Unveiling the phantom: What neuroimaging has taught us about phantom limb pain.

Phantom limb pain (PLP) is a complicated condition with diverse clinical challenges. It consists of pain perception of a previously amputated limb. The exact pain mechanism is disputed and includes mechanisms involving cerebral, peripheral, and spinal origins. Such controversy limits researchers' and clinicians' ability to develop consistent therapeutics or management. Neuroimaging is an essential tool that can address this problem. This review explores diffusion tensor imaging, functional magnetic resonance imaging, electroencephalography, and magnetoencephalography in the context of PLP. These imaging modalities have distinct mechanisms, implications, applications, and limitations. Diffusion tensor imaging can outline structural changes and has surgical applications. Functional magnetic resonance imaging captures functional changes with spatial resolution and has therapeutic applications. Electroencephalography and magnetoencephalography can identify functional changes with a strong temporal resolution. Each imaging technique provides a unique perspective and they can be used in concert to reveal the true nature of PLP. Furthermore, researchers can utilize the respective strengths of each neuroimaging technique to support the development of innovative therapies. PLP exemplifies how neuroimaging and clinical management are intricately connected. This review can assist clinicians and researchers seeking a foundation for applications and understanding the limitations of neuroimaging techniques in the context of PLP.

29Si Isotope-Enriched Silicon Nanoparticles for an Efficient Hyperpolarized Magnetic Resonance Imaging Probe.

Silicon particles have garnered attention as promising biomedical probes for hyperpolarized 29Si magnetic resonance imaging and spectroscopy. However, due to the limited levels of hyperpolarization for nanosized silicon particles, microscale silicon particles have primarily been the focus of dynamic nuclear polarization (DNP) applications, including in vivo magnetic resonance imaging (MRI). To address these current challenges, we developed a facile synthetic method for partially 29Si-enriched porous silicon nanoparticles (NPs) (160 nm) and examined their usability in hyperpolarized 29Si MRI agents with enhanced signals in spectroscopy and imaging. Hyperpolarization characteristics, such as the build-up constant, the depolarization time (T1), and the overall enhancement of the 29Si-enriched silicon NPs (10 and 15%), were thoroughly investigated and compared with those of a naturally abundant NP (4.7%). During optimal DNP conditions, the 15% enriched silicon NPs showed more than 16-fold higher enhancements─far beyond the enrichment ratio─than the naturally abundant sample, further improving the signal-to-noise ratio in in vivo 29Si MRI. The 29Si-enriched porous silicon NPs used in this work are potentially capable to serve as drug-delivery vehicles in addition to hyperpolarized 29Si in vivo, further enabling their potential future applicability as a theragnostic platform.

Radicular Pain After Hip Disarticulation: A Clinical Vignette.

ABSTRACT: A 36-yr-old man with a history of industrial accident causing traumatic left hip disarticulation, pubic symphysis, and right sacroiliac joint fractures presented with a 3-yr history of left-sided lower back pain radiating down the amputated limb. Computed tomography lumbar spine showed osteophytes surrounding the sacroiliac joint bilaterally with reduced left L4-L5 foraminal space. A fluoroscopically guided left sacroiliac steroid injection led to mild improvement in low back pain. Magnetic resonance imaging of the lumbar spine without contrast showed transitional type L5 vertebral body with left-sided flowing osteophytes abutting the extraforaminal L4 and L5 nerves. Ultimately, multilevel left fluoroscopically guided transforaminal epidural steroid injection at L4-L5 and L5-S1 significantly improved symptoms. Although phantom radiculopathy is a rare entity, clinical suspicion of degenerative spine disease or other pathology contributing to nerve impingement in patients with amputations should remain; this unique case discusses bony osteophyte complex as the cause for phantom radiculopathy instead of previously described disc herniation. Magnetic resonance imaging remains a key tool in delineating causes of low back pain among patients with lower limb amputations.

