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1.  Reinnervation of the Tibialis Anterior Following Sciatic Nerve Crush Injury: A Confocal Microscopic Study in Transgenic Mice 
Experimental neurology  2007;207(1):64-74.
Transgenic mice whose axons and Schwann cells express fluorescent chromophores enable new imaging techniques and augment concepts in developmental neurobiology. The utility of these tools in the study of traumatic nerve injury depends on employing nerve models that are amenable to microsurgical manipulation and gauging functional recovery. Motor recovery from sciatic nerve crush injury is studied here by evaluating motor endplates of the tibialis anterior muscle, which is innervated by the deep peroneal branch of the sciatic nerve. Following sciatic nerve crush, the deep surface of the tibialis anterior muscle is examined using whole mount confocal microscopy, and reinnervation is characterized by imaging fluorescent axons or Schwann cells (SCs). One week following sciatic crush injury, 100% of motor endplates are denervated with partial reinnervation at two weeks, hyperinnervation at three and four weeks, and restoration of a 1:1 axon to motor endplate relationship six weeks after injury. Walking track analysis reveals progressive recovery of sciatic nerve function by six weeks. SCs reveal reduced S100 expression within two weeks of denervation, correlating with regression to a more immature phenotype. Reinnervation of SCs restores S100 expression and a fully differentiated phenotype. Following denervation, there is altered morphology of circumscribed terminal Schwann cells demonstrating extensive process formation between adjacent motor endplates. The thin, uniformly innervated tibialis anterior muscle is well suited for studying motor reinnervation following sciatic nerve injury. Confocal microscopy may be performed coincident with other techniques of assessing nerve regeneration and functional recovery.
PMCID: PMC2000860  PMID: 17628540
transgenic mice; chromophore; sciatic nerve crush; motor endplate
2.  Electro-acupuncture promotes survival, differentiation of the bone marrow mesenchymal stem cells as well as functional recovery in the spinal cord-transected rats 
BMC Neuroscience  2009;10:35.
Bone marrow mesenchymal stem cells (MSCs) are one of the potential tools for treatment of the spinal cord injury; however, the survival and differentiation of MSCs in an injured spinal cord still need to be improved. In the present study, we investigated whether Governor Vessel electro-acupuncture (EA) could efficiently promote bone marrow mesenchymal stem cells (MSCs) survival and differentiation, axonal regeneration and finally, functional recovery in the transected spinal cord.
The spinal cords of adult Sprague-Dawley (SD) rats were completely transected at T10, five experimental groups were performed: 1. sham operated control (Sham-control); 2. operated control (Op-control); 3. electro-acupuncture treatment (EA); 4. MSCs transplantation (MSCs); and 5. MSCs transplantation combined with electro-acupuncture (MSCs+EA). After 2-8 weeks of MSCs transplantation plus EA treatment, we found that the neurotrophin-3 (NT-3), cAMP level, the differentiation of MSCs, the 5-HT positive and CGRP positive nerve fibers in the lesion site and nearby tissue of injured spinal cord were significantly increased in the MSCs+EA group as compared to the group of the MSCs transplantation or the EA treated alone. Furthermore, behavioral test and spinal cord evoked potentials detection demonstrated a significantly functional recovery in the MSCs +EA group.
These results suggest that EA treatment may promote grafted MSCs survival and differentiation; MSCs transplantation combined with EA treatment could promote axonal regeneration and partial locomotor functional recovery in the transected spinal cord in rats and indicate a promising avenue of treatment of spinal cord injury.
PMCID: PMC2679038  PMID: 19374777
3.  Acupuncture for treating fibromyalgia 
One in five fibromyalgia sufferers use acupuncture treatment within two years of diagnosis.
To examine the benefits and safety of acupuncture treatment for fibromyalgia.
Search methods
We searched CENTRAL, PubMed, EMBASE, CINAHL, National Research Register, HSR Project and Current Contents, as well as the Chinese databases VIP and Wangfang to January 2012 with no language restrictions.
Selection criteria
Randomised and quasi-randomised studies evaluating any type of invasive acupuncture for fibromyalgia diagnosed according to the American College of Rheumatology (ACR) criteria, and reporting any main outcome: pain, physical function, fatigue, sleep, total well-being, stiffness and adverse events.
Data collection and analysis
Two author pairs selected trials, extracted data and assessed risk of bias. Treatment effects were reported as standardised mean differences (SMD) and 95%confidence intervals (CI) for continuous outcomes using different measurement tools (pain, physical function, fatigue, sleep, total well-being and stiffness) and risk ratio (RR) and 95% CI for dichotomous outcomes (adverse events).We pooled data using the random-effects model.
Main results
Nine trials (395 participants) were included. All studies except one were at low risk of selection bias; five were at risk of selective reporting bias (favouring either treatment group); two were subject to attrition bias (favouring acupuncture); three were subject to performance bias (favouring acupuncture) and one to detection bias (favouring acupuncture). Three studies utilised electro-acupuncture (EA) with the remainder using manual acupuncture (MA) without electrical stimulation. All studies used ’formula acupuncture’ except for one, which used trigger points.
Low quality evidence from one study (13 participants) showed EA improved symptoms with no adverse events at one month following treatment. Mean pain in the non-treatment control group was 70 points on a 100 point scale; EA reduced pain by a mean of 22 points (95% confidence interval (CI) 4 to 41), or 22% absolute improvement. Control group global well-being was 66.5 points on a 100 point scale; EA improved well-being by a mean of 15 points (95% CI 5 to 26 points). Control group stiffness was 4.8 points on a 0 to 10 point; EA reduced stiffness by a mean of 0.9 points (95% CI 0.1 to 2 points; absolute reduction 9%, 95% CI 4% to 16%). Fatigue was 4.5 points (10 point scale) without treatment; EA reduced fatigue by a mean of 1 point (95% CI 0.22 to 2 points), absolute reduction 11% (2% to 20%). There was no difference in sleep quality (MD 0.4 points, 95% CI −1 to 0.21 points, 10 point scale), and physical function was not reported.
Moderate quality evidence from six studies (286 participants) indicated that acupuncture (EA or MA) was no better than sham acupuncture, except for less stiffness at one month. Subgroup analysis of two studies (104 participants) indicated benefits of EA. Mean pain was 70 points on 0 to 100 point scale with sham treatment; EA reduced pain by 13% (5% to 22%); (SMD −0.63, 95% CI −1.02 to −0.23). Global well-being was 5.2 points on a 10 point scale with sham treatment; EA improved well-being: SMD 0.65, 95% CI 0.26 to 1.05; absolute improvement 11% (4% to 17%). EA improved sleep, from 3 points on a 0 to 10 point scale in the sham group: SMD 0.40 (95% CI 0.01 to 0.79); absolute improvement 8% (0.2% to 16%). Low-quality evidence from one study suggested that MA group resulted in poorer physical function: mean function in the sham group was 28 points (100 point scale); treatment worsened function by a mean of 6 points (95% CI −10.9 to −0.7). Low-quality evidence from three trials (289 participants) suggested no difference in adverse events between real (9%) and sham acupuncture (35%); RR 0.44 (95% CI 0.12 to 1.63).
Moderate quality evidence from one study (58 participants) found that compared with standard therapy alone (antidepressants and exercise), adjunct acupuncture therapy reduced pain at one month after treatment: mean pain was 8 points on a 0 to 10 point scale in the standard therapy group; treatment reduced pain by 3 points (95% CI −3.9 to −2.1), an absolute reduction of 30% (21% to 39%). Two people treated with acupuncture reported adverse events; there were none in the control group (RR 3.57; 95% CI 0.18 to 71.21). Global well-being, sleep, fatigue and stiffness were not reported. Physical function data were not usable.
