Parkinson’s Disease

Logo of jneurorehab

BioMed Central Biomed Central Web Site search submit a manuscript register this article Journal of NeuroEngineering and Rehabilitation Journal Front Page
. 2019; 16: 19.
Published online 2019 Jan 31. doi: 10.1186/s12984-019-0491-2
PMCID: PMC6357382
PMID: 30704504

The effect of 8 weeks of treatment with transcranial pulsed electromagnetic fields on hand tremor and inter-hand coherence in persons with Parkinson’s disease

1Department of Neurology, Odense University Hospital, University of Southern Denmark, Odense, Denmark
2Department of Clinical Research, University of Southern Denmark, Odense, Denmark
3The Danish Rehabilitation Centre for Neuromuscular Diseases, Taastrup, Denmark
4Psychiatric Research Unit, Psychiatric Centre North Zealand, University of Copenhagen, Hillerød, Denmark
Anne Sofie Bøgh Malling, kd.uds.htlaeh@gnillamamoc.liamtoh@gnillamsa.
corresponding authorCorresponding author.
Received 2018 May 29; Accepted 2019 Jan 23.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Associated Data

Supplementary Materials
Data Availability Statement

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abstract

Background

Parkinson’s disease (PD) tremor comprises asymmetric rest and postural tremor with unilateral onset. Tremor intensity can be amplified by stress and reduced by attention, and the medical treatment is complex. Mirror movements and unintentional synchronization of bimanual movements, possibly caused by insufficient inhibition of inter-hemispheric crosstalk, have been reported in PD, indicating a lag of lateralization.

Potential neuroprotective effects of pulsed electromagnetic fields (PEMF) have been reported in-vitro and in rodents, as have influences of PEMF on human tremor.

The aim was to investigate the effect of 8?weeks daily transcranial PEMF treatment (T-PEMF) of persons with PD on rest and postural hand tremor characteristics and on inter-hand coherence.

Methods

Hand accelerations of 50 PD participants with uni- or bilateral tremor participating in a clinical trial were analysed. A rest and postural tremor task performed during serial subtraction was assessed before and after 8?weeks of T-PEMF (30?min/day, 50?Hz, ±50?V, 3?ms squared pulses) or placebo treatment (sham stimulation 30?min/day). Forty matched healthy persons (no treatment) were included as reference. Intensity and inter-hand coherence related measures were extracted.

Results

The T-PEMF treatment decreased the inter-hand coherence in the PD group with unilateral postural tremor. The PD group with unilateral postural tremor was less clinically affected by the disease than the PD group with bilateral postural tremor. However, no differences between T-PEMF and placebo treatment on either intensity related or coherence related measures were found when all persons with PD were included in the analyses. The peak power decreased and the tremor intensity tended to decrease in both treatment groups.

Conclusions

Eight weeks of T-PEMF treatment decreased inter-hand coherence in the PD group with unilateral postural tremor, while no effects of T-PEMF treatment were found for the entire PD group. The unilateral postural tremor group was less clinically affected than the bilateral postural tremor group, suggesting that early treatment initiation may be beneficial. In theory, a reduced inter-hand coherence could result from a neuronal treatment response increasing inter-hemispheric inhibition. However, this requires further studies to determine. Studies of even longer treatment periods would be of interest.

Trial registration

ClinicalTrials.gov, NCT02125032. Registered 29 April 2014, https://clinicaltrials.gov/ct2/show/NCT02125032?term=NCT02125032&rank=1

Electronic supplementary material

The online version of this article (10.1186/s12984-019-0491-2) contains supplementary material, which is available to authorized users.

Keywords: Parkinson’s disease, T-PEMF, PEMF, Rest tremor, Postural tremor, Inter-hand coherence, Accelerometry, Tremor intensity

Introduction

Parkinson’s disease (PD) is an asymmetric neurodegenerative disease affecting the dopaminergic neurons especially in the basal ganglia causing cardinal motor symptoms as bradykinesia, tremor, and rigidity. The asymmetric neural degeneration manifests itself as a unilateral onset of motor symptoms followed by a gradual involvement of the contralateral side, although the asymmetric manifestations of motor symptoms persist with disease progression [].

The classical PD tremor has a main frequency of 4–7 Hz and is most often present at rest in the hands or arms of the affected subjects. Postural and kinetic tremors are also common in the upper extremities whereas tremors in the lower extremities are rarer []. Furthermore, re-emergent tremor in terms of tremor re-occurring after repositioning of the limb is frequent []. It has been suggested that resting tremor and re-emergent tremor have similar origins as no differences in electromyographic or accelerometric characteristics have been found []. In addition, PD tremor intensity can be context-dependent e.g. amplified by stress []. The medical treatment of tremor in PD is complex. Thus, the effect of levodopa on tremor can be reduced with cognitive stress [] and some persons with PD experience levodopa-resistant tremor []. Investigation of new treatment methods is therefore warranted.

Mirror movements, where voluntary movements of one limb is accompanied by corresponding involuntary movements of the opposite limb, have been reported in several movement disorders and have been described as a result of inter-hemispheric cross-talk or motor overflow []. In accordance, mirror movements have been found to be highly present and persistent in persons with idiopathic PD [] and to be more pronounced than in healthy peers []. Furthermore, persons with PD tend to unintentionally synchronize asynchronic alternating bimanual movements at a lower movement frequency than healthy persons do []. The neural origin of such movements might either be uncrossed ipsilateral corticospinal pathways or insufficient inhibition of inter-hemispheric crosstalk, of which the latter is most likely in PD []. This phenomenon can be studied by analyzing inter-limb synchronization patterns []. Coherence analysis is a standard metric used for studying functional interconnectivity including coupling between body segments in the frequency domain. Inter-hand coherence can be calculated from synchronously measured acceleration of each hand during standardized conditions. Based on the above mentioned literature higher inter-hand coherence in persons with PD compared to healthy controls can be expected.

Treatment with pulsed electromagnetic fields (PEMF) has been suggested to have neuroprotective effects in in-vitro cell-line studies and in-vivo animal studies. For example, PEMF has been shown to enhance cell proliferation and differentiation [], enhance neurite outgrow [], regulate neutrophic factors such as BDNF, S100 and NGF [], stimulate angiogenesis [], increase microvascular perfusion and tissue oxygenation [], reduce apoptosis [], and stimulate neurogenesis in the hippocampal dentate gyrus [] and in the sub ventricular zone after lesion of substantia nigra []. Which molecular mechanisms that are initiated by PEMF are still not fully understood. However, PEMF may affect the tissue both directly through interaction mechanisms between the electromagnetic fields and the conductive tissue, and indirectly by initiating biological events leading to physiologic responses []. Recently, we found that 8weeks of daily treatment with weak transcranial pulsed electromagnetic fields (T-PEMF) improved motor function, in terms of increased rate of force development, in persons with mild PD []. Rate of force development depends on the corticospinal drive to the muscles and we proposed that treatment with T-PEMF may increase the corticospinal drive to the muscles through an increased thalamocortical input [].

To our knowledge, the influence of T-PEMF treatment on PD hand tremor intensity and inter-hand coherence has not previously been studied in a randomized clinical trial. However, a positive influence of weak pulsed electromagnetic fields in the pico-tesla range on tremor intensity in a person with PD has previously been reported in a case report []. In addition, extremely low frequent magnetic fields with flux densities in the millitesla-range may be capable of influencing physiologic tremor in healthy subjects shifting the frequency content of physiologic postural tremor towards lower frequencies []. This indicates an acute influence of low flux density electromagnetic stimulation on human tremor.

Based on our current knowledge, we hypothesize that repeatedly applied T-PEMF treatment may alter hand tremor characteristics and inter-hand coherence in persons with PD towards normal values measured in healthy controls. Thus, the aim of this study was to investigate the effect of 8?weeks of daily T-PEMF treatment compared to placebo treatment on rest and postural hand tremor characteristics as well as inter-hand coherence in persons with PD.

Method

Study design

The present study includes accelerometer data from a subsample of participants of a double-blinded randomized clinical trial []. In the trial, 97 participants diagnosed with idiopathic PD (Hoehn & Yahr I-IV) according to the United Kingdom Brain Bank Criteria were randomized to receive either 8?weeks of T-PEMF or placebo treatment in a 1:1 allocation ratio. Inclusion criteria for the trial were an unchanged and optimal medical treatment regarding PD six weeks prior to and during the intervention period; Mini Mental State Examination score >?22; age?>?18 years; and cognitive skills enabling certification in the use of the T-PEMF device and to give informed consent. Exclusion criteria were any known neuromuscular or neurological diseases other than PD that might interfere with motor function; psychopathological treatment of other conditions than depression; substance abuse; active medical implants; pregnancy or nursing; current or previous cancer in the brain, head or neck region; leukaemia; autoimmune disease; epilepsy; and open scalp wounds. The clinical trial was registered at clinicaltrials.gov(NCT02125032), was approved by the Regional Scientific Ethical Committees for Southern Denmark (S-20130114) and the Danish Health Authority (CIV-14-01-011780), and was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent prior to participation. For further details of the trial, please refer to Additional file 1 or [].

Participants

For the present study, trial participants diagnosed with idiopathic PD with at least one hand with pathological PD tremor defined by having a rest or postural tremor intensity larger than mean?+?2SD of a healthy reference group were included (cut-off values, rest: 0.300?m/s2, postural: 0.783?m/s2). Fifty of the 97 trial participants with PD had pathological PD tremor (hereinafter referred to as tremor). Seven of these had rest tremor only, 14 had postural tremor only, and 29 had both rest and postural tremor. Thus, 36 participants with PD (17 females, mean age (SD) of 66 (8.9) years, having a total of 52 hands with rest tremor) were included in the analysis of rest tremor, and 43 participants with PD (19 females, mean age (SD) of 65 (9.2), having a total of 64 hands with tremor) were included in the analysis of postural tremor. Endpoint data from participants with a post-interventional treatment compliance of less than 80% were excluded from the analyses. The participants with PD were evaluated by the Unified Parkinson’s Disease Rating Scale (UPDRS) for clinical disease severity characterization []. The UPDRS was chosen in preference to the MDS-UPDRS since the latter has not been translated to and validated in a Danish version.

Inspired by our previous finding suggesting that mildly affected persons with PD have a larger potential for neural rehabilitation than more severely affected persons with PD [], we sub-grouped the participants with PD. Thus, the participants with PD were divided into a group with unilateral tremor and a group with bilateral tremor to investigate the effect of T-PEMF treatment on different levels of disease progression from a tremor perspective.