Altered Cortical Reorganization and Brain Functional Connectivity in Phantom Limb Pain: A Functional MRI Study.

OBJECTIVES: Functional neuroimaging studies have shown that amputees have altered cortical reorganization and functional connectivity (FC). This study aimed to investigate whether patients with phantom limb pain (PLP) and PLP-free lower limb amputees exhibit changes in corresponding primary cortical motor area/somatosensory cortex (M1/S1) cortical reorganization and supplementary motor area (SMA) network FC. The association between functional magnetic resonance imaging (fMRI) changes and clinical parameters is also explored. METHODS: A total of 10 PLP patients were matched with 10 PLP-free amputees and 10 healthy controls (HCs). Before undergoing fMRI, all participants completed questionnaires evaluating pain, anxiety, depression, and health-related quality of life. Task-related activation and regions of interest (ROI)-wise connectivity analysis were applied to differentiate the brain regions of amputees from those of HCs. Linear correlation analysis was used to evaluate the correlation between altered FC and clinical manifestations. RESULTS: As compared with HCs, PLP patients showed increased cortical activation in M1/S1 when moving the intact foot, imagining phantom big toe movement, or having the corresponding thumb stimulated. The increased FC in the SMA network included the SMA-caudate nucleus, SMA-bilateral insula, and SMA-anterior cingulate cortex. Furthermore, results of the linear correlation analysis demonstrated that this increased FC was positively correlated with VAS scores, negatively correlated with Medical Outcomes Study 36-item Short-Form (SF-36) scores, and not correlated with anxiety or depression scores. CONCLUSIONS: Phantom limb pain in lower limb amputees is associated with M1/S1 cortical reorganization and altered SMA network FC in different areas of the brain, which could help to support our understanding of the central mechanism of PLP.

Structural and functional motor cortex asymmetry in unilateral lower limb amputation with phantom limb pain.

OBJECTIVE: The role of motor cortex reorganization in the development and maintenance of phantom limb pain (PLP) is still unclear. This study aims to evaluate neurophysiological and structural motor cortex asymmetry in patients with PLP and its relationship with pain intensity. METHODS: Cross-sectional analysis of an ongoing randomized-controlled trial. We evaluated the motor cortex asymmetry through two techniques: i) changes in cortical excitability indexed by transcranial magnetic stimulation (motor evoked potential, paired-pulse paradigms and cortical mapping), and ii) voxel-wise grey matter asymmetry analysis by brain magnetic resonance imaging. RESULTS: We included 62 unilateral traumatic lower limb amputees with a mean PLP of 5.9 (SD = 1.79). We found, in the affected hemisphere, an anterior shift of the hand area center of gravity (23 mm, 95% CI 6 to 38, p = 0.005) and a disorganized and widespread representation. Regarding voxel-wise grey matter asymmetry analysis, data from 21 participants show a loss of grey matter volume in the motor area of the affected hemisphere. This asymmetry seems negatively associated with time since amputation. For TMS data, only the ICF ratio is negatively correlated with PLP intensity (r = -0.25, p = 0.04). CONCLUSION: There is an asymmetrical reorganization of the motor cortex in patients with PLP, characterized by a disorganized, widespread, and shifted hand cortical representation and a loss in grey matter volume in the affected hemisphere. This reorganization seems to reduce across time since amputation. However, it is not associated with pain intensity. SIGNIFICANCE: These findings are significant to understand the role of the motor cortex reorganization in patients with PLP, showing that the pain intensity may be related with other neurophysiological factors, not just cortical reorganization.

Cortical plasticity in phantom limb pain: A fMRI study on the neural correlates of behavioral clinical manifestations.

