Optimizing Rehabilitation for Phantom Limb Pain Using Mirror Therapy and Transcranial Direct Current Stimulation (tDCS)

• Sponsor: Spaulding Rehabilitation Hospital
• Collaborator: Massachusetts Eye and Ear Infirmary
• Information provided by (Responsible Party): Felipe Fregni, Spaulding Rehabilitation Hospital

Study Description

Brief Summary:

This is a two-site study that explores the effects of mirror therapy and transcranial Direct Current Stimulation (tDCS, Soterix ©) in a randomized factorial controlled trial in which patients will be assigned to one of four groups: active tDCS and active MT; sham tDCS and active MT; active tDCS and sham MT (which consists of using a covered mirror for the therapy); and both sham tDCS and sham MT (covered mirror).

Condition or disease	Intervention/treatment	Phase
Phantom Limb Pain; Amputation, Traumatic	Device: transcranial Direct Current Stimulation (tDCS): active (Soterix ©); Behavioral: Mirror Therapy: active; Device: transcranial Direct Current Stimulation (tDCS): sham (Soterix ©); Behavioral: Mirror Therapy: Sham	Not Applicable

Detailed Description:

Phantom limb pain (PLP) belongs to a group of neuropathic pain syndromes that is characterized by pain in the amputated limb. Rehabilitation for chronic pain involves a structured treatment plan targeting all dimensions of the pain experience, and should include a comprehensive interdisciplinary approach that allows patients to receive the most benefit according to their needs. As in other chronic pain syndromes, chronic Phantom limb pain (PLP) is often difficult to treat; showing to be resistant to classical pharmacological and surgical treatment approaches.

In this context, we hypothesize that novel treatments of PLP need to target specific neural networks associated with this maladaptive plasticity. Transcranial direct current stimulation (tDCS,Soterix ©) is a powerful and non-invasive technique of brain stimulation that is known to significantly modulate plasticity and alleviate chronic pain in various syndromes. device for this trial. This study usiGiven tDCS underlying neural mechanisms, it is critical to use a multimodal approach to treatment - using both tDCS and behavioral therapy simultaneously. In this case, an ideal therapy is mirror therapy (MT).

Recently, we showed that anodal tDCS can induce a selective short-lasting relief from PLP, and repeated applications of anodal tDCS induces long-lasting analgesic effects. These preliminary results show that tDCS may be a promising rehabilitative tool for the management of chronic PLP. This neurorehabilitation technique is commonly used in PLP, and is designed to modulate cortical mechanisms of pain by performing movements using the unaffected limb in front of a mirror. We propose to carry out a mechanistic, factorial, randomized controlled trial to evaluate a novel rehabilitation approach combining tDCS and MT in PLP patients. We aim to compare the brain changes before and after treatment in order to study the mechanisms underlying PLP.