Additionally, a reference group (REF) of 40 healthy subjects matched on age and sex with no visual detectable tremor (19 females, mean age (SD) of 66 (1.3) years, having a total of 80 non-tremoring hands, Table 1) was included. The REF group was included to provide threshold values for tremor. The REF group was extracted from a larger reference group representing individuals across the adult lifespan (19–83?years) []. Initially, the group with ages within the range of the PD group were extracted (n?=?46). However, the age distribution of the PD group was screwed towards the older ages as expected, whereas the age-range matched reference group was not. Furthermore, women-to-men ratio in the age-range matched reference group was slightly higher than in the PD group. Therefore, six women in the age-range matched reference group were excluded to make the REF group match the PD group on age and sex distribution. This procedure was performed without any knowledge of the reference persons except their age and sex. Group and subgroup baseline descriptive variables are listed in Table ?Table11.

Table 1

Group and subgroup description

Group N N, females Age (years) Disease duration (years) LED (mg/day) UPDRS total UPDRS motor UPDRS hand tremor
PD, rest
?All T-PEMF 22 11 68 (6) 6 (5) 547 (439) 49 (15) 28 (9) 3 (2)
Placebo 14 6 63 (12) 3 (2) 399 (234) 43 (13) 25 (9) 3 (2)
?Unilateral T-PEMF 11 7 69 (5) 5 (5) 562 (470) 41 (12) 23 (8) 2 (1)
Placebo 9 4 62 (14) 3 (2) 405 (271) 41 (10) 24 (8) 2 (1)
?Bilateral T-PEMF 11 4 67 (7) 7 (5) 531 (427) 57 (12) 33 (8) 5 (2)
Placebo 5 2 65 (4) 3 (2) 389 (176) 46 (17) 27 (11) 4 (3)
PD, postural
?All T-PEMF 23 10 67 (6) 5 (5) 520 (440) 46 (16) 26 (10) 3 (2)
Placebo 20 9 63 (11) 4 (3) 474 (346) 46 (14) 26 (9) 3 (2)
?Unilateral T-PEMF 9 5 67 (6) 2 (2) 380 (402) 38 (11) 22 (7) 2 (1)
Placebo 13 6 62 (12) 4 (3) 436 (264) 43 (13) 25 (8) 2 (1)
?Bilateral T-PEMF 14 5 67 (7) 7 (5) 616 (455) 52 (18) 29 (11) 4 (2)
Placebo 7 3 63 (10) 4 (2) 545 (480) 50 (18) 29 (11) 3 (3)
REF 40 19 66 (8)

Baseline descriptive variables for Parkinson’s disease (PD) tremor groups, subgroups and the reference group (REF) according to treatment allocation. Disease duration reflects the number of whole years from the time of diagnosis to inclusion. Levodopa equivalent dose (LED) was calculated according to Tomlinson et al. 2010 []. The Unified Parkinson’s Disease Rating Scale (UPDRS) hand tremor score reflects the sum of scores for rest and postural hand tremor (item 20.2–3 and 21.1–2). Variables are presented as mean (SD)

T-PEMF treatment

The T-PEMF treatment has been described in details elsewhere []. In short, participants with PD received one 30-min session of home-based T-PEMF or placebo treatment daily for 8?weeks. The T-PEMF device (Re5 NTS Parkinson Treatment System, Re5, Frederiksberg, Denmark) consisted of a pulse generator and a head applicator with 7 electromagnetic coils located as follow: one in the central occipital region, one in the frontal-parietal region (bilateral), and two in the anterior-temporal and posterior-temporal region (bilateral). During T-PEMF treatment, the pulse generator supplied the coils with squared bipolar pulses of ±50?V at 50?Hz and with a pulse duration of 3?ms. The stimulation intensity depends on the distance from the surface of the coil and the radial distance from the centre of the coil. At the periphery of the coil and close to the skull, maximal stimulation was estimated to be 2.5?mV/cm and decreasing with distance []. The subjects could not feel this very low stimulation intensity. During placebo treatment, the same treatment duration and treatment device was used but no pulsed electromagnetic fields were generated (sham stimulation). Treatment allocation was encoded to a chip card that was inserted in the pulse generator. The generator interface was identical for the two treatment types. Thus, it was not possible for the participants to see or feel difference between T-PEMF and placebo treatment, and both participants and investigators were blinded to the allocation until after endpoint assessment of the last participant. Participants with PD were optimally medicated at baseline and followed their usual medication scheme throughout the intervention. The REF group did not receive any treatment.

Protocol and accelerometer measurements

Two-dimensional cylindrical accelerometers (Catsys PD, Danish Product Development Ltd., Snekkersten, Denmark) were fixed on the hand dorsum along and between metacarpal bone II and III on each hand. The accelerometers were sensitive to accelerations in the plane orthogonal to the metacarpal bones. Hand tremor was sampled synchronously from both hands at 50?Hz.

Tremor assessment was performed before (week 0) and within one day after the last treatment session (week 8). Measures at week 0 and 8 were performed on the same time of day for each individual to reduce the influence of intra-day fluctuations. The participants with PD were tested in self-reported ON-state. The subject sat on a chair with backrest and no arm support with their feet on the ground. Hand tremor was assessed in two conditions: 1) rest, while the hands were placed with palms down approximately on the middle of the thigh in a position allowing the subject to relax and 2) postural, while the arms, hands and fingers were extended in front of the body at shoulder height, approximate shoulder width between hands, and with palms facing towards the floor (Additional file 2). PD tremor can be related to the level of attention of the patient []. Thus, some patients can deliberately suppress the tremor when focusing on it. Furthermore, PD tremor can be affected by stress with more pronounced tremor in a stressed state []. We attempted to standardize the attention level of the participants without inducing stress. Thus, we asked the participants to close their eyes during the assessments to avoid distraction from the environment. Furthermore, we asked the participants to vocally perform a serial subtraction task to focus their attention on the subtraction task and not the tremor task. The use of a serial subtraction task was inspired by Lee et al. []. However, we modified the subtraction task and asked the participants to vocally count down from 100 in steps of two (instead of 7 or 8) in a self-paced manner (instead of as quickly as possible) to avoid stress. Finally, before each 30?s assessment, it was emphasized, that the subject should sit as calm and relaxed as possible while counting. The assessments were performed in calm surroundings and two 30-s trials of each condition were performed in the following order: rest, postural, rest, postural. Approximately 30?s pauses separated the assessments.

Data analysis

Data analyses were performed in MATLAB (Mathworks Inc., USA) using a custom-made script. The script was validated towards conventional tremor analysis software (Catsys PD software, Snekkersten, Denmark). Tremor intensity related measures and inter-hand coherence measures were calculated.

The resultant acceleration was calculated and the 30-s time series were divided into three 10-s time intervals. For each 10-s time interval, the following intensity related measures were calculated within the frequency band of 3–8?Hz (0.1?Hz frequency resolution). Results are presented as the mean across the three time intervals:

  • Tremor intensity was calculated as ?8Hz3Hz|fft|2N2?????????, where |fft| is the absolute value of the fast Fourier transformation of the resultant acceleration in the 3–8?Hz band, and N is the number of |fft| observations. According to Parseval’s theorem, this corresponds to the root mean square of the resultant acceleration within the 3–8?Hz frequency band.
  • Peak power was the maximal absolute power within the 3–8?Hz band.
  • Peak frequency was the frequency at peak power.

Coherence between two biological time series is a measure of similarity of the power spectra of the signals and high coherence between two signals is interpreted as a high common output from the brain. Inter-hand coherence was calculated on the resulting acceleration concatenated from the two 30-s trials of each condition. We calculated the magnitude squared coherence estimate using Welch’s overlapped averaged periodogram method (window length of 256 samples ~?5?s, 20% overlap, Hanning window (256 samples)). Three measures in the 3–8?Hz band were extracted:

  • Coherence, the integral of significant coherence (??=?0.05), being the magnitude squared coherence above a threshold, Z?=?0.2058, as described by Terry and Griffin [] within the 3–8?Hz band.
  • Peak coherence, the maximal value of magnitude squared coherence within the 3–8?Hz band.
  • Frequency of peak coherence, the frequency corresponding to peak coherence.

Statistics

Statistics were performed in SAS 9.4. To investigate potential treatment effects we used linear mixed models for the analysis of the intensity related measures (the log transform of tremor intensity and peak power were used for analyses to meet normal distribution). The analysis of inter-hand coherence related measures was performed by Wilcoxon statistics, as transformation of data did not induce a normal distribution. Age was not correlated to any of the effect measures among the PD group at baseline (Pearson correlation for tremor intensity related measures; Spearman correlation for coherence related measures) and was thus not included as covariate in the models. The level of significance was set to 0.05.

We investigated the effect of treatment on the intensity related measures by the model

dependent outcome=week?week×group

with unstructured covariance. Week entailed week 0 and week 8, and group entailed baseline adjusted treatment groups (T-PEMF and placebo subjects were all considered placebo subjects at week 0). In case of significant week × group interaction, pairwise comparison within group across weeks and between groupswithin week were performed and a 2-level Bonferroni correction was applied to adjust for multiple comparisons (corrected significance level 0.025). To determine if there was a difference in response to active and placebo treatment on coherence related measures, we used a Wilcoxon Ranked Sum test performed on the differences between week 0 and week 8. The effects of treatment on coherence related measures were evaluated both for the whole PD group and for the uni- and bilateral tremor subgroups.

Intergroup differences between PD and REF on intensity related measures were evaluated by the model dependent outcome?=?group, where group entailed PD and REF and measures from both hands from one subject regarded as repeated measures. To determine differences between participants with PD and REF on the inter-hand coherence measures we used a Wilcoxon Ranked Sum test. Intergroup differences in UPDRS measures were determined by t-test.

Normal distributed variables are presented by means and standard deviations (SD). Non-normal distributed variables are presented by medians and the inter quartile ranges (IQR) indicating where the middle 50% of the data lie.

Results

Participants

Of the 36 and 43 participants with PD having rest and postural tremor respectively, three participants with both rest and postural tremor had missing data at week 8 due to withdrawal (n?=?1) and exclusion from the analyses due to lag of compliance and change of medication (n?=?2) (all receiving T-PEMF treatment). In addition, one participant with postural tremor only did not show up for endpoint assessment due to personal reasons (placebo). Thus, rest data from 33 subjects (19?T-PEMF and 14 placebo) and postural data from 39 subjects (20?T-PEMF and 10 placebo) were available at week 8. The treatment compliance of the participants completing the intervention was on average 98%.

As expected, the group with unilateral postural tremor was less clinically affected by the disease than the group with bilateral postural tremor as they had a significantly lower UPDRS Total score (unilateral?=?41?±?12, bilateral?=?51?±?17, p?=?0.0361) and a tendency of lower UPDRS Motor score (unilateral?=?24?±?8, bilateral?=?29?±?11, p?=?0.0590). Thus, the subgroup with bilateral tremor represented a clinically more severely affected group than the subgroup with unilateral tremor. The subgroups with uni- and bilateral rest tremor consisted of 19 participants (10?T-PEMF, 9 placebo) and 13 participant (9?T-PEMF, 5 placebo) respectively. The subgroups with uni- and bilateral postural tremor consisted of 20 participants (8?T-PEMF, 12 placebo) and 19 participants (12?T-PEMF, 7 placebo) respectively.

