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.