Study Design

Layout table for study information

Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	132 participants
Allocation:	Randomized
Intervention Model:	Factorial Assignment
Masking:	Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	Optimizing Rehabilitation for Phantom Limb Pain Using Mirror Therapy and Transcranial Direct Current Stimulation (tDCS)
Study Start Date :	July 2015
Estimated Primary Completion Date :	July 2019
Estimated Study Completion Date :	July 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Active tDCS and Active Mirror Therapy; Subjects will receive 20 minutes of active tDCS, while receiving 15 minutes of active Mirror Therapy.	Device: transcranial Direct Current Stimulation (tDCS): active (Soterix ©); Subjects will undergo tDCS stimulation. For both active and sham stimulation, we will use electrodes of 35cm^2, at an intensity of 2mA on the primary motor cortex contralateral to the amputated leg. For active tDCS, the subject will undergo stimulation for 20 minutes.; Behavioral: Mirror Therapy: active; Subjects will be asked to perform movements (15 minutes daily) using the unaffected limb while watching its mirrored reflection superimposed over the affected limb. During Mirror Therapy, subjects will be asked to consciously relate the movement observed in the mirror to their phantom limb and to keep their attention focused on the task. Instructions will be explained verbally, demonstrated by a therapist, and performed by the subject in front of the therapist.
Experimental: Active tDCS and sham Mirror Therapy; Subjects will receive 20 minutes of active tDCS, while receiving 15 minutes of sham Mirror Therapy.	Device: transcranial Direct Current Stimulation (tDCS): active (Soterix ©); Subjects will undergo tDCS stimulation. For both active and sham stimulation, we will use electrodes of 35cm^2, at an intensity of 2mA on the primary motor cortex contralateral to the amputated leg. For active tDCS, the subject will undergo stimulation for 20 minutes.; Behavioral: Mirror Therapy: Sham; Subjects will be asked to perform movements (15 minutes daily) using the unaffected limb while watching its mirrored reflection superimposed over the affected limb, only the mirror will be covered. During Mirror Therapy, subjects will be asked to consciously relate the movement observed in the mirror to their phantom limb and to keep their attention focused on the task. Instructions will be explained verbally, demonstrated by a therapist, and performed by the subject in front of the therapist. We will use the same all of these techniques as active Mirror Therapy only the mirror will be covered during all activities.
Experimental: Sham tDCS and active Mirror Therapy; Subjects will receive 20 minutes of sham tDCS, while receiving 15 minutes of active Mirror Therapy.	Behavioral: Mirror Therapy: active; Subjects will be asked to perform movements (15 minutes daily) using the unaffected limb while watching its mirrored reflection superimposed over the affected limb. During Mirror Therapy, subjects will be asked to consciously relate the movement observed in the mirror to their phantom limb and to keep their attention focused on the task. Instructions will be explained verbally, demonstrated by a therapist, and performed by the subject in front of the therapist.; Device: transcranial Direct Current Stimulation (tDCS): sham (Soterix ©); Subjects will undergo tDCS stimulation. For both active and sham stimulation, we will use electrodes of 35cm^2, at an intensity of 2mA on the primary motor cortex contralateral to the amputated leg. The subject will undergo stimulation for 20 minutes. This is the same parameters as the active one, except the current will be ramped up and then down again (for 30 seconds total) to simulate the feeling of active stimulation.
Sham Comparator: Sham tDCS and sham Mirrory Therapy; Subjects will receive 20 minutes of sham tDCS, while receiving 15 minutes of sham Mirror Therapy.	Device: transcranial Direct Current Stimulation (tDCS): sham (Soterix ©); Subjects will undergo tDCS stimulation. For both active and sham stimulation, we will use electrodes of 35cm^2, at an intensity of 2mA on the primary motor cortex contralateral to the amputated leg. The subject will undergo stimulation for 20 minutes. This is the same parameters as the active one, except the current will be ramped up and then down again (for 30 seconds total) to simulate the feeling of active stimulation.; Behavioral: Mirror Therapy: Sham; Subjects will be asked to perform movements (15 minutes daily) using the unaffected limb while watching its mirrored reflection superimposed over the affected limb, only the mirror will be covered. During Mirror Therapy, subjects will be asked to consciously relate the movement observed in the mirror to their phantom limb and to keep their attention focused on the task. Instructions will be explained verbally, demonstrated by a therapist, and performed by the subject in front of the therapist. We will use the same all of these techniques as active Mirror Therapy only the mirror will be covered during all activities.

Outcome Measures

Primary Outcome Measures :

1. Changes in the Visual Analog Scale for Phantom Limb Pain [ Time Frame: Measured for approximately 13-14 weeks ]
   The primary end point will be severity of pain measured by changes in PLP as indexed by a Visual Analog Scale (VAS).

Secondary Outcome Measures :

