Neuropathy – Neuropathic Pain

J Neurosurg. 2018 May 18:1-12. doi: 10.3171/2017.12.JNS171333. [Epub ahead of print]

Added value of multiple versus single sessions of repetitive transcranial magnetic stimulation in predicting motor cortex stimulation efficacy for refractory neuropathic pain.

Pommier B1,2, Quesada C3,2, Fauchon C2, Nuti C1,2, Vassal F1, Peyron R4,2.

Author information

1
Service de Neurochirurgie.
2
INSERM U1028, UMR5292 Intégration Centrale de la Douleur chez l’Homme Centre de Recherche en Neurosciences de Lyon, Université Claude Bernard Lyon 1 & Université Jean Monnet, Saint-Etienne, France.
3
Centre d’Evaluation et de Traitement de la Douleur, Centre Hospitalier Régional Universitaire, Saint-Etienne; and.
4
Service de Neurologie.

Abstract

OBJECTIVE Selection criteria for offering patients motor cortex stimulation (MCS) for refractory neuropathic pain are a critical topic of research. A single session of repetitive transcranial magnetic stimulation (rTMS) has been advocated for selecting MCS candidates, but it has a low negative predictive value. Here the authors investigated whether multiple rTMS sessions would more accurately predict MCS efficacy. METHODS Patients included in this longitudinal study could access MCS after at least four rTMS sessions performed 3-4 weeks apart. The positive (PPV) and negative (NPV) predictive values of the four rTMS sessions and the correlation between the analgesic effects of the two treatments were assessed. RESULTS Twelve MCS patients underwent an average of 15.9 rTMS sessions prior to surgery; nine of the patients were rTMS responders. Postoperative follow-up was 57.8 ± 15.6 months (mean ± standard deviation). Mean percentage of pain relief (%R) was 21% and 40% after the first and fourth rTMS sessions, respectively. The corresponding mean durations of pain relief were respectively 2.4 and 12.9 days. A cumulative effect of the rTMS sessions was observed on both %R and duration of pain relief (p < 0.01). The %R value obtained with MCS was 35% after 6 months and 43% at the last follow-up. Both the PPV and NPV of rTMS were 100% after the fourth rTMS session (p = 0.0045). A significant correlation was found between %R or duration of pain relief after the fourth rTMS session and %R at the last MCS follow-up (R2 = 0.83, p = 0.0003). CONCLUSIONS Four rTMS sessions predicted MCS efficacy better than a single session in neuropathic pain patients. Taking into account the cumulative effects of rTMS, the authors found a high-level correlation between the analgesic effects of rTMS and MCS.

KEYWORDS:

%R MCS = percentage of pain relief following MCS; %R rTMS = percentage of pain relief following rTMS; LEP = laser evoked potential; MCS; MCS = motor cortex stimulation; MEP = motor evoked potential; NPV = negative predictive value; NRS = Numerical Rating Scale; PPV = positive predictive value; ROC = receiver operating characteristic; SSEP = somatosensory evoked potential; central pain; motor cortex stimulation; neuropathic pain; rTMS; rTMS = repetitive transcranial magnetic stimulation; repetitive transcranial magnetic stimulation

Oncotarget. 2017 Jan 3;8(1):1110-1116. doi: 10.18632/oncotarget.13584.

The change of HCN1/HCN2 mRNA expression in peripheral nerve after chronic constriction injury induced neuropathy followed by pulsed electromagnetic field therapy.

Liu H1,2, Zhou J3, Gu L1, Zuo Y2.

Author information

1
Department of Anesthesiology, Jiangsu Cancer Hospital, Jiangsu 210009, China.
2
Department of Anesthesiology, West China Hospital, Sichuan University, Sichuan 610041, China.
3
Department of Rehabilitation, West China Hospital, Sichuan University, Sichuan 610041, China.

Abstract

Neuropathic pain is usually defined as a chronic pain state caused by peripheral or central nerve injury as a result of acute damage or systemic diseases. It remains a difficult disease to treat. Recent studies showed that the frequency of action potentials in nociceptive afferents is affected by the activity of hyperpolarization-activated cyclic nucleotide-gated cation channels (HCN) family. In the current study, we used a neuropathy rat model induced by chronic constriction injury (CCI) of sciatic nerve to evaluate the change of expression of HCN1/HCN2 mRNA in peripheral nerve and spinal cord. Rats were subjected to CCI with or without pulsed electromagnetic field (PEMF) therapy. It was found that CCI induced neural cell degeneration while PEMF promoted nerve regeneration as documented by Nissl staining. CCI shortened the hind paw withdrawal latency (PWL) and hind paw withdrawal threshold (PWT) and PEMF prolonged the PWL and PWT. In addition, CCI lowers the expression of HCN1 and HCN2 mRNA and PEMF cannot restore the expression of HCN1 and HCN2 mRNA. Our results indicated that PEMF can promote nerve regeneration and could be used for the treatment of neuropathic pain.

KEYWORDS:

chronic constriction injury (CCI); hyperpolarization-activated cyclic nucleotide-gated cation channels (HCN); pulsed electromagnetic field (PEMF)

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PLoS One. 2013; 8(4): e61414.
Published online 2013 Apr 18. doi:  10.1371/journal.pone.0061414
PMCID: PMC3630223
PMID: 23637830

Therapeutic Effects of 15 Hz Pulsed Electromagnetic Field on Diabetic Peripheral Neuropathy in Streptozotocin-Treated Rats

Tao Lei,# 1 Da Jing,# 1 Kangning Xie,# 1 Maogang Jiang, 1 Feijiang Li, 1 Jing Cai, 2 Xiaoming Wu, 1 Chi Tang, 1Qiaoling Xu, 3 Juan Liu, 1 Wei Guo, 1 Guanghao Shen, 1 , * and Erping Luo 1 , *
Maria Rosaria Scarfi, Editor
1 School of Biomedical Engineering, Fourth Military Medical University, Xi’an, China,
2 Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, China,
3 School of Nursing, Fourth Military Medical University, Xi’an, China,
National Research Council, Italy,
#Contributed equally.
* E-mail: moc.361@nehshg (GS); moc.liamtoh@oulgnipre (EL)
Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: DJ GS EL TL KX. Performed the experiments: TL MJ FL JC. Analyzed the data: TL MJ. Contributed reagents/materials/analysis tools: XW CT QX JL WG. Wrote the paper: TL KX.

Author information ? Article notes ? Copyright and License information ? Disclaimer
Received 2012 Dec 11; Accepted 2013 Mar 8.

Abstract

Although numerous clinical studies have reported that pulsed electromagnetic fields (PEMF) have a neuroprotective role in patients with diabetic peripheral neuropathy (DPN), the application of PEMF for clinic is still controversial. The present study was designed to investigate whether PEMF has therapeutic potential in relieving peripheral neuropathic symptoms in streptozotocin (STZ)-induced diabetic rats. Adult male Sprague–Dawley rats were randomly divided into three weight-matched groups (eight in each group): the non-diabetic control group (Control), diabetes mellitus with 15 Hz PEMF exposure group (DM+PEMF) which were subjected to daily 8-h PEMF exposure for 7 weeks and diabetes mellitus with sham PEMF exposure group (DM). Signs and symptoms of DPN in STZ-treated rats were investigated by using behavioral assays. Meanwhile, ultrastructural examination and immunohistochemical study for vascular endothelial growth factor (VEGF) of sciatic nerve were also performed. During a 7-week experimental observation, we found that PEMF stimulation did not alter hyperglycemia and weight loss in STZ-treated rats with DPN. However, PEMF stimulation attenuated the development of the abnormalities observed in STZ-treated rats with DPN, which were demonstrated by increased hind paw withdrawal threshold to mechanical and thermal stimuli, slighter demyelination and axon enlargement and less VEGF immunostaining of sciatic nerve compared to those of the DM group. The current study demonstrates that treatment with PEMF might prevent the development of abnormalities observed in animal models for DPN. It is suggested that PEMF might have direct corrective effects on injured nerves and would be a potentially promising non-invasive therapeutic tool for the treatment of DPN.