The adverse events of the treatments have been reported elsewhere. They were benign, mild and transient and the frequency did not differ between treatment groups [].

PD vs REF

The PD group had a much larger median tremor intensity (rest: PD 1330% of REF, p <?0.0001, Fig. 1A; postural: PD 445% of REF, p <?0.0001, Fig. ?Fig.1D)1D) and median peak power (rest: PD 2336% of REF, p <?0.0001, Fig. ?Fig.1B;1B; postural: PD 770% of REF, p <?0.0001, Fig. ?Fig.1E)1E) than the REF group in both conditions. In addition, the PD group had slightly lower estimated mean peak frequency at rest (PD 85% of REF, p <?0.0001, Fig. ?Fig.1C)1C) but a slightly higher peak frequency than the REF group at the postural condition (PD 107% of REF, p =?0.0421, Fig. ?Fig.1F).1F). We found a higher median coherence (rest: PD 384% of REF, p <?0.0001, Fig. 2A; postural: PD 185% of REF, p =?0.0704, Fig. ?Fig.2D),2D), median peak coherence (rest: PD 165% of REF, p?<?0.0001, Fig. ?Fig.2B;2B; postural: PD 130% of REF, p =?0.0271, Fig. ?Fig.2E),2E), and median frequency of peak coherence (postural: PD 114% of REF, p =?0.0339, Fig. ?Fig.2F)2F) in the PD group compared to REF in both conditions, except for the frequency of peak coherence at rest where no between group difference was found (p =?0.7784, Fig. ?Fig.2C).2C). When dividing into the uni- and bilateral tremor subgroups, both subgroups had significantly higher median coherence (unilateral: 0.233 ? 384% of REF, p?<?0.0001; bilateral; 0.277 ? 456% of REF, p?=?0.0010) and median peak coherence (unilateral: 0.620 ? 178% of REF, p?<?0.0001; bilateral; 0.555 ? 159% of REF, p?=?0.0011) than REF in the rest condition. However, in the postural condition only the bilateral tremor group differed from REF (coherence: 0.416 ? 251% of REF, p?=?0.0042; peak coherence: 0.666 ? 46%, p?=?0.0097).

An external file that holds a picture, illustration, etc. Object name is 12984_2019_491_Fig1_HTML.jpg

Treatment effect on intensity related measures for the rest and postural condition, measured values. A and DTremor intensity (TI). B and E Peak power (Powpeak). C and F Peak power (Freqpeak). T-PEMF?=?transcranial pulsed electromagnetic fields. REF?=?healthy reference group. *?=?significant difference from week 0 to week 8 across treatment groups (P???0.05). (*)?=?tendency of difference from week 0 to week 8 across treatment groups (0.05?<?P???0.1). #?=?significant difference between the treatment groups combined at week 0 and REF (P???0.05)

An external file that holds a picture, illustration, etc. Object name is 12984_2019_491_Fig2_HTML.jpg

Treatment effect on inter-hand coherence measures for the rest and postural condition, measured values. A and D Coherence (Coh). B and E Peak coherence (Cohpeak). C and F Frequency of peak coherence (Cohfreq). T-PEMF?=?transcranial pulsed electromagnetic fields. REF?=?healthy reference group. *?=?significant difference from week 0 to week 8 across treatment groups (P???0.05). #?=?significant difference between the treatment groups combined at week 0 and REF (P???0.05). (#)?=?tendency of difference between the treatment groups combined at week 0 and REF (0.05?<?P???0.1)

Effect of the T-PEMF treatment

The statistical analysis showed no statistical difference between the effect of T-PEMF and placebo treatment on tremor intensity, peak power or peak frequency. However, main effects of time across treatment groups were found. Thus, the tremor intensity tended to decrease from week 0 to week 8 in both treatment groups in the resting (p?=?0.0604, model estimated change in median for each group: T-PEMF -22%, placebo ??23%, Fig. ?Fig.1A)1A) and in the postural condition (p?=?0.0585, model estimated change in median for each group: T-PEMF -3%, placebo ??19%, Fig. ?Fig.1D),1D), but no difference of improvement between groups was found. Likewise, peak power decreased significantly from week 0 to week 8 across groups (rest: p?=?0.0453, model estimated change in median for each group: T-PEMF -32%, placebo ??22%, Fig. ?Fig.1B;1B; postural: p?=?0.0128, model estimated change in median for each group: T-PEMF -7%, placebo ??28%, Fig. ?Fig.1E),1E), but no difference of improvement between groups was found. The peak frequency did not change (Fig. ?(Fig.1C1C & F).

With all participants included, no statistical differences in coherence, peak coherence or frequency of peak coherence were found between T-PEMF and placebo treatment (Fig. ?(Fig.2).2). However, when rerunning the analysis after sub-grouping into unilateral and bilateral tremor groups, a statistically significant treatment effect was found for the PD group with unilateral tremor in the postural condition (p?=?0.0339). Thus, coherence was reduced in the T-PEMF group with unilateral postural tremor (?coherence from week 0 to 8, median (IQR): ??0.10 (??0.190 to ??0.0019)) while the corresponding coherence values for the placebo group was not (?coherence from week 0 to 8, median (IQR): +?0.068 (??0.052 to +?0.147)).

Discussion

A major finding of the study was that an 8-week?T-PEMF treatment decreased the inter-hand coherence in the PD group with unilateral postural tremor. The PD group with unilateral postural tremor was less clinically affected by the disease than the PD group with bilateral postural tremor. However, no differences between T-PEMF and placebo treatment on either intensity related or coherence related measures were found when all persons with PD were included in the analyses. The peak power decreased and the tremor intensity tended to decrease across treatment groups.

Effect of T-PEMF on inter-hand coherence

A major new finding was that eight weeks of treatment with T-PEMF plausibly reduced coherence relative to placebo treatment among the participants with unilateral postural tremor. Thus, T-PEMF seemed to lower the common input to movement-patterns of the limbs within the PD frequency range (3–8?Hz). Interestingly, the group having unilateral postural tremor was less clinically affected by the disease evaluated by UPDRS Total and Motor scores. This pattern of the T-PEMF treatment positively affecting a less affected group distinctively from placebo treatment was also found in the analysis of the influence of T-PEMF treatment on functional rate of force development in the clinical trial. Here, the least functionally impaired PD group benefitted from the T-PEMF treatment relative to placebo treatment by increasing their functional rate of force development, while the most functionally impaired PD group did not []. A recent study on repetitive transcranial magnetic stimulation in PD rats showed that functional dopaminergic neurons in substantia nigra are required to induce motor plasticity []. Thus, a certain level of neural functionality may need to be present to gain positive effects of neurostimulation. This emphasizes the importance of early initiation of daily treatment with T-PEMF in PD.

A possible neural explanation for the positive effect of T-PEMF in the unilateral postural tremor group (least affected) could be an increased inhibition of the inter-hemispheric crosstalk [].

Extending the treatment period could potentially induce a larger effect, and could maybe induce effects in more affected persons with PD as well. However, this requires further investigations to determine.

Effect of treatments on intensity related measures

Both T-PEMF and placebo treatment reduced peak power and tended to reduce tremor intensity in both the postural and resting condition. However, the T-PEMF group did not differ statistically from the placebo group. We attempted to induce a calm environment during the assessments, as stress is known to amplify tremor in PD []. However, we cannot exclude the possibility that the participants experienced less stress post treatment due to the familiarity of the test situation. Furthermore, previous studies have reported significant placebo effects on PD tremor. A recent study of the effect of placebo on resting tremor in persons with PD showed a major reduction of tremor amplitude 30?min after a subcutaneous injection of saline, which they were told was apomorphine, a dopamine agonist. This effect was found in approximately half of the subjects classified as placebo responders who benefitted equally from a saline and an apomorphine injection []. Thus, using tremor intensity as an effect measure in clinical trials is challenging, as it is highly sensitive to other factors such as stress, level of attention, and placebo effects and thereby may mask a potential treatment effect. Thus, we cannot exclude the possibility of an effect of 8-weeks of T-PEMF treatment on tremor intensity and peak power, but we can conclude that the group effect of the T-PEMF treatment was not statistically different from the effect of the placebo treatment.

Inter-hand coherence PD vs. REF

Our results showed that inter-hand coherence and peak coherence were larger in the PD group than in the REF group. At first, this seems to be in contrast to a recent finding by Morrison et al. of no difference of peak coherence of postural hand tremor accelerations between persons with PD having bilateral tremor and healthy peers []. However, this discrepancy may be caused by analytic differences, as our analyses were specified to the parkinsonian tremor band (4–7?Hz extended by 1?Hz to 3–8?Hz) to focus the analysis. The study by Morrison et al. included tremor frequencies up to 40?Hz and thus included frequencies of both the parkinsonian and physiological tremor bands. Morrison et al. found that 75% of the accumulated proportional tremor power in the healthy group extended up to 10–11?Hz while it was found below 5–6?Hz in the PD group []. In addition, they found the mean frequency of peak coherence for the healthy group to be 8.9?Hz. Thus, when focussing on tremor in the 3–8?Hz band in our study, we by-passed most of the physiological tremor band and may not have included the frequencies of largest coherence in the REF group. However, the peak coherence values found by Morrison et al. (2012) were lower for both the PD and healthy peers (both group means around 0.2), than the values of the present study. The findings of higher peak coherence in the present study during both rest and postural conditions may be attributed to the attention distracting counting task. Performing attention distracting subtraction tasks has been shown to increase intra-limb inter-muscular coherence at rest in persons with PD [], and to decrease the complexity (i.e. lower the sample entropy) of an EMG signal while performing an isometric contraction in healthy subjects []. In addition, inter-hemispheric connectivity has been shown to increase with the addition of a counting task to a unimanual tapping task, though this increase was not significant during a bimanual tapping task []. Together, this indicates that performing a task while distracting attention gives rise to a more synchronized motor unit activation that could plausibly occur bilaterally and thus affect inter-hand coherence.

In addition, it is an interesting finding that coherence was higher in the PD group with unilateral rest tremor than in healthy peers, which suggests a more similar frequency content of hand movements between hands during the resting condition in the PD group with unilateral tremor. This indicates that the lag of relaxation and/or control of movement are bilaterally affected despite the fact that only unilateral tremor was present.

Methodologic considerations

In participants with substantial tremor, there is a risk of mechanical transmission of tremor from leg to hand and even from one hand to the other especially during the resting condition. However, in the present randomized study we expect both treatment groups to be equally affected.

Conclusion

Our findings revealed that eight weeks of T-PEMF treatment decreased the inter-hand coherence in the PD group with unilateral tremor, while no effects of T-PEMF treatment were found for the entire PD group. The unilateral postural tremor group was less clinically affected by the disease than the bilateral postural tremor group, which suggests that early treatment initiation may be beneficial. In theory, a reduced inter-hand coherence could be a result of a neuronal treatment response increasing inter-hemispheric inhibition. However, this requires further studies to determine. Likewise, it would be of interest to explore if even longer treatment period would enhance the treatment effect.