1. Changes in the Visual Analog Scale for Phantom Limb Stump Pain [ Time Frame: Measured for approximately 13-14 weeks ]
   The end point will be severity of pain measured by changes in PLP as indexed by a Visual Analog Scale (VAS).
2. Changes in the Visual Analog Scale for Phantom Limb Sensation [ Time Frame: Measured for approximately 13-14 weeks ]
   The end point will be severity of pain measured by changes in PLP as indexed by a Visual Analog Scale (VAS).
3. Changes in the Visual Analog Scale for Phantom Limb telescoping [ Time Frame: Measured for approximately 13-14 weeks ]
   The end point will be severity of pain measured by changes in PLP as indexed by a Visual Analog Scale (VAS).
4. Adapted Groningen Questionnaire after Arm Amputation [ Time Frame: Baseline (first visit after screening; usually will occur approximately within 1 week from enrollment) ]
   This questionnaire is originally meant to obtain information's concerning complaints that may be developed after arm amputation. We adapted the current arm version for lower limb amputation. This questionnaire has been used in several clinical trials assessing PLP.
5. Pain and medication diary [ Time Frame: Measured for approximately 13-14 weeks ]
   To help monitor pain levels and medication use information, as well as safety. Subjects will be asked to record the number of phantom limb episodes on a daily basis, using a pain diary. They will record the intensity of the strongest episode as well as phantom limb sensation and stump pain on a colored visual analog scale included in the diary, where 0 represents no pain at all and 10 represents the highest pain the patient has ever felt. Moreover subjects will record their current medications and dosages daily in a pain medication diary, until completion of the study.
6. Beck depression Inventory [ Time Frame: Screening (first study visit; usually done same day as enrollment) and follow-ups (~3-4, ~5-6, ~ 9-10, and ~13-15 weeks after enrollment) ]
   This self-report inventory consists of 21 multiple-choice questions and is widely used method to classify depression severity. It assesses for the presence of several symptoms related to depression, such as irritability, hopelessness and decreased cognitive performance. Physical symptoms such as weight loss and fatigue are also included. This instrument has been used previously to evaluate depression severity in patients with phantom limb pain, as well as in other chronic pain conditions.
7. Beck anxiety Inventory [ Time Frame: Baseline (approximately within 1 week from enrollment) and follow-ups (~3-4, ~5-6, ~ 9-10, and ~13-15 weeks after enrollment) ]
   This self-report inventory consists of 21 multiple-choice questions about how the subject has been feeling in the last week, expressed as common symptoms of anxiety (such as numbness and tingling, sweating not due to heat, and fear of the worst happening). It is designed for an age range of 17-80 years old. Each question has the same set of four possible answer choices, which are arranged in columns and are answered by marking the appropriate one with a cross.
8. Mini Mental State examination (MMSE) [ Time Frame: Baseline (approximately within 1 week from enrollment) ]
   This is a sensitive, valid and reliable 30-point questionnaire that is used extensively in clinical and research settings to measure cognitive impairment. This instrument will be used as a brief screening of cognitive abilities. It will be used as a baseline evaluation
9. Quality of Life Assessment (Short version of SF-36) [ Time Frame: Baseline (approximately within 1 week from enrollment) and some follow-ups (~5-6 weeks and ~13-14 weeks after enrollment) ]
   The short version of the SF-36 health survey is used as a measurement of quality of life. It provides a profile of functional health and well-being scores. It is also used as a psychometrical index of physical and mental health. This instrument is widely used as a quality of life assessment in patients after an amputation and those suffering from phantom limb pain.
10. Stroop test [ Time Frame: Baseline (approximately within 1 week from enrollment) and some follow-ups (~3-4, ~5-6, and ~13-14 weeks after enrollment) ]
    In this task the subject is presented with names of colors written in the same color or in a different color, thus on the one hand the word names a color (red) and is written in another color (blue). In this task, the automatized behavior (reading) is in conflict with the desired response (naming the color). The Subject has to inhibit/suppress the automatic response of reading and naming the color the word is written in. The Stroop is one of the most commonly used tools for determining attentional problems, also used to assess executive function and working memory. Stroop test will be applied as a preliminary safety assessment of cognitive changes from baseline to post and follow-up visits.
11. Side Effects Questionnaire for tDCS [ Time Frame: During the intervention sessions of tDCS (at least one 1 week after screening for 2 consecutive weeks) ]
    At each stimulation session, subjects will complete a questionnaire to evaluate potential adverse effects of tDCS (tingling, burning sensation, headache, neck pain, mood alterations) and mirror therapy (anxiety, grief, dizziness) on a 4-point scale (None, mild, moderate and severe). The subjects will be asked whether they have experienced any side effects in an open-ended manner and they will then be specifically asked about headache, neck pain, scalp pain, scalp burns, tingling, skin redness, sleepiness, trouble concentrating, and acute mood change. If any side effects are reported, the degree of relatedness to the intervention will be assessed on a 5-point scale. This type of adverse events questionnaire has been used frequently in our previous tDCS studies , including in patients with phantom limb pain .
12. Side Effects Questionnaire for TMS [ Time Frame: During TMS evaluations: Baseline (approximately within 1 week from enrollment); last day of tDCS stimulation (~3-4 weeks from enrollment); last day mirror therapy (~5-6 weeks from enrollment); last follow-up (~13-14 weeks from enrollment) ]
    At each TMS assessment session, subjects will complete a questionnaire to evaluate potential adverse effects of rTMS (headache, neck pain, itching and redness at the site of stimulation) on a 5-point scale.
13. tDCS blinding questionnaire [ Time Frame: Last day of tDCS sessions (~3-4 weeks from enrollment) ]
    After the stimulation session, subjects will complete a questionnaire to determine if our blinding methods were effective. We are using a 30s sham montage, just as we use in our other trials, keeping the device on the subject for the duration of the session
14. Patient's Global Impression of Change scale [ Time Frame: Last day of Mirror Therapy (~5-6 weeks from enrollment) ]
    Subjects will complete a questionnaire to assess their perception of change (if any) in the activity limitations, symptoms, emotions and overall quality of life after their participation in intervention's visits of the trial
15. Single and Paired Pulse TMS [ Time Frame: During TMS evaluations: Baseline (~within 1 week from enrollment); last day of t); last day of tDCS stimulation (~3-4 weeks from enrollment); last day mirror therapy (~5-6 weeks from enrollment); last follow-up (~13-14 weeks from enrollment) ]
    Subjects will undergo several sessions of TMS to assess cortical excitability and cortical reorganization.
16. Functional magnetic resonance imaging (fMRI) [ Time Frame: Baseline (approximately within 1 week from enrollment) and last day of Mirror Therapy (~5-6 weeks from enrollment) ]
    This is to quantify maladaptive cortical reorganization before and after treatment.

