Chronic Migraine Treatment With Botulinum Toxin-A: an Investigation of Functional Magnetic Resonance Imaging Changes.
Chronic Migraine Treatment With Botulinum Toxin-A: an Investigation of Functional Magnetic Resonance Imaging Changes.
Pilot study evaluating effect of Botox injection treatment for 12 individuals suffering from
 chronic migraine on function MRI imaging, before and after treatment.
A proposed 12 patients will be recruited for participation in the pilot study. Consenting
 patients between the ages of 18-65 years old with confirmed chronic migraine (as defined by
 International Headache Society criteria) and meeting all other inclusion criteria (to be
 described in full protocol) will be enrolled for participation in the trial. Participants
 currently receiving migraine prophylaxis will be tapered off the specified medication
 (tapering regimen to be determined by clinicians) and a 4-week washout period will be
 observed prior to baseline assessments and Botox treatment. These patients will be permitted
 to use acute migraine medications as required. Participants will undergo baseline migraine
 significance assessments, which will include Headache Impact Test (HIT-6), the Migraine
 Disability Assessment (MIDAS) questionnaire and the Migraine Impact Questionnaire. Baseline
 neurological assessment will also be conducted at this visit. Additionally, baseline Beck
 Depression and Anxiety Inventories will be completed.

 Participants will also undergo baseline fMRI on the 3Tesla Siemens MRI magnet at the National
 Research Council (NRC) Building located at 435 Ellice Avenue in Winnipeg, Manitoba. At this
 time, both structural and resting state fMRI data will be acquired. A 72-hour minimum
 migraine-free period will be ensured before each individual is allowed to proceed with
 imaging. A localizer image will be obtained. This is used for determining the participant's
 head position and for setting up the field of view for all subsequent images. Next, a
 high-resolution 3-dimensional image will be taken of the whole brain. This will be acquired
 with the following imaging parameters [Siemens MP-RAGE sequence, 1mm thick slices, zero
 spacing between slices, repetition time of 1900 ms, echo time of 2.2 ms, in plane resolution
 of 0.94 x 0.94, 256 x 256 matrix size with a 24 cm field of view, 176 volumes, resulting in a
 8 minute 6 second scan time]. After the high-resolution image has been acquired, the resting
 state fMRI data will be acquired with the following parameters [Siemens echo planar imaging
 (EPI) sequence, 3 mm thick slices, zero spacing between slices, repetition time of 3000 ms,
 echo time of 30 ms, flip angle of 90°, 64 x 64 matrix size, 24 cm field of view, 140 volumes,
 resulting in a 7 minute 9 second scan time]. This provides the data set for the functional
 connectivity analysis. The high-resolution anatomical data serves as the background for the
 display of the superimposed resting state fMRI data. All image data will be acquired with an
 alpha-numeric code representing the study protocol number and participant number; the data
 will be transferred to a flash drive and copied to the principal investigator's hard drive
 for analysis. All participant paperwork and data back-up will be securely stored in the
 principal investigator's locked filing cabinet.

 Following baseline screening, participants will receive two subsequent treatments with
 botulinum-A toxin, each separated by 12 weeks. Participants will receive standardized
 botulinum-A toxin dosing for chronic migraine prophylaxis, comprised of 155 total units given
 at 31 specified sites across 7 head/neck muscles (protocol to be explicitly described in full
 protocol). Second dose of botulinum-A toxin will either be maintained at 155 total units as
 dosed initially, or be increased to 195 total units, depending on response to clinical
 questionnaires and examination to evaluate response and efficacy (to be described in full
 protocol, consistent with the "Follow-the-Pain Injection Paradigm"). Following initial
 treatment (Day=0) participants will be requested to maintain daily headache diaries, in which
 they will be asked to record symptoms of active migraine as well as the use of acute migraine
 medications on a daily basis, in order to track migraine frequency and severity (example of
 headache diary will be included in full protocol). Participant timeline will be as follows:
 Day 0 (baseline assessments, fMRI and first Botox injection), Day 28 (clinic follow-up), Day
 56 (second fMRI), Day 84 (clinic follow-up and second injection), Day 112 (clinic follow-up)
 and Day 140 (third fMRI). Clinic follow-up will be scheduled for Days 28, 84 and 112 at which
 time adverse events will be reviewed, as well as headache frequency reported in daily
 headache diaries. At these time points, participants will also repeat the same assessments
 completed at the baseline visit, including the HIT-6, MIDAS and Migraine Impact
 Questionnaire. At study termination (Day=140) patients will undergo a final fMRI scan as per
 baseline MRI protocol previously described.
Inclusion Criteria:

 -  Female and male patients, 18-65 years of age with confirmed chronic migraine (defined
 as migraine headache with or without aura, occurring on > 15 days of each month for at
 least 3 months

 -  Headaches must have at least two of the following characteristics: unilateral
 location, pulsating quality, moderate-severe pain intensity and/or aggravation by or
 causing avoidance of routine physical activity (eg. Walking or climbing stairs)

 -  Headaches must also have at least one of: nausea and/or vomiting or photophobia and/or
 phonophobia.

 -  Patients must be cognitively able to understand questionnaires and be able to complete
 Headache Logs.

 -  Patients must be physically able to undergo treatment administration, including the
 required positional changes needed for administration.

 Exclusion Criteria:

 -  Headaches that could be attributed to other causes, as determined by clinician,
 including medication overuse headaches and chronic tension type headache.

 -  Females of childbearing age with confirmed or suspected pregnancy, those planning on
 conceiving during the trial duration and women who are breastfeeding.

 -  Previous treatment with botulinum toxin-A for chronic migraine.

 -  Confirmed allergy to botulinum toxin-A or any of the product components.

 -  Contraindications to fMRI procedure.

 -  Patients unable to discontinue migraine prophylaxis medications, including tricyclic
 antidepressants, beta-blockers and various antiepileptic medications, either due to
 unwillingness or safety issues (eg. Antiepileptics being used to manage seizure
 disorder). This will be determined by clinician.

 -  Participants exhibiting severe depression (BDI score >40) and/or suicidal ideation.
 These individuals will receive appropriate medical follow-up for psychological
 management.

 -  Active skin infection at planned injection site(s).