Low quality evidence from one study (38 participants) showed a short-term benefit of acupuncture over antidepressants in pain relief: mean pain was 29 points (0 to 100 point scale) in the antidepressant group; acupuncture reduced pain by 17 points (95% CI −24.1 to −10.5). Other outcomes or adverse events were not reported.
Moderate-quality evidence from one study (41 participants) indicated that deep needling with or without deqi did not differ in pain, fatigue, function or adverse events. Other outcomes were not reported.
Four studies reported no differences between acupuncture and control or other treatments described at six to seven months follow-up.
No serious adverse events were reported, but there were insufficient adverse events to be certain of the risks.
Authors’ conclusions
There is low tomoderate-level evidence that compared with no treatment and standard therapy, acupuncture improves pain and stiffness in people with fibromyalgia. There is moderate-level evidence that the effect of acupuncture does not differ from sham acupuncture in reducing pain or fatigue, or improving sleep or global well-being. EA is probably better than MA for pain and stiffness reduction and improvement of global well-being, sleep and fatigue. The effect lasts up to one month, but is not maintained at six months follow-up. MA probably does not improve pain or physical functioning. Acupuncture appears safe. People with fibromyalgia may consider using EA alone or with exercise and medication. The small sample size, scarcity of studies for each comparison, lack of an ideal sham acupuncture weaken the level of evidence and its clinical implications. Larger studies are warranted.
PMCID: PMC4105202  PMID: 23728665
Acupuncture Therapy [*methods]; Fibromyalgia [*therapy]; Pain Management [methods]; Randomized Controlled Trials as Topic; Humans
4.  Reduced Renshaw Recurrent Inhibition after Neonatal Sciatic Nerve Crush in Rats 
Neural Plasticity  2014;2014:786985.
Renshaw recurrent inhibition (RI) plays an important gated role in spinal motion circuit. Peripheral nerve injury is a common disease in clinic. Our current research was designed to investigate the change of the recurrent inhibitory function in the spinal cord after the peripheral nerve crush injury in neonatal rat. Sciatic nerve crush was performed on 5-day-old rat puppies and the recurrent inhibition between lateral gastrocnemius-soleus (LG-S) and medial gastrocnemius (MG) motor pools was assessed by conditioning monosynaptic reflexes (MSR) elicited from the sectioned dorsal roots and recorded either from the LG-S and MG nerves by antidromic stimulation of the synergist muscle nerve. Our results demonstrated that the MSR recorded from both LG-S or MG nerves had larger amplitude and longer latency after neonatal sciatic nerve crush. The RI in both LG-S and MG motoneuron pools was significantly reduced to virtual loss (15–20% of the normal RI size) even after a long recovery period upto 30 weeks after nerve crush. Further, the degree of the RI reduction after tibial nerve crush was much less than that after sciatic nerve crush indicatig that the neuron-muscle disconnection time is vital to the recovery of the spinal neuronal circuit function during reinnervation. In addition, sciatic nerve crush injury did not cause any spinal motor neuron loss but severally damaged peripheral muscle structure and function. In conclusion, our results suggest that peripheral nerve injury during neonatal early development period would cause a more sever spinal cord inhibitory circuit damage, particularly to the Renshaw recurrent inhibition pathway, which might be the target of neuroregeneration therapy.
PMCID: PMC3981522  PMID: 24778886
5.  Traumatic neuroma in continuity injury model in rodents: a preliminary report 
Selected abstracts delivered at the 8th Annual AOSpine North America Fellows Forum
Consistent with EBSJ's commitment to fostering quality research, we are pleased to feature some of the most highly rated abstracts from the 8th Annual AOSpine North America Fellows Forum in Banff Canada. Enhancing the quality of evidence in spine care means acknowledging and supporting the efforts of young researchers within our AOSpine North America network. We look forward to seeing more from these promising researchers in the future.
Study type: Basic science research report
Introduction: Spinal nerve-injury management and prevention constitute a substantial proportion of a spinal surgeon's practice. Functional recovery after peripheral nerve injuries is often unsatisfactory and to optimize the outcomes, an intimate understanding of these injuries is required. Sunderland classified peripheral nerve injuries into five grades.1 Grade 1 (neurapraxia) and grade 2 (axonal disruption) injuries usually recover with no or insignificant functional deficits within weeks to a few months, respectively. Injuries that are most difficult to manage clinically are the often mixed grade 3 (endoneurial disruption) and grade 4 (perineurial disruption) lesions where spontaneous functional recovery is limited or absent, resulting in neuroma in continuity (NIC). Traumatic NIC is characterized by aberrant intra- and extra- fascicular axonal regeneration and scar formation within an unsevered injured nerve, resulting in impaired and erroneous end-organ reinnervation.2,3 Animal models reproducing grade 1, 2, 3, and 5 lesions have been developed, but to our knowledge a clinically relevant rodent model of NIC has not been developed.4,5,6,7,8 The effective peripheral nerve regeneration and resilience of rodents make it challenging to recreate the NIC scenario.
Objective: Our goal was to develop a practical rodent model for focal traumatic NIC, demonstrating the characteristic histological features, supported by concordant functional deficits. Such a model may help us to identify this injury pattern earlier and allow development of intervention strategies to reduce neuronal misdirection, scar formation, and enhance regeneration for improved functional recovery.
Methods: Various injury techniques were tested on freshly harvested Lewis rat sciatic nerves ex vivo, and examined histologically before inflicting more refined injuries in vivo. The optimal experimental injuries combined a 50 g traction force applied with a spring scale hooked around the sciatic nerve, and focal three second maximal compression using a malleus nipper (Figure 1). Nerves were harvested at 0, 5, 13, 21, and 65 days, and processed for longitudinal 8 micron cryostat sectioning, H&E, laminin, neurofilament, and Masson's trichrome staining. Skilled locomotion (tapered beam, ladder rung) and flat plane locomotion for ground reaction force (GRF) analysis were performed serially up to 9 weeks with the experimental (n = 4) and simple (control) crush (n = 1) injuries by blinded animal behavior experts, using methods as recently described.9
Photograph illustrating the experimental injury. Fifty grams of traction is applied in a direction orthogonal to the native nerve course after external neurolysis, simultaneously, three second maximal compression is applied at the sciatic trifurcation, just distal to a mesoneurial suture. Malleus nipper with tip detail and 100 g spring scale in bottom left. In situ sciatic nerve immediately after injury (top right).
Results: Disruption of the endoneurium and perineurium with aberrant intra- and extrafascicular axonal regeneration and progressive fibrosis was consistently demonstrated histologically in ten out of ten nerves with experimental injuries. In contrast, crush injuries showed only signs of Wallerian degeneration (Figure 2). At 8 weeks, experimental animals made more errors during skilled locomotion as compared to nerve crush animals. GRFs revealed impaired vertical and fore-aft force generation by the injured limbs at week 9 in the experimental group, whereas GRFs from the simple crush animal revealed recovery at the same time point (Figure 3).
Injury zones at five days (a–d, bar = 200 µm) and 65 days (e–h, bar = 50 µm), comparing crush (top) to experimental (bottom) injuries; Masson's trichrome and neurofilament. Note the aberrant axonal sprouting and regeneration in the experimental injury group, associated with increased intrafascicular collagen, in contrast to orderly regeneration and lack of scar in the simple crush group.