 

Additional files

Additional file 1:(20K, docx)

Specifications of the clinical trial. (DOCX 19 kb)

Additional file 2:(320K, pdf)

Pictures of tremor assessments. (PDF 319 kb)

Acknowledgements

Not applicable.

Funding

This work was supported by Den A. P. Møllerske Støttefond, Copenhagen, Denmark (10415) and Grosserer L. F. Foght Foundation, Charlottenlund, Denmark (20825). The funding sources had no involvement in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

IQR Inter-Quartile Range
PD Parkinson’s disease
PEMF Pulsed electromagnetic fields
REF Healthy reference participants
T-PEMF Transcranial Pulsed Electromagnetic Fields

Authors’ contributions

ASBM has been involved in designing the study; acquisition, analysis and interpretation of data; and drafting the manuscript. BMM has been involved in designing the study, data acquisition, critically revising the manuscript, and has approved the final manuscript. LW has been involved in designing the study, critically revising the manuscript, and has approved the final manuscript. OG has been involved in designing the study, critically revising the manuscript, and has approved the final manuscript. PB has been involved in designing the study and critically revising the manuscript. BRJ has been involved in designing the study, interpreting data, partly drafting and critically revising the manuscript, and has approved the final manuscript.

Notes

Ethics approval and consent to participate

The study was approved by the Regional Scientific Ethical Committees for Southern Denmark (S-20130114) and the Danish Health Authority (CIV-14-01-011780), and was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent prior to participation.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Footnotes

Per Bech is deceased. This paper is dedicated to his memory.

References

1. Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, Obeso J, Marek K, Litvan I, Lang AE, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord. 2015;30:1591–1601. [PubMed]
2. Gigante AF, Pellicciari R, Iliceto G, Liuzzi D, Mancino PV, Custodero GE, Guido M, Livrea P, Defazio G. Rest tremor in Parkinson’s disease: body distribution and time of appearance. J Neurol Sci. 2017;375:215–219. [PubMed]
3. Liu K, Gu Z, Dong L, Shen L, Sun Y, Zhang T, Shi N, Zhang Q, Zhang W, Zhao M, Sun X. Clinical profile of Parkinson’s disease in the Gumei community of Minhang district, Shanghai. Clinics (Sao Paulo) 2014;69:457–463. [PMC free article] [PubMed]
4. Belvisi D, Conte A, Bologna M, Bloise MC, Suppa A, Formica A, Costanzo M, Cardone P, Fabbrini G, Berardelli A. Re-emergent tremor in Parkinson’s disease. Parkinsonism Relat Disord. 2017;36:41–46.[PubMed]
5. Ayturk Z, Yilmaz R, Akbostanci MC. Re-emergent tremor in Parkinson’s disease: clinical and accelerometric properties. J Clin Neurosci. 2017;37:31–33. [PubMed]
6. Mailankody P, Thennarasu K, Nagaraju BC, Yadav R, Pal PK. Re-emergent tremor in Parkinson’s disease: a clinical and electromyographic study. J Neurol Sci. 2016;366:33–36. [PubMed]
7. Zach H, Dirkx M, Bloem BR, Helmich RC. The clinical evaluation of Parkinson’s tremor. J Parkinsons Dis. 2015;5:471–474. [PMC free article] [PubMed]
8. Lee HJ, Lee WW, Kim SK, Park H, Jeon HS, Kim HB, Jeon BS, Park KS. Tremor frequency characteristics in Parkinson’s disease under resting-state and stress-state conditions. J Neurol Sci. 2016;362:272–277. [PubMed]
9. Zach H, Dirkx MF, Pasman JW, Bloem BR, Helmich RC. Cognitive stress reduces the effect of levodopa on Parkinson’s resting tremor. CNS Neurosci Ther. 2017;23:209–215. [PMC free article] [PubMed]
10. Fishman PS. Paradoxical aspects of parkinsonian tremor. Mov Disord. 2008;23:168–173. [PubMed]
11. Cox BC, Cincotta M, Espay AJ. Mirror movements in movement disorders. Tremor Other Hyperkinet Mov. 2012;2. http://tremorjournal.org/article/view/59[PMC free article] [PubMed]
12. van Wijk BC, Beek PJ, Daffertshofer A. Neural synchrony within the motor system: what have we learned so far? Front Hum Neurosci. 2012;6:252. [PMC free article] [PubMed]
13. Chatterjee P, Banerjee R, Choudhury S, Mondal B, Kulsum MU, Chatterjee K, Kumar H. Mirror movements in Parkinson’s disease: an under-appreciated clinical sign. J Neurol Sci. 2016;366:171–176.[PubMed]
14. van den Berg C, Beek PJ, Wagenaar RC, van Wieringen PC. Coordination disorders in patients with Parkinson’s disease: a study of paced rhythmic forearm movements. Exp Brain Res. 2000;134:174–186.[PubMed]
15. Byblow WD, Summers JJ, Lewis GN, Thomas J. Bimanual coordination in Parkinson’s disease: deficits in movement frequency, amplitude, and pattern switching. Mov Disord. 2002;17:20–29. [PubMed]
16. Johnson KA, Cunnington R, Bradshaw JL, Phillips JG, Iansek R, Rogers MA. Bimanual co-ordination in Parkinson’s disease. Brain. 1998;121(Pt 4):743–753. [PubMed]
17. Disbrow EA, Sigvardt KA, Franz EA, Turner RS, Russo KA, Hinkley LB, Herron TJ, Ventura MI, Zhang L, Malhado-Chang N. Movement activation and inhibition in Parkinson’s disease: a functional imaging study. J Parkinsons Dis. 2013;3:181–192. [PMC free article] [PubMed]
18. Hei WH, Byun SH, Kim JS, Kim S, Seo YK, Park JC, Kim SM, Jahng JW, Lee JH. Effects of electromagnetic field (PEMF) exposure at different frequency and duration on the peripheral nerve regeneration: in vitro and in vivo study. Int J Neurosci. 2016;126:739–748. [PubMed]
19. Urnukhsaikhan E, Cho H, Mishig-Ochir T, Seo YK, Park JK. Pulsed electromagnetic fields promote survival and neuronal differentiation of human BM-MSCs. Life Sci. 2016;151:130–138. [PubMed]
20. Zhang Y, Ding J, Duan W. A study of the effects of flux density and frequency of pulsed electromagnetic field on neurite outgrowth in PC12 cells. J Biol Phys. 2006;32:1–9. [PMC free article][PubMed]
21. Longo FM, Yang T, Hamilton S, Hyde JF, Walker J, Jennes L, Stach R, Sisken BF. Electromagnetic fields influence NGF activity and levels following sciatic nerve transection. JNeurosciRes. 1999;55:230–237. [PubMed]
22. Tepper OM, Callaghan MJ, Chang EI, Galiano RD, Bhatt KA, Baharestani S, Gan J, Simon B, Hopper RA, Levine JP, Gurtner GC. Electromagnetic fields increase in vitro and in vivo angiogenesis through endothelial release of FGF-2. FASEB J. 2004;18:1231–1233. [PubMed]
23. Bragin DE, Statom GL, Hagberg S, Nemoto EM. Increases in microvascular perfusion and tissue oxygenation via pulsed electromagnetic fields in the healthy rat brain. J Neurosurg. 2015;122:1239–1247.[PMC free article] [PubMed]
24. Cuccurazzu B, Leone L, Podda MV, Piacentini R, Riccardi E, Ripoli C, Azzena GB, Grassi C. Exposure to extremely low-frequency (50 Hz) electromagnetic fields enhances adult hippocampal neurogenesis in C57BL/6 mice. Exp Neurol. 2010;226:173–182. [PubMed]
25. Arias-Carrion O, Verdugo-Diaz L, Feria-Velasco A, Millan-Aldaco D, Gutierrez AA, Hernandez-Cruz A, Drucker-Colin R. Neurogenesis in the subventricular zone following transcranial magnetic field stimulation and nigrostriatal lesions. J Neurosci Res. 2004;78:16–28. [PubMed]
26. Di Lazzaro V, Capone F, Apollonio F, Borea PA, Cadossi R, Fassina L, Grassi C, Liberti M, Paffi A, Parazzini M, et al. A consensus panel review of central nervous system effects of the exposure to low-intensity extremely low-frequency magnetic fields. Brain Stimul. 2013;6:469–476. [PubMed]
27. Malling ASB, Morberg BM, Wermuth L, Gredal O, Bech P, Jensen BR. Effect of transcranial pulsed electromagnetic fields (T-PEMF) on functional rate of force development and movement speed in persons with Parkinson’s disease: a randomized clinical trial. PLoS One. 2018;13:e0204478. [PMC free article][PubMed]
28. Sandyk R. Weak magnetic fields in the treatment of Parkinson’s disease with the “on-off” phenomenon. Int J Neurosci. 1992;66:97–106. [PubMed]
29. Legros A, Beuter A. Effect of a low intensity magnetic field on human motor behavior. Bioelectromagnetics. 2005;26:657–669. [PubMed]
30. Morberg BM, Malling AS, Jensen BR, Gredal O, Bech P, Wermuth L. Parkinson’s disease and transcranial pulsed electromagnetic fields: a randomized clinical trial. Mov Disord. 2017;32:625–626.[PubMed]
31. Morberg BM, Malling AS, Jensen BR, Gredal O, Bech P, Wermuth L. Effects of transcranial pulsed electromagnetic field stimulation on quality of life in Parkinson’s disease. Eur J Neurol. 2018;25:963–e974.[PubMed]
32. Fahn S, Elton RL, Committee. MotUD: Unified Parkinson’s Disease Rating Scale. In Recent development in Parkinson’s disease. Volume 2. Edited by Fahn S, Marsden CD, Calne DB, Goldstein M. Florham Park, NJ: Macmillan Health Care Information; 1987: 153–164.
33. Spedden ME, Malling ASB, Andersen KK, Jensen BR. Association between gross-motor and executive function depends on age and motor task complexity. Dev Neuropsychol. 2017;42:495–506. [PubMed]
34. Rahbek UL, Tritsaris K, Dissing S. Interaction of low-frequency, pulsed electromagnetic fields with living tissue: biochemical responses and clinical results. Oral Bioscience Med. 2005;2:1–12.
35. Terry K, Griffin L. How computational technique and spike train properties affect coherence detection. J Neurosci Methods. 2008;168:212–223. [PMC free article] [PubMed]
36. Terry K, Griffin L. Corrigendum to “how computational technique and spike train properties affect coherence detection” [J. Neurosci. Methods 168 (2008) 212–223] J Neurosci Methods. 2008;171:180.[PMC free article] [PubMed]
37. Hsieh TH, Huang YZ, Rotenberg A, Pascual-Leone A, Chiang YH, Wang JY, Chen JJ. Functional dopaminergic neurons in substantia Nigra are required for transcranial magnetic stimulation-induced motor plasticity. Cereb Cortex. 2015;25:1806–1814. [PubMed]
38. Barbagallo G, Nistico R, Vescio B, Cerasa A, Olivadese G, Nigro S, Crasa M, Quattrone A, Bianco MG, Morelli M, et al. The placebo effect on resting tremor in Parkinson’s disease: an electrophysiological study. Parkinsonism Relat Disord. 2018.
39. Morrison S, Newell KM, Kavanagh JJ. Differences in postural tremor dynamics with age and neurological disease. Exp Brain Res. 2017;235:1719–1729. [PubMed]
40. Hurtado JM, Lachaux JP, Beckley DJ, Gray CM, Sigvardt KA. Inter- and intralimb oscillator coupling in parkinsonian tremor. Mov Disord. 2000;15:683–691. [PubMed]
41. Cruz-Montecinos C, Calatayud J, Iturriaga C, Bustos C, Mena B, Espana-Romero V, Carpes FP. Influence of a self-regulated cognitive dual task on time to failure and complexity of submaximal isometric force control. Eur J Appl Physiol. 2018. [PubMed]
42. Serrien DJ. Verbal-manual interactions during dual task performance: an EEG study. Neuropsychologia. 2009;47:139–144. [PubMed]
43. Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE. Systematic review of levodopa dose equivalency reporting in Parkinson’s disease. Mov Disord. 2010;25:2649–2653. [PubMed]