Introduction

Diabetic peripheral neuropathy (DPN) is generally considered to be one of the most common complications of diabetes mellitus, affecting both types of diabetes equally . Studies suggest that about 30% of patients with diabetes mellitus are affected by DPN and 16–26% of diabetic patients experience chronic pain .

DPN is characterized by aberrant symptoms of stimulus-evoked pain including allodynia and hyperalgesia , and it often leads to mood and sleep disturbance, and thus can substantially impair the quality and expectancy of life . Therefore, it imposes a huge burden on both individuals and society, and represents a major public health problem. However, beyond the careful management of the diabetes itself via glycemic control and pain relief for neuropathy, no treatment for DPN exists . Potential toxicity, poor tolerability and ineffectiveness for some percent of diabetic patients are major disadvantages of the current therapeutic options. For this reason, there is a need to explore other non-pharmacological novel therapeutic modalities with efficacy and safety, particularly when diabetic patients require a combined treatment with an oral antidiabetic drug to prevent the development of DPN.

Numerous clinical studies have reported that pulsed electromagnetic fields (PEMF) are able to modify some parameters of nerve function in diabetic patients , and a voluminous amount of literature has suggested that PEMF can stimulate nerve growth, regeneration, and functional recovery of nerves in cells in vitro or in animal models with nerve disease . However, the application of PEMF for clinic is still controversial . Therefore, more research is needed to confirm the therapeutic effects of PEMF on DPN and then to justify the applicability of PEMF for clinical practice. Since few studies have examined the effects of PEMF on neuropathy induced by diabetes mellitus in animals at present, this study aimed to test whether PEMF has therapeutic potential in relieving diabetes-induced neuropathy in animals.

Streptozotocin (STZ)-induced diabetic rat model has been used extensively as a model of DPN to demonstrate many abnormalities observed in patients with DPN and to assess the efficacies of potential therapeutic interventions . Diabetic rats develop tactile allodynia and hyperalgesia to mechanical or thermal stimuli in the hind paws two or three weeks after STZ injection . In the current study, we examined the effects of whole-body exposure to 15 Hz PEMF whose peak magnetic flux density (MFD) was approximately 1.6×10?3 T on improving signs and symptoms of DPN in STZ-treated rats by using behavioral assays. The PEFM was generated by a modified Helmholtz coils and the exposure duration was 8 hours everyday, 6 days a week for 7 weeks. Meanwhile, ultrastructural examination and immunohistochemical study for vascular endothelial growth factor (VEGF) of sciatic nerve were also performed seven weeks after PEMF stimulation. Moreover, the potential action mechanism of PEMF on DPN was preliminarily investigated.

Methods

Experimental Diabetes

Thirty adult male Sprague–Dawley rats, weighting 350±20 g, were provided by Animal Center of the Fourth Military Medical University and housed in a room (Animal Center of the Fourth Military Medical University, Xi’an, China) with controlled temperature (23±1°C), relative humidity (50?60%), and alternately light-dark cycle (12 h/12 h), with access to standard pellet and clean water. Diabetes mellitus was induced by an intraperitoneal injection of STZ (Sigma Chemicals, St. Louis, MO, USA) at 45 mg/kg in freshly prepared 0.1 mM citrate buffer (pH 4.5) after an overnight fast . Confirmation of hyperglycemia was made three days after STZ injection, and only STZ-treated rats whose glucose concentration of the tail venous blood measured by OneTouch SureStep Plus glucometer (Lifescan, Milpitas, CA, USA) was higher than 20 mM were considered as qualified diabetic models . Six rats were excluded from the study after confirmation of success of diabetic models because of low blood glucose levels. The rest of rats were randomized into three weight-matched groups (eight in each group): the non-diabetic control group (Control), diabetes mellitus with sham PEMF exposure group (DM), diabetes mellitus with PEMF exposure group (DM+PEMF) which were subjected to whole-body exposure to PEMF 8 hours (09:00–17:00) everyday, 6 days a week for 7 weeks. Although the same PEMF apparatus was employed in DM group, the PEMF stimulation was not activated. PEMF stimulation was carried out the next day after confirmation of hyperglycemia. The current study was performed in adherence to the National Institutes of Health guidelines for the use of experimental animals, and all animal protocols were approved by the Committee for Ethical Use of Experimental Animals of the Fourth Military Medical University.

PEMF Apparatus

Three identical coils with coil diameters of 800 mm constituted the PEMF stimulation apparatus (the modified Helmholtz coils). The coils were in series connection and placed coaxially with a distance of 304 mm apart (Fig. 1A). Each coil was made up of enameled coated copper wire with 0.8 mm diameter. The assembly of three identical coils significantly upgraded the uniformity of MFD by decreasing the deviation of the MFD between the central reference point (origin, center of the middle coil) and other areas in the magnetic field .

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Schematic drawing of PEMF exposure system and PEMF pulse protocol.

(A) Modified Helmholtz coils consisted of three identical coils with diameters of 800 mm which were in series connection and mounted coaxially at a distance of 304 mm apart. Two cubic plastic rat cages whose length was along O–Y direction (Origin is the center of the middle coil, O–X direction is the axial direction of the coil and the coordinate system meets right-hand rule) were put in the center of every two neighboring coils and cages were supported by stands to let the activities of rats restrict on the XY plane. The modified Helmholtz coils were wired to the GHY-III pulse generator. (B) The pulse stimulator (GHY-III) generated an open-circuit voltage waveform of PEMF with a repetitive burst frequency at 15 Hz (burst width, 5 ms; burst wait, 60 ms; pulse width, 0.2 ms; pulse wait, 0.02 ms; pulse rise and fall time: 0.3 µs, 2.0 µs).

The MFD value along the O–X direction (axial direction of the coil, the coordinate system meets right-hand rule) is expressed as:

equation image

Where An external file that holds a picture, illustration, etc.
Object name is pone.0061414.e002.jpg is the permeability of vacuum, I is the current through the coils, R is the radius of the coils, An external file that holds a picture, illustration, etc.
Object name is pone.0061414.e003.jpg is the distance between the central coil and the outside coil, An external file that holds a picture, illustration, etc.
Object name is pone.0061414.e004.jpg is the abscissa relative to origin, N is the number of turns of the outside coil, and k×N is the number of turns of the middle coil. By setting the parameters An external file that holds a picture, illustration, etc.
Object name is pone.0061414.e005.jpg?=?0.7601R and k?=?0.5315, the second and fourth derivative of B(x) will become zero at the position of origin and then the maximum uniformity of the MFD will be obtained . In the present study, we set the number of turns of the two outside coils as 500. Therefore, the number of turns of the central coil has been determined as 266. Besides, the distance between the central coil and the outside coil was approximately 304 mm. The modified Helmholtz coils were wired to a pulse generator (GHY-III, FMMU, Xi’an, China; China Patent no.ZL02224739.4) which produced a PEMF signal (Fig. 1A). The open-circuit voltage waveform of the PEFM consisted of a pulsed burst (burst width, 5 ms; burst wait, 60 ms; pulse width, 0.2 ms; pulse wait, 0.02 ms; pulse rise and fall time: 0.3 µs, 2.0 µs ) repeated at 15 Hz (Fig. 1B). The reason for selecting this particular waveform was that it had been proven to be effective in diabetes-induced diseases in our previous studies which were performed by our study group over a long period of time .

