Examining Brain Changes Using Functional Magnetic Resonance Imaging (fMRI) in Amputees With Phantom Limb Pain Following Mirror Therapy

This is a prospective trial that will use fMRI to identify brain regions critical to the
generation of PLP, examine the role of mirror therapy and the visual system in the
de-activation of pain pathways, and observe how changes in the brain may be correlated with
the level of PLP. Subjects must have PLP and have sustained a unilateral lower extremity
amputation prior to enrollment. All subjects will be screened initially by a neurologist,
physiatrist, or research coordinator according to the inclusion and exclusion criteria. A
detailed medical history will be taken and documented, and a neurologist will conduct a
documented physical examination. Subjects who do not meet the study inclusion criteria will
not be eligible to participate in this research study, but will continue to receive current
best practice of care. If a subject's pain becomes severe during the course of the study,
pain medication will be available to them.

All subjects willing to participate in the study will be required to sign a DA 5303-R (see
appendix for Voluntary Agreement Affidavit) prior to enrollment in the study. Once enrolled,
all subjects will undergo baseline entry evaluations quantifying their current pain
perception using the following evaluation tools: the Visual Analogue Scale (VAS) and the
short version of the McGill Pain Questionnaire (Appendix 1) along with a short questionnaire
on phantom limb pain frequency and duration (Appendix 5). Subjects will also be queried
about their use of current pain medications along with the dosages on a weekly basis.
Although helpful tools in the standard of care, the questionnaires completed by the subjects
and the list of medications reported by the subjects in this study are for research data
collection purposes only. In order to maintain subject confidentiality, only the subject's
identification code-and not the subject's name-will appear on the questionnaires and
evaluation forms. Subjects will be identified only through the use of coded identifiers. For
instance, amputees would be coded as RLE1, RLE2, LLE1, LLE2, etc.

Dr. Jack Tsao, Katie Hughes, and Lindsay Hussey-Andersen will administer both the treatments
and the questionnaires. They will train all research subjects on the appropriate technique
for using a 2' X 4' mirror and perform the cognitive tests. Unilateral limb amputee subjects
will be asked to place their intact foot in front of a mirror and then to view the mirror
image of the intact foot moving while performing a series of foot movements with the
amputated, or phantom, foot. The sequence of foot movements include: abduction of the great
toe, adduction of the great toe, flexion of the foot, extension of the foot, inversion of
the foot, eversion of the foot, rotation of the foot, flexion of the toes, and extension of
the toes. These sessions will be supervised by a clinician or research coordinator and will
occur 5 times a week for 4 weeks (20 days), with each session lasting 15 minutes. Prior to
each daily treatment period, subjects will be asked to report PLP using the VAS and McGill
forms and also to report the number and duration of PLP in the previous 24 hours. All
subjects will also participate in rehabilitation therapy (muscle-strengthening exercises,
use of prosthesis, and range of motion exercises) per standard medical care for limb
amputation.

Concurrent use of pain medications and muscle relaxants is permitted and will be recorded by
the research assistant in a medication diary (Appendix 2). Scores on the VAS and McGill pain
questionnaire will be used to assess the subject's level of disability and to evaluate
outcomes. Subjects will be evaluated weekly in the hospital for quantification of the amount
of analgesic medications used (NSAIDs, muscle relaxants, opioids), and VAS and McGill scores
will be quantified daily for 4 weeks. The primary outcome will be changes in brain areas
which are activated at weeks 2 and 4 compared to areas activated prior to starting mirror
therapy. Secondary outcomes will be pain relief on the VAS, with responders defined as
subjects with a significant decrease in the VAS score. All respondents will be released from
the study after the final pain evaluation at 4 weeks.

