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There is no clear understanding of the mechanisms causing persistent pain in patients with whiplash-associated disorder (WAD). The aim of this systematic review was to assess the evidence for nerve pathology and neuropathic pain in patients with WAD. EMBASE, PubMed, CINAHL (EBSCO), and MEDLINE were searched from inception to September 1, 2020. Study quality and risk of bias were assessed using the Newcastle-Ottawa Quality Assessment Scales. Fifty-four studies reporting on 390,644 patients and 918 controls were included. Clinical questionnaires suggested symptoms of predominant neuropathic characteristic in 34% of patients (range 25%-75%). The mean prevalence of nerve pathology detected with neurological examination was 13% (0%-100%) and 32% (10%-100%) with electrodiagnostic testing. Patients independent of WAD severity (Quebec Task Force grades I-IV) demonstrated significantly impaired sensory detection thresholds of the index finger compared with controls, including mechanical (SMD 0.65 [0.30; 1.00] P0.005), current (SMD 0.82 [0.25; 1.39] P = 0.0165), cold (SMD -0.43 [-0.73; -0.13] P = 0.0204), and warm detection (SMD 0.84 [0.25; 1.42] P = 0.0200). Patients with WAD had significantly heightened nerve mechanosensitivity compared with controls on median nerve pressure pain thresholds (SMD -1.10 [-1.50; -0.70], P0.0001) and neurodynamic tests (SMD 1.68 [0.92; 2.44], P = 0.0004). Similar sensory dysfunction and nerve mechanosensitivity was seen in WAD grade II, which contradicts its traditional definition of absent nerve involvement. Our findings strongly suggest a subset of patients with WAD demonstrate signs of peripheral nerve pathology and neuropathic pain. Although there was heterogeneity among some studies, typical WAD classifications may need to be reconsidered and include detailed clinical assessments for nerve integrity.

Carpal tunnel release provides an opportunity to study sensory nerve regeneration in humans. Schmid et al. show that cutaneous reinnervation correlates with symptom improvement after surgery. ADCYAP1 (encoding PACAP) expression is associated with sensory reinnervation in vivo and facilitates neuron outgrowth in vitro., We only have a rudimentary understanding of the molecular and cellular determinants of nerve regeneration and neuropathic pain in humans. This cohort study uses the most common entrapment neuropathy (carpal tunnel syndrome) as a human model system to prospectively evaluate the cellular and molecular correlates of neural regeneration and its relationship with clinical recovery. In 60 patients undergoing carpal tunnel surgery [36 female, mean age 62.5 (standard deviation 12.2) years], we used quantitative sensory testing and nerve conduction studies to evaluate the function of large and small fibres before and 6 months after surgery. Clinical recovery was assessed with the global rating of change scale and Boston Carpal Tunnel Questionnaire. Twenty healthy participants provided normative data [14 female, mean age 58.0 (standard deviation 12.9) years]. At 6 months post-surgery, we noted significant recovery of median nerve neurophysiological parameters (P

Background Mechanisms underpinning ongoing symptoms in chronic whiplash associated‐disorder (WAD) are not well understood. People with chronic WAD can exhibit sensory dysfunction consistent with small nerve fibre pathology, including thermal hypoaesthesia and hyperalgesia. This study investigated small fibre structure and function in chronic WAD. Methods Twenty‐four people with chronic WAD (median [IQR] age 49 [15] years, 16 females) and 24 pain‐free controls (50 [17] years, 16 females) were recruited. Intraepidermal nerve fibre density (IENFD) and dermal innervation were assessed by skin biopsy. This was performed at (a) the lateral index finger on the primary side of pain and (b) superior to the lateral malleolus on the contralateral side. Quantitative sensory testing was performed over the hand. Results The WAD group exhibited lower IENFD at the finger (WAD: median [IQR] 4.5 [4.9] fibres/mm; control 7.3 [3.9]; p = .010), but not the ankle (WAD: mean [SD] 7.3 [3.7] fibres/mm; control 9.3 [3.8]; p = .09). Dermal innervation was lower in the WAD group at the finger (WAD: median [IQR] 3.7 [2.8] nerve bundles/mm2; controls: 4.9 [2.1]; p = .017) but not the ankle (WAD: median [IQR] 2.1 [1.9] nerve bundles/mm2; controls: 1.8 [1.8]; p = .70). In the WAD group, hand thermal and light touch detection were impaired, and heat pain thresholds were lowered (p ≤ .037). Conclusions Findings suggest small fibre structural and functional deficits in chronic WAD, implicating potential involvement of small fibre pathology. Significance Our study found decreased intraepidermal nerve fibre density, reduced dermal innervation, thermal hypoaesthesia and hypersensitivity in people with chronic WAD, suggestive of small fibre pathology. This observation of peripheral nervous system pathology in chronic whiplash provides novel insights on mechanisms underpinning symptoms and challenges commonly held beliefs regarding this condition.