Two cubic plastic rat cages containing rats in PEFM group were put in the center of every two neighboring coils (the length of the cage was along O-Y direction) and cages were supported by stands to let the activities of rats restrict on the XY plane which had higher intensity and better uniformity of MFD (Fig. 1A). Moreover, whole body exposure to PEMF for rats was applied eight hours everyday. The distribution of the peak MFD was measured by using a Gaussmeter (Model 455 DMP Gaussmeter, Lake Shore Cryotronics, USA), and the measurement result was (1.6±0.1)×10?3 T (average ± standard deviation) in the exposure area (cage: 50 cm long, 20 cm wide and 15 cm high).

A small resistor of 2 ? was placed in series with the modified Helmholtz coils. The voltage drop across the resistor was observed with an oscilloscope (Agilent 6000 Series, Agilent Technologies, Inc., Santa Clara, CA). Peak value of voltage drop was observed to calculate the peak value of current in the coils so as to obtain the peak value of MFD. In order to make the distribution of MFD in the modified Helmholtz coils more intuitive, the finite element engineering software called COMSOL Multiphysics (v4.3 COMSOL AB, Burlington, MA, USA) was applied to simulate the three dimensional distribution of the MFD in the modified Helmholtz coils when the current in the coils reached peak value (approximately 1.5A). A physics-controlled mesh setting whose element size is coarse was employed to avoid memory overflow caused by too many mesh elements. By establishing the geometric model, setting boundary conditions, meshing models and obtaining numerical solutions, the distributions of MFD of modified Helmholtz coils are shown in Fig. 2. We can find that the MFD on rats’ behavior plane (XY plane) was uniform and the peak MFD was about 1.6×10?3 T which approximately coincided with the practical measurement result ((1.6±0.1)×10?3 T).

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The three dimensional distribution of peak MFD at XY plane (the activity plane of rats) of modified Helmholtz coils and two dimensional distribution of peak MFD on O–X and O–Y cut line of XY plane when the current in the coils reached peak value (approximately 1.5 A).

(A) Three dimensional distribution of peak MFD at XY plane of modified Helmholtz coils whose homogeneous color (blue) indicates the peak MFD at XY plane was uniform and approximately 1.6×10?3 T and red arrows indicates the instantaneous direction of MFD. (B) Two dimensional distribution of peak MFD on O–X cut line of XY plane whose major parts at the activity plane of rats was uniform and approximately 1.6×10?3 T. (C) Two dimensional distribution of peak MFD on O–Y cut line of XY plane whose major parts at the activity plane of rats was uniform and approximately 1.6×10?3 T.

Evaluation of Mechanical Allodynia

Tactile allodynia was assessed by measuring the hind paw withdrawal threshold to the application of a calibrated series of 6 von Frey filaments (bending forces of 2, 4, 6, 8, 10 and 15 g) (Stoelting, Wood Dale, IL, USA) using a modification of the up-down method . Rats were placed in acrylic cages with a wire grid ?oor and allowed to sit in a quiet room for 30 min before beginning the tests. Starting with the filament that has the lowest force (2 g), the filament was applied perpendicularly to the mid-plantar surface of hind paw with sufficient force to cause the filament to buckle slightly. Brisk withdrawal or hind paw flinching was considered as the positive response. Each filament was applied five times to each hind paw (for 6–8 s per stimulation, with a stimulus interval of 1–2 min). Minimum recording of five positive responses (50%) out of 10 stimulations for both paws was considered to be the mechanical withdrawal threshold (MWT) (in grams). Absence of a response (less than five withdrawals) prompted use of the next graded filament. The cut-off of a 15 g filament was selected as the upper limit for testing, since stiffer filaments tended to raise the entire limb rather than to buckle, substantially changing the nature of the stimulus. A significant decrease in the threshold of hind paw withdrawal in response to the mechanical stimulus was interpreted as indicating the presence of mechanical allodynia as compared to the baseline threshold.

Evaluation of Thermal Hyperalgesia

The thermal stimulation system (Commat, Ankara, Turkey) consisting of a clear plastic chamber (10×20×24 cm3) that sits on a clear smooth glass ?oor was used to assess thermal hyperalgesia by measuring nociceptive thermal threshold. Before beginning the test, rats were placed individually in the chamber and allowed approximately 30 min to acclimate to the testing environment. A radiant heat source (8 V, 50 W halogen bulb) mounted on a movable holder below a glass pane was positioned to deliver a thermal stimulus to the mid-plantar region of the hind paw. The intensity of the heat stimulus was maintained constant throughout all experiments. When the rat feels pain and withdraws its paw, a photocell detects interruption of a light beam re?ection, the infrared generator is automatically switched off, and the timer stops, determining the withdrawal threshold. Each rat was unilaterally tested three times at 3-min interval. The average of the three measurements was taken as thermal withdrawal threshold (TWT). In order to avoid excessive suffering of rats, the thermal source was automatically discontinued after 25 s (cut-off latency) if the rat fails to withdraw its paw. A significant decrease in the latency of hind paw withdrawal in response to the noxious thermal stimulus was interpreted as indicating the presence of thermal hyperalgesia as compared to the baseline latency.

Time Course for Measurements of Weight, Blood Glucose, Mechanical Allodynia and Thermal Hyperalgesia

The weights, blood glucose levels and responses to mechanical and thermal stimuli of all rats were evaluated prior to STZ administration, and there were no statistically significant differences for these parameters among three groups. Weights and blood glucose levels of all rats were regularly measured in the Friday morning (9:00–11:00) in weeks 0, 1, 3, 5 and 7 after PEMF stimulation. Mechanical allodynia and thermal hyperalgesia were evaluated at the Friday night (19:00–23:00) in weeks 0, 1, 3, 5 and 7 after PEMF stimulation. For these two tests, measurements were done by two experimenters who were not aware of the treatment groups respectively and responsible for each test until the study finished.

Ultrastructural Examination of Sciatic Nerve

Seven weeks after PEMF stimulation in STZ-treated rats with DPN, all rats were anesthetized by an intraperitoneal injection of 7% chloral hydrate solution (0.45 ml/100 g) prior to collecting the sciatic nerve . The distal part of the sciatic nerve was dissected and post fixed by immersion in the fixative solution (2% paraformaldehyde, 2% glutaraldehyde, 0.1 M cacodylate buffer at pH 7.3) for 2 h at 4°C, and washed in 0.1 M cacodylate buffer, and osmicated for 4 h in 1% OsO4 (Fluka). Nerves were rinsed in 0.1 M cacodylate buffer, dehydrated and embedded in epoxy 812-Araldite (Polysciences). Ultra-thin sections (80 nm) were subsequently cut, collected on cellodincoated single slot grids and stained with uranyl acetate and lead citrate. Photographs were obtained using a transmission electron microscope (JEM-2000EX, Japan) operated at 80 keV.