A research assistant will provide transportation to and from the National Institutes of
Health (NIH) where the fMRI scans will take place. Amputee subjects will be asked to first
use mental visualization to move their phantom foot and report their pain level, followed by
viewing of their intact foot moving in a mirror while moving their phantom foot. fMRI
scanning will be performed during both types of phantom foot movements to determine which
additional brain regions are activated with visual observation. A fMRI will be done at the
beginning of the study to establish a baseline and follow-up scanning will occur 2 and 4
weeks after daily mirror therapy begins to assess changes in brain activation. Fourteen (14)
control subjects will be recruited and asked to perform the same tasks during the fMRI scans
but will not undergo mirror therapy. Control subjects will complete the McGill pain
questionnaire as well as the VAS during each of their 3 visits to NIH for fMRI scanning. All
subjects will be queried about their current medication use on a weekly basis. Both amputee
and control subjects will be a part of this study for one month; both will undergo 3 fMRI
scanning sessions, interspersed by the same 2 week period. fMRI evaluations will take up to
two (2) hours per session and mirror therapy will last fifteen (15) minutes, totaling six
(6) hours of fMRI and five (5) hours and fifteen (15) minutes of mirror therapy.

Inclusion Criteria:

For Amputee Subjects:

- Male or female subjects

- 18 to 75 years of age

- Active duty military

- Military healthcare beneficiary

- Military retiree

- Written informed consent and written authorization for use or release of health and
research study information

- Unilateral lower limb amputation

- Right-handed

- Any level of prosthetic experience

- No prior history of vertebral disk disease/condition

- Sciatica

- Radiculopathy

- Neurological examination that will not interfere with participation in the study

- Minimum of 3 phantom limb pain episodes each week

- Degree of pain evaluated by VAS scoring a minimum of 3 cm at time of screening for
entry into study.

- Ability to follow study instructions and likely to complete all required visits

For Control Subjects:

- Male or female subjects

- 18 to 75 years of age

- Written informed consent and written authorization for use or release of health and
research study information

- Right-handed.

- No prior history of vertebral disk disease/condition

- Sciatica

- Radiculopathy

- Normal neurological examination

- Ability to follow study instructions and likely to complete all required visits

Exclusion Criteria:

For Amputee Subjects:

- Age less than 18 or greater than 75 years

- Unilateral upper limb or multiple limb amputation.

- Amputation due to diabetes or vascular claudication

- No known pending revision surgeries

- Presence of embedded metallic shrapnel or other metal not compatible with MRI
scanning

- Presence of traumatic brain injury - permanent or temporary impairments of cognitive,
physical, and psychosocial functions with an associated diminished or altered state
of consciousness - as indicated by neuropsychological screening, including DVBIC
testing, which is currently performed routinely on patients by the TBI program at
WRAMC and noted in the patient's medical record

- Known uncontrolled systemic disease- known cancer not in remission

- Known on-going infection

- Lupus

- Kidney disease requiring dialysis, any other systemic disease which might affect
ability to participate in this study to its conclusion

- Concurrent participation in another investigational drug or device study for phantom
limb pain or participation in the 30 days immediately prior to study enrollment

- Any condition or situation that, in the investigator's opinion, may put the subject
at significant risk, confound the study results, or interfere significantly with the
subject's participation in the study

- Significant Axis I or II diagnosis determined by a neurologist or psychiatrist in the
6 months prior to entry into the study

- Subjects with lack of effort as determined by the neurologist or physiatrist

- Subjects will be screened for effort using the Test of Memory Malingering (TOMM)
first in order to exclude those with blatant exaggeration or malingering

For Control Subjects:

- Age less than 18 or greater than 75 years

- Presence of an amputation

- Presence of embedded metallic shrapnel or other metal not compatible with MRI
scanning

- Presence of traumatic brain injury - permanent or temporary impairments of cognitive,
physical, and psychosocial functions with an associated diminished or altered state
of consciousness - as indicated by neuropsychological screening which is currently
performed routinely on patients by the TBI program at WRAMC and noted in the
patient's medical record

- Known uncontrolled systemic disease- known cancer not in remission

- Known on-going infection

- Lupus

- Kidney disease requiring dialysis

- Any other systemic disease which might affect ability to participate in this study to
its conclusion

- Any condition or situation that, in the investigator's opinion, may put the subject
at significant risk, confound the study results, or interfere significantly with the
subject's participation in the study

- Significant Axis I or II diagnosis determined by a neurologist or psychiatrist in the
6 months prior to entry into the study