Mean vertical and fore-aft ground reaction forces at both baseline and 9 weeks from representative animals. Compared to baseline and crush-injured animal at 9 weeks, animals in the experimental group bear less weight on both their right (surgical) hind limb (solid line), and fore limb (dotted line) at 9 weeks. Comparable with historical data, the crush animal have improved braking (*) and propulsive (#) forces in fore and hind limbs (injured side) compared to the experimental group, though these have not returned to baseline values.
Conclusions: We have demonstrated histological features and poor functional recovery consistent with NIC formation in a rodent model. The injury mechanism employed combines traction and compression forces akin to the physical forces at play in clinical nerve injuries. Additional validating experiments are in progress.
PMCID: PMC3623102  PMID: 23637668
Locomotion; nerve regeneration; Sunderland grade 4 nerve injury
6.  Accelerating axonal growth promotes motor recovery after peripheral nerve injury in mice 
The Journal of Clinical Investigation  2011;121(11):4332-4347.
Although peripheral nerves can regenerate after injury, proximal nerve injury in humans results in minimal restoration of motor function. One possible explanation for this is that injury-induced axonal growth is too slow. Heat shock protein 27 (Hsp27) is a regeneration-associated protein that accelerates axonal growth in vitro. Here, we have shown that it can also do this in mice after peripheral nerve injury. While rapid motor and sensory recovery occurred in mice after a sciatic nerve crush injury, there was little return of motor function after sciatic nerve transection, because of the delay in motor axons reaching their target. This was not due to a failure of axonal growth, because injured motor axons eventually fully re-extended into muscles and sensory function returned; rather, it resulted from a lack of motor end plate reinnervation. Tg mice expressing high levels of Hsp27 demonstrated enhanced restoration of motor function after nerve transection/resuture by enabling motor synapse reinnervation, but only within 5 weeks of injury. In humans with peripheral nerve injuries, shorter wait times to decompression surgery led to improved functional recovery, and, while a return of sensation occurred in all patients, motor recovery was limited. Thus, absence of motor recovery after nerve damage may result from a failure of synapse reformation after prolonged denervation rather than a failure of axonal growth.
PMCID: PMC3223863  PMID: 21965333
7.  Use of hybrid chitosan membranes and human mesenchymal stem cells from the Wharton jelly of umbilical cord for promoting nerve regeneration in an axonotmesis rat model★ 
Neural Regeneration Research  2012;7(29):2247-2258.
Many studies have been dedicated to the development of scaffolds for improving post-traumatic nerve regeneration. The goal of this study was to assess the effect on nerve regeneration, associating a hybrid chitosan membrane with non-differentiated human mesenchymal stem cells isolated from Wharton's jelly of umbilical cord, in peripheral nerve reconstruction after crush injury. Chromosome analysis on human mesenchymal stem cell line from Wharton's jelly was carried out and no structural alterations were found in metaphase. Chitosan membranes were previously tested in vitro, to assess their ability in supporting human mesenchymal stem cell survival, expansion, and differentiation. For the in vivo testing, Sasco Sprague adult rats were divided in 4 groups of 6 or 7 animals each: Group 1, sciatic axonotmesis injury without any other intervention (Group 1-Crush); Group 2, the axonotmesis lesion of 3 mm was infiltrated with a suspension of 1 250–1 500 human mesenchymal stem cells (total volume of 50 μL) (Group 2-CrushCell); Group 3, axonotmesis lesion of 3 mm was enwrapped with a chitosan type III membrane covered with a monolayer of non-differentiated human mesenchymal stem cells (Group 3-CrushChitIIICell) and Group 4, axonotmesis lesion of 3 mm was enwrapped with a chitosan type III membrane (Group 4-CrushChitIII). Motor and sensory functional recovery was evaluated throughout a healing period of 12 weeks using sciatic functional index, static sciatic index, extensor postural thrust, and withdrawal reflex latency. Stereological analysis was carried out on regenerated nerve fibers. Results showed that infiltration of human mesenchymal stem cells, or the combination of chitosan membrane enwrapment and human mesenchymal stem cell enrichment after nerve crush injury provide a slight advantage to post-traumatic nerve regeneration. Results obtained with chitosan type III membrane alone confirmed that they significantly improve post-traumatic axonal regrowth and may represent a very promising clinical tool in peripheral nerve reconstructive surgery. Yet, umbilical cord human mesenchymal stem cells, that can be expanded in culture and induced to form several different types of cells, may prove, in future experiments, to be a new source of cells for cell therapy, including targets such as peripheral nerve and muscle.
PMCID: PMC4268725  PMID: 25538746
stem cells; mesenchymal stem cells; Wharton jelly; umbilical cord; biomaterials; chitosan; axonotmesis; functional analysis; rat; karyotype analysis; stereological analysis
8.  Beneficial effects of treadmill training in experimental diabetic nerve regeneration 
Clinics  2010;65(12):1329-1337.
We investigated the effects of treadmill training (10 weeks) on hindlimb motor function and nerve morphometric parameters in diabetic rats submitted to sciatic nerve crush.
Wistar rats (n = 64) were divided into the following groups: non-diabetic; trained non-diabetic; non-diabetic with sciatic nerve crush; trained non-diabetic with sciatic nerve crush; diabetic; trained diabetic; diabetic with sciatic nerve crush or trained diabetic with sciatic nerve crush. Diabetes was induced by streptozotocin injection (50 mg/kg, iv). Hindlimb motor function was evaluated weekly by assessing sciatic functional indices, and the proximal and distal portions of the sciatic nerve were used for morphometric analysis.
At 13 weeks post-injury, the distal nerve portion of all injured groups and the proximal nerve portion of the diabetic with sciatic nerve crush group presented altered morphometric parameters such as decreased myelinated fiber diameter (∼7.4±0.3µm vs ∼4.8±0.2µm), axonal diameter (∼5±0.2µm vs ∼3.5±0.1µm) and myelin sheath thickness (∼1.2±0.07µm vs ∼0.65±0.07µm) and an increase in the percentage of area occupied by endoneurium (∼28±3% vs ∼60±3%). In addition, in the non-diabetic with sciatic nerve crush group the proximal nerve portion showed a decreased myelinated fiber diameter (7.4±0.3µm vs 5.8±0.3µm) and myelin sheath thickness (1.29±0.08µm vs 0.92±0.08µm). The non-diabetic with sciatic nerve crush, trained non-diabetic with sciatic nerve crush, diabetic with sciatic nerve crush and trained diabetic with sciatic nerve crush groups showed normal sciatic functional index from the 4th, 4th, 9th and 7th week post-injury, respectively. Morphometric alterations in the proximal nerve portion of the diabetic with sciatic nerve crush and non-diabetic with sciatic nerve crush groups were either prevented or reverted to values similar to the non-diabetic group by treadmill training.
Diabetic condition promoted delay in sciatic nerve regeneration. Treadmill training is able to accelerate hindlimb motor function recovery in diabetic injured rats and prevent or revert morphometric alterations in proximal nerve portions in non-diabetic and diabetic injured rats.
PMCID: PMC3020345  PMID: 21340223
Diabetes; Sciatic nerve crush; Motor function; Nerve morphometry; Treadmill training
9.  Antiallodynic Effects of Acupuncture in Neuropathic Rats 
Yonsei Medical Journal  2006;47(3):359-366.
