Phantom limb is a sensation of a missing hand that patients feel after amputation, and phantom limb pain or phantom pain is a pain in a phantom limb. Phantom limb pain occurs in 45%–85% of amputees, and a part of them becomes refractory. Thus, it is needed to fully understand the pathophysiology of phantom limb pain for the development of effective treatments. To elucidate the central mechanisms of phantom limb pain, functional and anatomical changes in the brain has been explored by using non–invasive brain activity recording technique such as electroencephalography (EEG), magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI). In 1995, Flor and colleagues reported that the somatotopic organization of the primary somatosensory cortex had altered in patients with phantom limb pain and the magnitude of this alteration had been associated with the intensity of their phantom limb pain. Based on these results, they proposed a model that alterations in the somatotopic organization of a missing hand are involved in phantom limb pain. Now, this model is known as the maladaptive reorganization model. Over the following 20 years, a variety of supporting evidence has been provided, and this model has been widely accepted. However, Makin and colleagues provided evidence against this model in 2013. They demonstrated that cortical representation of a missing hand had been preserved and activation evoked by phantom limb movement had been related to the severity of phantom limb pain. After that, the maladaptive reorganization model has been revisited, and recent studies have suggested that functional alterations in the primary motor cortex rather than the primary sensory cortex are associated with phantom limb pain. Most recently, by using brain–machine interface technology, Yanagisawa and colleagues demonstrated that the activity of the missing hand area in the sensorimotor cortex is closely related to phantom limb pain. However, detailed neural mechanisms of phantom limb pain remain unclear so far, although many changes in the peripheral and central nervous system after amputation have been found in phantom limb pain patients. Therefore, new models integrating various findings and further studies designed specifically for verifying the new models are needed in the future, to fully understand the pathophysiology of phantom limb and phantom limb pain.

Phantom limb refers to a phenomenon whereby the patient still feels sensation and movements originating in the missing part after amputation. The patient is therefore aware of a part of the body that does not actually exist. The patient may also experience pain at this site, despite the actual body part not existing. Such a condition is referred to as phantom limb pain. Asomatognosia, however, refers to loss of awareness of a part of the body. It is a state in which the patient’s awareness of their body differs from reality. While this condition is normally widely–recognized as occurring after brain injury and right hemisphere damage in particular, it has been found to occur in many cases of neuropathic pain such as complex regional pain syndrome. In such cases, these are termed neglect–like symptoms. Thus, physical modification such as declines in sense of ownership and sense of agency may also be noted in motor disorders. Such cases involve dysfunction of the parietal lobe, which is involved in body representation. Therefore, in recent years, techniques for approaches to brain dysfunction similar to rehabilitation for stroke patients have been developed for cases of phantom limb not associated with brain damage and cases of motor disorders. The effects of such techniques are gradually being demonstrated. In this review, we described distorted body representation mechanisms from the viewpoints of neuro­phenomenology, neuropsychology and neurophysiology, and present the newly developed technique termed neurorehabilitation.

The brain monitors motor outputs and sensory inputs about limb movements and information communication of limb movements between the motor system and the sensory system all along the line. This information communication of limb move­ments is called as the sensorimotor loop. In the normal condition, the sensorimotor loop maintains congruent. Recent advancement of cognitive neuroscience can propose that pathologic pain like as phantom limb pain can emerge and sustains and finally impairs patients’ quality of life when the loop becomes incongruent. We have treated phantom limb pain with the mirror visual feedback (MVF) and recently virtual reality (VR) treatment. The MVF and VR treatments can re–construct movement representations of a phantom limb and then improve phantom limb pain. We have successfully evaluated such movement representations of a phantom limb by assessing the intact upper limb movements on the basis of the bimanual coupling effect, which is physiologically equipped with the brain. The analgesic effect of the VR system is closely linked to the objectively–assessed reemergence of movement representations of a phantom limb.

Accumulating evidence sheds light on the crucial role of a neuroimmune crosstalk in neurogenic inflammation and diverse neurological diseases associated with neuro­inflammation. High mobility group box 1 (HMGB1), one of damage–associated molecular patterns (DAMPs) ⁄ alarmins, is now considered a pro–inflammatory ⁄ pro–nociceptive molecule, and participates in the pathogenesis of neuropathic and inflammatory pain. In this review, we focus on the role of HMGB1 in visceral pain signaling in the bladder, pancreas and colon. In rodent models for cystitis–related bladder pain, macrophage–derived HMGB1 activates the receptor for advanced glycation end–products (RAGE), and induces NF–κB–dependent overexpression of cystathionine–γ–lyase, an H2S–generating enzyme, resulting in excessive excitation of nociceptors through the H2S ⁄ Cav3.2 T–type calcium channel pathway and subsequent bladder pain. The macrophage–derived HMGB1 also appears to play a role in the development of pancreatic pain accompanying acute pancreatitis and of colonic pain in a mouse model for irritable bowel syndrome (IBS). Thus, HMGB1 is considered a key mediator for a neuroimmune crosstalk involved in visceral pain signaling in the bladder, pancreas and colon, and may serve as a novel therapeutic target for treatment of visceral pain in patients with interstitial cystitis ⁄ bladder pain syndrome, acute pancreatitis or IBS.