We only have a rudimentary understanding of the molecular and cellular determinants of human nerve regeneration. Here, we use carpal tunnel syndrome (CTS) as a human model system to prospectively evaluate correlates of neural regeneration and their relationship with clinical recovery after decompression surgery. At 6 months post-surgery, we noted a significant improvement of median nerve neurophysiological and somatosensory function. Serial skin biopsies revealed a partial recovery of intraepidermal innervation, whose extent correlated with symptom improvement. In myelinated afferents, nodal length increased postoperatively. Transcriptional profiling of the skin revealed 23 differentially expressed genes following decompression, with ADCYAP1 (encoding PACAP) being the most strongly upregulated and showing an association with regeneration of intraepidermal nerve fibres. Using human induced pluripotent stem cell-derived sensory neurons, we confirmed that PACAP significantly enhances axon outgrowth in vivo. Since PACAP signals through G-protein receptors, this pathway provides an interesting therapeutic target for human sensory nerve regeneration.

Study design Longitudinal case-controlled animal study. Objective To investigate putative cellular mechanisms to explain structural changes in muscle and adipose and connective tissues of the back muscles after intervertebral disc (IVD) injury. Summary of background data Structural back muscle changes are ubiquitous with back pain/injury and considered relevant for outcome, but their exact nature, time course, and cellular mechanisms remain elusive. We used an animal model that produces phenotypic back muscle changes after IVD injury to study these issues at the cellular/molecular level. Methods Multifidus muscle was harvested from both sides of the spine at L1-L2 and L3-L4 IVDs in 27 castrated male sheep at 3 (n = 10) or 6 (n = 17) months after a surgical anterolateral IVD injury at both levels. Ten control sheep underwent no surgery (3 mo, n = 4; 6 mo, n = 6). Tissue was harvested at L4 for histological analysis of cross-sectional area of muscle and adipose and connective tissue (whole muscle), plus immunohistochemistry to identify proportion and cross-sectional area of individual muscle fiber types in the deepest fascicle. Quantitative polymerase chain reaction measured gene expression of typical cytokines/signaling molecules at L2. Results Contrary to predictions, there was no multifidus muscle atrophy (whole muscle or individual fiber). There was increased adipose and connective tissue (fibrotic proliferation) cross-sectional area and slow-to-fast muscle fiber transition at 6 but not 3 months. Within the multifidus muscle, increases in the expression of several cytokines (tumor necrosis factor α and interleukin-1β) and molecules that signal trophic/atrophic processes for the 3 tissue types (e.g., growth factor pathway [IGF-1, PI3k, Akt1, mTOR], potent tissue modifiers [calcineurin, PCG-1α, and myostatin]) were present. Conclusion This study provides cellular evidence that refutes the presence of multifidus muscle atrophy accompanying IVD degeneration at this intermediate time point. Instead, adipose/connective tissue increased in parallel with the expression of the genes that provide putative mechanisms for multifidus structural remodeling. This provides novel targets for pharmacological and physical interventions. Level of evidence N/A.