Peripheral nerve injury often results in abnormal neuropathic pain such as allodynia or hyperalgesia. Acupuncture, a traditional Oriental medicine, has been used to relieve pain and related symptoms. However, the efficiency of acupuncture in relieving neuropathic pain is not clear. The aim of this study was to investigate the anti-allodynic effects of acupuncture through behavioral and electrophysiological examinations. Male Sprague-Dawley rats were subjected to neuropathic surgery consisting of a tight ligation and transection of the left tibial and sural nerves, under pentobarbital anesthesia. The acupuncture experiment consisted of four different groups, one treated at each of three different acupoints (Zusanli (ST36), Yinlingquan (SP9), and a sham-acupoint) and a control group. Behavioral tests for mechanical allodynia and cold allodynia were performed for up to two weeks postoperatively. Extracellular electrophysiological recordings were made from the dorsal roots using platinum wire electrodes. Mechanical and cold allodynia were significantly reduced after acupuncture treatment at the Zusanli and Yinlingquan acupoints, respectively. Electrophysiological neural responses to von Frey and acetone tests were also reduced after acupuncture at the same two acupoints. These results suggest that acupuncture may be beneficial in relieving neuropathic pain.
PMCID: PMC2688155  PMID: 16807985
Neuropathic pain; acupuncture; acupoint; allodynia; electrophysiology
10.  Brain-Derived Neurotrophic Factor from Bone Marrow-Derived Cells Promotes Post-Injury Repair of Peripheral Nerve 
PLoS ONE  2012;7(9):e44592.
Brain-derived neurotrophic factor (BDNF) stimulates peripheral nerve regeneration. However, the origin of BNDF and its precise effect on nerve repair have not been clarified. In this study, we examined the role of BDNF from bone marrow-derived cells (BMDCs) in post-injury nerve repair. Control and heterozygote BDNF knockout mice (BDNF+/−) received a left sciatic nerve crush using a cerebral blood clip. Especially, for the evaluation of BDNF from BMDCs, studies with bone marrow transplantation (BMT) were performed before the injury. We evaluated nerve function using a rotarod test, sciatic function index (SFI), and motor nerve conduction velocity (MNCV) simultaneously with histological nerve analyses by immunohistochemistry before and after the nerve injury until 8 weeks. BDNF production was examined by immunohistochemistry and mRNA analyses. After the nerve crush, the controls showed severe nerve dysfunction evaluated at 1 week. However, nerve function was gradually restored and reached normal levels by 8 weeks. By immunohistochemistry, BDNF expression was very faint before injury, but was dramatically increased after injury at 1 week in the distal segment from the crush site. BDNF expression was mainly co-localized with CD45 in BMDCs, which was further confirmed by the appearance of GFP-positive cells in the BMT study. Variant analysis of BDNF mRNA also confirmed this finding. BDNF+/− mice showed a loss of function with delayed histological recovery and BDNF+/+→BDNF+/− BMT mice showed complete recovery both functionally and histologically. These results suggested that the attenuated recovery of the BDNF+/− mice was rescued by the transplantation of BMCs and that BDNF from BMDCs has an essential role in nerve repair.
PMCID: PMC3446933  PMID: 23028564
11.  Retrograde tracing and toe spreading after experimental autologous nerve transplantation and crush injury of the sciatic nerve: a descriptive methodological study 
Evaluation of functional and structural recovery after peripheral nerve injury is crucial to determine the therapeutic effect of a nerve repair strategy. In the present study, we examined the relationship between the structural evaluation of regeneration by means of retrograde tracing and the functional analysis of toe spreading. Two standardized rat sciatic nerve injury models were used to address this relationship. As such, animals received either a 2 cm sciatic nerve defect (neurotmesis) followed by autologous nerve transplantation (ANT animals) or a crush injury with spontaneous recovery (axonotmesis; CI animals). Functional recovery of toe spreading was observed over an observation period of 84 days. In contrast to CI animals, ANT animals did not reach pre-surgical levels of toe spreading. After the observation period, the lipophilic dye DiI was applied to label sensory and motor neurons in dorsal root ganglia (DRG; sensory neurons) and spinal cord (motor neurons), respectively. No statistical difference in motor or sensory neuron counts could be detected between ANT and CI animals.
In the present study we could indicate that there was no direct relationship between functional recovery (toe spreading) measured by SSI and the number of labelled (motor and sensory) neurons evaluated by retrograde tracing. The present findings demonstrate that a multimodal approach with a variety of independent evaluation tools is essential to understand and estimate the therapeutic benefit of a nerve repair strategy.
PMCID: PMC3473253  PMID: 22546145
Peripheral nerve injury; Repair strategy; Peripheral nerve regeneration; Neurotmesis; SSI; Sciatic nerve injury; Rat model
12.  Misdirection of regenerating motor axons after nerve injury and repair in the rat sciatic nerve model 
Experimental neurology  2008;211(2):339-350.
Misdirection of regenerating axons is one of the factors that can explain the poor results often found after nerve injury and repair. In this study, we quantified the degree of misdirection and the effect on recovery of function after different types of nerve injury and repair in the rat sciatic nerve model; crush injury, direct coaptation, and autograft repair. Sequential tracing with retrograde labeling of the peroneal nerve before and 8 weeks after nerve injury and repair was performed to quantify the accuracy of motor axon regeneration. Digital video analysis of ankle motion was used to investigate the recovery of function. In addition, serial compound action potential recordings and nerve and muscle morphometry were performed. In our study, accuracy of motor axon regeneration was found to be limited; only 71% (±4.9%) of the peroneal motoneurons were correctly directed 2 months after sciatic crush injury, 42% (±4.2%) after direct coaptation, and 25% (±6.6%) after autograft repair. Recovery of ankle motion was incomplete after all types of nerve injury and repair and demonstrated a disturbed balance of ankle plantar and dorsiflexion. The number of motoneurons from which axons had regenerated was not significantly different from normal. The number of myelinated axons was significantly increased distal to the site of injury. Misdirection of regenerating motor axons is a major factor in the poor recovery of nerves that innervate different muscles. The results of this study can be used as basis for developing new nerve repair techniques that may improve the accuracy of regeneration.
PMCID: PMC2967197  PMID: 18448099
Aberrant reinnervation; Accuracy of regeneration; Ankle motion analysis; Double labeling; Sequential retrograde tracing
13.  A Combination of Schwann-Cell Grafts and Aerobic Exercise Enhances Sciatic Nerve Regeneration 
PLoS ONE  2014;9(10):e110090.
Despite the regenerative potential of the peripheral nervous system, severe nerve lesions lead to loss of target-organ innervation, making complete functional recovery a challenge. Few studies have given attention to combining different approaches in order to accelerate the regenerative process.
Test the effectiveness of combining Schwann-cells transplantation into a biodegradable conduit, with treadmill training as a therapeutic strategy to improve the outcome of repair after mouse nerve injury.
Sciatic nerve transection was performed in adult C57BL/6 mice; the proximal and distal stumps of the nerve were sutured into the conduit. Four groups were analyzed: acellular grafts (DMEM group), Schwann cell grafts (3×105/2 µL; SC group), treadmill training (TMT group), and treadmill training and Schwann cell grafts (TMT + SC group). Locomotor function was assessed weekly by Sciatic Function Index and Global Mobility Test. Animals were anesthetized after eight weeks and dissected for morphological analysis.