Logo of plosone

PLoS One View this Article Submit to PLoS Get E-mail Alerts Contact Us Public Library of Science (PLoS)
PLoS One. 2018; 13(9): e0204478.
Published online 2018 Sep 25. doi: 10.1371/journal.pone.0204478
PMCID: PMC6155540
PMID: 30252895

Effect of transcranial pulsed electromagnetic fields (T-PEMF) on functional rate of force development and movement speed in persons with Parkinson’s disease: A randomized clinical trial

Anne Sofie Bøgh MallingConceptualizationData curationFormal analysisFunding acquisitionInvestigationMethodologyProject administrationSoftwareVisualizationWriting – original draft,1,2,* Bo Mohr MorbergConceptualizationData curationFunding acquisitionInvestigationProject administrationResourcesWriting – review & editing,1,2 Lene WermuthConceptualizationFunding acquisitionProject administrationResourcesSupervisionWriting – review & editing,1,2 Ole GredalConceptualizationFunding acquisitionResourcesSupervisionWriting – review & editing,3 Per BechConceptualizationFunding acquisitionSupervisionWriting – review & editing,4 and Bente Rona JensenConceptualizationFormal analysisFunding acquisitionMethodologySupervisionWriting – review & editing1,*
Alfonso Fasano, Editor
Author information Article notes Copyright and License information Disclaimer
1 Department of Neurology, Odense University Hospital, University of Southern Denmark, Odense, Denmark
2 Department of Clinical Research, University of Southern Denmark, Odense, Denmark
3 The Danish Rehabilitation Centre for Neuromuscular Diseases, Taastrup, Denmark
4 Psychiatric Research Unit, Psychiatric Centre North Zealand, University of Copenhagen, Hillerød, Denmark
University of Toronto, CANADA
Competing Interests: The authors have declared that no competing interests exist.
Received 2018 Jan 30; Accepted 2018 Sep 6.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Associated Data

Supplementary Materials
Data Availability Statement
All relevant data are within the paper and its Supporting Information files.

Abstract

Background

Parkinson’s disease is caused by dopaminergic neurodegeneration resulting in motor impairments as slow movement speed and impaired balance and coordination. Pulsed electromagnetic fields are suggested to have neuroprotective effects, and could alleviate symptoms.

Objective

To study 1) effects of 8-week daily transcranial pulsed electromagnetic field treatment on functional rate of force development and movement speed during two motor tasks with different levels of complexity, 2) if treatment effects depend on motor performance at baseline.

Methods

Ninety-seven persons with Parkinson’s disease were randomized to active transcranial pulsed electromagnetic field (squared bipolar 3 ms pulses, 50 Hz) or placebo treatment with homebased treatment 30 min/day for 8 weeks. Functional rate of force development and completion time of a sit-to-stand and a dynamic postural balance task were assessed pre and post intervention. Participants were sub-grouped in high- and low-performers according to their baseline motor performance level. Repeated measure ANOVAs were used.

Results

Active treatment tended to improve rate of force development during chair rise more than placebo (P = 0.064). High-performers receiving active treatment improved rate of force development during chair rise more than high-performers receiving placebo treatment (P = 0.049, active/placebo: 11.9±1.1 to 12.5±1.9 BW/s ? 5% / 12.4±1.3 to 12.2±1.3 BW/s, no change). No other between-treatment-group or between-treatment-subgroup differences were found. Data on rate of force development of the dynamic balance task and completion times of both motor tasks improved but did not allow for between-treatment differentiation.

Conclusion

Treatment with transcranial pulsed electromagnetic fields was superior to placebo regarding functional rate of force development during chair rise among high-performers. Active treatment tended to increase functional rate of force development while placebo did not. Our results suggest that mildly affected persons with Parkinson’s disease have a larger potential for neural rehabilitation than more severely affected persons and indicate that early treatment initiation may be beneficial.

Introduction

Parkinson’s disease (PD) is a neurodegenerative disease primarily affecting the dopaminergic neurons in the basal ganglia resulting in functional motor impairments such as slow movement speed (bradykinesia), rigidity, tremor and impaired balance and coordination of movements. The disease influences the ability to activate the muscles fast and without co-activation of inappropriate muscles []. This is reflected in a lower voluntary rate of force development (RFD) in both isometric and functional setups compared to age-matched healthy peers [] in spite of an intact capacity of force generation at the muscular level []. RFD is important in performing daily activities where the time available for force generation is short, e.g. managing balance challenging tasks, response to sudden mechanical perturbations, and safe locomotion.

According to the UK Parkinson’s Disease Society Brain Bank Diagnostic Criteria, the criteria for being diagnosed with PD is bradykinesia along with at least one of the following: muscular rigidity, rest tremor (4–6 Hz) and/or postural instability. Although the diagnostic criteria are clear, the progression of the disease and the relative severity of a given symptom are quite heterogenic between patients []. This results in heterogeneity of specific motor function. Therefore, investigations of subgroups based on motor performance may be valuable.

In vitro (cell-line studies) and in vivo (animal studies) treatment with pulsed electromagnetic fields (PEMF) has been suggested to have potential neuroprotective effects. For example, PEMF were shown to regulate neutrophic factors such as BDNF, S100 and NGF [], enhance cell proliferation and differentiation [], enhance neurite outgrow [], reduce apoptosis [], stimulate angiogenesis [], increase microvascular perfusion and tissue oxygenation [], and stimulate neurogenesis in the hippocampal dentate gyrus [] and in the sub ventricular zone after lesion of substantia nigra []. The molecular mechanisms initiated by the applied PEMF are not yet fully understood. However, PEMF may affect the tissue directly by the interaction mechanism between the electromagnetic fields and conductive tissue, and indirectly by initiating biological events leading to a physiologic response [].

In healthy humans, PEMF applied transcranially (T-PEMF) has been suggested to acutely induce enhanced excitatory neurotransmission and/or decreased inhibitory neurotransmission, though resting or active motor threshold was not affected []. This could increase the capability to activate muscles fast, since an enhanced excitatory neurotransmission may facilitate a larger neural drive to the muscles during explosive force production, and thus increase RFD.

To our knowledge, the effect of T-PEMF on motor function in PD has not previously been studied, whereas other non-invasive neuromodulation techniques have been shown to improve motor function in persons with PD. For example, repetitive transcranial magnetic stimulation was shown to induce positive effects on motor function that last at least a month []. However, transcranial magnetic stimulation usually involves stimulation of the cortical neurons at intensities close to or above the resting motor threshold, and it has to be performed in a clinical setup. On the contrary, the T-PEMF technique uses low intensity stimulation [] and may be applicable as a homebased treatment.

Based on the literature, we hypothesized that treatment with T-PEMF has the potential to improve RFD and movement speed in persons with PD. Our aims were 1) to study the effect of an 8-week daily homebased T-PEMF treatment on functional RFD and movement speed during two lower extremity motor tasks with different levels of movement complexity, and 2) to study if the treatment effect is dependent on motor performance level at baseline.

Methods

Study design

All persons with idiopathic Parkinson’s disease (PDPs) included in the present study were participants in a double-blinded block randomized clinical trial investigating the effect of T-PEMF on PD (clinicaltrials.gov registration# NCT02125032) []. PDPs were recruited from Odense University Hospital and private neurologists in Denmark from May 2014 to August 2015. They were randomized to receive 8 weeks of active or placebo treatment. The active and placebo group were of equal size. A third party person conducted the allocation. PDPs were allocated to a number on the allocation sequence list in order of inclusion. Sample size calculation for the trial was based on the primary outcome of the trial, The Unified Parkinson’s Disease Rating Scale (UPDRS) [], which is a partly subjective clinical measure of disease severity based on observations and patient reports. The mean difference on the UPDRS between active and placebo treatment was estimated to be 3 points from baseline to endpoint with a pooled standard deviation of this mean difference of 7. With a significance level of 0.05 and a power of 0.80, the sample size was estimated to be 90 participants, i.e. 45 in each treatment group. For details, see S2 Text. The trial was approved by The Regional Scientific Ethical Committees for Southern Denmark (S-20130114) and The Danish Health Authority (CIV-14-01-011780), and was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent prior to participation. No statistical detectable effect of T-PEMF relative to placebo treatment was found for the primary outcome []. The present study reports on secondary outcomes.

Participants

Ninety-seven PDPs were included in the clinical trial (Fig 1). Inclusion criteria were a diagnosis of idiopathic PD (Hoehn & Yahr I-IV) according to United Kingdom Brain Bank Criteria; stable and optimal medical treatment regarding PD six weeks prior to and during the intervention period; Mini Mental State Examination >22; age >18 and cognitive skills enabling certification in the use of the T-PEMF device. Exclusion criteria were structural brain damage affecting the ability to give consent; severe psychopathological disturbances; substance abuse; active medical implants; pregnancy or nursing; current or previous cancer in the brain, neck or head region; leukemia; autoimmune disease; epilepsy; and open scalp wounds. In addition, participants with a post interventional treatment compliance of less than 80% were excluded from the analyses.

An external file that holds a picture, illustration, etc. Object name is pone.0204478.g001.jpg

Participant flow diagram.

Flow of participants with Parkinson’s disease (PD) during enrollment, allocation to active or placebo treatment with transcranial pulsed electromagnetic fields, follow-up after 8 weeks of treatment, and analysis. Sit-to-stand (STS). Dynamic postural balance (DPB). Completion time of DPB (CTDPB). Functional rate of force development during DPB (RFDDPB).

To describe the severity of the disease and medication level, the Unified Parkinson’s Disease Rating Scale Total score (UPDRS Total) and Motor score (UPDRS Motor) [] were assessed and daily levodopa equivalent dose (LED) were calculated according to Tomlinson et al. [].