Despite normal neurological integrity tests, some patients with non-specific neck-arm pain (NSNAP) have heightened nerve mechanosensitivity upon neurodynamic testing. The aim of this study was to determine whether or not a nerve dysfunction is present in patients with positive neurodynamic tests compared to those with negative neurodynamic tests or healthy controls. Somatosensory profiling using quantitative sensory testing (QST) was established in 40 consecutive patients with unilateral NSNAP; 23 had positive upper limb neurodynamic tests (ULNTPOS) and 17 had negative neurodynamic tests (ULNTNEG) and in 26 healthy controls. QST included measurement of thermal and mechanical detection and pain thresholds in the maximal pain area on the symptomatic side as well as the corresponding contralateral area. Fifty-seven percent of patients with NSNAP had positive neurodynamic tests. Somatosensory profiling revealed a loss of function phenotype in NSNAP patients compared to healthy controls both in the maximal pain area and asymptomatic side. Hyperalgesia (cold, heat and pressure) was present bilaterally in both NSNAP groups. Direct comparison between the patient groups revealed no significant differences in somatosensory profiles. However, the ULNTPOS group demonstrated sensory loss compared to healthy controls in more parameters than the ULNTNEG group. The ULNTNEG subgroup represented an intermediate phenotype between ULNTPOS patients and healthy controls in most detection thresholds as well as thermal and pressure pain thresholds. Even though patients with NSNAP present as a spectrum, it remains unclear whether the sensory changes are indicative of a nerve dysfunction/lesion or rather a marker of altered central pain processing.

Purpose Intervertebral disk (IVD) lesion and its subsequent degeneration have a profound effect on the multifidus muscle. The subacute/early chronic phase of multifidus remodeling after IVD lesion has been proposed to be regulated by inflammatory processes. The balance between pro-inflammatory (M1) and anti-inflammatory (M2) macrophages plays an important role in maintaining tissue integrity after injury. The localization, polarization of macrophage subtypes and their mediation of the pro-inflammatory cytokine tumor necrosis factor (TNF) are unknown in paraspinal muscles during IVD degeneration. A sheep model of IVD degeneration was used to investigate the role of macrophages and TNF in the structural alterations that occur within the multifidus muscle. Methods Anterolateral lesions were induced at L3–4 IVD in sheep. Multifidus muscle tissue at L4 was harvested 3 and 6 months after lesion and used for immunofluorescence assays to examine total macrophage number, macrophage polarization between M1 and M2, and to assess the localization of TNF expression in muscle, adipose and connective tissues from injured and naïve control animals. Results A greater proportion of M1 macrophages is present in muscle at both 3 and 6 months after IVD lesion, and adipose tissue at 6 months. Total number of macrophages is unchanged. At 6 months, expression of TNF is increased in adipose and connective tissue and the proportion of TNF expressed by M1 macrophages is increased. Conclusions These data support the proposal that macrophages and TNF (pro-inflammatory cytokine) play an active role in the subacute/early chronic phase of remodeling in muscle, adipose and connective tissues of the multifidus during IVD degeneration. This presents a novel target for treatment.

BACKGROUND Small-nerve fiber, or small-fiber, degeneration commonly occurs in patients with peripheral neuropathies, resulting in a deterioration of nerve function. Currently, the gold standard to identify small-fiber degeneration is through skin biopsy. Simple clinical tests aim to identify small-fiber degeneration, but their validity remains unknown. OBJECTIVES To examine the validity of clinical tests to assess small-nerve fiber degeneration, using carpal tunnel syndrome as a model neuropathy. METHODS One hundred seven participants (22 healthy, 85 with carpal tunnel syndrome) in this prospective, cross-sectional diagnostic accuracy study underwent pinprick testing of the index finger and were assessed for cold detection threshold and warm detection threshold using quantitative sensory testing. In a subgroup of patients with carpal tunnel syndrome (n = 51), cold and warm sensations were also tested, using coins at room and body temperature, respectively. The validity of these clinical tests was established against intra-epidermal nerve fiber density measured in skin biopsies from the index finger. RESULTS Optimal validity occurred with clusters of tests. Specifically, normal warm or cold sensation is highly sensitive to rule out small-fiber degeneration (sensitivity, 0.98; 95% confidence interval [CI]: 0.85, 0.99), but has a low specificity (0.20; 95% CI: 0.03, 0.52). By contrast, a reduction in pinprick is highly specific (0.88; 95% CI: 0.72, 0.95), and so can be used to rule in small-fiber degeneration. For quantitative sensory testing, the highest specificity (0.83) occurs for warm detection threshold and the highest sensitivity (0.84; 95% CI: 0.72, 0.91) for cold detection threshold or warm detection threshold. CONCLUSION Pinprick testing, followed by warm and cold tests if pinprick is normal, is a valid and cost-effective method to detect small-fiber degeneration. For quantitative sensory testing, warm detection threshold is useful for ruling in small-fiber degeneration. To rule out small-fiber degeneration, both cold detection threshold and warm detection threshold must be negative. LEVEL OF EVIDENCE Diagnosis, level 2. J Orthop Sports Phys Ther 2018;48(10):767-774. Epub 22 Jun 2018. doi:10.2519/jospt.2018.8230.