Combined therapies improved nerve regeneration, and increased the number of myelinated fibers and myelin area compared to the DMEM group. Motor recovery was accelerated in the TMT + SC group, which showed significantly better values in sciatic function index and in global mobility test than in the other groups. The TMT + SC group showed increased levels of trophic-factor expression compared to DMEM, contributing to the better functional outcome observed in the former group. The number of neurons in L4 segments was significantly higher in the SC and TMT + SC groups when compared to DMEM group. Counts of dorsal root ganglion sensory neurons revealed that TMT group had a significant increased number of neurons compared to DMEM group, while the SC and TMT + SC groups had a slight but not significant increase in the total number of motor neurons.
These data provide evidence that this combination of therapeutic strategies can significantly improve functional and morphological recovery after sciatic injury.
PMCID: PMC4198198  PMID: 25333892
14.  Thermographic evaluation of hind paw skin temperature and functional recovery of locomotion after sciatic nerve crush in rats 
Clinics  2011;66(7):1259-1266.
Peripheral nerves are often damaged by direct mechanical injury, diseases, and tumors. The peripheral nerve injuries that result from these conditions can lead to a partial or complete loss of motor, sensory, and autonomic functions, which in turn are related to changes in skin temperature, in the involved segments of the body. The aim of this study was to evaluate the changes in hind paw skin temperature after sciatic nerve crush in rats in an attempt to determine whether changes in skin temperature correlate with the functional recovery of locomotion.
Wistar rats were divided into three groups: control (n = 7), sham (n = 25), and crush (n = 25). All groups were subjected to thermographic, functional, and histological assessments.
ΔT in the crush group was different from the control and sham groups at the 1st, 3rd and 7rd postoperative days (p<0.05). The functional recovery from the crush group returned to normal values between the 3rd and 4th week post-injury, and morphological analysis of the nerve revealed incomplete regeneration at the 4th week after injury.
This study is the first demonstration that sciatic nerve crush in rats induces an increase in hind paw skin temperature and that skin temperature changes do not correlate closely with functional recovery
PMCID: PMC3148474  PMID: 21876984
Thermography; Skin temperature; Nerve crush; Functional recovery
15.  The differential effects of pathway- versus target-derived glial cell line–derived neurotrophic factor on peripheral nerve regeneration 
Journal of neurosurgery  2010;113(1):1-8.
Glial cell line–derived neurotrophic factor (GDNF) has potent survival effects on central and peripheral nerve populations. The authors examined the differential effects of GDNF following either a sciatic nerve crush injury in mice that overexpressed GDNF in the central or peripheral nervous systems (glial fibrillary acidic protein [GFAP]–GDNF) or in the muscle target (Myo-GDNF).
Adult mice (GFAP-GDNF, Myo-GDNF, or wild-type [WT] animals) underwent sciatic nerve crush and were evaluated using histomorphometry and muscle force and power testing. Uninjured WT animals served as controls.
In the sciatic nerve crush, the Myo-GDNF mice demonstrated a higher number of nerve fibers, fiber density, and nerve percentage (p < 0.05) at 2 weeks. The early regenerative response did not result in superlative functional recovery. At 3 weeks, GFAP-GDNF animals exhibit fewer nerve fibers, decreased fiber width, and decreased nerve percentage compared with WT and Myo-GDNF mice (p < 0.05). By 6 weeks, there were no significant differences between groups.
Peripheral delivery of GDNF resulted in earlier regeneration following sciatic nerve crush injuries than that with central GDNF delivery. Treatment with neurotrophic factors such as GDNF may offer new possibilities for the treatment of peripheral nerve injury.
PMCID: PMC2891941  PMID: 19943736
glial cell line-derived neurotrophic factor; chromophore; transgenic mouse; sciatic nerve crush; peripheral nerve injury; motor endplate; muscle force; power testing
16.  C3 Peptide Promotes Axonal Regeneration and Functional Motor Recovery after Peripheral Nerve Injury 
Neurotherapeutics  2011;9(1):185-198.
Peripheral nerve injuries are frequently seen in trauma patients and due to delayed nerve repair, lifelong disabilities often follow this type of injury. Innovative therapies are needed to facilitate and expedite peripheral nerve regeneration. The purpose of this study was to determine the effects of a 1-time topical application of a 26-amino-acid fragment (C3156-181), derived from the Clostridium botulinum C3-exoenzyme, on peripheral nerve regeneration in 2 models of nerve injury and repair in adult rats. After sciatic nerve crush, different dosages of C3156-181 dissolved in buffer or reference solutions (nerve growth factor or C3bot-wild-type protein) or vehicle-only were injected through an epineurial opening into the lesion sites. After 10-mm nerve autotransplantation, either 8.0 nmol/kg C3156-181 or vehicle were injected into the proximal and distal suture sites. For a period of 3 to 10 postoperative weeks, C3156-181-treated animals showed a faster motor recovery than control animals. After crush injury, axonal outgrowth and elongation were activated and consequently resulted in faster motor recovery. The nerve autotransplantation model further elucidated that C3156-181 treatment accounts for better axonal elongation into motor targets and reduced axonal sprouting, which are followed by enhanced axonal maturation and better axonal functionality. The effects of C3156-181 are likely caused by a nonenzymatic down-regulation of active RhoA. Our results indicate the potential of C3156-181 as a therapeutic agent for the topical treatment of peripheral nerve repair sites.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-011-0072-y) contains supplementary material, which is available to authorized users.
PMCID: PMC3271155  PMID: 21866396
Sciatic nerve; Crush injury; 10-mm nerve gap; Autotransplantation; C3156-181 peptide
17.  C3 Peptide Promotes Axonal Regeneration and Functional Motor Recovery after Peripheral Nerve Injury 
Neurotherapeutics  2011;9(1):185-198.
Peripheral nerve injuries are frequently seen in trauma patients and due to delayed nerve repair, lifelong disabilities often follow this type of injury. Innovative therapies are needed to facilitate and expedite peripheral nerve regeneration. The purpose of this study was to determine the effects of a 1-time topical application of a 26-amino-acid fragment (C3156-181), derived from the Clostridium botulinum C3-exoenzyme, on peripheral nerve regeneration in 2 models of nerve injury and repair in adult rats. After sciatic nerve crush, different dosages of C3156-181 dissolved in buffer or reference solutions (nerve growth factor or C3bot-wild-type protein) or vehicle-only were injected through an epineurial opening into the lesion sites. After 10-mm nerve autotransplantation, either 8.0 nmol/kg C3156-181 or vehicle were injected into the proximal and distal suture sites. For a period of 3 to 10 postoperative weeks, C3156-181-treated animals showed a faster motor recovery than control animals. After crush injury, axonal outgrowth and elongation were activated and consequently resulted in faster motor recovery. The nerve autotransplantation model further elucidated that C3156-181 treatment accounts for better axonal elongation into motor targets and reduced axonal sprouting, which are followed by enhanced axonal maturation and better axonal functionality. The effects of C3156-181 are likely caused by a nonenzymatic down-regulation of active RhoA. Our results indicate the potential of C3156-181 as a therapeutic agent for the topical treatment of peripheral nerve repair sites.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-011-0072-y) contains supplementary material, which is available to authorized users.