In addition, 43 healthy participants matched on age and sex distribution were included from Dec 2015 to May 2016 as a reference group. The reference group was tested once and used as a reference frame for subgrouping.

To explore if the baseline performance level of each evaluation parameter had an influence on the effect of T-PEMF, we divided the PDP group into two subgroups according to their baseline performance level of each parameter in each task. Since RFD is influenced by age [] and all the performance parameters correlated with age (S1 Table), we conducted a linear regression analysis on each parameter as a function of age in the reference group to gain expected values of each parameter at a given age. The standard deviation of the parameter of the whole reference group was used as tolerance. Thus, if a PDP had a baseline RFD value below the expected mean according to age minus 1 SD (higher values of RFD represent better performance) he/she was considered a low-performer (PDPLow) of the particular RFD-parameter. Equally, if a PDP had a baseline completion time (CT) above the expected mean according to age plus 1 SD (lower values of CT represent better performance) he/she was considered a PDPLow of the particular CT-parameter. Otherwise, a PDP was considered a high-performer (PDPHigh) of the particular parameter.

T-PEMF treatment

The PDPs received one daily 30-min session of homebased active T-PEMF or placebo treatment for 8 weeks. The T-PEMF device (Re5 NTS Parkinson Treatment System, Re5, Frederiksberg, Denmark) consisted of a pulse generator and a head applicator with 7 circular coils located as follow: one in the central occipital region, one in the frontal-parietal region (bilateral), and two in the anterior-temporal and posterior-temporal region (bilateral). During active T-PEMF treatment, the pulse generator supplied the coils with squared bipolar pulses of ±50 V at 50 Hz with a pulse duration of 3 ms. The stimulation intensity depends on distance from coil and also the closeness to the coil in horizontal position. At the periphery of the coil and close to the skull maximal stimulation was 2.5 mV/cm and decreased with distance []. During placebo treatment, no pulsed electromagnetic fields were generated (sham stimulation). The treatment type (active or placebo) was determined by a chip-card inserted in the pulse generator. A third party person encoded the chip cards. The interface on the pulse generator had the same appearance no matter if the chip card was encoded with an active T-PEMF or a placebo treatment. All use of the T-PEMF device was stored on the chip-card and these records were used to determine treatment compliance. During generation of electromagnetic fields, the T-PEMF device produced a very faint humming sound (6.1 dB, ~50 Hz, below the level of detection according to ISO 266:2003) but no heat or skin sensation []. Thus, it was not possible to see or feel difference between active and placebo treatment, and both PDPs and investigators were blinded to the treatment allocation until all PDPs had completed their treatment period and endpoint assessments.

The PDPs were certified in use of the equipment at baseline. They received a home visit during the first week of the treatment period to ensure correct use. Furthermore, they received two telephone calls each week from an investigator to encourage high compliance and register potential adverse events.

The reference group did not receive any treatment.

Assessment of motor function

The participants were evaluated on RFD and CT of two motor function tasks: a six-cycle sit-to-stand (STS) and a dynamic postural balance (DPB) task assessed in a movement laboratory. Assessments were performed at baseline before the initiation of treatment later the same day, and at endpoint the day after the last treatment session. PDPs followed their usual medication schedule throughout the study and all assessments were performed in self-reported ON-state at baseline and at endpoint.

Sit-to-stand (STS)

While seated in a custom-built chair allowing only the bare feet to exert force on a force plate (AMTI, USA, 1 kHz sampling), the participant performed trials of six STS cycles as fast as possible [] (Fig 2A). The seat height was 120% tibia length []. The inter-feet distance was the width of the shoulders, the knee angle was 90°-100°, and the arms were placed across the chest. At least three approved trials were performed after task familiarization. A trial was approved if the knees were fully extended while standing, the back touched the backrest while seated, and the feet and hands retained their positions throughout the trial. To ensure maximal performance, an additional trial was performed if the last approved trial was the fastest. The test-retest reliability of the completion time conducted by the described protocol has previously been shown to be high among persons with PD (intraclass correlation coefficient of 0.97 []).

An external file that holds a picture, illustration, etc. Object name is pone.0204478.g002.jpg

Illustration of the sit-to-stand (left) and dynamic postural balance task (right).

A Schematic illustration of the tasks. B Example of raw data from a representative healthy reference participant. C Example of raw data from a representative person with Parkinson’s Disease. Completion time for dynamic postural balance (CTDPB). Completion time for sit-to-stand (CTSTS).

Dynamic postural balance (DPB)

While standing barefooted on a force plate, 46 side-to-side movements were performed as fast as possible producing sufficient alternating ground reaction torque around the anterior-posterior axis to exceed predetermined target torques without lifting the feet [] (Fig 2A). Standardized feet positions with 50% leg length (trochanter major to ground, barefooted) between the posterior midpoints of the calcanei and a 10° outward rotation of the feet were used. The target torque was 90% of the torque produced by one-legged still stance in the standardized foot-positions. Visual on-line feedback on produced torque and target torques were provided. Standardized verbal pacing was given. The arms were used as desired by the participant. At least three approved trials were performed after task familiarization. A trial was approved for analysis if at least 35 of the sixth to the 46th torque peaks exceeded 95% of the target torque. To ensure maximal performance, an additional trial was performed if the last approved trial was the fastest. The test-retest reliability of the completion time conducted by the described protocol has previously been found to be high among persons with PD (intraclass correlation coefficient of 0.92 []).

Data analysis

The analyses below were performed for the whole active and placebo groups as well as for the PDPLowand PDPHigh subgroups of the active and placebo groups.

Raw data from the force plate of the STS test were A/D converted (16-bit, Data Translation Inc., USA) and filtered with a zero phase second order 25 Hz low pass Butterworth filter. The vertical ground reaction force was analyzed according to a previous study []. In short, the completion time (CTSTS) was calculated as the time-period from the 1st vertical ground reaction force peak of the first repetition to the first peak of the 6th repetition (Fig 2B and 2C). Thus, CTSTS reflected the time period of five repetitions. The rate of force development (RFDSTS) was determined as the mean slope of the rising force of the first force peak of each of the 2nd to the 6th repetition in the interval of 30–70% exerted peak force. Results are reported as the mean of the two fastest approved trials in body weight per second (BW/s).

The analyses of the DPB test were performed in line with previously described principles []. In short, the completion time (CTDPB) was calculated as the time from the 6th to the 46th torque peak (Fig 2B and 2C). The reported CTDPB was calculated as the average of the two fastest approved trials. The rate of force development (RFDDPB) was determined as the mean slope of the rising resultant force in the coronal plane in the interval of 30–70% of maximal exerted force for each side-to-side movement. Results are reported as the means of the two fastest approved trials averaged between left and right leg in BW/s.

Statistics

Group differences between active, placebo and REF at baseline were assessed by a one-way ANOVA for age, height and weight, and by ?2 test for sex distribution. Group differences between active and placebo at baseline were assessed by a t-test for UPDRS Total, UPDRS Motor, disease duration and LED.

The four parameters CTSTS, RFDSTS, CTDPB and RFDDPB were tested for normal distribution (Anderson-Darling). Since CTDPB did not show a normal distribution, the log10 transformation of these data were used for further analysis. All four parameters had equal variances across group (active and placebo) and time levels (baseline and endpoint) as assessed by the Levene’s test. The interventional effects on CTSTS, RFDSTS, CTDPB and RFDDPB were analyzed by repeated measure two-way ANOVAs (2 groups × 2 time points) performed as general linear models to identify the differences between groups (active and placebo) and between time points of testing (baseline and endpoint). The model was: Response parameter = group + subject(group) + time + group×time. Post hoc analysis of significant or a tendency of significant interaction term (group×time) was performed by paired t-test within each group across time. Statistics were performed in Minitab (Minitab Release 13.32). The level of significance was set at P ? 0.05, and 0.05<P?0.10 was presented as a tendency.

Results

Participants

Of the 97 participants originally included in the clinical trial, two withdrew, one were excluded during the intervention, and two were lost to follow up (Fig 1). In addition, two subjects were excluded because of lag of compliance, three subjects were incapable of performing both the STS and DPB at baseline because of PD related motor deficits, two had developed supervening musculoskeletal problems at follow-up and could not perform STS or DPB, and one had changed the daily levodopa intake. Thus, 84 participants (42 active, 42 placebo) completed baseline and endpoint testing with a treatment compliance above 80%. Of these, some had minor supervening musculoskeletal problems making them uncomfortable in performing one of the tasks. In total, 82 subjects (41 active, 41 placebo) were included in the STS analysis and 80 subjects (39 active, 41 placebo) were included in the DPB analysis. In addition, three subjects (1 active, 2 placebo) were excluded from the analysis of RFDDPB since the data analysis could not be conducted due to irregularity of the resultant force (Fig 1). Group descriptive variables are presented in Table 1. No differences regarding age, height, body weight, disease duration, LED, UPDRS Total, or UPDRS Motor were found between groups at baseline (Table 1). The baseline UPDRS Total and UPDRS Motor grand average scores for the PDPLow subgroups were 47 and 27, respectively, and 42 and 23, respectively, for the PDPHigh subgroups. The treatment compliance for all 84 participants included in the analyses of at least one of the motor assessments was 98.2%.

Table 1

Group descriptive variables.
All PDP Active PDP Placebo PDP REF P
N 84 42 42 43
Females/males 37/47 18/24 19/23 20/23 0.943
Age (years) 66±8.3 67±6.5 65±9.6 66±8.1 0.775
Height (cm) 173±8.4 173±9.2 174±7.7 174±9.2 0.861
Weight (kg) 77±15.4 77±15.2 76±15.8 75±11.4 0.792
Disease duration (years) 4.9±4.0 5.4±4.6 4.3±3.6 0.242
LED (mg/day) 509±335 533±376 485±292 0.512
UPDRS Total 44±12.8 45±13.4 43±12.1 0.441
UPDRS Motor 25±8.1 26±8.7 24±7.4 0.321

Group descriptive variables at baseline for all persons with Parkinson’s disease (PDP), the active group (Active PDP), the placebo group (Placebo PDP), and the healthy reference group (REF). Disease duration is expressed in whole years from diagnose to inclusion. Daily levodopa equivalent dose (LED). Unified Parkinson’s Disease Rating Scale total score (UPDRS Total) and motor score (UPDRS Motor). Data are presented as the mean ± SD.

The adverse events were benign, mild and transient and the frequency did not differ between treatment groups [].

