Background: Most amputees experience phantom limb pain (PLP), for years after amputation. Virtually all PLP research to date has focused on the mechanisms of chronic PLP, ignoring the mechanisms of chronification. This research project will focus on combined neuromodulatory interventions of mirror therapy (MT) and trans direct-cranial stimulation (tDCS), applied for the first time at the acute state of PLP, with an aim to prevent its chronification and chronicity. In PLP, maladaptive plasticity associated with sensory deafferentation following an amputation is one of the contributors for excessive pain.
MT is a well-accepted yet limited option, which is thought to counterbalance abnormal plasticity. tDCS is an emerging approach believed to affect the membrane potential and activity threshold of cortical neurons. tDCS analgesic effectiveness, however, is mild and short, rendering it a noneffective stand-alone treatment. The researchers' objectives are to investigate whether the combined therapy of MT and tDCS will prevent chronic PLP and improve its related clinical characteristics. In addition, the researchers will investigate the behavioral manifestations effects of the combined treatment. The investigators expect that the combined treatment applied at the acute stage of PLP will have synergistic effects on PLP intensity and thus avert its chronification. In addition, it will reduce phantom sensations, and negative affect, and will improve the sense of body ownership and agency and endogenous inhibition efficiency.
Research design: This randomized-controlled double-blinded study will be held at Israel's 3 largest rehabilitation centers. The study consists of 3 randomized patient arms (36 in each): (1) no-intervention, natural-course group; (2) MT + sham tDCS; (3) MT + real tDCS.
MT and tDCS neuromodulatory interferences will be self-administered and consist of 20 sessions, completed during 4 weeks. The researchers outcome measures include: primary outcome: pain intensity, network-related behavioral markers, and amputation-related clinical characteristics. The data gathered will be collected at 5 timepoints.
Research novelty and innovation: The researchers proposed model will provide insights on the prevention of PLP and, potentially, other neurological pathologies involving the dysfunction of sensory systems and integration and body perception.
Adults (age ≥18);
Amputation of a single limb ≤12 weeks ago; during this period of time, 80% of amputees develop PLP. Both upper and lower limb amputees are included to increase feasibility;
Acute PLP stage (2 weeks since first report), with intensity ≥3 on a 0-10 VAS;
No change in medication in past week, excluding pro re nata analgesics;
Stump wound not healed;
Other psychological, psychiatric, or neurological conditions;
Contraindications for tDCS or magnetic resonance imaging (MRI) (MRI data will not be analyzed in the proposed PhD project), including previous seizure, loss of consciousness due to head injury, metal in the head, implanted devices, claustrophobia, a skin condition or an unhealed wound on the scalp, and possibility of being pregnant;
Inability to provide informed consent or understand or carry out the experiment.
Parallel
Trans Direct-Cranial Stimulation (tDCS)
DeviceThe tDCS electrodes will be inserted into 5×7 cm (35 cm2) sponges soaked with saline (0.9 M) and placed as follows: anode over the M1 contralateral to the amputated limb (adjusted based on lower/upper amputation), and cathode over the forehead, contralateral to the anode (ipsilateral to amputated limb). Total stimulation duration will be 20 min, with a rise and decline time of 30 sec and stimulus intensity of 1.5 mA for the real tDCS real. The intensity of 1.5 mA is in the midrange of recommended intensities (1-2 mA) and supports successful blinding. The sham tDCS will be identical to the real tDCS, except no current will be applied. However, as recommended, during the first and last 30 sec, the current will be ramped up to 1.5 mA and immediately back to 0 to induce scalp sensations similar to those in real tDCS, further supporting blinding. The Mini-CT tDCS Stimulator device has been developed for home use and allows double-blind administration.
Mirror therapy
BehavioralParticipants will be seated with a portable mirror between their limbs so that the unaffected limb is reflected in the mirror. The participants will focus their attention on the reflection in the mirror and perform the following movements: plantarflexion and dorsiflexion and inversion and eversion of the foot, flexion and extension of the wrist and ulnar and radial deviation, for lower and upper limp amputates, respectively. The participants will continue performing the 2 sets of movements for 20 minutes (with short intermissions if needed)
A 0-100 VAS of mean pain intensity during one week
completed during 7 days, will be used to capture the weekly average of pain intensity (0 = no pain to 100 = the worst imaginable pain, via pain diary). This data will be used either in its raw, continuous form or as a transformed dichotomous variable, yes/no chronic PLP. A cutoff value of PLP intensity ≤20/100 will be used, because from a clinical perspective, pain intensity ≤20 is considered low and will seldom prompt a request for analgesic treatment.
Sense of ownership and agency over phantom limb
Sense of ownership and agency over phantom limb will be a behavioral marker for function of the multisensory integration network. It will be evaluated using a self-report questionnaire with demonstrated sensitivity to detect changes after MT. Six of the questionnaire's 8 items (on a 5-point Likert scale) will be used to assess sense of ownership and agency of upper limb and will be adjusted for the lower limb. Mean scores of 3 questions will evaluate the sense of ownership, and 3 others, the sense of agency, as recommended.
The Hospital Anxiety and Depression Scale (HADS)
The researchers' marker for function of the fronto-striatal-amygdala circuit, will be assessed via the Hospital Anxiety and Depression Scale (HADS), a self-report 14-item questionnaire focusing on nonphysical symptoms, which measures anxiety and depression, both demonstrated associations with changes in fronto-striatal connectivity. The HADS uses a 0-21 scoring scale, with each item rated on a 4-point Likert scale (0-3). A score of 0-7 is considered normal, 8-10 indicates a mild disorder, 11-14 suggests a moderate disorder, and 15-21 points to a severe disorder.
The Short Form McGill Pain Questionnaire
The researchers' marker for function of the fronto-striatal-amygdala circuit, will also be assessed via the Short Form McGill Pain Questionnaire, which assesses various affective qualities of pain and has demonstrated validity in neuropathic populations. Four affective descriptors rated on a 0-10 numerical rating scale will be summarized.
The Conditioned Pain Modulation (CPM)
Endogenous pain inhibition will be a psychophysical marker for function of the fronto-PAG circuit. It will be evaluated by the conditioned pain modulation (CPM) paradigm, based on the systemic pain-inhibits-pain phenomenon. The conditioning stimulus will be administrated by immersing the palm in a cold-water bath (14°C). The test stimulus applied on the contralateral (to the conditioning stimulus) lower leg will include individually calibrated heat pain stimulus applied for 20 sec, while averaging pain intensity scores on a VAS Scale (0=no pain, 100= the worst imaginable pain) reported at time 0, 10, and 20 sec. CPM is calculated by subtracting pain scores of the test stimulus given alone from those given with the conditioning stimulus, as recommended.
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University of Haifa
Lead sponsor
Loewenstein Hospital
Collaborator
Reuth Rehabilitation Hospital
Collaborator
Sheba Medical Center
Collaborator