Reduced pain perception during painful stimulation to another body region (ie, conditioned pain modulation [CPM]) is considered important for pain modulation and development of pain disorders. The various methods used to study CPM limit comparison of findings. We investigated the influence of key methodologic variations on CPM and the properties of CPM when the back is used for the test stimulus or the conditioning stimulus (CS). Two different test stimuli (pressure pain threshold and pain response to suprathreshold heat [Pain-45, ie, pain rated at 45 on a 0-100 numeric rating scale]) were assessed before and during application of a noxious or non-noxious (sham) CS. Eight blocks of trials varied the anatomic location (back and forearms) and arrangement (body side) of the stimuli. Pressure pain threshold (as the test stimulus) increased during application of noxious, but not non-noxious, CS when stimuli were applied to opposite body sides or heterotopic sites on one body side. Inconsistent with pain-induced CPM, Pain-45 decreased during both noxious and non-noxious CS. These findings indicate that 1) pressure pain threshold can be more confidently interpreted with respect to CPM evoked by a painful stimulus than Pain-45, 2) the back and forearm are equally effective as sites for stimuli, and 3) stimuli arrangement does not influence CPM, except for identical anatomic regions on the same body side. Perspective: This study indicates that pressure pain threshold as the test stimulus provides a more valid measure of pain-induced CPM than pain response to a suprathreshold heat stimulus. Induction and magnitude of CPM is independent of stimuli arrangement, as long as ipsilateral homotopic sites are avoided. These findings clarify methods to study CPM. (C) 2015 by the American Pain Society Refereed/Peer-reviewed

The diagnosis of entrapment neuropathies can be difficult because symptoms and signs often do not follow textbook descriptions and vary significantly between patients with the same diagnosis. Signs and symptoms which spread outside of the innervation territory of the affected nerve or nerve root are common. This Masterclass provides insight into relevant mechanisms that may account for this extraterritorial spread in patients with entrapment neuropathies, with an emphasis on neuroinflammation at the level of the dorsal root ganglia and spinal cord, as well as changes in subcortical and cortical regions. Furthermore, we describe how clinical tests and technical investigations may identify these mechanisms if interpreted in the context of gain or loss of function. The management of neuropathies also remains challenging. Common treatment strategies such as joint mobilisation, neurodynamic exercises, education, and medications are discussed in terms of their potential to influence certain mechanisms at the site of nerve injury or in the central nervous system. The mechanism-oriented approach for this Masterclass seems warranted given the limitations in the current evidence for the diagnosis and management of entrapment neuropathies.

Elevated carpal tunnel pressure is an important pathomechanism in carpal tunnel syndrome (CTS). Several invasive methods have been described for direct measurement of carpal tunnel pressure, but all have two important limitations. The pressure gauge requires sterilisation between uses, which makes time-efficient data collection logistically cumbersome, and more importantly, the reliability of carpal tunnel pressure measurements has not been evaluated for any of the methods in use. This technical note describes a new method to measure carpal tunnel pressure using inexpensive, disposable pressure sensors and reports the within and between session reliability of the pressure recordings in five different wrist positions and during typing and computer mouse operation. Intraclass correlation coefficients (ICC[3,1]) were calculated for recordings within one session for healthy participants (n = 7) and patients with CTS (n = 5), and for recordings between two sessions for patients with CTS (n = 5). Overall, the reliability was high. With the exception of two coefficients, the reliability of the recordings at different wrist angles varied from 0.63 to 0.99. Reliability for typing and mouse operation ranged from 0.86 to 0.99. The new method described in this report is inexpensive and reliable, and data collection can be applied more efficiently as off-site sterilisation of equipment is not required. These advances are likely to promote future research into carpal tunnel pressure, such as investigation of the therapeutic mechanisms of various conservative treatment modalities that are believed to reduce elevated carpal tunnel pressure.