PMCID: PMC3271155  PMID: 21866396
Sciatic nerve; Crush injury; 10-mm nerve gap; Autotransplantation; C3156-181 peptide
18.  Acetyl salicylic acid augments functional recovery following sciatic nerve crush in mice 
Cyclin-dependent kinase 5 (CDK-5) appears to play a significant role in peripheral nerve regeneration as CDK-5 inhibition retards nerve regeneration following nerve crush. Anti-inflammatory drug acetyl salicylic acid elevates CDK-5 and reduces ischemia – reperfusion injury in cultured neurons. In this study we have evaluated the effect of acetyl salicylic acid on functional recovery following sciatic nerve crush in mice. Eighteen Swiss albino mice underwent unilateral sciatic nerve crush. Test animals received acetyl salicylic acid (100 mg/kg/day, n = 6 or 50 mg/kg/day, n = 6) and control animals (n = 6) received normal saline for 14 days following surgery. Functional recovery was assessed with improvement in Sciatic Function Index, nociception and gait. In comparison with normal saline treatment, acetyl salicylic acid (100 mg/kg/day) significantly improved functional recovery following sciatic nerve crush. Anti-inflammatory drug acetyl salicylic acid appears to be a promising agent for treating peripheral nerve injuries and hence elucidation of its neuroprotective pathways is necessary.
PMCID: PMC1802865  PMID: 17274829
19.  Prednisolone and acupuncture in Bell's palsy: study protocol for a randomized, controlled trial 
Trials  2011;12:158.
There are a variety of treatment options for Bell's palsy. Evidence from randomized controlled trials indicates corticosteroids can be used as a proven therapy for Bell's palsy. Acupuncture is one of the most commonly used methods to treat Bell's palsy in China. Recent studies suggest that staging treatment is more suitable for Bell's palsy, according to different path-stages of this disease. The aim of this study is to compare the effects of prednisolone and staging acupuncture in the recovery of the affected facial nerve, and to verify whether prednisolone in combination with staging acupuncture is more effective than prednisolone alone for Bell's palsy in a large number of patients.
In this article, we report the design and protocol of a large sample multi-center randomized controlled trial to treat Bell's palsy with prednisolone and/or acupuncture. In total, 1200 patients aged 18 to 75 years within 72 h of onset of acute, unilateral, peripheral facial palsy will be assessed. There are six treatment groups, with four treated according to different path-stages and two not. These patients are randomly assigned to be in one of the following six treatment groups, i.e. 1) placebo prednisolone group, 2) prednisolone group, 3) placebo prednisolone plus acute stage acupuncture group, 4) prednisolone plus acute stage acupuncture group, 5) placebo prednisolone plus resting stage acupuncture group, 6) prednisolone plus resting stage acupuncture group. The primary outcome is the time to complete recovery of facial function, assessed by Sunnybrook system and House-Brackmann scale. The secondary outcomes include the incidence of ipsilateral pain in the early stage of palsy (and the duration of this pain), the proportion of patients with severe pain, the occurrence of synkinesis, facial spasm or contracture, and the severity of residual facial symptoms during the study period.
The result of this trial will assess the efficacy of using prednisolone and staging acupuncture to treat Bell's palsy, and to determine a best combination therapy with prednisolone and acupuncture for treating Bell's palsy.
Trial Registration NCT01201642
PMCID: PMC3132722  PMID: 21693007
20.  Improvement of Painful Bortezomib-Induced Peripheral Neuropathy Following Acupuncture Treatment in a Case Series of Multiple Myeloma Patients 
Medical Acupuncture  2012;24(3):181-187.
Bortezomib-induced peripheral neuropathy (BIPN) is a common and severe dose-limiting side effect in multiple myeloma (MM) patients. Treatment with narcotics, antidepressants, and anticonvulsants are of limited value in reducing symptoms, and they have the potential for significant side effects. Acupuncture has been reported to be effective in treating neuropathic pain. There has been limited reporting on the effect of acupuncture in treating BIPN.
The aim of this study was to report on the effect of acupuncture in treating BIPN.
Design and Patients
This study was a retrospective case series of five MM patients experiencing painful BIPN.
The patients were treated with the same acupuncture protocol on a weekly basis, adjusted to twice a week or once every 2 weeks based on response. Treatment included insertion of disposable sterile acupuncture needles, which were retained for 25 minutes, at the following bilateral ear points: shen men, point zero, and two auricular points where electro-dermal signal was detected; and bilateral body acupuncture points: LI 4, TE 5, LI 11, ST 40, and Ba Feng in the upper and lower extremities.
Main Outcome Measures
All patients were assessed for severity of painful BIPN using a 0–10 numeric pain scale, with one patient assessed using the Clinical Total Neuropathy Score, Functional Assessment of Cancer Therapy-Neurotoxicity questionnaire, and Neuropathy Pain Scale.
All five patients experienced immediate pain reduction after one acupuncture treatment. Two of three patients who had more than three acupuncture treatments experienced long-lasting pain reduction and function improvement. There were no adverse events associated with acupuncture.
Acupuncture is a viable treatment option for MM patients experiencing painful BIPN. However, further prospective research is needed.
PMCID: PMC3579197
Acupuncture; Bortezomib; Peripheral Neuropathy; Multiple Myeloma
21.  Decreased MHC I expression in IFN gamma mutant mice alters synaptic elimination in the spinal cord after peripheral injury 
The histocompatibility complex (MHC) class I expression in the central nervous system (CNS) regulates synaptic plasticity events during development and adult life. Its upregulation may be associated with events such as axotomy, cytokine exposition and changes in neuron electrical activity. Since IFNγ is a potent inducer of the MHC I expression, the present work investigated the importance of this pro-inflammatory cytokine in the synaptic elimination process in the spinal cord, as well as the motor recovery of IFN−/−, following peripheral injury.
The lumbar spinal cords of C57BL/6J (wild type) and IFNγ−/− (mutant) mice, subjected to unilateral sciatic nerve transection, were removed and processed for immunohistochemistry and real time RT-PCR, while the sciatic nerves from animals subjected to unilateral crush, were submitted to immunohistochemistry and electron microscopy for counting of the axons. Gait recovery was monitored using the Cat Walk system. Newborn mice astrocyte primary cultures were established in order to study the astrocytic respose in the absence of the IFNγ expression.
IFNγ−/− mutant mice showed a decreased expression of MHC I and β2-microglobulin mRNA coupled with reduced synaptophysin immunolabelling in the lesioned spinal cord segment. Following unilateral nerve transection, the Iba-1 (ionized calcium binding adaptor molecule 1) and glial fibrillary acid protein (GFAP) reactivities increased equally in both strains. In vitro, the astrocytes demonstrated similar GFAP levels, but the proliferation rate was higher in the wild type mice. In the crushed nerves (distal stump), neurofilaments and p75NTR immunolabeling were upregulated in the mutant mice as compared to the wild type and an improvement in locomotor recovery was observed.
The present results show that a lack of IFNγ affects the MHC I expression and the synaptic elimination process in the spinal cord. Such changes, however, do not delay peripheral nerve regeneration after nerve injury.
PMCID: PMC3409034  PMID: 22564895
22.  Therapy of unspecific tinnitus without organic cause 
There is a variety of medical and non-medical therapies in practice, which were not evaluated regarding its effectiveness by any systematic evidence oriented investigation.
A number of therapies of medical and non-medical type try to treat the different types of tinnitus. The evidence in the scientific literature also had to be cleared in the field of diagnosis and classification as well as medical/psychiatric/psychological procedures of existing medical therapy.
The HTA report had to investigate the following questions:
Which evidence do diagnostic methods in recognition of tinnitus have? Which types of therapy show medical effectiveness at the acute or chronic tinnitus without an organic cause? Which consequences (need for further research, future procedures) can be drawn?