Immunohistochemical Study for VEGF of Sciatic Nerve

The distal part of the sciatic nerve was dissected and post fixed by immersion in the fixative solution (10% paraformaldehyde), and routine paraffin embedding was performed. Longitudinal sections (12 An external file that holds a picture, illustration, etc.
Object name is pone.0061414.e006.jpgm) of sciatic nerve were thaw-mounted onto Superfrost Plus Slides (VWR). Sections were washed with PBS, and then incubated in blocking buffer (10% normal goat serum, 0.2% Triton-X 100 in PBS) for 1 h at room temperature. Slides were incubated overnight at 4°C with primary antibodies (in blocking buffer): anti–VEGF (1:100; EMD Millipore, USA). Slides were washed and then incubated with goat anti-rabbit IgG (1:200; Jackson ImmunoResearch, USA) for 1 h at room temperature. Digital images were acquired using light microscope (ECLIPSE50i, Nikon, Japan).

Statistical Analysis

Statistical analyses were carried out using SPSS (version 14.0, SPSS, IL, USA). All values were expressed as means ± standard error of the mean (SEM). P<0.05 was considered statistically significant. Data sets (body weight, blood glucose level and mechanical and thermal withdrawal threshold) of time course study were analyzed by two-way repeated measures analysis of variance (ANOVA). All results were interpreted using the Greenhous–Geisser correction to reduce the probability of obtaining a significant result by chance alone. Between subject factors consisted of intervention (Control, DM and DM+PEMF) and within subject factors consisted of time (weeks 0, 1, 3, 5 and 7 after PEMF stimulation) resulted in a 3×5 ANOVA. Data was analyzed for intervention and time main effects. Bonferroni-adjusted pairwise comparisons were performed for multiple comparisons of the means between the groups. PEMF effect would be indicated by a significant main effect for intervention.

Results

Body Weight and Whole Blood Glucose Level

Two-way repeated measures ANOVA with a Greenhouse-Geisser correction determined that a significant main effect for time (F (2.109, 75.936)?=?9.502, P<0.001) was found for means of body weight throughout the time course. The body weight differed significantly between time points. Post hoc tests using the Bonferroni correction revealed that the mean body weight of DM group and DM+PEMF group were significantly lower than in the Control group (P<0.01) (Fig. 3). After STZ injection, rats consistently lost weight. Although there was slightly less loss of the body weight in PEMF treated diabetic rats, no significant difference between DM+PEMF group and DM group was found (P>0.05). PEMF stimulation did not significantly affect the loss of body weight caused by diabetes.

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Object name is pone.0061414.g003.jpg

Trends of body weight in Control, DM and DM+PEMF groups in weeks 0, 1, 3, 5 and 7 after PEMF stimulation.

Data are presented as means ± SEM for 8 rats in each group. **P<0.01, statistically significant compared to the Control group (Bonferroni-adjusted pairwise comparison regarding the main group effect after two-way repeated measures ANOVA).

Similarly, a significant main effect for time (F (1.841, 38.651)?=?92.331, P<0.001) was observed for average blood glucose level throughout the time course. The average blood glucose level differed significantly between time points. Bonferroni-adjusted pairwise comparisons revealed that the average blood glucose levels of DM group and DM+PEMF group were significantly higher than in the Control group (P<0.01) (Fig. 4). STZ administration caused a rapid elevation of average blood glucose levels (>500 mg/dl) within one week, which persisted for up to 7 weeks. Although the blood glucose levels were slightly lower in PEMF treated diabetic rats, there was no significant difference between DM+PEMF group and DM group (P>0.05). PEMF stimulation did not significantly affect the hyperglycemia caused by diabetes.

An external file that holds a picture, illustration, etc.
Object name is pone.0061414.g004.jpg
Trends of blood glucose levels in Control, DM and DM+PEMF groups in weeks 0, 1, 3, 5 and 7 after PEMF stimulation.

Data are presented as means ± SEM for 8 rats in each group. **P<0.01, statistically significant compared to the Control group (Bonferroni-adjusted pairwise comparison regarding the main group effect after two-way repeated measures ANOVA).

Effects of PEMF on Mechanical Allodynia

A significant main effect for time (F (2.975, 62.470)?=?176.065, P<0.001) was observed for MWT throughout the time course. MWT differed significantly between time points. Bonferroni-adjusted pairwise comparisons revealed that the MWT of DM group and DM+PEMF group were significantly lower than in the Control group (P<0.01) (Fig. 5). There was a significant difference between DM+PEMF group and DM group (P<0.05) (Fig. 5). PEMF stimulation significantly prevented the development of hypersensitivity to mechanical stimulus in diabetic rats (Fig. 5).

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Trends of MWT in Control, DM and DM+PEMF groups in weeks 0, 1, 3, 5 and 7 after PEMF stimulation.

Data are presented as means ± SEM for 8 rats in each group. **P<0.01, statistically significant compared to the Control group, #P<0.05, statistically significant compared to the DM group (Bonferroni-adjusted pairwise comparison regarding the main group effect after two-way repeated measures ANOVA).

Effects of PEMF on Thermal Hyperalgesia

A significant main effect for time (F (2.564, 53.840)?=?56.742, P<0.001) was observed for TWT. TWT differed significantly between time points. Bonferroni-adjusted pairwise comparisons revealed that the TWT of DM group and DM+PEMF group were significantly lower than in the Control group (P<0.01) (Fig. 6). There was a significant difference between DM+PEMF group and DM group (P<0.05) (Fig. 6). PEMF stimulation significantly prevented the development of hypersensitivity to noxious thermal stimulus in diabetic rats (Fig. 6).

An external file that holds a picture, illustration, etc.
Object name is pone.0061414.g006.jpg
Trends of TWT in Control, DM and DM+PEMF groups in weeks 0, 1, 3, 5 and 7 after PEMF stimulation.

Data are presented as means ± SEM for 8 rats in each group. **P<0.01, statistically significant compared to the Control group, #P<0.05, statistically significant compared to the DM group (Bonferroni-adjusted pairwise comparison regarding the main group effect after two-way repeated measures ANOVA).

Electron Microscopy of Sciatic Nerve

Ultrastructural examination of sciatic nerve was obtained by using transmission electron microscopy after a 7-week experimental period in all rats. In Control group, myelinated fiber with normal structure and morphology was observed (Fig. 7A). In DM group, some evidences of axonal degeneration such as demyelination and axon enlargement were observed. Myelin sheath showed infolding, splitting, swelling and deformation, and layers were separated or disappeared (Fig. 7B). In DM+PEMF group, myelin sheath of sciatic nerve was abnormal, the densities of layer on myelin sheath were uneven and rarefaction, but the damage was slighter than in the DM group (Fig. 7C). Seven-week exposure to PEMF stimulation partially prevented the development of axonal degeneration in STZ-treated rats with DPN.

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Electron micrographs of sciatic nerves in Control, DM, and DM+PEMF groups after a 7-week experimental period in all rats (magnification: ×6000).

(A) Control group: Myelinated fiber had normal structure and morphology. Myelin sheath was in integrity and lined up in order. (B) DM group: Demyelination and axon enlargement were observed. Myelin sheath showed infolding, splitting, swelling and deformation, and layers were separated or disappeared. (C) DM+PEMF group: Myelin sheath of sciatic nerve was abnormal, the densities of layer on myelin sheath were uneven and rarefaction, but the damage was slighter than in the DM group.

Immunostaining for VEGF in Sciatic Nerve

After a 7-week experimental period, no VEGF immunostaining in sciatic nerve was seen in Control group (Fig. 8A). In contrast, diabetic rats with DPN showed intense VEGF immunostaining in sciatic nerve (Fig. 8B). Diabetic animals treated with PEMF stimulation showed less VEGF immunostaining intensity in sciatic nerve compared to that of the DM group (Fig. 8C).