The neural mechanism of phantom limb pain (PLP) is related to the intense brain reorganization process implicating plasticity after deafferentation mostly in sensorimotor system. There is a limited understanding of the association between the sensorimotor system and PLP. We used a novel task-based functional magnetic resonance imaging (fMRI) approach to (1) assess neural activation within a-priori selected regions-of-interested (motor cortex [M1], somatosensory cortex [S1], and visual cortex [V1]), (2) quantify the cortical representation shift in the affected M1, and (3) correlate these changes with baseline clinical characteristics. In a sample of 18 participants, we found a significantly increased activity in M1 and S1 as well as a shift in motor cortex representation that was not related to PLP intensity. In an exploratory analyses (not corrected for multiple comparisons), they were directly correlated with time since amputation; and there was an association between increased activity in M1 with a lack of itching sensation and V1 activation was negatively correlated with PLP. Longer periods of amputation lead to compensatory changes in sensory-motor areas; and itching seems to be a protective marker for less signal changes. We confirmed that PLP intensity is not associated with signal changes in M1 and S1 but in V1.

Assessment of cortical reorganization and preserved function in phantom limb pain: a methodological perspective.

Phantom limb pain (PLP) has been associated with reorganization in primary somatosensory cortex (S1) and preserved S1 function. Here we examined if methodological differences in the assessment of cortical representations might explain these findings. We used functional magnetic resonance imaging during a virtual reality movement task, analogous to the classical mirror box task, in twenty amputees with and without PLP and twenty matched healthy controls. We assessed the relationship between task-related activation maxima and PLP intensity in S1 and motor cortex (M1) in individually-defined or group-conjoint regions of interest (ROI) (overlap of task-related activation between the groups). We also measured cortical distances between both locations and correlated them with PLP intensity. Amputees compared to controls showed significantly increased activation in M1, S1 and S1M1 unrelated to PLP. Neural activity in M1 was positively related to PLP intensity in amputees with PLP when a group-conjoint ROI was chosen. The location of activation maxima differed between groups in S1 and M1. Cortical distance measures were unrelated to PLP. These findings suggest that sensory and motor maps differentially relate to PLP and that methodological differences might explain discrepant findings in the literature.

Phantom radiculopathy: a rare postoperative phenomenon.

Limb amputations are carried out for a number of reasons, which include trauma, vascular disorders, infection, oncology and congenital abnormalities. These patients can develop multiple complications postoperatively with phantom limb pain being a well-recognised issue. That being said, phantom radiculopathy is far less encountered and can therefore be easily overlooked. There are limited cases described in literature and as a result pathophysiology is poorly understood. In this report, we present a patient who had developed phantom radiculopathy decades after his left above knee amputation surgery, which was performed after a road traffic accident. However, we were successfully able to treat the patient with foraminal epidural corticosteroid injection.

Brain (re)organisation following amputation: Implications for phantom limb pain.

Following arm amputation the region that represented the missing hand in primary somatosensory cortex (S1) becomes deprived of its primary input, resulting in changed boundaries of the S1 body map. This remapping process has been termed 'reorganisation' and has been attributed to multiple mechanisms, including increased expression of previously masked inputs. In a maladaptive plasticity model, such reorganisation has been associated with phantom limb pain (PLP). Brain activity associated with phantom hand movements is also correlated with PLP, suggesting that preserved limb functional representation may serve as a complementary process. Here we review some of the most recent evidence for the potential drivers and consequences of brain (re)organisation following amputation, based on human neuroimaging. We emphasise other perceptual and behavioural factors consequential to arm amputation, such as non-painful phantom sensations, perceived limb ownership, intact hand compensatory behaviour or prosthesis use, which have also been related to both cortical changes and PLP. We also discuss new findings based on interventions designed to alter the brain representation of the phantom limb, including augmented/virtual reality applications and brain computer interfaces. These studies point to a close interaction of sensory changes and alterations in brain regions involved in body representation, pain processing and motor control. Finally, we review recent evidence based on methodological advances such as high field neuroimaging and multivariate techniques that provide new opportunities to interrogate somatosensory representations in the missing hand cortical territory. Collectively, this research highlights the need to consider potential contributions of additional brain mechanisms, beyond S1 remapping, and the dynamic interplay of contextual factors with brain changes for understanding and alleviating PLP.