In the following databases "tinnitus" was searched according to the search string:
HTA97; INAHTA; CDAR94; CDSR93; CCTR93; ME66; ME0A; HT83; SM78; CA66; CB85; BA70; BA93; EM74; IS74; ET80; EB94; IA70; AZ72; CV72; GE79; EU93; HN69; ED93; EA08
Result: 1932 studies, unsorted after assessment in accordance with EBM criterions, selection: 409 studies.
Due to the completely heterogeneous representation modes of the therapeutic approaches at the treatment of the chronic tinnitus no quantitative synthesis method could be performed. Therefore the methodology of a qualitative overview has been carried out.
The diagnostic confirmation of the non-specific tinnitus without organic cause meets with the problem of the assurance of the diagnosis tinnitus. According to the current opinion the stepwise diagnostics is carried out also in the case of the so called subjective tinnitus. Nothing can be said about the evidence of these procedures since no publication was found about that. A study concerning the evidence of the diagnostic questionnaires from Goebel and Hiller [1] comes to the end that the tinnitus questionnaire frequently used (TF) [2] is the best evaluated procedure.
The number of therapies which treat tinnitus is exceptionally high and makes clear, that the search for "the" tinnitus therapy is still going on. According to the current knowledge tinnitus genesis is multifactorial and therefore there can’t be any standard therapy for tinnitus. The following seven categories can be distinguished:
Ad 1: Machine-aided acoustic therapies
From many studies regarding machine-aided acoustic therapy of tinnitus only two showed an evidence degree that allows scientifically correct statements about the effectiveness of these procedures. Selectively significant improvements could be shown in the comparison with a placebo (apparatus switched off) a superiority of tinnitus-maskers.
Ad 2: Electrostimulation
In an application study of electro-stimulation the results were not evaluated statistically, but it was described descriptively that a successful medical treatment can be expected in about 50% of the cases.
Ad 3: Psychological therapy procedures
Hypnosis did not show positive effectiveness. With regard to biofeedback it can be concluded that this method can be effective in individual cases, however regarded as unreliable from missing reproducibility. Neurobiofeedback could prove that it had a positive therapeutic effect.
From eight controlled studies to relaxation techniques and cognitive behaviour therapy four studies showed a therapeutic effectiveness and four failed. Combined therapies proved generally to be more effective than individual types.
The behaviour medical psychotherapy could show a positive therapy effect. In a study with cognitive therapy and relaxation (three groups, a passive relaxation, an active relaxation and a cognitive therapy) short-term successes could be stated (for one month), however, the parameters of success returned on the initial value after four months.
Also only coincidental and short-term successes could be achieved with cognitive behaviour therapy training, autogenic training and structured group psychotherapy.
Ad 4: Tinnitus Retraining Therapy (TRT)
Unfortunately, the published results of the TRT are methodically frequently bad and scientific of a poor value. Many of the studies presented until now regarding tinnitus retraining therapy are not informative in their scientific context.
In a study with 95 patients with a chronic tinnitus TRT could show a significant, more than six months lasting stable success by comparison to a combination of TET with group behaviour therapy (improvement be achieved around at least ten points in the tinnitus questionnaire (TF)).
Ad 5: Pharmacological therapies
Rheological drugs (medicines for hemodilution) could not show any statistically significant effect in the treatment of tinnitus.
Studies to the medical treatment with tocainides (lidocaine) showed repeatable positive effects on tinnitus in higher dosages (as of 1.2 mg/day). Lamotrigine as a medicine had an effect positively only at with a small fraction of patients. Two studies with GABA receptor agonists could not prove therapeutic effects for tinnitus. Undesired side-effects were observed. Injections with Carvoverine (a glutamate antagonist) achieved significantly successes with a special form of tinnitus, the “Cochlear-synaptic tinnitus (CST)".
A tricyclic antidepressant (Amitriptilin) could prove superiority against placebo. This effect could be confirmed in another study. However Clonazepame (a benzodiazepine), could not achieve any improvement. Short-term improvements were achieved with other benzodiazepines (Clonazepame, Diazepam, Flurazepame, Oxacepame and Alprazolame).
A German retrospective study suggests a graded pharmacological therapy by means of rheological infusion therapy, applications of neurotransmitters, and injections of lidocaine. This method achieved a disappearance or a recovery of the complaints at 95.3% of the acute and 26.7% of the chronic cases.
Ad 6: Surgical procedures
The effects of the operative excision of the stapes (stapedectomy) showed significant effects concerning tinnitus. This method is a routine operation to recover hearing, effects on tinnitus were observed only coincidently.
There are generally high frequencies of improvements of tinnitus after cochlea implantations; however the risk of deterioration is present with this method.
Ad 7: Other and alternative therapy procedures
The hyperbaric oxygen therapy can be considered successful after acute events with tinnitus. The therapy should be started in the first month after appearance of the tinnitus.
The methods transcranial-, electromagnetic and transcutaneous nerve stimulations did not show any significant effects on tinnitus. Also low laser medical treatment showed disappointing effects.
The “pneumatic external contra-pulsation” is described as an unproblematic usable procedure by the authors of the examination, but 10% of the patients had to stop the medical treatment because of complications associated with the medical treatment.
Acupuncture showed significant improvements in comparison to medical treatment. The effectiveness of this therapy could not be reproduced in another study. Five other studies between 1993 and 1999 also did not show any therapeutic effect of this method. Gingko-Biloba preparations did not show any positive effects in large-scale studies on tinnitus.
Neither the diagnostic procedures nor the therapeutic methods or the individual therapies reach a usual scientific level in medicine. Unsolved problems concerning insurance, economic as well as legal problems have resulted for the patients and for caring stuff from this unsatisfactory situation.
Numerous competitive tinnitus emergence models led to an incredible creativity in trying out different therapy approaches. No convergence of the therapy procedures can be seen within the last decades of tinnitus research, contrariwise there is always more and more “creativity” of new approaches.
Priority has to be given to find the cause of tinnitus since therapies are a consequence of a better understanding of these symptoms that evidence oriented investigations on an usual scientific level can be started.
The innumerable therapeutic approaches, seeming completely incoherent to their effects should be coordinated on the meaningfulness, on the success parameters and with patient safety in light of the most plausible explanation models for non-specific chronic Tinnitus. To this the facilities of competence centres or related science- directing facilities are recommendable.
Examinations which are carried out also with small numbers show often methodical insufficiencies. It is necessary that minimal requirements on a scientifically clinical experiment, such as design, case number calculation, analytic statistics, control group, are fulfilled.
It is recommendable, that further research has to be promoted regarding tinnitus causes that a coordinated evidence-orientated treatment will be developed.
PMCID: PMC3011356  PMID: 21289968
23.  Characterization of the "deqi" response in acupuncture 
Acupuncture stimulation elicits deqi, a composite of unique sensations that is essential for clinical efficacy according to traditional Chinese medicine (TCM). There is lack of adequate experimental data to indicate what sensations comprise deqi, their prevalence and intensity, their relationship to acupoints, how they compare with conventional somatosensory or noxious response. The objective of this study is to provide scientific evidence on these issues and to characterize the nature of the deqi phenomenon in terms of the prevalence of sensations as well as the uniqueness of the sensations underlying the deqi experience.