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Immunohistochemical staining for VEGF in sciatic nerves in Control, DM and DM+PEMF groups after a 7-week experimental period in all rats (magnification: ×200).

(A) Control group: No VEGF immunostaining in sciatic nerve. (B) DM group: Intense VEGF immunostaining in sciatic nerve. (C) DM+PEMF group: Less VEGF immunostaining intensity in sciatic nerve compared to that of the DM group.

Discussion

Our data in the present study support the hypothesis that PEMF might play a therapeutic role in the development of DPN in STZ-treated rats. Efficacy was evaluated by the assessment of hypersensitivity using behavioral assays of neuropathic pain that included hind paw withdrawal threshold to non-noxious mechanical stimuli (mechanical allodynia) and thermal hind paw withdrawal latency to noxious heat stimuli (thermal hyperalgesia). In our experiments, 3 weeks after the STZ injection, rats with diabetes developed mechanical allodynia and thermal hyperalgesia, which is consistent with previous studies which demonstrated that DPN often comes alone with altered sensitivity by producing both allodynia and hyperalgesia both in STZ-induced diabetic animal models and diabetic patients . Our results also revealed that application of PEMF attenuated the development of painful DPN. PEMF stimulation showed protective effects to non-noxious mechanical stimuli and noxious heat stimuli and caused an increase in hind paw withdrawal threshold to mechanical stimuli and response time to thermal pain compared to the diabetic rats with sham PEMF stimulation. Our findings are similar to a previous investigation which asserted that treatment with PEMF may prevent the development or may reverse the abnormalities observed in animal models for painful DPN . Although different types of PEMF were employed by these two studies, the same anti-neuropathic pain efficacy emerged.

In the current investigation, a marked decrease in body weight of diabetic rats was observed on week 3 as compared to non-diabetic control rats. The reduction in body weight is probably related to the osmotic diuresis and dehydration induced by diabetic hyperglycemia . Meanwhile, blood glucose level rose immediately after the STZ injection, reached quite a high level at first week, and then remained approximately at a stable value. The results of the current study have confirmed previous findings that blood glucose level is elevated and body weight is decreased in diabetic rats after STZ administration . Our results also revealed that PEMF stimulation did not significantly prevent the weight loss caused by diabetes, which is consistent to a previous investigation . However, contrary to the findings researched by Mert et al. , who observed that PEMF had efficacy in anti-hyperglycemia in diabetic rats, we found that the application of PEMF did not significantly alter hyperglycemia in diabetic rats during the whole experimental observation (7 weeks). This finding is consistent with the fact that the hematoxylin and eosin staining for pancreatic islets in diabetic rats with PEMF stimulation and sham PEMF stimulation showed similar atrophy and reduction in cell numbers (not illustrated) in the current study. The different effects of PEMF in hyperglycemia might be ascribed to the different types of PEMF adopted by Mert et al. and us. These inconsistent findings concerning PEMF effects on DPN often come from varying stimulation parameters and exposure durations .

Obviously, a prerequisite for a clear understanding of the pathophysiological mechanisms of neuropathic appearance and treatment is to know if there are definite structural changes in the nerve fibers and to what extent they exist in the patients or experimental animal models. The pathology of DPN is characterized by progressive nerve fiber loss . Our morphological analysis was performed on the sciatic nerve because the common type of DPN associated with diabetes in humans is the loss of the distal region of long and large-diameter axons. In the present study, some evidences of axonal degeneration such as demyelination and axon enlargement were observed in STZ-treated rats with DPN. Similar results were also reported by other investigators . The sciatic nerve degeneration associated with morphologic changes was confirmed by hyperalgesia and allodynia in diabetic rats with neuropathy in our study, which is consistent with the findings that pathological changes in diabetic rats with DPN are characteristically associated with altered pain sensitivity . In addition to this, our morphological study of sciatic nerve revealed that long-term PEMF stimulation partially attenuated the development of axonal degeneration observed in STZ-treated rats with DPN, which appears to be seldom reported in animal models for DPN by other investigators.

Our findings demonstrate that diabetic rats with DPN express VEGF in peripheral nerves such as sciatic nerve, while adult and healthy rats did not express the VEGF. Similar findings were also revealed by a previous study . Since it is known that angiogenesis takes primarily place in metabolically altered or in injured peripheral nerves and VEGF has demonstrated neurotrophic functions in both central and peripheral neurons , it is not surprising to find elevated levels of the most potent vascular growth substance in peripheral nerves of diabetic rats with DPN. Intriguingly, on the one hand, direct neuroprotective role for VEGF comes from both in vitro and in vivo studies , but on the other hand, a potential consequence of high levels of VEGF observed in diabetes will be enhanced vascular permeability which often results in the extravasation of plasma protein as well as the formation of lesions in peripheral nerves. This abnormal angiogenesis caused by up-regulated VEGF expression initiates chronic insidious progressive damage and loss in unmyelinated and myelinated peripheral nerve fibers . The fact that sciatic nerve of diabetic rats with DPN over seven weeks’ PEMF stimulation showed less VEGF immunostaining might indicate that restitution of nerve function induced by PEMF stimulation leads to down-regulation for VEGF, what’s more, the down-regulated VEGF might in turn cause less damage to peripheral nerve fibers.

This present experimental study demonstrated that treatment with PEMF may attenuate the development of abnormalities observed in animal models for DPN. However, the underlying mechanism of PEMF on DPN is still ambiguous. Previous study reported that PEMF had an significant anti-hyperglycemia efficacy in diabetic rats, and this PEMF-induced reduction in blood glucose level could have a positive effect on nerve function that may result in diminished pain intensity . However, the significant anti-hyperglycemia efficacy of PEMF stimulation was not observed in STZ-treated rats with DPN during the whole experimental observation (7 weeks) in our study. Therefore, we hypothesized that long-term PEMF stimulation would have direct corrective effects on injured nerves, which might lead to diminished pain intensity observed in present studies. Moreover, our hypothesis is supported by in vitro and in vivo studies which have indicated that PEMF stimulation can accelerate nerve conduction velocity and increase compound action potentials of sciatic nerve, enhance nerve growth factor levels, and reduce both oxidative damage and neuronal loss .

In summary, the results from our present study demonstrate that treatment with PEMF might prevent the development of abnormalities observed in animal models for DPN. Moreover, it is suggested that PEMF might have direct corrective effects on injured nerves and would be a potentially promising non-invasive therapeutic tool for the treatment of DPN. However, further research is required to elucidate the specific mechanisms of PEMF on DPN and to confirm the applicability of PEMF for clinical practice.

Acknowledgments

The authors would like to thank M. Ye (Department of Physiology, Xijing hospital, Fourth Military Medical University), H. Dong (Department of Pathology, Fourth Military Medical University) and X. Huang (Department of Immunology, Fourth Military Medical University) for their excellent technical assistance.

Funding Statement

This work was supported by grants from the National Natural Science Foundation of China (Grant no.31000491, 51077128, 31000381 and 31270889). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Neurosci Behav Physiol. 2010 Mar;40(3):347-50.

Non-pharmacological correction of impaired microcirculation in children with diabetic polyneuropathy.

Nikolaeva NV, Bolotova NV, Luk’yanov VF, Raigorodskii YM, Tkacheva EN.

Saratov State Medical University, Saratov, Russia.

Abstract

A total of 25 boys and 20 girls aged 5-17 years with type I diabetes mellitus and disease durations of 2-10 years were studied. All had diabetic polyneuropathy. The microcirculation was studied by laser Doppler flowmetry. Treatment consisted of using a running impulse magnetic field. This method was found to be effective in diabetic polyneuropathy with the running field along the limb towards the periphery at a run velocity (field modulation frequency) being a multiple of the nerve fiber spike conduction velocity.

