Preventing Chronification of Phantom Limb Pain Through Mirror Therapy in Conjunction With Transcranial Direct Current Stimulation
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 108
- 试验地点
- 4
- 主要终点
- A 0-100 VAS of mean pain intensity during one week
研究概览
简要总结
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.
详细描述
Approximately 80% of amputees experience PLP, often severe, for years after amputation and most amputees will experience phantom limb sensations, including kinetic, proprioceptive (i.e. feeling of length or volume) and exteroceptive sensations (e.g. touch, pressure, itching). Treatment options for PLP have generally been limited, and there is no clear consensensus on the optimal treatment regimen. In PLP maladaptive plasticity associated with sensory defferentation following an amputation is one of the contributors for excessive pain.
This research project will focus on combined known neuromodulatory interventions of MT and tDCS, applied for the first time at the acute state of PLP in traumatic and non-traumatic amputees, with an aim to prevent maladaptive plasticity associated with PLP chronification and chronicity.
MT and tDCS related literature is based on data collected from patients who already developed PLP for years, before enrollment in the study. The investigators suggest that tDCS and MT applied at the acute stage of PLP will have synergistic effects on PLP intensity and thus avert its chronification. The researchers rationale is based on recent evidence from basic neuroscience on the phantom perception of other non-pain sensory modalities and the neuroscience of chronification of other pain conditions.
The fundamental mechanism for PLP suggests initial changes at the peripheral nervous system, including loss of afferent somatosensory input and exaggerated input from ectopic activity generated in the axotomized nociceptive neurons. Subsequent central changes include thalamic and cortical functional reorganization in the sensorimotor cortex, manifested as maladaptive cortical reorganization: an "invasion" of neighboring areas to the representation of the amputated limb.
Evidence in the literature suggests that the 2 noninvasive neuromodulation techniques- MT and tDCS applied to motor cortex (M1-tDCS)-may interfere with the maladaptive plasticity accompanied PLP and respectively will reduced PLP and negative affects. With MT, the moving, healthy limb reflected in the mirror makes the missing limb appear intact and functioning. The analgesic effect attributed to MT likely results from enhanced coherence between sensory feedback and motor command, counterbalancing the amputation-induced maladaptive neuroplasticity. In chronic PLP, MT conducted over several weeks reversed sensorimotor reorganization and reduced PLP intensity, suggesting a correlation between reorganization and PLP. MT also modulates the activity of the multisensory integration network to resolve the post-amputation perceptual incongruence, and modulates the activity of networks which help integrate the perceptual and motor areas to affect the sense of body ownership and agency. Indeed, an improved sense of agency has been reported after MT. Yet, these studies examined patients with chronic PLP and found mild analgesic effects. The investigators argue that MT applied at the acute PLP stage may interfere with the maladaptive plasticity of the multisensory integration network, and accordingly will improve the sense of agency and ownership over phantom limb, and reduce PLP intensity.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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;
- •Can understand the study's purpose and instructions;
- •Agrees to participate and to provide written informed consent.
排除标准
- •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.
研究组 & 干预措施
Mirror Therapy + real tDCS
Both MT and tDCS neuromodulatory interferences (separately or combined) will consist of 20 sessions, each lasting 20 min, completed during 4 weeks, once daily (excluding weekends). The neuromodulatory interferences will be self-administered by the participants. The first 2 sessions (at the clinic) will include training to familiarize participants (and their primary caregivers) with the procedure and to instruct them on the self-administering techniques that the researchers and others successfully employed. After training, neuromodulatory interferences will be applied either at the clinic (during hospitalization) or at home (after discharge). This approach promotes participants' retention and reduces dropouts, especially when the study constitutes multiple sessions.
干预措施: Trans Direct-Cranial Stimulation (tDCS) (Device)
Mirror Therapy + real tDCS
Both MT and tDCS neuromodulatory interferences (separately or combined) will consist of 20 sessions, each lasting 20 min, completed during 4 weeks, once daily (excluding weekends). The neuromodulatory interferences will be self-administered by the participants. The first 2 sessions (at the clinic) will include training to familiarize participants (and their primary caregivers) with the procedure and to instruct them on the self-administering techniques that the researchers and others successfully employed. After training, neuromodulatory interferences will be applied either at the clinic (during hospitalization) or at home (after discharge). This approach promotes participants' retention and reduces dropouts, especially when the study constitutes multiple sessions.
