Brain Rhythms in Fibromyalgia: A Magnetoencephalography (MEG) Study
| Status: | Completed |
|---|---|
| Conditions: | Fibromyalgia, Pain |
| Therapuetic Areas: | Musculoskeletal, Rheumatology |
| Healthy: | No |
| Age Range: | 18 - 70 |
| Updated: | 4/21/2016 |
| Start Date: | December 2010 |
| End Date: | June 2015 |
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.
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.
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.
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.
Inclusion Criteria:
- female from any racial/ethnic background
- general good health, with no serious or unstable medical conditions
- normal or corrected-to-normal vision and hearing
- meets the American College of Rheumatology criteria for the diagnosis of fibromyalgia
for at least 1 year
- has had continued presence of pain for more than 50% of the last month
- a score of >1 on the unidimensional 100-cm visual analog scale (VAS) for pain level
- has been on a stable medication regimen for at least 3 weeks, with no change greater
than +/- 20% variation on total daily dosage
- 18-70 years of age
- is right handed
- willing to complete all study procedures
- is capable of giving written informed consent
Exclusion Criteria:
- in-patient
- a history of brain abnormalities such as stroke, ventriculomegaly or periventricular
white matter abnormalities
- has not been on a stable medication regimen for at least 3 weeks, with any change
greater than +/- 20% variation on medication total daily dosage
- has a history of substance abuse
- has the presence of concurrent autoimmune or inflammatory disease such as rheumatoid
arthritis, systemic lupus erythematosus, inflammatory bowel disease, etc. that causes
pain
- has concurrent participation in other therapeutic trials
- pregnant and nursing mothers
- has severe psychiatric illnesses (current schizophrenia, major depression with
suicidal ideation, substance abuse within two years)
- or has current major depression. [Depression in these patients will be assessed with
the Hospital Anxiety and Depression Scale (HADS). Categorization of fibromyalgia
patients with high depressive symptoms is defined as >8 for the HADS
- has contraindications for MRI scanning or MEG recording, including any of the
following: cardiac pacemaker, intracranial clips, metal implants, or external clips
within 10 mm of the head, metal in eyes, claustrophobia, obesity and/or any other
reason leading to difficulty getting in the MEG chair or laying supine in the MRI
magnet for up to one hour
- Existence of any other chronic pain conditions, in addition to fibromyalgia
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