Bioelectromagnetics. 2010 Jan;31(1):39-47.

Neurobiological effects of pulsed magnetic field on diabetes-induced neuropathy.

Mert T, Gunay I, Ocal I.

Faculty of Medicine, Department of Biophysics, Cukurova University, Balcali, Adana, Turkey.tufanmert@yahoo.com

Abstract

In the clinic, although several pharmacological agents or surgical procedures are used to treat diabetes and diabetes-induced neuropathic pain, their success has been limited. Therefore, development of different alternatives in treatments is very important. The purpose of this study was to determine the efficacy of pulsed magnetic field (PMF) in improving signs and symptoms of diabetic neuropathy. In this study, the effects of PMF treatment were investigated in Streptozotocin (STZ)-induced acute and chronic diabetic rats by measuring the thermal latencies, mechanical thresholds, whole blood glucose levels and body weights. After STZ administration to rats, blood glucose level elevated and body weight decreased. Although PMF treatment did not affect changes in body weight, the blood glucose levels of PMF-treated diabetic rats exhibited a decrease during the treatments. Diabetic animals displayed marked decrease in mechanical thresholds and thermal latencies. While treatment of PMF partially restored the mechanical thresholds and thermal latency in acute diabetic rats, PMF caused a corrective effect on only mechanical threshold of chronic diabetic rats. These results suggested that treatment of PMF can potentially ameliorate the painful symptoms of diabetes, such as hyperalgesia and allodynia, by partially preventing the hyperglycemia. (c) 2009 Wiley-Liss, Inc.

Bioelectromagnetics. 2009 Sep;30(6):438-45.

Exposure of inhomogenous static magnetic field ceases mechanical allodynia in neuropathic pain in mice.

Antal M, László J.

Department of Anatomy, Histology, and Embriology, University of Debrecen, Debrecen, Hungary.

Abstract

Magnetic therapy as a self-care intervention has led to the conduct of numerous human trials and animal experiments. Results concerning the analgesic efficacy of magnetic exposure, however, are inconsistent. By using a magnetic device generating an inhomogeneous static magnetic field (iSMF), here we studied how the whole-body exposure to iSMF may influence the mechanical withdrawal threshold (MWT) of the hind paw in different stages of neuropathic pain evoked by partial ligation of the sciatic nerve in mice. It was found that iSMF exposure did not prevent the decrease of MWT in the first postoperative week. A 2-week long iSMF treatment that was started just after the nerve ligation elevated MWT values to a modest extent. However, the effectiveness of a daily exposure to iSMF was much more prominent when it was applied between postoperative days 15 and 28. In this case, MWT was already noticeably increased after the first treatment and it practically reached the control values by the end of the 2-week long exposure period. The results suggest that exposure to iSMF cannot prevent the development of mechanical allodynia, but can inhibit processes that maintain the increased sensitivity to mechanical stimuli in neuropathic pain.

Arch Phys Med Rehabil. 2009 Jul;90(7):1102-9.

Pulsed electromagnetic fields to reduce diabetic neuropathic pain and stimulate neuronal repair: a randomized controlled trial.

Weintraub MI, Herrmann DN, Smith AG, Backonja MM, Cole SP.

Department of Neurology, New York Medical College, Valhalla, NY, USA. miwneuro@pol.net

Abstract

OBJECTIVE: To determine whether repetitive and cumulative exposure to low-frequency pulsed electromagnetic fields (PEMF) targeting painful feet can reduce neuropathic pain (NP), influence sleep in symptomatic diabetic peripheral neuropathy (DPN), and influence nerve regeneration.

DESIGN: Randomized, double-blind, placebo-controlled parallel study.

SETTING: Sixteen academic and clinical sites in 13 states.

PARTICIPANTS: Subjects (N=225) with DPN stage II or III were randomly assigned to use identical devices generating PEMF or sham (placebo) 2 h/d to feet for 3 months.

INTERVENTIONS: Nerve conduction testing was performed serially.

MAIN OUTCOME MEASURES: Pain reduction scores using a visual analog scale (VAS), the Neuropathy Pain Scale (NPS), and the Patient’s Global Impression of Change (PGIC). A subset of subjects underwent serial 3-mm punch skin biopsies from 3 standard lower limb sites for epidermal nerve fiber density (ENFD) quantification.

RESULTS: Subjects (N=225) were randomized with a dropout rate of 13.8%. There was a trend toward reductions in DPN symptoms on the PGIC, favoring the PEMF group (44% vs 31%; P=.04). There were no significant differences between PEMF and sham groups in the NP intensity on NPS or VAS. Twenty-seven subjects completed serial biopsies. Twenty-nine percent of PEMF subjects had an increase in distal leg ENFD of at least 0.5 SDs, while none did in the sham group (P=.04). Increases in distal thigh ENFD were significantly correlated with decreases in pain scores.

CONCLUSIONS: PEMF at this dosimetry was noneffective in reducing NP. However neurobiological effects on ENFD, PGIC and reduced itching scores suggest future studies are indicated with higher dosimetry (3000-5000 G), longer duration of exposure, and larger biopsy cohort.

Zh Nevrol Psikhiatr Im S S Korsakova. 2008;108(11):43-6.

Non-pharmacological treatment of microcirculation disturbance in children with diabetic polyneuropathy.

[Article in Russian]

Nikolaeva NV, Bolotova V, Luk’ianov VF, Ra?gorodski? IuM, Tkacheva EN.

Abstract

Twenty-five boys and 20 girls, aged 5-17 years, with diabetes mellitus type I and illness duration from 2 to 10 years have been studied. All of them suffered from diabetic neuropathy. Laser-Doppler flowmetry has been used. The treatment has been conducted using running impulse magnetic field. The efficacy of the influence of running field along the extremity with the velocity of run (frequency of field modulation) divisible by the impulse conduction velocity along the nerve fiber in diabetic polyneuropathy has been shown.

Altern Ther Health Med. 2006 Sep-Oct;12(5):42-9

Regenerative effects of pulsed magnetic field on injured peripheral nerves.

Mert T, Gunay I, Gocmen C, Kaya M, Polat S.

Department of Biophysics, University of Cukurova School of Medicine, Adana, Turkey.

Previous studies confirm that pulsed magnetic field (PMF) accelerates functional recovery after a nerve crush lesion. The contention that PMF enhances the regeneration is still controversial, however. The influence of a new PMF application protocol (trained PMF) on nerve regeneration was studied in a model of crush injury of the sciatic nerve of rats. To determine if exposure to PMF influences regeneration, we used electrophysiological recordings and ultrastructural examinations. After the measurements of conduction velocity, the sucrose-gap method was used to record compound action potentials (CAPs) from sciatic nerves. PMF treatment during the 38 days following the crush injury enhanced the regeneration. Although the axonal ultrastructures were generally normal, slight to moderate myelin sheath degeneration was noted at the lesion site. PMF application for 38 days accelerated nerve conduction velocity, increased CAP amplitude and decreased the time to peak of the CAP. Furthermore, corrective effects of PMF on. the abnormal characteristics of sensory nerve fibers were determined. Consequently, long-periodic trained-PMF may promote both morphological and electrophysiological properties of the injured nerves. In addition, corrective effects of PMF on sensory fibers may be considered an important finding for neuropathic pain therapy.

Diabetologia. 2005 May;48(5):817-23. Epub 2005 Apr 15.