Eligibility Criteria

Layout table for eligibility information

Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Able to provide informed consent to participate in the study.
2. Subject is older than 18 years.
3. Unilateral lower limb amputation.
4. Traumatic amputation greater than 1 year ago.
5. Chronic PLP for at least 3 months previous to enrollment in the study, experienced regularly for at least once a week.
6. Average pain of at least 4 on a numeric rating scale in the previous week (NRS; ranging from 0 to 10).
7. If the subject is taking any medications, dosages must be stable for at least 2 weeks prior to the enrollment of the study.

Exclusion Criteria:

1. Pregnancy or trying to become pregnant in the next 2 months.
2. History of alcohol or drug abuse within the past 6 months as self-reported.

3. Presence of the following contraindication to transcranial direct current stimulation and transcranial magnetic stimulation

   • Ferromagnetic metal in the head (e.g., plates or pins, bullets, shrapnel)
   • Implanted neck or head electronic medical devices (e.g., cochlear implants, vagus nerve stimulator)
4. History of chronic pain previous to the amputation.
5. Head injury resulting in loss of consciousness for at least 30 min or pos-traumatic amnesia for greater than 24 hours, as self-reported
6. Unstable medical conditions (e.g. uncontrolled diabetes, uncompensated cardiac issues, heart failure or chronic obstructive pulmonary disease).
7. Uncontrolled Epilepsy or prior seizures within the last 1 year.
8. Suffering from severe depression (as defined by a score of >30 in the Beck Depression Inventory).*
9. History of unexplained fainting spells or loss of consciousness as self-reported during the last 2 years.
10. History of neurosurgery, as self-reported.
11. Mirror Therapy in the previous 3 months

Contacts and Locations

Contacts

Layout table for location contacts

Contact: Felipe Fregni, MD, PhD, MPH	617-573-2326	ffregni@partners.org
Contact: Camilla Pinto, M.Sc.	617-952-6160	cbpinto@partners.org

Locations

Layout table for location information

United States, Massachusetts
Spaulding Rehabilitation Network Research Institute	Recruiting
Charlestown, Massachusetts, United States, 02129
Contact: Felipe Fregni, MD PhD MPH 617-952-6156 ffregni@partners.org
Contact: Camilla Pinto, M.Sc. 617-952-6160 cbpinto@partners.org
Principal Investigator: Felipe Fregni, MD PhD MPH
Brazil
IMREA HCFMUSP - Rede Lucy Montoro	Recruiting
São Paulo, Brazil, 04116-030
Contact: Dra. Linamara Rizzo Battistella, MD PhD 55 (11) 5180-7800 linamara@usp.br
Contact: Elice Carneiro, BS 55 (11) 5180-7897 elice.carneiro@hc.fm.usp.br
Principal Investigator: Dra. Linamara Rizzo Battistella, MD PhD

Sponsors and Collaborators

Spaulding Rehabilitation Hospital

Massachusetts Eye and Ear Infirmary

Investigators

Layout table for investigator information

Principal Investigator:	Felipe Fregni, MD, PhD, MPH	Spaulding Rehabilitation Hospital

More Information

Publications of Results:

Flor H. Phantom-limb pain: characteristics, causes, and treatment. Lancet Neurol. 2002 Jul;1(3):182-9. Review.

Nikolajsen L, Staehelin Jensen T. Phantom limb pain. Curr Rev Pain. 2000;4(2):166-70. Review.

Manchikanti L, Singh V. Managing phantom pain. Pain Physician. 2004 Jul;7(3):365-75.

Birbaumer N, Lutzenberger W, Montoya P, Larbig W, Unertl K, Töpfner S, Grodd W, Taub E, Flor H. Effects of regional anesthesia on phantom limb pain are mirrored in changes in cortical reorganization. J Neurosci. 1997 Jul 15;17(14):5503-8.

Borsook D, Becerra L, Fishman S, Edwards A, Jennings CL, Stojanovic M, Papinicolas L, Ramachandran VS, Gonzalez RG, Breiter H. Acute plasticity in the human somatosensory cortex following amputation. Neuroreport. 1998 Apr 20;9(6):1013-7.

Flor H, Elbert T, Knecht S, Wienbruch C, Pantev C, Birbaumer N, Larbig W, Taub E. Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature. 1995 Jun 8;375(6531):482-4.

Grüsser SM, Winter C, Mühlnickel W, Denke C, Karl A, Villringer K, Flor H. The relationship of perceptual phenomena and cortical reorganization in upper extremity amputees. Neuroscience. 2001;102(2):263-72.

Montoya P, Ritter K, Huse E, Larbig W, Braun C, Töpfner S, Lutzenberger W, Grodd W, Flor H, Birbaumer N. The cortical somatotopic map and phantom phenomena in subjects with congenital limb atrophy and traumatic amputees with phantom limb pain. Eur J Neurosci. 1998 Mar;10(3):1095-102.

Ramachandran VS, Rogers-Ramachandran D, Stewart M. Perceptual correlates of massive cortical reorganization. Science. 1992 Nov 13;258(5085):1159-60.