Effect of treatment on motor performance

Results from the STS showed a tendency of group×time interaction effect on RFDSTS (F1,80 = 3.53, P = 0.064) and a significant main effect of time (F1,80 = 8.32, P = 0.005). Post hoc analysis showed that the active group improved their RFDSTS by 5% from 10.1±2.3 BW/s at baseline to 10.6±2.6 BW/s at endpoint (T = -3.17, P = 0.003), whereas the placebo group did not change from baseline to endpoint (baseline: 10.7±1.9 BW/s, endpoint: 10.8±1.8 BW/s, T = -0.76, P = 0.450) (Fig 3B). Further, we found a significant effect of time on CTSTS as the two groups combined improved 4.8% from 10.3±2.1 s at baseline to 9.8±1.9 s at endpoint. (F1,80 = 17.08, P<0.001). No difference between groups (F1,80 = 0.09, P<0.760) or group×time interaction effect (F1,80 = 0.08, P<0.773) was found (Fig 3A).

An external file that holds a picture, illustration, etc. Object name is pone.0204478.g003.jpg

Results for all persons with Parkinson’s disease.

A Completion time of the sit-to-stand task (CTSTS), B rate of force development of the sit-to-stand task (RFDSTS), C completion time of the dynamic postural balance task (CTDPB), and D rate of force development of the dynamic postural balance task (RFDDPB) for all participants with Parkinson’s disease receiving active (PDP active) or placebo (PDP placebo) transcranial pulsed electromagnetic fields and for healthy reference participants (REF). Bodyweight (BW). Data presented as the mean ± SD. * P?0.05 for main effect of time. (#)0.05 < P < 0.1 for the group×time interaction effect.

Concerning the DPB, no significant interaction or main effects were found for RFDDPB (Fig 3D). However, the ANOVA showed a significant effect of time in CTDPB (F1,78 = 19.09, P<0.001) across groups but no significant main effects of group (F1,78 = 1.57, P = 0.214) or group×time interaction effects (F1,78 = 0.12, P = 0.734). The mean CTDPB for both groups combined improved 9.4% (baseline: 21.9±11.6 s, endpoint: 19.8±9.8 s) (Fig 3C).

Effect of T-PEMF on low- and high-performers

For the RFDSTS we found a significant group×time interaction (F1,36 = 4.16, P = 0.049) among PDPHigh. Thus, the active PDPHigh group increased functional RFD during chair rise superiorly to the placebo group. The active PDPHigh group had a tendency towards improvement of 5% from 11.9±1.1 BW/s at baseline to 12.5±1.9 BW/s at endpoint (T = -1.95, P = 0.066), whereas the placebo PDPHigh group did not change (baseline 12.4±1.30.30 BW/s, endpoint 12.2±1.30.31 BW/s, T = 0.86, P = 0.404) (Fig 4B). In contrast, in the PDPLow group we found significant improvement with treatment across the active and placebo groups (F1,42 = 10.02, P = 0.003) along with a difference between groups across time (F1,42 = 4.45, P = 0.041), but no difference in improvement between groups (Fig 4B).

An external file that holds a picture, illustration, etc. Object name is pone.0204478.g004.jpg

Results for subgroups.

A Completion time of the sit-to-stand task (CTSTS), B rate of force development of the sit-to-stand task (RFDSTS), C completion time of the dynamic postural balance task (CTDPB), and D rate of force development of the dynamic postural balance task (RFDDPB) for low-performers (PDPLow) and high-performers (PDPHigh) of the persons with Parkinson’s disease receiving active or placebo transcranial pulsed electromagnetic fields. Bodyweight (BW). Data presented as the mean ± SD. * P?0.05 for main effect of time. (*) 0.05 < P < 0.1 for the main effect of time. # P?0.05 for the group×time interaction effect.

For the CTSTS and CTDPB we found improvements with treatment across groups in both PDPLow (CTSTS: F1,30 = 10.75, P = 0.003; CTDPB: F1,16 = 10.05, P = 0.006;) and PDPHigh (CTSTS: F1,48 = 7.07, P = 0.011; CTDPB: F1,60 = 10.15, P = 0.002) (Fig 4A & 4C). For RFDDPB the improvement with treatment across groups was only found in the PDPLow (F1,18 = 9.88, P = 0.006). In addition, we found a tendency of difference between groups across time in the PDPLow (F1,18 = 3.09, P = 0.096) (Fig 4D). For PDPHigh no differences across time or groups were found (Fig 4D).

Discussion

The main finding of this study indicates a probable positive effect of treatment with T-PEMF on RFD during chair rise, and that this positive effect was present among the participants with high performance levels at baseline. In addition, we found improved motor performance in PDP from baseline to endpoint independently of the treatment received.

Our data showed that the T-PEMF treatment was superior to placebo in the PDPHigh group for RFDSTS, whereas this was not the case among the PDPLow group indicating a group specific effect. Muscle activation deficit is common in PD and maximal voluntary activation of the quadriceps muscle during isometric knee extension has been shown to be negatively associated with disease severity in terms of UPDRS Motor score []. Furthermore, the UPDRS Motor score has been shown to correlate with the degree of dopaminergic degeneration in PD []. Thus, it seems plausible that the PDPHigh group is less affected by dopaminergic degeneration than the PDPLow group. It is therefore likely that the PDPHighgroup has a higher capacity for neuro repair than the PDPLow group. This emphasizes that early initiation of T-PEMF treatment in PDP is important. However, the present results do not exclude the possibility of a positive effect of T-PEMF in the PDPLow group if the treatment period is longer than 8 weeks. Therefore, a study on the effect of long-term treatment with T-PEMF is warranted.

The rate of force development depends on the corticospinal drive to the muscles along with the muscle morphology. In healthy subjects, studies have shown that early explosive force generation is primarily determined by neural components in terms of agonist activation, whereas the later phase of explosive force generation is primarily determined by muscle mechanical components including muscle strength []. Both maximal voluntary contraction force and RFD measured during electric stimulation of the quadriceps femoris muscles are intact in persons with mild motor symptoms of PD. However, these patients have a lower voluntary RFD [] indicating that mechanical muscle performance is intact, that the muscle can be activated maximal voluntarily if the time frame is sufficient, and that what most likely constitutes the problem in voluntary RFD in PD is insufficient rate of corticospinal drive to the muscles in the early muscle contraction phase. This early phase determined by the rate of corticospinal drive may be of utter importance, since the maximal voluntary contraction level is usually not reached during activities of daily living. For example, around 70% of maximal knee extensor strength is produced during self-paced rising from a chair in healthy older adults [].

Indeed, the agonist drive was shown to be decreased in PD and to be related to the RFD during explosive isometric knee extension []. In addition, functional RFD can be improved in PD, for example, by physical training []. Thus, the observed increased functional RFD in the present study may be explained by increased rate of agonist drive to the muscles, driven by increased corticospinal output.

Based on the literature, an increased rate of corticospinal drive could be explained by an increased thalamocortical input to the motor cortex regulated by the basal ganglia or an increased excitability of motor cortex. Increased intercortical facilitation, suggested to reflect enhanced excitatory neurotransmission, has been shown as an acute effect of T-PEMF with an intensity of 1.8 mT (75 Hz, mono pulses of 1.3 ms) in healthy subjects [] indicating a potential of electromagnetic fields of very low intensity to induce cortical changes. To our knowledge, the present clinical trial has applied daily T-PEMF stimulation for the longest period to date, and the influence of repeated stimulation on cortical excitability in this context has not been previously investigated. High frequent rTMS (> 1 Hz) of motor cortex in healthy participants was shown to increase the cortical excitability []. Whether this was also the case for the T-PEMF regime used in the present study is uncertain since it implied electromagnetic fields of very low intensity and did not particularly target the motor cortex. Thus, we hypothesize that the observed increased RFDSTS can be explained by an increased thalamocortical input.

Furthermore, increased co-contraction has been reported among persons with PD during both isometric [] and dynamic assessments []. Although an increased rate of corticospinal drive seems to be a likely explanation for the increased functional RFD we cannot exclude that reduced co-contraction of the thigh muscles play a role as well, since we did not perform an electromyography assessment in the present study.

If the corticospinal drive has been increased by T-PEMF, it is peculiar that no significant between-group difference in the RFDDPB was observed. This may, however, reflect the considerable higher complexity of the DPB in terms of the demand for rapid integration and implementation of online visual feedback on timing and coordination of a novel, non-routine task []. When evaluating the rate of resulting ground reaction force development, we measure how fast the whole body exerts force to the ground. The more complex a task the more components are influencing the rate of force development besides the force development of the muscles. Further, the more components affecting performance the more within subject variability is expected. Thus, the fact that no change in RFDDPB was found is not necessarily in conflict with the finding of increased RFDSTS in PDPHigh.

The 5% increase in RFDSTS in PDPHigh is considered to be clinically relevant as any systematic improvement in functional rate of force development reflect improved motor control and motor ability during daily living, although the improvement may not be perceived by all the participants. The 5% increase may not represent the maximal obtainable effect of T-PEMF as 8 weeks of treatment is a relatively short period available to initiate structural changes in the brain. The Danish Health Authority did not permit a longer treatment period in this first study of homebased T-PEMF treatment in PD. We suggest the use of even longer treatment periods in future studies to determine if the improvement can be further amplified.

For RFDSTS, CTSTS, and CTDPB, we found a significant improvement from baseline to endpoint when disregarding the treatment groups. These improvements could reflect placebo effects, learning effects, or a mix of both. We aimed at reducing the potential effect of learning by familiarizing the participants to the tests before measuring and by continuing measurements until reaching a plateau of performance. Test-retest reliability of the tests in PDPs are substantial []. Considerable placebo effects were also reported in clinical trials of PD when investigating invasive and non-invasive neuromodulation techniques (e.g. see [] for review). For example, sham rTMS was shown to reduce [11C] raclopride binding potentials in the striatum of patients with PD, which indicated a placebo induced increase in dopaminergic neurotransmission []. Non-motor placebo effects of T-PEMF performed in other patient populations have also been reported []. Therefore, although we cannot determine the cause of improvement across groups, we expect the learning effect to be negligible and consider the improvements on CTSTS and CTDBP to be a result of the placebo effect.

Strengths and limitations

A strength of this clinical trial was the high treatment compliance and the large amount of participants relative to previous studies of brain stimulation. To our knowledge, the present clinical trial applied daily T-PEMF stimulation for the longest time period to date, which is a strength. However, further studies on even longer treatment periods are warranted to enable structural neural changes and thereby to get further insight concerning the neuro-mechanical mechanisms associated with T-PEMF in PD.

Placebo effect among PDPs participating in clinical trials is a well-known phenomenon due to the pathophysiology of the disease. In the present study, we have accounted for this by including a placebo group receiving sham stimulation.

Three participants were not able to conduct the motor tasks because of PD-related motor deficits. These participants were among the most severely affected PDPs.

We did not perform adjustment of the P-value in the sub group analysis as we aimed at reducing the risk of confirming a false null-hypothesis. Thus, the reported effects of T-PEMF on subgroup level should be interpreted as probable effects.

All assessments were performed in ON-state. Thus, we did not determine an eventual effect of T-PEMF treatment on motor function in OFF-state. This should be considered in future studies.

