequency range is present in FM
           patients and it if decreases in MEG recording made with the eyes open compared to
           recordings with the eyes closed. Such normal activity is expected in both FM patients
           and healthy controls.

        4. To determine the location of the sources generating abnormal brain rhythms and normal
           alpha rhythms in FM patients in pain and in healthy controls and patients not in pain.
           The hypothesis predicts that low frequency regions with high frequency 'edges' will have
           two locations: a) if the pain is localized, the somatosensory cortex in the region of
           pain, b) the orbitofrontal cortex in portion of the pain pathway associated with the
           emotional aspects of pain. The source of normal alpha rhythms in both patients and
           controls will be localized to the posterior brain, particularly the visual cortex.

      A multi-disciplinary treatment approach is taken for FM patients. This includes life style
      changes such as exercise, dietary changes, cognitive-behavioral therapy as well as
      medications and even surgery. There is no accepted "best" treatment, and not even a "best"
      medication. This is partly because the underlying cause of the pain is not well understood.
      The design of this study is to record brain activity to find if there are abnormal brain
      rhythms in patients with FM that are not present in healthy adults of the same age. Such a
      finding would inform more direct treatments that would be directed to the cause of the pain,
      rather then the symptoms.

      Recently, abnormal brain connectivity has been reported in FM patients (Napadow et al.,
      2010). Also, activation of the frontal cortex, motor and cingulate brain regions has been
      seen in FM patients during pain anticipation that were correlated with the subsequent pain
      reported (Burgmer et al., 2010).

      These results will be considered in the context of a comprehensive clinical evaluation to
      determine if thalamocortical dysrhythmia (TCD) is present in patients in pain (Jeanmonod,
      1993; Llinas et al, 1999, 2001, 2005). The investigators will also find if abnormal brain
      rhythms are correlated with the presence and degree of pain and if there is a difference
      between patients in pain and healthy adults.

      II. Study Design. The investigators will follow a recent protocol used in our study of
      abnormal rhythms in complex regional pain syndrome (Walton et al., 2010). Those who meet
      criteria for inclusion but not exclusion will be enrolled in the study.

      III. METHODS AND PROCEDURES

        1. Clinical Examination of Patients

           Information collected during the clinical assessment will include:

             -  Demographics: age, sex, employment status.

             -  A detailed history of fibromyalgia.

             -  A review of pain characteristics: location and severity, quality of pain, timing,
                duration and context of pain, associated signs and symptoms, exacerbating factors,
                alleviating factors, motor/sensory loss, and effect of activities of daily living.

             -  A complete medical history and important family medical history.

             -  A social history: tobacco, alcohol, and illicit drug use.

             -  A review of all concomitant medications.

             -  Vital signs: blood pressure, heart rate, respiratory rate, height, weight.

             -  A physical exam.

             -  Confirmation of the presence of the American College of Rheumatism's 1990 criteria
                for fibromyalgia.

             -  Completion of the following clinical assessments by the patient:

             -  Visual Analogue Scale-average weekly recall of pain

             -  Pain Drawing for localization

             -  Fibromyalgia Impact Questionnaire

             -  Patient's Global Assessment of Fibromyalgia

             -  Medical Outcomes Study Sleep Scale

             -  Hospital Anxiety and Depression Scale

           Healthy Controls will have the same procedures as the patients; Clinical Screening, MEG
           and MRI.

        2. MEG recordings Informed consent will be obtained before the MEG recording. If it has
           been obtained, this will be confirmed. (A member of the study team will bring a copy of
           the signed informed consent before the MEG recording session.)

           The head shape, including the location of the three fiducial markers (left and right
           preauricular points, and the nasion) will be obtained for each subject using a 3D
           tracking system by moving a stylus to each fiducial point and over the surface of the
           head (Fastrak, Polhemus, Colchester, VT).

           Each participant will be seated in the MEG instrument that is located inside a
           multi-layer mu-metal magnetically shielded room. The location of the head will be
           monitored at the beginning and end of each run using electrodes attached to the three
           fiducial marker points used to obtain the head shape. Head position changes up to ≈0.5
           cm will be accepted. (The same fiducial points will be used for the MRI to co-register
           the MEG and MRI data.)

           Each person will have three MEG recording sessions. Two MEGs will be recorded with the
           eyes closed (EC), and one will be recorded with the eyes open (EO). Including the time
           to fill out paperwork, measure their head shape, and the time between MEG recordings,
           the investigators estimate that each participant will spend 60-90 minutes at the New
           York University Center for Neuromagnetism.