Davis KD, Kwan CL, Crawley AP, Mikulis DJ. Event-related fMRI of pain: entering a new era in imaging pain. Neuroreport. 1998 Sep 14;9(13):3019-23.

Foell J, Bekrater-Bodmann R, Diers M, Flor H. Mirror therapy for phantom limb pain: brain changes and the role of body representation. Eur J Pain. 2014 May;18(5):729-39. doi: 10.1002/j.1532-2149.2013.00433.x. Epub 2013 Dec 10.

Lotze M, Flor H, Grodd W, Larbig W, Birbaumer N. Phantom movements and pain. An fMRI study in upper limb amputees. Brain. 2001 Nov;124(Pt 11):2268-77.

Gandiga PC, Hummel FC, Cohen LG. Transcranial DC stimulation (tDCS): a tool for double-blind sham-controlled clinical studies in brain stimulation. Clin Neurophysiol. 2006 Apr;117(4):845-50. Epub 2006 Jan 19.

Bolognini N, Olgiati E, Maravita A, Ferraro F, Fregni F. Motor and parietal cortex stimulation for phantom limb pain and sensations. Pain. 2013 Aug;154(8):1274-80. doi: 10.1016/j.pain.2013.03.040. Epub 2013 Apr 19.

Bolognini N, Spandri V, Olgiati E, Fregni F, Ferraro F, Maravita A. Long-term analgesic effects of transcranial direct current stimulation of the motor cortex on phantom limb and stump pain: a case report. J Pain Symptom Manage. 2013 Oct;46(4):e1-4. doi: 10.1016/j.jpainsymman.2013.06.014. Epub 2013 Aug 7.

Facchini S, Romani M, Tinazzi M, Aglioti SM. Time-related changes of excitability of the human motor system contingent upon immobilisation of the ring and little fingers. Clin Neurophysiol. 2002 Mar;113(3):367-75.

Rioult-Pedotti MS, Friedman D, Hess G, Donoghue JP. Strengthening of horizontal cortical connections following skill learning. Nat Neurosci. 1998 Jul;1(3):230-4.

Boggio PS, Castro LO, Savagim EA, Braite R, Cruz VC, Rocha RR, Rigonatti SP, Silva MT, Fregni F. Enhancement of non-dominant hand motor function by anodal transcranial direct current stimulation. Neurosci Lett. 2006 Aug 14;404(1-2):232-6. Epub 2006 Jun 30.

Fregni F, Boggio PS, Mansur CG, Wagner T, Ferreira MJ, Lima MC, Rigonatti SP, Marcolin MA, Freedman SD, Nitsche MA, Pascual-Leone A. Transcranial direct current stimulation of the unaffected hemisphere in stroke patients. Neuroreport. 2005 Sep 28;16(14):1551-5.

Hummel F, Cohen LG. Improvement of motor function with noninvasive cortical stimulation in a patient with chronic stroke. Neurorehabil Neural Repair. 2005 Mar;19(1):14-9.

Floel A, Cohen LG. Contribution of noninvasive cortical stimulation to the study of memory functions. Brain Res Rev. 2007 Feb;53(2):250-9. Epub 2006 Oct 4. Review.

Monti A, Cogiamanian F, Marceglia S, Ferrucci R, Mameli F, Mrakic-Sposta S, Vergari M, Zago S, Priori A. Improved naming after transcranial direct current stimulation in aphasia. J Neurol Neurosurg Psychiatry. 2008 Apr;79(4):451-3. Epub 2007 Dec 20.

Iyer MB, Mattu U, Grafman J, Lomarev M, Sato S, Wassermann EM. Safety and cognitive effect of frontal DC brain polarization in healthy individuals. Neurology. 2005 Mar 8;64(5):872-5.

Fregni F, Boggio PS, Nitsche M, Bermpohl F, Antal A, Feredoes E, Marcolin MA, Rigonatti SP, Silva MT, Paulus W, Pascual-Leone A. Anodal transcranial direct current stimulation of prefrontal cortex enhances working memory. Exp Brain Res. 2005 Sep;166(1):23-30. Epub 2005 Jul 6.

MacIver K, Lloyd DM, Kelly S, Roberts N, Nurmikko T. Phantom limb pain, cortical reorganization and the therapeutic effect of mental imagery. Brain. 2008 Aug;131(Pt 8):2181-91. doi: 10.1093/brain/awn124. Epub 2008 Jun 20.

Rothgangel AS, Braun SM, Beurskens AJ, Seitz RJ, Wade DT. The clinical aspects of mirror therapy in rehabilitation: a systematic review of the literature. Int J Rehabil Res. 2011 Mar;34(1):1-13. doi: 10.1097/MRR.0b013e3283441e98. Review.

Chan BL, Witt R, Charrow AP, Magee A, Howard R, Pasquina PF, Heilman KM, Tsao JW. Mirror therapy for phantom limb pain. N Engl J Med. 2007 Nov 22;357(21):2206-7.