Alterations in Brain Structural Connectivity After Unilateral Upper-Limb Amputation.

Previous studies have indicated that amputation induces reorganization of functional brain network. However, the influence of amputation on structural brain network remains unclear. In this study, using diffusion tensor imaging (DTI), we aimed to investigate the alterations in fractional anisotropy (FA) network after unilateral upper-limb amputation. We acquired DTI from twenty-two upper-limb amputees (15 dominant-side and 7 nondominant-side amputees) as well as fifteen healthy controls. Using DTI tractography and graph theoretical approaches, we examined the topological changes in FA network of amputees. Compared with healthy controls, dominant-side amputees showed reduced global mean strength, increased characteristic path length, and decreased nodal strength in the contralateral sensorimotor system and visual areas. In particular, the nodal strength of the contralateral postcentral gyrus was negatively correlated with residual limb usage, representing a use-dependent reorganization. In addition, the nodal strength of the contralateral middle temporal gyrus was positively correlated with the magnitude of phantom limb sensation. Our results suggested a degeneration of FA network after dominant-side upper-limb amputation.

Real-time Video Projection in an MRI for Characterization of Neural Correlates Associated with Mirror Therapy for Phantom Limb Pain.

Mirror therapy (MT) has been proposed as an effective rehabilitative strategy to alleviate pain symptoms in amputees with phantom limb pain (PLP). However, establishing the neural correlates associated with MT therapy have been challenging given that it is difficult to administer the therapy effectively within a magnetic resonance imaging (MRI) scanner environment. To characterize the functional organization of cortical regions associated with this rehabilitative strategy, we have developed a combined behavioral and functional neuroimaging protocol that can be applied in participants with a leg amputation. This novel approach allows participants to undergo MT within the MRI scanner environment by viewing real-time video images captured by a camera. The images are viewed by the participant through a system of mirrors and a monitor that the participant views while lying on the scanner bed. In this manner, functional changes in cortical areas of interest (e.g., sensorimotor cortex) can be characterized in response to the direct application of MT.

Lower limb amputees undergo long-distance plasticity in sensorimotor functional connectivity.

Amputation in adults is associated with an extensive remapping of cortical topography in primary and secondary sensorimotor areas. Here, we used tactile residual limb stimulation and 3T functional magnetic resonance imaging in humans to investigate functional connectivity changes in the sensorimotor network of patients with long-term lower limb traumatic amputations with phantom sensation, but without pain. We found a pronounced reduction of inter-hemispheric functional connectivity between homologous sensorimotor cortical regions in amputees, including the primary (S1) and secondary (S2) somatosensory areas, and primary (M1) and secondary (M2) motor areas. We additionally observed an intra-hemispheric increased functional connectivity between primary and secondary somatosensory regions, and between the primary and premotor areas, contralateral to amputation. These functional connectivity changes in specialized small-scale sensory-motor networks improve our understanding of the functional impact of lower limb amputation in the brain. Our findings in a selective group of patients with phantom limb sensations, but without pain suggest that disinhibition of neural inputs following traumatic limb amputation disrupts sensorimotor topology, unbalancing functional brain network organization. These findings step up the description of brain plasticity related with phantom sensations by showing that pain is not critical for sensorimotor network changes after peripheral injury.

Neural basis of induced phantom limb pain relief.