Study Design: Longitudinal case-control animal model. Objective: To investigate effects of mesenchymal stem cell (MSC) treatment on multifidus muscle remodeling after intervertebral disc (IVD) lesion. Summary of Background Data: Lesion and degeneration of IVDs cause structural remodeling of the multifidus muscle. Proinflammatory cytokines are thought to contribute. MSC treatment restores IVD health after lesion but its effects on surrounding tissues remains unknown. Using an animal model of IVD degeneration, we assessed the effects of MSC treatment of IVDs on the structural remodeling and cytokine expression within the multifidus muscle. Methods: An anterolateral lesion was performed on the L1–2, L3–4, and L5–6 IVDs in sheep. At either 4 (early treatment) or 12 (late treatment) weeks after IVD lesion, MSCs were injected into the lesioned IVD. Multifidus muscle was harvested from L2 (gene expression analysis) and L4 (histological analysis) at 3 or 6 months after IVD lesion and naïve controls for histological analysis of muscle, adipose, and connective tissue cross-sectional areas, and immunohistochemistry to study muscle fiber types. Real-time polymerase chain reactions quantified expression of tumor necrosis factor, interleukin-1β, and transforming growth factor-β1. Results: MSC treatment of IVD lesion prevented the increased adipose and connective tissue cross-sectional area expected after IVD lesion. MSC treatment did not prevent slow-to-fast muscle fiber type transformation. Gene expression of proinflammatory cytokines within the muscle was altered by the MSC treatment of IVD. Increased interleukin-1β expression was prevented in the early treatment group and tumor necrosis factor and transforming growth factor-β1 expression was upregulated at 6 months. Conclusion: Results show that although MSC treatment prevents fatty infiltration and fibrosis of the multifidus muscle after IVD lesion, it cannot prevent a muscle inflammatory response and muscle fiber transformation. These findings highlight the potential role of MSC therapy after IVD injury, but reveals that other interventions may also be necessary to optimize recovery of muscle. Level of Evidence: 4

A high prevalence of dual nerve disorders is frequently reported. How a secondary nerve disorder may develop following a primary nerve disorder remains largely unknown. Although still frequently cited, most explanatory theories were formulated many years ago. Considering recent advances in neuroscience, it is uncertain whether these theories still reflect current expert opinion. A Delphi study was conducted to update views on potential mechanisms underlying dual nerve disorders. In three rounds, seventeen international experts in the field of peripheral nerve disorders were asked to list possible mechanisms and rate their plausibility. Mechanisms with a median plausibility rating of ≥7 out of 10 were considered highly plausible. The experts identified fourteen mechanisms associated with a first nerve disorder that may predispose to the development of another nerve disorder. Of these fourteen mechanisms, nine have not previously been linked to double crush. Four mechanisms were considered highly plausible (impaired axonal transport, ion channel up or downregulation, inflammation in the dorsal root ganglia and neuroma-in-continuity). Eight additional mechanisms were listed which are not triggered by a primary nerve disorder, but may render the nervous system more vulnerable to multiple nerve disorders, such as systemic diseases and neurotoxic medication. Even though many mechanisms were classified as plausible or highly plausible, overall plausibility ratings varied widely. Experts indicated that a wide range of mechanisms has to be considered to better understand dual nerve disorders. Previously listed theories cannot be discarded, but may be insufficient to explain the high prevalence of dual nerve disorders.

Objective: Cervical mobilization has been shown to elicit effects on pain perception, autonomic function, and motor function in subjects who experience musculoskeletal pain. The improvement in motor function may be a direct effect of the treatment or secondary to a hypoalgesic effect. This study tested whether it is possible to alter motor function following joint mobilization in situations where motor performance is not impaired by pain. Methods: Twenty-four asymptomatic subjects participated in this double-blind, controlled, within-subjects crossover study. Pressure pain thresholds and electromyographic activity of the superficial neck flexor muscles were compared with repeated-measures analysis of variance between a posteroanterior cervical mobilization, manual contact, and noncontact condition. Results: The results indicate no significant change in the pressure pain threshold (P =.846) after posteroanterior cervical mobilization. There was no significant difference in superficial neck flexor muscle activity during the craniocervical flexion test (P =.713). Post hoc power analysis demonstrated the ability to detect a 15% difference in electromyographic activity with 70% power. Conclusion: The improvement in motor function demonstrated in previous studies was not replicated, suggesting that either it is only possible to produce an effect when motor function is impaired or the change in motor function is secondary to the pain inhibitory effect of the treatment.