Microglia are parenchymal tissue–resident macrophage within the central nervous system (CNS) and originate from erythromyeloid precursor cells in the yolk sac. A growing body of evidence suggests that microglia engage in CNS development, homeostasis and diseases, including chronic pain. Peripheral nerve injury and inflammation produce persistent pain hypersensitivity via CNS sensitization, in which activated microglia have critical roles. Activation of microglia occurs at both spinal and supraspinal levels after nerve injury and inflammation; however, their spatial distribution in the intact tissue remains poorly understood. Recently, tissue clearing methods and high–resolution imaging techniques have been greatly advanced, and these techniques will improve our understanding of pain mechanisms. Therefore, we attempted to clarify the three–dimensional localization of microglia in the intact CNS after peripheral inflammation by analyzing the reporter mouse line Iba–1 (iCre/+); CAG–floxed STOP tdTomato with CUBIC (Clear, Unobstructed Brain ⁄ Body Imaging Cocktails and Computational analysis). In this review, we focus on recent advances in understanding of microglial activation under pathological pain conditions.

Subjective movability of phantom hand has been suggested to relate to phantom pain; however, cortical activities that represent the movement of phantom hand is unclear. Here, we recorded magnetoencephalographic signals while phantom limb patients moved their phantom hand and compared with the subjective movability of the phantom hand. During the experiment, the patients with phantom limb pain performed grasping and opening of phantom, and intact hands. Cortical potentials in the sensorimotor cortex contralateral to the tested hand were estimated from the magneto­encephalographic signals, and used to infer movement type. Subjective movabili­ty of the phantom hands were evaluated by duration of time required to perform grasping and opening. During movement of phantom hand, sensorimotor cortex contralateral to the phantom hand was activated similarly to the movement of intact hand. The decoding accuracy of movement type of phantom hand was deteriorated in the patient who was not able to move his phantom hand fast. In conclusion, it was suggested that the decoding accuracy of phantom hand movement represented the subjective movability of the phantom hand.

Multidisciplinary pain management is one of the useful methods for the treatment of chronic musculoskeletal pain, as has been demonstrated in the USA since 1950s. A biopsychosocial model of well–being is a very important concept in the multidisciplinary treatment. This model is a general model or approach stating that biological, psycho­logical, and social factors play a significant role in human functioning in the context of disease or illness. Currently there are few facilities in Japan that administer a multidisciplinary pain treatment, especially an inpatient pain management program.

We are implementing a multidisciplinary pain management program based on biopsychosocial model guided by the IASP recommendations for such a program in Fukushima, Japan. The purpose of this study was to describe our initial efforts in creating a Japanese inpatient pain management program using the biopsychosocial method of self–pain management.

The pain management center was started in April 2015 with a team consisting of ortho­paedic surgeons, psychiatrists, nurses, physical therapists, clinical psychologists, pharmacists, and nutritionists. Our 3–week inpatient pain management program is indicated for patients who find it hard to work or go to school due to chronic musculoskeletal pain, and/or are confined to life at home but want to return to work or school. This program consists of exercise therapy, psychotherapy, and cognitive behavior­al therapy. Using this program, our inpatients with intractable chronic muscu­loskeletal pain were evaluated using brief pain inventory (BPI), pain catastrophizing scale (PCS) (rumination, magnification, and helplessness), pain disability assessment scale (PDAS), hospital anxiety and depression scale (HADS), pain self–efficacy questionnaire (PSEQ), EQ–5D, and physical functions (flexibility, muscle endurance, walking ability, and physical fitness). Statistical analyses were performed using the paired t–test and Wilcoxon matched pairs signed rank sum test with Bonferroni correction after Friedman test. Twenty–one patients (7 male and 14 female; 20–79 years old (Average 52.2 years old)) were analyzed from April 2015 to December 2017. Comparing results before and after the program, the following statistically significant improvement were seen in BPI, PCS (rumination, magnification, helplessness), PDAS, HADS anxiety and depression scale, PSEQ, EQ–5D, 30–sec sit to stand test (muscle endurance), 2 step test (walking ability), and 6–minute walking test (physical fitness). Six (3 male and 3 female; 20–69 years old (Average 45.3 years old) of the twenty–one patients could be analyzed not only before and just after the program, but 3 and 6 months after the program. Statistically significant improvement was seen in PCS (helplessness) (before the program – three months after the program) and PSEQ (before the program – after the program and before the program – three months after the program).

We developed an inpatient pain management program. We may be able to improve the coping mechanisms of our patients for dealing with intractable chronic musculoskeletal pain, and that the program can improve their quality of life and physical function. Our inpatient multidisciplinary pain management program is being expanded to better assist the patients with intractable chronic musculoskeletal pain

Objective: Repetitive transcranial magnetic stimulation over the primary motor cortex has been shown to provide an analgesic effect on refractory neuropathic pain. It is thought that the primary motor cortex may be involved in pain–related cognitive processing. In this study, navigation–guided transcranial magnetic stimulation (TMS) was applied to investigate cortical motor representation and cortical excitability related to pain.

Methods: Subjects were seven patients with refractory neuropathic pain (60.4 ± 13.5 years; stroke, n=5; peripheral nerve injury, n=1; brachial plexus avulsion, n=1). Pain intensity was measured using a visual analog scale, a numeric rating scale and the short–form McGill Pain Questionnaire 2 (SF–MPQ–2). We measured motor representation and cortical excitability assessed by motor evoked potentials with navigation–guided TMS around the primary motor cortex. A resting motor threshold (RMT), and motor map area and extent were measured in the both hemispheres. The relations between pain assessment items and each measurement (the RMT ratio of affected hemisphere (AH) to unaffected hemisphere (UH), AH ⁄ UH area ratio, and AH ⁄ UH extent ratio) were examined.

Results: The RMT of AH trended to be higher than that of UH (p=0.07). The AH ⁄ UH area ratio significantly correlated to SF–MPQ2 (r_s=−0.85, p=0.02). The other analyses showed no significant correlations between pain assessment items and each measurement with TMS.

Conclusions: This study suggested that refractory neuropathic pain might lead to changes of cortical motor representation and cortical excitability.