OBJECTIVE: Phantom limb pain (PLP) is notoriously difficult to treat, partly due to an incomplete understanding of PLP-related disease mechanisms. Noninvasive brain stimulation (NIBS) is used to modulate plasticity in various neuropathological diseases, including chronic pain. Although NIBS can alleviate neuropathic pain (including PLP), both disease and treatment mechanisms remain tenuous. Insight into the mechanisms underlying both PLP and NIBS-induced PLP relief is needed for future implementation of such treatment and generalization to related conditions. METHODS: We used a within-participants, double-blind, and sham-controlled design to alleviate PLP via task-concurrent NIBS over the primary sensorimotor missing hand cortex (S1/M1). To specifically influence missing hand signal processing, amputees performed phantom hand movements during anodal transcranial direct current stimulation. Brain activity was monitored using neuroimaging during and after NIBS. PLP ratings were obtained throughout the week after stimulation. RESULTS: A single session of intervention NIBS significantly relieved PLP, with effects lasting at least 1 week. PLP relief associated with reduced activity in the S1/M1 missing hand cortex after stimulation. Critically, PLP relief and reduced S1/M1 activity correlated with preceding activity changes during stimulation in the mid- and posterior insula and secondary somatosensory cortex (S2). INTERPRETATION: The observed correlation between PLP relief and decreased S1/M1 activity confirms our previous findings linking PLP with increased S1/M1 activity. Our results further highlight the driving role of the mid- and posterior insula, as well as S2, in modulating PLP. Lastly, our novel PLP intervention using task-concurrent NIBS opens new avenues for developing treatment for PLP and related pain conditions. ANN NEUROL 2019;85:59-73.

Referred cramping phantom hand pain elicited in the face and eliminated by peripheral nerve block.

Phantom limb pain is a restricting condition for a substantial number of amputees with quite different characteristics of pain. Here, we report on a forearm amputee with constant phantom pain in the hand, in whom we could regularly elicit the rare phenomenon of referred cramping phantom pain by touching the face. To clarify the underlying mechanisms, we followed the cramp during the course of an axillary blockade of the brachial plexus. During the blockade, both phantom pain and the referred cramp were abolished, while a referred sensation of "being touched at the phantom" persisted. Furthermore, to identify the cortical substrate, we elicited the cramp during functional magnetic imaging. Imaging revealed that referred cramping phantom limb pain was associated with brain activation of the hand representation in the primary sensorimotor cortex. The results support the hypothesis that referred cramping phantom limb pain in this case is associated with a substantial brain activation in the hand area of the deafferented sensorimotor cortex. However, this alone is not sufficient to elicit referred cramping phantom limb pain. Peripheral inputs, both, from the arm nerves affected by the amputation and from the skin in the face at which the referred cramp is evoked, are a precondition for referred cramping phantom limb pain to occur, at least in this case.

Retrieving autobiographical experience of painful events in a phantom limb: brain concomitants in a case report.

We report the case of a patient who had an important experience with painful events, allowing the investigation of brain concomitants to painful (P) memories in fMRI. The patient had to recall P events that were contrasted with non-painful (NP) memories. Painful memories of the right lower limb activated the left paracentral lobule,fronto-insular operculum and superior parietal cortex. Additionally, whilst the recall of non-painful events activated the hippocampus, the recall of painful events did not enhance the hippocampal signal to significant levels. These suggest that brain activations differ for the autobiographical recall of painful and non-painful memories.

Resting-state fMR evidence of network reorganization induced by navigated transcranial magnetic repetitive stimulation in phantom limb pain.

Objectives Repetitive transcranial magnetic stimulation (rTMS) is a promising tool for treatment of chronic pain. We describe the use of navigated rTMS to treat a patient affected by phantom limb pain (PLP) and to modulate brain functional connectivity. We reviewed the literature on the use of rTMS as a tool for relieving central pain by promoting brain plasticity. Methods A 69-year-old patient came to our observation blaming severe pain (Visual Analog scale, VAS, score 9) to a phantom right lower limb. We mapped left primary motor area (PMA) by navigated TMS and assessed connectivity with resting-state functional MR (rsfMR). The patient underwent 30-days navigated rTMS treatment. We applied low-frequency stimulation (1 Hz) over the primary somatosensory area (PSA) and high-frequency stimulation (10 Hz) over PMA and dorsolateral prefrontal cortex (DLPFC) of the left hemisphere. Results This strategy allowed a pain relief with a reduction of 5 points of the VAS score after 1 month. Post-treatment rsfMR showed increased connectivity, mainly in the sensory-motor network and the unaffected hemisphere (P < 0.05). Discussion This report represents a proof-of-concept that navigated rTMS can be effectively used to stimulate selected brain areas in PLP patients in order to promote brain connectivity, and that rsfMR is a useful tool able to analyze functional results. In the literature, we found data supporting the assumption that, in patients affected by PLP, a reduced connectivity in interhemispherical and sensory-motor network plays a role in generating pain and that rTMS has the potential to restore impaired connectivity.