Darnall BD, Li H. Home-based self-delivered mirror therapy for phantom pain: a pilot study. J Rehabil Med. 2012 Mar;44(3):254-60. doi: 10.2340/16501977-0933.

MacLachlan M, McDonald D, Waloch J. Mirror treatment of lower limb phantom pain: a case study. Disabil Rehabil. 2004 Jul 22-Aug 5;26(14-15):901-4.

Kim SY, Kim YY. Mirror therapy for phantom limb pain. Korean J Pain. 2012 Oct;25(4):272-4. doi: 10.3344/kjp.2012.25.4.272. Epub 2012 Oct 4.

Soler MD, Kumru H, Pelayo R, Vidal J, Tormos JM, Fregni F, Navarro X, Pascual-Leone A. Effectiveness of transcranial direct current stimulation and visual illusion on neuropathic pain in spinal cord injury. Brain. 2010 Sep;133(9):2565-77. doi: 10.1093/brain/awq184. Epub 2010 Aug 4.

Fregni F, Boggio PS, Lima MC, Ferreira MJ, Wagner T, Rigonatti SP, Castro AW, Souza DR, Riberto M, Freedman SD, Nitsche MA, Pascual-Leone A. A sham-controlled, phase II trial of transcranial direct current stimulation for the treatment of central pain in traumatic spinal cord injury. Pain. 2006 May;122(1-2):197-209. Epub 2006 Mar 27.

Cheatle MD. Depression, chronic pain, and suicide by overdose: on the edge. Pain Med. 2011 Jun;12 Suppl 2:S43-8. doi: 10.1111/j.1526-4637.2011.01131.x.

Brodie EE, Whyte A, Niven CA. Analgesia through the looking-glass? A randomized controlled trial investigating the effect of viewing a 'virtual' limb upon phantom limb pain, sensation and movement. Eur J Pain. 2007 May;11(4):428-36. Epub 2006 Jul 20.

Moseley GL. Graded motor imagery for pathologic pain: a randomized controlled trial. Neurology. 2006 Dec 26;67(12):2129-34. Epub 2006 Nov 2.

Kooijman CM, Dijkstra PU, Geertzen JH, Elzinga A, van der Schans CP. Phantom pain and phantom sensations in upper limb amputees: an epidemiological study. Pain. 2000 Jul;87(1):33-41.

Whyte AS, Niven CA. Psychological distress in amputees with phantom limb pain. J Pain Symptom Manage. 2001 Nov;22(5):938-46.

Villamar MF, Wivatvongvana P, Patumanond J, Bikson M, Truong DQ, Datta A, Fregni F. Focal modulation of the primary motor cortex in fibromyalgia using 4×1-ring high-definition transcranial direct current stimulation (HD-tDCS): immediate and delayed analgesic effects of cathodal and anodal stimulation. J Pain. 2013 Apr;14(4):371-83. doi: 10.1016/j.jpain.2012.12.007. Epub 2013 Feb 14.

Portilla AS, Bravo GL, Miraval FK, Villamar MF, Schneider JC, Ryan CM, Fregni F. A feasibility study assessing cortical plasticity in chronic neuropathic pain following burn injury. J Burn Care Res. 2013 Jan-Feb;34(1):e48-52. doi: 10.1097/BCR.0b013e3182700675.

Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol. 1988 Dec;56(6):893-7.

Pangman VC, Sloan J, Guse L. An examination of psychometric properties of the mini-mental state examination and the standardized mini-mental state examination: implications for clinical practice. Appl Nurs Res. 2000 Nov;13(4):209-13.

Aldington D, Small C, Edwards D, Ralph J, Woods P, Jagdish S, Moore RA. A survey of post-amputation pains in serving military personnel. J R Army Med Corps. 2014 Mar;160(1):38-41. doi: 10.1136/jramc-2013-000069. Epub 2013 Jul 13.

Rahimi A, Mousavi B, Soroush M, Masumi M, Montazeri A. Pain and health-related quality of life in war veterans with bilateral lower limb amputations. Trauma Mon. 2012 Summer;17(2):282-6. doi: 10.5812/traumamon.5135. Epub 2012 Jul 31.

Sinha R, van den Heuvel WJ, Arokiasamy P, van Dijk JP. Influence of adjustments to amputation and artificial limb on quality of life in patients following lower limb amputation. Int J Rehabil Res. 2014 Mar;37(1):74-9. doi: 10.1097/MRR.0000000000000038.

Ware JE Jr, Gandek B, Kosinski M, Aaronson NK, Apolone G, Brazier J, Bullinger M, Kaasa S, Leplège A, Prieto L, Sullivan M, Thunedborg K. The equivalence of SF-36 summary health scores estimated using standard and country-specific algorithms in 10 countries: results from the IQOLA Project. International Quality of Life Assessment. J Clin Epidemiol. 1998 Nov;51(11):1167-70.