Context:Various studies report decreased muscle activation in the concavity of the curve in patients with scoliosis. Such decreased muscle-performance capacity could lead to sustained postural deficits.Objective:To investigate whether specific asymmetrical sports therapy exercises rather than symmetrical back strengthening can increase EMG amplitudes of paraspinal muscles in the concavity of the curve.Design:Cross-sectional.Setting:Laboratory.Participants:16 patients with idiopathic scoliosis.Interventions:Patients performed 4 back-strengthening exercises (front press, lat pull-down, roman chair, bent-over barbell row) during 1 test session. Each exercise was performed in a symmetrical and asymmetrical variant and repeated 3 times.Main Outcome Measure:EMG amplitudes of the paraspinal muscles were recorded in the thoracic and lumbar apexes of the scoliotic curve during each exercise. Ratios of convex- to concave-side EMG activity were calculated.Results:Statistical analysis revealed that the asymmetrical variants of front press at the lumbar level (P = .002) and roman chair and bent-over barbell row at the thoracic level (P < .0001, .001 respectively) were superior in increasing EMG amplitudes in the concavity of the scoliotic curve.Conclusions:Specific asymmetrical exercises increase EMG amplitudes of paraspinal muscles in the concavity. If confirmed in longitudinal studies measuring improvements of postural deficits, these exercises may advance care of patients with scoliosis.

Non-neutral wrist positions and external pressure leading to increased carpal tunnel pressure during computer use have been associated with a heightened risk of carpal tunnel syndrome (CTS). This study investigated whether commonly used ergonomic devices reduce carpal tunnel pressure in patients with CTS. Carpal tunnel pressure was measured in twenty-one patients with CTS before, during and after a computer mouse task using a standard mouse, a vertical mouse, a gel mouse pad and a gliding palm support. Carpal tunnel pressure increased while operating a computer mouse. Although the vertical mouse significantly reduced ulnar deviation and the gel mouse pad and gliding palm support decreased wrist extension, none of the ergonomic devices reduced carpal tunnel pressure. The findings of this study do therefore not endorse a strong recommendation for or against any of the ergonomic devices commonly recommended for patients with CTS. Selection of ergonomic devices remains dependent on personal preference.

Study design Longitudinal case-controlled animal study. Objective To investigate the effect of an intervertebral disc (IVD) lesion on the proportion of slow, fast, and intermediate muscle fiber types in the multifidus muscle in sheep, and whether muscle fiber changes were paralleled by local gene expression of the proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 1-β. Summary of background data Structure and behavior of the multifidus muscle change in acute and chronic back pain, but the mechanisms are surprisingly poorly understood and the link between structure and behavior is tenuous. Although changes in muscle fiber types have the potential to unify the observations, the effect of injury on muscle fiber distribution has not been adequately tested, and understanding of possible mechanisms is limited. Methods The L1-L2, L3-L4, and L5-L6 IVDs of 11 castrated male sheep received anterolateral lesions. Six control sheep underwent no surgical procedures. Multifidus muscle tissue was harvested at L4 for muscle fiber analysis using immunohistochemistry and L2 for cytokine analysis with polymerase chain reaction for local gene expression of TNF-α and interleukin-1β. Results The proportion of slow muscle fibers in multifidus was significantly less in the lesioned animals both ipsilateral and contralateral to the IVD lesion. The greatest reduction in slow fibers was in the deep medial muscle region. A greater prevalence of intermediate fibers on the uninjured side implies a delayed fiber-type transformation on that side. TNF-α gene expression in multifidus was greater on both sides in the lesion animals than in the muscle of control animals. Interleukin-1β was increased only on the injured side. Conclusion These data provide evidence of muscle fiber changes after induction of an IVD lesion and a parallel increase in TNF-α expression. Proinflammatory cytokine changes provide a novel mechanism to explain behavioral and structural changes in multifidus. Level of evidence N/A.