Ultrasound Findings of Young and Traumatic Amputees With Lower Extremity Residual Limb Pain in Turkey.

OBJECTIVE: The current study was designed to document clinical and ultrasound (US) findings of patients with residual limb pain (RLP) after amputation and to investigate the relationship between these findings. MATERIALS AND METHODS: A chart review was performed to identify demographic and clinical data including the age (current and at the time of injury), time since amputation, gender, reason for amputation, affected limb number, side and level of limb loss, and ultrasonographic findings of young and traumatic amputees with RLP. RESULTS: The study included a total of 147 patients. Inflammation and neuroma were the leading pathologies in 20-29 years and 30-39 years age groups, respectively. Inflammation/edema were detected significantly more in patients with <1 year since amputation (P = 0.001). Neuroma was found at a significantly high rate in patients at 1-5 years (P = 0.029) and infection/abscess was more common in patients at >5 years since amputation (P = 0.051). The percentage of neuromas in below-the-knee amputees was significantly higher than in non-below-the-knee amputees (45.8% vs. 28.6%). Neuroma formation was detected in 50% of the patients with land mine-related amputation and at 27% in patients with amputation secondary to other traumatic reasons. Regression analysis showed below-the-knee-level amputation to be an associated factor for US abnormality. CONCLUSION: The leading US findings were inflammation/edema, neuroma, and infection/abscess in traumatic amputees with RLP. The US findings might be different in patients according to the time since amputation. Patient with land mine-related amputations may have different US findings.

Percutaneous Image-Guided Cryoablation for the Treatment of Phantom Limb Pain in Amputees: A Pilot Study.

PURPOSE: To prospectively evaluate percutaneous image-guided nerve cryoablation for treatment of refractory phantom limb pain (PLP) in a pilot cohort for purposes of deriving parameters to design a larger, randomized, parallel-armed, controlled trial. MATERIALS AND METHODS: From January 2015 to January 2016, 21 patients with refractory PLP underwent image-guided percutaneous cryoneurolysis procedures. Visual analog scale scores were documented at baseline and 7, 45, and 180 days after the procedure. Responses to a modified Roland Morris Disability Questionnaire were documented at baseline and 7 and 45 days after the procedure. RESULTS: Technical success rate of the procedures was 100%. There were 6 (29%) minor procedure-related complications. Disability scores decreased from a baseline mean of 11.3 to 3.3 at 45-day follow-up (95% confidence interval 5.8, 10.3; P < .0001). Pain intensity scores decreased from a baseline mean of 6.2 to 2.0 at long-term follow-up (95% confidence interval 2.8, 5.6; P < .0001). CONCLUSIONS: Image-guided percutaneous nerve cryoablation is feasible and safe and may represent a new efficacious therapeutic option for patients with phantom pains related to limb loss.

An MR safe algometer to study phantom and residual limb pain.

Researchers are interested in understanding phantom limb pain (PLP) and residual limb pain (RLP) in amputees and the neural mechanisms leading to it. fMRI can provide information on the intensity and the location of activated centers in the brain that control PLP and RLP. MR safe algometers are important to this work. This paper described the new pneumatically actuated algometer and the evaluation methods for MR safety. Our results indicate that the custom device is an improved MR safe algometer capable of autonomously producing reproducible pressure profiles.