Chan EA, Chung JW, Wong TK, Lien AS, Yang JY. Application of a virtual reality prototype for pain relief of pediatric burn in Taiwan. J Clin Nurs. 2007 Apr;16(4):786-93.

Baudic S, Attal N, Mhalla A, Ciampi de Andrade D, Perrot S, Bouhassira D. Unilateral repetitive transcranial magnetic stimulation of the motor cortex does not affect cognition in patients with fibromyalgia. J Psychiatr Res. 2013 Jan;47(1):72-7. doi: 10.1016/j.jpsychires.2012.09.003. Epub 2012 Oct 15.

Souto G, Borges IC, Goes BT, de Mendonça ME, Gonçalves RG, Garcia LB, Sá KN, Coutinho MR, Galvão-Castro B, Fregni F, Baptista AF. Effects of tDCS-induced motor cortex modulation on pain in HTLV-1: a blind randomized clinical trial. Clin J Pain. 2014 Sep;30(9):809-15. doi: 10.1097/AJP.0000000000000037.

Rossi S, Hallett M, Rossini PM, Pascual-Leone A; Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol. 2009 Dec;120(12):2008-2039. doi: 10.1016/j.clinph.2009.08.016. Epub 2009 Oct 14. Review.

Brunoni AR, Schestatsky P, Lotufo PA, Benseñor IM, Fregni F. Comparison of blinding effectiveness between sham tDCS and placebo sertraline in a 6-week major depression randomized clinical trial. Clin Neurophysiol. 2014 Feb;125(2):298-305. doi: 10.1016/j.clinph.2013.07.020. Epub 2013 Aug 30.

Klein MM, Treister R, Raij T, Pascual-Leone A, Park L, Nurmikko T, Lenz F, Lefaucheur JP, Lang M, Hallett M, Fox M, Cudkowicz M, Costello A, Carr DB, Ayache SS, Oaklander AL. Transcranial magnetic stimulation of the brain: guidelines for pain treatment research. Pain. 2015 Sep;156(9):1601-14. doi: 10.1097/j.pain.0000000000000210. Review.

Williams JA, Pascual-Leone A, Fregni F. Interhemispheric modulation induced by cortical stimulation and motor training. Phys Ther. 2010 Mar;90(3):398-410. doi: 10.2522/ptj.20090075. Epub 2010 Jan 28.

Rossini PM, Micera S, Benvenuto A, Carpaneto J, Cavallo G, Citi L, Cipriani C, Denaro L, Denaro V, Di Pino G, Ferreri F, Guglielmelli E, Hoffmann KP, Raspopovic S, Rigosa J, Rossini L, Tombini M, Dario P. Double nerve intraneural interface implant on a human amputee for robotic hand control. Clin Neurophysiol. 2010 May;121(5):777-83. doi: 10.1016/j.clinph.2010.01.001. Epub 2010 Jan 27.

Kujirai T, Sato M, Rothwell JC, Cohen LG. The effect of transcranial magnetic stimulation on median nerve somatosensory evoked potentials. Electroencephalogr Clin Neurophysiol. 1993 Aug;89(4):227-34.

Reuter M, Fischl B. Avoiding asymmetry-induced bias in longitudinal image processing. Neuroimage. 2011 Jul 1;57(1):19-21. doi: 10.1016/j.neuroimage.2011.02.076. Epub 2011 Mar 3.

Villiger M, Estévez N, Hepp-Reymond MC, Kiper D, Kollias SS, Eng K, Hotz-Boendermaker S. Enhanced activation of motor execution networks using action observation combined with imagination of lower limb movements. PLoS One. 2013 Aug 28;8(8):e72403. doi: 10.1371/journal.pone.0072403. eCollection 2013.

Iseki K, Hanakawa T, Shinozaki J, Nankaku M, Fukuyama H. Neural mechanisms involved in mental imagery and observation of gait. Neuroimage. 2008 Jul 1;41(3):1021-31. doi: 10.1016/j.neuroimage.2008.03.010. Epub 2008 Mar 20.

Bajwa S, Bermpohl F, Rigonatti SP, Pascual-Leone A, Boggio PS, Fregni F. Impaired interhemispheric interactions in patients with major depression. J Nerv Ment Dis. 2008 Sep;196(9):671-7. doi: 10.1097/NMD.0b013e318183f86f.

Schwenkreis P, Witscher K, Janssen F, Dertwinkel R, Zenz M, Malin JP, Tegenthoff M. Changes of cortical excitability in patients with upper limb amputation. Neurosci Lett. 2000 Oct 27;293(2):143-6.

Möller HJ, Müller H, Borison RL, Schooler NR, Chouinard G. A path-analytical approach to differentiate between direct and indirect drug effects on negative symptoms in schizophrenic patients. A re-evaluation of the North American risperidone study. Eur Arch Psychiatry Clin Neurosci. 1995;245(1):45-9.