Manual acupuncture was performed at LI4, ST36 and LV3 on the extremities in randomized order during fMRI in 42 acupuncture naïve healthy adult volunteers. Non-invasive tactile stimulation was delivered to the acupoints by gentle tapping with a von Frey monofilament prior to acupuncture to serve as a sensory control. At the end of each procedure, the subject was asked if each of the sensations listed in a questionnaire or any other sensations occurred during stimulation, and if present to rate its intensity on a numerical scale of 1–10. Statistical analysis including paired t-test, analysis of variance, Spearman's correlation and Fisher's exact test were performed to compare responses between acupuncture and sensory stimulation.
The deqi response was elicited in 71% of the acupuncture procedures compared with 24% for tactile stimulation when thresholded at a minimum total score of 3 for all the sensations. The frequency and intensity of individual sensations were significantly higher in acupuncture. Among the sensations typically associated with deqi, aching, soreness and pressure were most common, followed by tingling, numbness, dull pain, heaviness, warmth, fullness and coolness. Sharp pain of brief duration that occurred in occasional subjects was regarded as inadvertent noxious stimulation. The most significant differences in the deqi sensations between acupuncture and tactile stimulation control were observed with aching, soreness, pressure and dull pain. Consistent with its prominent role in TCM, LI4 showed the most prominent response, the largest number of sensations as well as the most marked difference in the frequency and intensity of aching, soreness and dull pain between acupuncture and tactile stimulation control. Interestingly, the dull pain generally preceded or occurred in the absence of sharp pain in contrast to reports in the pain literature. An approach to summarize a sensation profile, called the deqi composite, is proposed and applied to explain differences in deqi among acupoints.
The complex pattern of sensations in the deqi response suggests involvement of a wide spectrum of myelinated and unmyelinated nerve fibers, particularly the slower conducting fibers in the tendinomuscular layers. The study provides scientific data on the characteristics of the 'deqi' response in acupuncture and its association with distinct nerve fibers. The findings are clinically relevant and consistent with modern concepts in neurophysiology. They can provide a foundation for future studies on the deqi phenomenon.
PMCID: PMC2200650  PMID: 17973984
24.  Pain and sensory detection threshold response to acupuncture is modulated by coping strategy and acupuncture sensation 
Acupuncture has been shown to reduce pain, and acupuncture-induced sensation may be important for this analgesia. In addition, cognitive coping strategies can influence sensory perception. However, the role of coping strategy on acupuncture modulation of pain and sensory thresholds, and the association between acupuncture sensation and these modulatory effects, is currently unknown.
Electroacupuncture (EA) was applied at acupoints ST36 and GB39 of 61 healthy adults. Different coping conditions were experimentally designed to form an active coping strategy group (AC group), who thought they could control EA stimulation intensity, and a passive coping strategy group (PC group), who did not think they had such control. Importantly, neither group was actually able to control EA stimulus intensity. Quantitative sensory testing was performed before and after EA, and consisted of vibration (VDT), mechanical (MDT), warm (WDT), and cold (CDT) detection thresholds, and pressure (PPT), mechanical (MPT), heat (HPT) and cold (CPT) pain thresholds. Autonomic measures (e.g. skin conductance response, SCR) were also acquired to quantify physiological response to EA under different coping conditions. Subjects also reported the intensity of any acupuncture-induced sensations.
Coping strategy was induced with successful blinding in 58% of AC subjects. Compared to PC, AC showed greater SCR to EA. Under AC, EA reduced PPT and CPT. In the AC group, improved pain and sensory thresholds were correlated with acupuncture sensation (VDTchange vs. MI: r=0.58, CDTchange vs. tingling: r=0.53, CPTchange vs. tingling; r=0.55, CPTchange vs. dull; r=0.55). However, in the PC group, improved sensory thresholds were negatively correlated with acupuncture sensation (CDTchange vs. intensity sensitization: r=-0.52, WDTchange vs. fullness: r=-0.57).
Our novel approach was able to successfully induce AC and PC strategies to EA stimulation. The interaction between psychological coping strategy and acupuncture sensation intensity can differentially modulate pain and sensory detection threshold response to EA. In a clinical context, our findings suggest that instructions given to the patient can significantly affect therapeutic outcomes and the relationship between acupuncture intensity and clinical response. Specifically, acupuncture analgesia can be enhanced by matching physical stimulation intensity with psychological coping strategy to acupuncture contexts.
Trial registration
Electronic supplementary material
The online version of this article (doi:10.1186/1472-6882-14-324) contains supplementary material, which is available to authorized users.
PMCID: PMC4167271  PMID: 25175308
Coping strategy; Acupuncture; Acupuncture sensation; Pain; Sensory threshold
25.  Low back pain (acute) 
Clinical Evidence  2008;2008:1102.
Low back pain (LBP) affects about 70% of people in resource-rich countries at some point. Acute low back pain is usually perceived as self-limiting; however, one year later, as many as 33% of people still have moderate-intensity pain and 15% have severe pain. It has a high recurrence rate; 75% of those with a first episode have a recurrence. Although acute episodes may resolve completely, they may also increase in severity and duration over time.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of oral drug treatments for low back pain? What are the effects of local injections for low back pain? What are the effects of non-drug treatments for low back pain? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 34 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, advice to stay active, analgesics (paracetamol, opioids), back exercises, back schools, bed rest, behavioural therapy, electromyographic biofeedback, epidural corticosteroid injections, lumbar supports, massage, multidisciplinary treatment programmes, muscle relaxants, non-steroidal anti-inflammatory drugs (NSAIDs), spinal manipulation (in the short term), temperature treatments (short wave diathermy, ultrasound, ice, heat), traction, and transcutaneous electrical nerve stimulation (TENS).
Key Points
Low back pain is pain, muscle tension, or stiffness, localised below the costal margin and above the inferior gluteal folds, with or without referred or radicular leg pain (sciatica), and is defined as acute when pain persists for less than 12 weeks. Low back pain affects about 70% of people in resource-rich countries at some point.Acute low back pain is usually self-limiting, although 2-7% develop chronic pain. Acute low back pain has a high recurrence rate with less-painful symptoms recurring in 50-80% of people within a year; one year later, as high as 33% still experience moderate-intensity pain and 15% experience severe pain.
NSAIDs have been shown to effectively improve symptoms compared with placebo. However, their use is associated with gastrointestinal adverse effects. Muscle relaxants may also reduce pain and improve overall clinical assessment, but are associated with some severe adverse effects including drowsiness, dizziness, and nausea.The studies examining the effects of analgesics such as paracetamol or opioids were generally too small to detect any clinically important differences.
We found no studies examining the effectiveness of epidural injections of corticosteroids in treating people with acute low back pain.
With regard to non-drug treatments, advice to stay active (be it as a single treatment or in combination with other interventions such as back schools, a graded activity programme, or behavioural counselling) seems the most effective. Spinal manipulation (in the short term) also seems to reduce pain, but not functional outcomes, compared with sham treatments.We found insufficient evidence to judge the effectiveness of acupuncture, back schools, behavioural therapy, massage, multidisciplinary treatment programmes (for either acute or subacute low back pain), ortemperature treatments in treating people with acute low back pain.We found no evidence examining the effectiveness of electromyographic biofeedback, lumbar supports, traction, or TENS in the treatment of acute low back pain. Back exercises do not seem to increase recovery time compared with no treatment, although there is considerable heterogeneity among studies with regard to the definition of back exercise. There is also disparity among studies in the definition of generic and specific back exercise. Bed rest does not improve symptoms any more effectively than other treatments, but does produce a number of adverse effects including joint stiffness, muscle wasting, loss of bone mineral density, pressure sores, and venous thromboembolism.
PMCID: PMC2907975  PMID: 19445792

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