After experimental nerve injuries that extensively disrupt axons, such as chronic constriction injury, immune cells invade the nerve, related dorsal root ganglia (DRGs), and spinal cord, leading to hyperexcitability, raised sensitivity, and pain. Entrapment neuropathies, such as carpal tunnel syndrome, involve minimal axon damage, but patients often report widespread symptoms. To understand the underlying pathology, a tube was placed around the sciatic nerve in 8-week-old rats, leading to progressive mild compression as the animals grew. Immunofluorescence was used to examine myelin and axonal integrity, glia, macrophages, and T lymphocytes in the nerve, L5 DRGs, and spinal cord after 12 weeks. Tubes that did not constrict the nerve when applied caused extensive and ongoing loss of myelin, together with compromise of small-, but not large-, diameter axons. Macrophages and T lymphocytes infiltrated the nerve and DRGs. Activated glia proliferated in DRGs but not in spinal cord. Histologic findings were supported by clinical hyperalgesia to blunt pressure and cold allodynia. Tubes that did not compress the nerve induced only minor local inflammation. Thus, progressive mild nerve compression resulted in chronic local and remote immune-mediated inflammation depending on the degree of compression. Such neuroinflammation may explain the widespread symptoms in patients with entrapment neuropathies.

IntroductionThe multifidus muscle undergoes structural and behavioral changes with back pain and injury. After intervertebral disc (IVD) lesion in animals the multifidus muscle undergoes a transformation of muscle fiber types from slow-to-fast, and extensive structural remodelling with increased adipose and connective tissue. Increased expression of pro-inflammatory cytokines (tumor necrosis factor (TNF) and interleukin 1β (ΙΛ−1β)) parallel these changes and may be responsible. Treatment of IVD lesions with mesenchymal stem cells (MSC) prevents or restores loss of IVD height and proteoglycans in the nucleus pulposus, depending on the timing of application. Whether the resolution of IVD changes by MCS treatment prevents or restores changes in the multifidus muscle structure and muscle fiber composition is unknown. This study aimed to investigate whether muscle changes are prevented or restored by early or late MSC treatment of the IVD lesion, respectively, and whether this is related to modification of inf...

Splinting and nerve and tendon gliding exercises are commonly used to treat carpal tunnel syndrome (CTS). It has been postulated that both modalities reduce intraneural edema. To test this hypothesis, 20 patients with mild to moderate CTS were randomly allocated to either night splinting or a home program of nerve and tendon gliding exercises. Magnetic resonance images of the wrist were taken at baseline, immediately after 10 min of splinting or exercise, and following 1 week of intervention. Primary outcome measures were signal intensity of the median nerve at the wrist as a measure of intraneural edema and palmar bowing of the carpal ligament. Secondary outcome measures were changes in symptom severity and function. Following 1 week of intervention, but not immediately after 10 min, signal intensity of the median nerve was reduced by ≈ 11% at the radioulnar level for both interventions (p = 0.03). This was accompanied by a mild improvement in symptoms and function (p0.004). A similar reduction in signal intensity is not observed in patients who only receive advice to remain active. No changes in signal intensity were identified further distally (p0.28). Ligament bowing remained unchanged (p0.08). Intraneural edema reduction is a likely therapeutic mechanism of splinting and exercise.

Segmental neurological modulation, neural hysteresis and biomechanical effects have been proposed as mechanisms underpinning the effects of manual therapy. An increasing number of studies hypothesise activation of the central nervous system resulting in a non-segmental hypoalgesic effect with concurrent activation of other neural pathways as a potential mechanism of action. Whether this model is consistent with the current literature is unknown. This systematic review aims to assess the consistency of evidence supporting an involvement of supraspinal systems in mediating the effects of passive cervical joint mobilisation. We searched randomised trials in three electronic databases from inception to November 2007, without language restriction, and checked reference lists of included studies. We assessed study validity and extracted salient features in duplicate. Fifteen studies met our inclusion criteria. The overall quality was high. We found consistency for concurrent hypoalgesia, sympathetic nervous system excitation and changes in motor function. Pooling of data suggested that joint mobilisation improved outcomes by approximately 20% relative to controls. This specific pattern suggests that descending pathways might play a key role in manual therapy induced hypoalgesia. Our review supports the existence of an alternative neurophysiological model, in which passive joint mobilisation stimulates areas within the central nervous system.