Effectiveness of frequency-modulated electromagnetic neural stimulation in the treatment of painful diabetic neuropathy.

Bosi E, Conti M, Vermigli C, Cazzetta G, Peretti E, Cordoni MC, Galimberti G, Scionti L.

Diabetes and Endocrinology Unit, Department of General Medicine, Vita-Salute San Raff aele University Hospital, Via Olgettina 60, 20132 Milan, Italy. bosi.emanuele@hsr.it

Abstract

AIMS/HYPOTHESIS: The largely unsatisfactory results reported for the pharmacological treatment of diabetic neuropathy has spurred the search for alternative therapies. The aim of this study was to evaluate the efficacy of frequency-modulated electromagnetic neural stimulation (FREMS) as a novel treatment for painful diabetic neuropathy.

METHODS: Patients (n=31) with painful neuropathy associated with decreased nerve conduction velocity (<40 m/s) and increased vibration perception threshold (>25 V) were enrolled in a randomised, double-blind, crossover study designed to compare the effects of FREMS with those of placebo. Each patient received two series of ten treatments of either FREMS or placebo in random sequence, with each series lasting no more than 3 weeks. The primary efficacy end point was the change in pain measured by a visual analogue scale (VAS).

RESULTS: FREMS induced a significant reduction in daytime and night-time VAS pain score (all p<0.02). Furthermore, FREMS induced a significant increase in sensory tactile perception, as assessed by monofilament; a decrease in foot vibration perception threshold, as measured by a biothesiometer; and an increase in motor nerve conduction velocity (all p<0.01). No significant changes were observed after placebo. Comparison of measurements at the 4-month follow-up with those at baseline revealed that a significant benefit persisted for all measures that showed an improvement at the end of treatment, with an additional improvement in quality of life evaluated by the Short Form-36 questionnaire (all p<0.05). No significant side effects were recorded during the study.

CONCLUSIONS/INTERPRETATION: FREMS is a safe and effective therapy for neuropathic pain in patients with diabetes and is able to modify some parameters of peripheral nerve function.

Neurorehabil Neural Repair. 2004 Mar;18(1):42-6.

Pulsed magnetic field therapy in refractory neuropathic pain secondary to peripheral neuropathy: electrodiagnostic parameters–pilot study.

Weintraub MI, Cole SP.

New York Medical College, Briarcliff Manor, New York 10510, USA.

CONTEXT: Neuropathic pain (NP) from peripheral neuropathy (PN) arises from ectopic firing of unmyelinated C-fibers with accumulation of sodium and calcium channels. Because pulsed electromagnetic fields (PEMF) safely induce extremely low frequency (ELF) quasirectangular currents that can depolarize, repolarize, and hyperpolarize neurons, it was hypothesized that directing this energy into the sole of one foot could potentially modulate neuropathic pain.

OBJECTIVE: To determine if 9 consecutive 1-h treatments in physician’s office (excluding weekends) of a pulsed signal therapy can reduce NP scores in refractory feet with PN.

DESIGN/SETTING/PATIENTS: 24 consecutive patients with refractory and symptomatic PN from diabetes, chronic inflammatory demyelinating polyneuropathy (CIDP), pernicious anemia, mercury poisoning, paraneoplastic syndrome, tarsal tunnel, and idiopathic sensory neuropathy were enrolled in this nonplacebo pilot study. The most symptomatic foot received therapy. Primary endpoints were comparison of VAS scores at the end of 9 days and the end of 30 days follow-up compared to baseline pain scores. Additionally, Patients’ Global Impression of Change (PGIC) questionnaire was tabulated describing response to treatment. Subgroup analysis of nerve conduction scores, quantified sensory testing (QST), and serial examination changes were also tabulated. Subgroup classification of pain (Serlin) was utilized to determine if there were disproportionate responses.

INTERVENTION: Noninvasive pulsed signal therapy generates a unidirectional quasirectangular waveform with strength about 20 gauss and a frequency about 30 Hz into the soles of the feet for 9 consecutive 1-h treatments (excluding weekends). The most symptomatic foot of each patient was treated.

RESULTS: All 24 feet completed 9 days of treatment. 15/24 completed follow-up (62%) with mean pain scores decreasing 21% from baseline to end of treatment (P=0.19) but with 49% reduction of pain scores from baseline to end of follow-up (P<0.01). Of this group, self-reported PGIC was improved 67% (n=10) and no change was 33% (n=5). An intent-to-treat analysis based on all 24 feet demonstrated a 19% reduction in pain scores from baseline to end of treatment (P=0.10) and a 37% decrease from baseline to end of follow-up (P<0.01). Subgroup analysis revealed 5 patients with mild pain with nonsignificant reduction at end of follow-up. Of the 19 feet with moderate to severe pain, there was a 28% reduction from baseline to end of treatment (P<0.05) and a 39% decrease from baseline to end of follow-up (P<0.01). Benefit was better in those patients with axonal changes and advanced CPT baseline scores. The clinical examination did not change. There were no adverse events or safety issues.

CONCLUSIONS: These pilot data demonstrate that directing PEMF to refractory feet can provide unexpected short term analgesic effects in more than 50% of individuals. The role of placebo is not known and was not tested. The precise mechanism is unclear yet suggests that severe and advanced cases are more magnetically sensitive. Future studies are needed with randomized placebo-controlled design and longer treatment periods.

Arch Phys Med Rehabil. 2003 May;84(5):736-46.

Static magnetic field therapy for symptomatic diabetic neuropathy: a randomized, double-blind, placebo-controlled trial.

Weintraub MI, Wolfe GI, Barohn RA, Cole SP, Parry GJ, Hayat G, Cohen JA, Page JC, Bromberg MB, Schwartz SL

Magnetic Research Group. Department of Neurology, New York Medical College, Valhalla, NY, USA. miwneuro@pol.net

OBJECTIVE: To determine if constant wearing of multipolar, static magnetic (450G) shoe insoles can reduce neuropathic pain and quality of life (QOL) scores in symptomatic diabetic peripheral neuropathy (DPN). DESIGN: Randomized, placebo-control, parallel study.

SETTING: Forty-eight centers in 27 states.

PARTICIPANTS: Three hundred seventy-five subjects with DPN stage II or III were randomly assigned to wear constantly magnetized insoles for 4 months; the placebo group wore similar, unmagnetized device.

INTERVENTION: Nerve conduction and/or quantified sensory testing were performed serially.

MAIN OUTCOME MEASURES: Daily visual analog scale scores for numbness or tingling and burning and QOL issues were tabulated over 4 months. Secondary measures included nerve conduction changes, role of placebo, and safety issues. Analysis of variance (ANOVA), analysis of covariance (ANCOVA), and chi-square analysis were performed.

RESULTS: There were statistically significant reductions during the third and fourth months in burning (mean change for magnet treatment, -12%; for sham, -3%; P<.05, ANCOVA), numbness and tingling (magnet, -10%; sham, +1%; P<.05, ANCOVA), and exercise-induced foot pain (magnet, -12%; sham, -4%; P<.05, ANCOVA). For a subset of patients with baseline severe pain, statistically significant reductions occurred from baseline through the fourth month in numbness and tingling (magnet, -32%; sham, -14%; P<.01, ANOVA) and foot pain (magnet, -41%; sham, -21%; P<.01, ANOVA).

CONCLUSIONS: Static magnetic fields can penetrate up to 20mm and appear to target the ectopic firing nociceptors in the epidermis and dermis. Analgesic benefits were achieved over time.

Fiziol Zh. 2003;49(2):85-90.