           Instructions to participants for MEG recordings. An investigator will explain that the
           purpose of the recording is to look at brain activity while the patient is relaxed.
           There will be three 7-minute recordings. The first will be with the eyes closed. They
           will be told to please relax, but try not to fall asleep. Next, there will be a
           recording period with the eyes open. They will be told to please try not to move the
           eyes, but look at something the entire time. Third, there will another recording with
           the eyes closed. The investigator will let the person know when the recording begins,
           half way through each recording, and come in to see how they are doing after each
           recording. The person will be asked to please try not to move the head during the
           recordings.

           Magnetoencephalography is FDA approved and is routinely used for brain mapping in
           epilepsy and in pre-surgical patients and is standard of care in these cases (Shiraishi
           et al., 2005; Makela et al., 2006). However, these recordings are being performed
           exclusively for research purposes. Magnetic fields will be recorded using a 275-channel
           whole-head MEG system (CTF Systems Inc., Port Coquitlam, British Columbia, Canada)
           (McCubbin et al., 2004). A third-order software gradient (Weinberg et al., 1984) will be
           used with a recording bandpass of 0.25-125 Hz.

        3. Data Analysis and Data Monitoring. During each run magnetic fields will be recorded in
           42 consecutive 10-sec trials. In this way, if the person moves during the session, the
           10 sec trial during which this occurs can be eliminated from analysis. Neuromagnetic
           fields will be recorded in the eyes-closed state to minimize signals from ocular muscles
           and high-frequency visual system activation, and in the eyes-open and fixated state to
           decrease the amplitude of the alpha-range (8-12 Hz) peak (and thereby better facilitate
           the examination of spectrally proximal signals). Spectral analysis and independent
           component analysis will be carried out as in our previous studies (Walton et al, 2010).

      MRI and Source Reconstruction The purpose of the MRI (without contrast) is to provide an
      anatomical image of the person's brain that will be used to localize the brain activity
      recorded by the MEG. The MEG and MRI recordings must be co-registered so that they can be
      aligned accurately. The same location markers, called fiducial markers (see above), must be
      used for the MEG and the MRI. So, it is best if both recordings are done on the same day. The
      MRI is after the MEG because the MEG instrument can detect magnetic field as small as 10-15
      Tesla. The MRI generates a magnetic field that, although small, can be detected by the MEG
      instrument and interferes with recording brain activity. The location of the three MEG
      fiducials is marked using a fine point magic marker. The person is then escorted to the MRI
      suit and the 3 MRI fiducials are put on the person using the magic marker points as guides.

      All MRI scans will be carried out on the 3 T Alegra platform, due to its better
      single-to-noise ration (SNR), spatial and spectral resolution, compared with the 1.5 T
      instruments. Where MRI data is present the investigators will maintain a degree of uniformity
      across experiments by performing MRI constrained modified minimum norm inverse modeling on
      each data set. The MRI constrained inverse will be computed by assuming that the current
      source density is confined to grey matter as segmented from the MRI data. Each subject's MRI
      is segmented, and a tessellated cortical surface is reconstructed for each hemisphere using
      the software FreeSurfer (Dale et al., 1999). These cortical surfaces are then sub-sampled to
      create a sources pace of ~40,000 vertices. The lead field matrix, L, is computed for the
      dipole moments normal to the cortical surface or for all components.

      Potential biases or problems. A potential bias is during analysis of the MEG data. This will
      be mitigated since the person analyzing the data will be blinded to the pain status of the
      subject. Study subjects are identified by a code only in all data.

      Procedures, situations, or materials that may be hazardous. None.

      3. Data Storage and Confidentiality. Trained staff will conduct interviews in a respectful
      and sensitive manner. Records will be coded, stored and reviewed by participant number only.
      These coded records will be kept in locked files in locked offices. Access to computer-based
      data will be restricted by protection codes and login passwords, and all computers will be
      kept in rooms with restricted access.
    

Intervention name(s): experience brain activity recording
Intervention type(s): Behavioral
Intervention description(s): Intervention: experience brain activity recording
Other intervention name(s): Change in pain level
Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Women with fibromyalgia pain in the greater New York City area.

        Pain-free women in the greater New York City area.
      
Keywords: Fibromyalgia; Pain