干预措施: Mirror therapy (Behavioral)
Mirror Therapy + sham tDCS
Both MT and tDCS neuromodulatory interferences (separately or combined) will consist of 20 sessions, each lasting 20 min, completed during 4 weeks, once daily (excluding weekends). 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
干预措施: Trans Direct-Cranial Stimulation (tDCS) (Device)
Mirror Therapy + sham tDCS
Both MT and tDCS neuromodulatory interferences (separately or combined) will consist of 20 sessions, each lasting 20 min, completed during 4 weeks, once daily (excluding weekends). 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
干预措施: Mirror therapy (Behavioral)
No-intervention, natural-course group
The participants will receive the regular treatment regimen at the rehabilitation center, including physical-therapy and pharmacological treatment, without intervention of Mirror-therapy and tDCS.
结局指标
主要结局
A 0-100 VAS of mean pain intensity during one week
时间窗: Pain will be compared between baseline and 4 weeks after the end of the 4 weeks intervention (meaning, comparing baseline to timepoint number 3, which is exactly 8 weeks from the end of the baseline 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.
次要结局
- Sense of ownership and agency over phantom limb(Sense of ownership and agency over phantom limb will be compared between baseline and 4 weeks after the end of the 4 weeks intervention (meaning, comparing baseline to timepoint number 3, which is exactly 8 weeks from the end of the baseline week))
- The Hospital Anxiety and Depression Scale (HADS)(Anxiety and Depression will be compared between baseline and 4 weeks after the end of the 4 weeks intervention (meaning, comparing baseline to timepoint number 3, which is exactly 8 weeks from the end of the baseline week))
- The Short Form McGill Pain Questionnaire(The Affective qualities of pain will be compared between baseline and 4 weeks after the end of the 4 weeks intervention (meaning, comparing baseline to timepoint number 3, which is exactly 8 weeks from the end of the baseline week))
- The Conditioned Pain Modulation (CPM)(The CPM score will be compared between baseline and 4 weeks after the end of the 4 weeks intervention (meaning, comparing baseline to timepoint number 3, which is exactly 8 weeks from the end of the baseline week))
- Stump pain(Stump pain will be compared between baseline and 4 weeks after the end of the 4 weeks intervention (meaning, comparing baseline to timepoint number 3, which is exactly 8 weeks from the end of the baseline week))
- Phantom sensations(Phantom sensations be compared between baseline and 4 weeks after the end of the 4 weeks intervention (meaning, comparing baseline to timepoint number 3, which is exactly 8 weeks from the end of the baseline week))
- Telescoping(Telescoping be compared between baseline and 4 weeks after the end of the 4 weeks intervention (meaning, comparing baseline to timepoint number 3, which is exactly 8 weeks from the end of the baseline week))
- Sense of ownership and agency over phantom limb(Sense of ownership and agency over phantom limb will be compared between baseline and 4 weeks after the end of the 4 weeks intervention (meaning, comparing baseline to timepoint number 3, which is exactly 8 weeks from the end of the baseline week))
- The Short Form McGill Pain Questionnaire(The Affective qualities of pain will be compared between baseline and 4 weeks after the end of the 4 weeks intervention (meaning, comparing baseline to timepoint number 3, which is exactly 8 weeks from the end of the baseline week))
- The Hospital Anxiety and Depression Scale (HADS)(Anxiety and Depression will be compared between baseline and 4 weeks after the end of the 4 weeks intervention (meaning, comparing baseline to timepoint number 3, which is exactly 8 weeks from the end of the baseline week))
- Phantom sensations(Phantom sensations be compared between baseline and 4 weeks after the end of the 4 weeks intervention (meaning, comparing baseline to timepoint number 3, which is exactly 8 weeks from the end of the baseline week))
- The Conditioned Pain Modulation (CPM)(The CPM score will be compared between baseline and 4 weeks after the end of the 4 weeks intervention (meaning, comparing baseline to timepoint number 3, which is exactly 8 weeks from the end of the baseline week))
- Frequency of PLP paroxysms(Frequency of PLP paroxysms will be compared between baseline and 4 weeks after the end of the 4 weeks intervention (meaning, comparing baseline to timepoint number 3, which is exactly 8 weeks from the end of the baseline week))
- Stump pain(Stump pain will be compared between baseline and 4 weeks after the end of the 4 weeks intervention (meaning, comparing baseline to timepoint number 3, which is exactly 8 weeks from the end of the baseline week))
- Telescoping(Telescoping be compared between baseline and 4 weeks after the end of the 4 weeks intervention (meaning, comparing baseline to timepoint number 3, which is exactly 8 weeks from the end of the baseline week))