Use of low-power electromagnetic therapy in diabetic polyneuropathy.

[Article in Ukrainian]

Chebotar’ova LL, Chebotar’ov HIe.

Abstract

The clinical-electroneuromyography investigations were performed for objective evaluation of low-power electromagnetic therapy effectiveness in 12 patients with diabetic polyneuropaties. It is established that combination of low-power electromagnetic therapy using “ANET-UHF”, “ANET-SHF” apparatus (Ukraine) and low-power variable magnetic field using AMT apparatus (Ukraine) give the stable positive effects. The positive changes were confirmed by following: the decrease of neurological deficit and required insulin daily dose, nerve conduction velocity increase, increase of the muscle compound action potentials (muscle power) and peripheral outflow in some patients.

Neurosci Behav Physiol. 2003 Oct;33(8):745-52.

The use of pulsed electromagnetic fields with complex modulation in the treatment of patients with diabetic polyneuropathy.

Musaev AV, Guseinova SG, Imamverdieva SS.

Science Research Institute of Medical Rehabilitation, Baku, Azerbaidzhan.

Clinical and electroneuromyographic studies were performed in 121 patients with diabetic polyneuropathy (DPN) before and after courses of treatment with pulsed electromagnetic fields with complex modulation (PEMF-CM) at different frequencies (100 and 10 Hz). Testing of patients using the TSS and NIS LL scales demonstrated a correlation between the severity and frequency of the main subjective and objective effects of disease and the stage of DPN. The severity of changes in the segmental-peripheral neuromotor apparatus–decreases in muscle bioelectrical activity, the impulse conduction rate along efferent fibers of peripheral nerves, and the amplitude of the maximum M response–depended on the stage of DPN and the duration of diabetes mellitus. The earliest and most significant electroneuromyographic signs of DPN were found to be decreases in the amplitude of the H reflex and the Hmax/Mmax ratio in the muscles of the lower leg. Application of PEMF-CM facilitated regression of the main clinical symptoms of DPN, improved the conductive function of peripheral nerves, improved the state of la afferents, and improved the reflex excitability of functionally diverse motoneurons in the spinal cord. PEMF-CM at 10 Hz was found to have therapeutic efficacy, especially in the initial stages of DPN and in patients with diabetes mellitus for up to 10 years.

Vopr Kurortol Fizioter Lech Fiz Kult. 1993 Sep-Oct;(5):38-41.

The use of combined methods of magnetoelectrotherapy in treating polyneuropathies.

[Article in Russian]

Shiman AG, Lobzin VS, Maksimov AV, Zabolokov IG.

A comparative evaluation by such parameters as alleviation of pain syndrome, improvement of peripheral resistance and vegetotrophic processes, a decline in pareses and sensory disorders has been performed in 3 groups of patients: group 1 underwent benzohexonium electrophoresis, group 2 benzohexonium electrophoresis in the magnetic field produced by the unit “Polyus-I” followed by low-frequency electrotherapy with bipolar impulse current, group 3 benzohexonium electrophoresis in the magnetic field from the unit “ADMT-Magnipuls” followed by low-frequency electrotherapy with bipolar impulse current. The best clinical and physiological results were reported in group 3 patients.

Wiad Lek. 2003;56(9-10):434-41.

Application of variable magnetic fields in medicine–15 years experience.

[Article in Polish]

Sieron A, Cieslar G.

Katedra i Klinika Chorob Wewnetrznych, Angiologii i Medycyny Fizykalnej SAM, ul. Batorego 15, 41-902 Bytom. sieron@mediclub.pl

The results of 15-year own experimental and clinical research on application of variable magnetic fields in medicine were presented. In experimental studies analgesic effect (related to endogenous opioid system and nitrogen oxide activity) and regenerative effect of variable magnetic fields with therapeutical parameters was observed. The influence of this fields on enzymatic and hormonal activity, free oxygen radicals, carbohydrates, protein and lipid metabolism, dielectric and rheological properties of blood as well as behavioural reactions and activity of central dopamine receptor in experimental animals was proved. In clinical studies high therapeutic efficacy of magnetotherapy and magnetostimulation in the treatment of osteoarthrosis, abnormal ossification, osteoporosis, nasosinusitis, multiple sclerosis, Parkinson’s disease, spastic paresis, diabetic polyneuropathy and retinopathy, vegetative neurosis, peptic ulcers, colon irritable and trophic ulcers was confirmed.

Lik Sprava. 1996 Oct-Dec;(10-12):155-8.

The medical effect of magnetic-laser therapy in patients with diabetic angiopathies of the lower extremities.

[Article in Ukrainian]

Shved MI, Dudnik AP.

Conventional antidiabetic therapy with insulin and sugar-lowering agents helps in achieving compensation of diabetes mellitus but fails to exert high effect on subjective and objective manifestations of diabetic microangiopathies of the lower extremities. A course of magnetic-laser therapy results in significant reduction of concentration of the lipid oxidation products as one of the pathogenetic mechanisms of diabetic microangiopathies, normalization of immunologic reactivity as well as attenuation of clinical manifestations of hemocirculatory disorders in the lower extremities and improvement of parameters of thermo- and rheovasography.

Klin Med (Mosk). 1996;74(5):39-41.

Magentotherapy in the comprehensive treatment of vascular complications of diabetes mellitus.

[Article in Russian]

Kirillov IB, Suchkova ZV, Lastushkin AV, Sigaev AA, Nekhaeva TI.

320 diabetes mellitus (DM) patients were exposed to impulsed magnetic field, 100 control DM patients received conservative therapy alone. 270 patients had microangiopathy, macroangiopathy was diagnosed in 50 patients. Good and satisfactory results of magnetotherapy in combination with conservative methods were achieved in 74% of patients versus 28% in control group. Metabolism stabilization resulted in some patients in reduced blood sugar. Use of magnetic field produced faster and longer response than conservative therapy.

Srp Arh Celok Lek. 1993 Aug-Dec;121(8-12):124-6.

Use of pulsating high-frequency electromagnetic fields in patients with diabetic neuropathies and angiopathies.

[Article in Serbian]

Vesovi?-Poti? V, Coni? S.

Belgrade Institute of Rehabilitation.

Abstract

High-frequency pulsating electromagnetic field therapy was carried out in 22 patients with diabetic polyneuropathy and angiopathy manifested on lower extremities (18 men, 4 women, aged 48.2 +/- 6.3 years; 10 insulin-dependent persons, and 12 on oral antidiabetic treatment). The aim of the study was to verify the effect of this therapy on symptoms, neurophysiological findings and peripheral circulation. The diagnose of diabetic polyneuropathy was based on the electromyographic examination of foot and calf muscles, measurement of motor nerve conduction velocity of peroneal and tibial nerve, and sensory nerve conduction velocity of sural nerve. Diagnosis of diabetic polyneuropathy was based on electromyographic examination of the foot and calf muscles, measurement of the motor nerve conduction velocity of peroneal and tibial nerves, and the sensory nerve conduction velocity of the sural nerve. Diagnosis of diabetic angiopathy was established by oscillometric examination, measurement of skin temperature and claudication distance. The same methods were used for the evaluation of the therapeutical effect of electromagnetic field. Significant improvement of symptoms, and of all registered parameters of peripheral circulation was established after the therapy, but there were no significant changes of neurophysiological parameters. Therefore, high-frequency pulsating electromagnetic field is recommended for the treatment of diabetic angiopathy. In patients with neuropathic changes it can be used as an introduction procedure, or as an additional procedure to physical agents which are commonly used in the treatment of peripheral nerve lesion.