Boynton GM, Engel SA, Glover GH, Heeger DJ. Linear systems analysis of functional magnetic resonance imaging in human V1. J Neurosci. 1996 Jul 1;16(13):4207-21.

Forman SD, Cohen JD, Fitzgerald M, Eddy WF, Mintun MA, Noll DC. Improved assessment of significant activation in functional magnetic resonance imaging (fMRI): use of a cluster-size threshold. Magn Reson Med. 1995 May;33(5):636-47.

Fregni F, Boggio PS, Nitsche MA, Marcolin MA, Rigonatti SP, Pascual-Leone A. Treatment of major depression with transcranial direct current stimulation. Bipolar Disord. 2006 Apr;8(2):203-4.

Nitsche MA, Schauenburg A, Lang N, Liebetanz D, Exner C, Paulus W, Tergau F. Facilitation of implicit motor learning by weak transcranial direct current stimulation of the primary motor cortex in the human. J Cogn Neurosci. 2003 May 15;15(4):619-26.

Nitsche MA, Fricke K, Henschke U, Schlitterlau A, Liebetanz D, Lang N, Henning S, Tergau F, Paulus W. Pharmacological modulation of cortical excitability shifts induced by transcranial direct current stimulation in humans. J Physiol. 2003 Nov 15;553(Pt 1):293-301. Epub 2003 Aug 29.

Nitsche MA, Liebetanz D, Antal A, Lang N, Tergau F, Paulus W. Modulation of cortical excitability by weak direct current stimulation--technical, safety and functional aspects. Suppl Clin Neurophysiol. 2003;56:255-76. Review.

Priori A. Brain polarization in humans: a reappraisal of an old tool for prolonged non-invasive modulation of brain excitability. Clin Neurophysiol. 2003 Apr;114(4):589-95.

Nitsche MA, Liebetanz D, Lang N, Antal A, Tergau F, Paulus W. Safety criteria for transcranial direct current stimulation (tDCS) in humans. Clin Neurophysiol. 2003 Nov;114(11):2220-2; author reply 2222-3.

Nitsche MA, Cohen LG, Wassermann EM, Priori A, Lang N, Antal A, Paulus W, Hummel F, Boggio PS, Fregni F, Pascual-Leone A. Transcranial direct current stimulation: State of the art 2008. Brain Stimul. 2008 Jul;1(3):206-23. doi: 10.1016/j.brs.2008.06.004. Epub 2008 Jul 1. Review.

Nitsche MA, Jaussi W, Liebetanz D, Lang N, Tergau F, Paulus W. Consolidation of human motor cortical neuroplasticity by D-cycloserine. Neuropsychopharmacology. 2004 Aug;29(8):1573-8.

Schley MT, Wilms P, Toepfner S, Schaller HP, Schmelz M, Konrad CJ, Birbaumer N. Painful and nonpainful phantom and stump sensations in acute traumatic amputees. J Trauma. 2008 Oct;65(4):858-64. doi: 10.1097/TA.0b013e31812eed9e.

Fregni F, Gimenes R, Valle AC, Ferreira MJ, Rocha RR, Natalle L, Bravo R, Rigonatti SP, Freedman SD, Nitsche MA, Pascual-Leone A, Boggio PS. A randomized, sham-controlled, proof of principle study of transcranial direct current stimulation for the treatment of pain in fibromyalgia. Arthritis Rheum. 2006 Dec;54(12):3988-98.

CREUTZFELDT OD, FROMM GH, KAPP H. Influence of transcortical d-c currents on cortical neuronal activity. Exp Neurol. 1962 Jun;5:436-52.

Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Electroencephalogr Clin Neurophysiol. 1998 Jan;108(1):1-16.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Pinto CB, Saleh Velez FG, Bolognini N, Crandell D, Merabet LB, Fregni F. Optimizing Rehabilitation for Phantom Limb Pain Using Mirror Therapy and Transcranial Direct Current Stimulation: A Randomized, Double-Blind Clinical Trial Study Protocol. JMIR Res Protoc. 2016 Jul 6;5(3):e138. doi: 10.2196/resprot.5645.

Layout table for additonal information

Responsible Party:	Felipe Fregni, Principal Investigator, Spaulding Rehabilitation Hospital
ClinicalTrials.gov Identifier:	NCT02487966 History of Changes
Other Study ID Numbers:	2015P001065
First Posted:	July 2, 2015
Last Update Posted:	March 8, 2018
Last Verified:	March 2018

Layout table for additional information

Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Felipe Fregni, Spaulding Rehabilitation Hospital:

tDCS; Mirror Therapy; Phantom Limb Pain; Traumatic amputation

Additional relevant MeSH terms:

Layout table for MeSH terms

Phantom Limb; Amputation, Traumatic; Perceptual Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases	Pain, Postoperative; Postoperative Complications; Pathologic Processes; Signs and Symptoms; Pain; Wounds and Injuries