Conclusion

In this study, which is the first on the effect of long-term T-PEMF treatment on functional rate of force development and movement speed in PD, we found that T-PEMF treatment was superior to placebo treatment to increase functional RFD during chair rise in the PDPHigh group. Specifically, the functional RFD tended to increase in the PDPHigh group receiving T-PEMF treatment, whereas no effect was found in the PDPHigh group receiving placebo treatment. Thus, our results support the idea that mildly affected persons with PD have a larger potential for neural rehabilitation than more severely affected PDP. Our data on functional RFD during the more complex DPB task and completion times of both the STS and DPB task improved but did not allow for differentiation between T-PEMF and placebo treatments. In perspective, long-term treatment with T-PEMF could have a potential as an add-on treatment for PD, and the results of the present study suggest that an early treatment initiation may be beneficial. However, studies with even longer treatment periods and in vivo mechanisms of action are recommended.

 

Supporting information

S1 Table

Correlation between age and outcome measures.

(DOCX)

S1 Data

(XLSX)

S1 Text

Explanation to S2 Data.

(DOCX)

S2 Text

Sample size calculation.

(DOCX)

S3 Text

Study protocol.

(PDF)

S1 File

CONSORT checklist.

(DOC)

Acknowledgments

Professor MD DM.Sc. Per Bech passed away before the submission of the final version of this manuscript. Anne Sofie Bøgh Malling accepts responsibility for the integrity and validity of the data collected and analyzed. The authors would like to thank Meaghan E. Spedden and Ken K. Andersen for assistance during data acquisition of the healthy control group.

Abbreviations

BW bodyweight
CT completion time
DPB dynamic postural balance
LED daily levodopa equivalent dose
PD Parkinson’s disease
PDPHigh high-performers
PDPLow low-performers
PDPs Parkinson’s disease participants
PEMF pulsed electromagnetic fields
REF healthy reference group
RFD rate of force development
STS sit-to-stand
T-PEMF transcranial pulsed electromagnetic fields
UPDRS Unified Parkinson’s Disease Rating Scale

Funding Statement

This work was supported by Den A. P. Møllerske Støttefond, Copenhagen, Denmark (grant# 10415, https://www.apmollerfonde.dk/ansoegning/stoettefonden, received by Lene Wermuth) and Grosserer L. F. Foghts Fond, Charlottenlund, Denmark (grant# 20825, http://foghtsfond.dk, received by Ole Gredal). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data Availability

All relevant data are within the paper and its Supporting Information files.

References

1. Stevens-Lapsley J, Kluger BM, Schenkman M. Quadriceps muscle weakness, activation deficits, and fatigue with Parkinson diseaseNeurorehabilNeural Repair. 2012;26(5):533–41. 10.1177/1545968311425925 [PubMed] [CrossRef]
2. Rose MH, Løkkegaard A, Sonne-Holm S, Jensen BR. Isometric Tremor Irregularity, Torque Steadiness and Rate of Force Development in Parkinson’s DiseaseMotor Control. 2013;17:203–16. [PubMed]
3. Malling AS, Jensen BR. Motor intensive anti-gravity training improves performance in dynamic balance related tasks in persons with Parkinson’s diseaseGait & posture. 2016;43:141–7. 10.1016/j.gaitpost.2015.09.013 . [PubMed] [CrossRef]
4. Hammond KG, Pfeiffer RF, LeDoux MS, Schilling BK. Neuromuscular rate of force development deficit in Parkinson diseaseClin Biomech (Bristol, Avon). 2017;45:14–8. 10.1016/j.clinbiomech.2017.04.003 . [PubMed] [CrossRef]
5. Paasuke M, Ereline J, Gapeyeva H, Joost K, Mottus K, Taba P. Leg-extension strength and chair-rise performance in elderly women with Parkinson’s diseaseJAging PhysAct. 2004;12(4):511–24. [PubMed]
6. Kalia LV, Lang AE. Parkinson’s diseaseLancet. 2015;386(9996):896–912. 10.1016/S0140-6736(14)61393-3 . [PubMed] [CrossRef]
7. Fereshtehnejad SM, Postuma RB. Subtypes of Parkinson’s Disease: What Do They Tell Us About Disease Progression? Curr Neurol Neurosci Rep. 2017;17(4):34 10.1007/s11910-017-0738-x . [PubMed] [CrossRef]
8. Hei WH, Byun SH, Kim JS, Kim S, Seo YK, Park JC, et al. Effects of electromagnetic field (PEMF) exposure at different frequency and duration on the peripheral nerve regeneration: in vitro and in vivo studyInt J Neurosci. 2016;126(8):739–48. 10.3109/00207454.2015.1054032 . [PubMed] [CrossRef]
9. Longo FM, Yang T, Hamilton S, Hyde JF, Walker J, Jennes L, et al. Electromagnetic fields influence NGF activity and levels following sciatic nerve transectionJNeurosciRes. 1999;55(2):230–7. 10.1002/(SICI)1097-4547(19990115)55:2<230::AID-JNR10>3.0.CO;2-3 [PubMed] [CrossRef]
10. Urnukhsaikhan E, Cho H, Mishig-Ochir T, Seo YK, Park JK. Pulsed electromagnetic fields promote survival and neuronal differentiation of human BM-MSCsLife Sci. 2016;151:130–8. 10.1016/j.lfs.2016.02.066 . [PubMed] [CrossRef]
11. Zhang Y, Ding J, Duan W. A study of the effects of flux density and frequency of pulsed electromagnetic field on neurite outgrowth in PC12 cellsJ Biol Phys. 2006;32(1):1–9. 10.1007/s10867-006-6901-2 ; [PMC free article] [PubMed] [CrossRef]
12. Tepper OM, Callaghan MJ, Chang EI, Galiano RD, Bhatt KA, Baharestani S, et al. Electromagnetic fields increase in vitro and in vivo angiogenesis through endothelial release of FGF-2FASEB J. 2004;18(11):1231–3. 10.1096/fj.03-0847fje [PubMed] [CrossRef]
13. Bragin DE, Statom GL, Hagberg S, Nemoto EM. Increases in microvascular perfusion and tissue oxygenation via pulsed electromagnetic fields in the healthy rat brainJ Neurosurg. 2015;122(5):1239–47. 10.3171/2014.8.JNS132083 . [PMC free article] [PubMed] [CrossRef]
14. Cuccurazzu B, Leone L, Podda MV, Piacentini R, Riccardi E, Ripoli C, et al. Exposure to extremely low-frequency (50 Hz) electromagnetic fields enhances adult hippocampal neurogenesis in C57BL/6 miceExp Neurol. 2010;226(1):173–82. 10.1016/j.expneurol.2010.08.022 . [PubMed] [CrossRef]
15. Arias-Carrion O, Verdugo-Diaz L, Feria-Velasco A, Millan-Aldaco D, Gutierrez AA, Hernandez-Cruz A, et al. Neurogenesis in the subventricular zone following transcranial magnetic field stimulation and nigrostriatal lesionsJournal of neuroscience research. 2004;78(1):16–28. 10.1002/jnr.20235 . [PubMed] [CrossRef]
16. Di Lazzaro V, Capone F, Apollonio F, Borea PA, Cadossi R, Fassina L, et al. A consensus panel review of central nervous system effects of the exposure to low-intensity extremely low-frequency magnetic fieldsBrain Stimul. 2013;6(4):469–76. 10.1016/j.brs.2013.01.004 . [PubMed] [CrossRef]
17. Capone F, Dileone M, Profice P, Pilato F, Musumeci G, Minicuci G, et al. Does exposure to extremely low frequency magnetic fields produce functional changes in human brain? J Neural Transm (Vienna). 2009;116(3):257–65. 10.1007/s00702-009-0184-2 . [PubMed] [CrossRef]
18. Khedr EM, Farweez HM, Islam H. Therapeutic effect of repetitive transcranial magnetic stimulation on motor function in Parkinson’s disease patientsEur J Neurol. 2003;10(5):567–72. . [PubMed]
19. Khedr EM, Rothwell JC, Shawky OA, Ahmed MA, Hamdy A. Effect of daily repetitive transcranial magnetic stimulation on motor performance in Parkinson’s diseaseMov Disord. 2006;21(12):2201–5. . [PubMed]
20. Morberg BM, Malling AS, Jensen BR, Gredal O, Bech P, Wermuth L. Parkinson’s disease and transcranial pulsed electromagnetic fields: A randomized clinical trialMov Disord. 2017;32(4):625–6. 10.1002/mds.26927 . [PubMed] [CrossRef]
21. Morberg BM, Malling AS, Jensen BR, Gredal O, Bech P, Wermuth L. The effect of transcranial pulsed electromagnetic field stimulation on quality of life in Parkinson’s diseaseEuropean Journal of Neurology. 2018;In press. [PubMed]
22. Fahn S, Elton RL, Committee. MotUD. Unified Parkinson’s Disease Rating Scale In: Fahn S, Marsden CD, Calne DB, Goldstein M, editors. Recent development in Parkinson’s disease2 Florham Park, NJ: Macmillan Health Care Information; 1987. p. 153–64.
23. Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE. Systematic review of levodopa dose equivalency reporting in Parkinson’s diseaseMov Disord. 2010;25(15):2649–53. 10.1002/mds.23429 . [PubMed] [CrossRef]
24. Thompson BJ, Ryan ED, Herda TJ, Costa PB, Herda AA, Cramer JT. Age-related changes in the rate of muscle activation and rapid force characteristicsAge (Dordr). 2014;36(2):839–49. 10.1007/s11357-013-9605-0 ; [PMC free article] [PubMed] [CrossRef]
25. Rahbek UL, Tritsaris K, Dissing S. Interaction of Low-frequency, Pulsed Electromagnetic Fields with Living Tissue: Biochemical Responses and Clinical ResultsOral Bioscience and Medicine. 2005;2(1):1–12.
26. Martiny K, Lunde M, Bech P. Transcranial low voltage pulsed electromagnetic fields in patients with treatment-resistant depressionBiolPsychiatry. 2010;68(2):163–9. 10.1016/j.biopsych.2010.02.017 [PubMed] [CrossRef]
27. Rose MH. Rehabilitation in Parkinson’s Disease: University of Copenhagen, Department of Nutrition, Exercise and Sports; 2013.
28. Weiner DK, Long R, Hughes MA, Chandler J, Studenski S. When older adults face the chair-rise challenge. A study of chair height availability and height-modified chair-rise performance in the elderlyJAmGeriatrSoc. 1993;41(1):6–10. [PubMed]
29. Berthelsen MP, Husu E, Christensen SB, Prahm KP, Vissing J, Jensen BR. Anti-gravity training improves walking capacity and postural balance in patients with muscular dystrophyNeuromusculDisord. 2014;24(6):492–8. 10.1016/j.nmd.2014.03.001 [PubMed] [CrossRef]
30. Brucke T, Asenbaum S, Pirker W, Djamshidian S, Wenger S, Wober C, et al. Measurement of the dopaminergic degeneration in Parkinson’s disease with [123I] beta-CIT and SPECT. Correlation with clinical findings and comparison with multiple system atrophy and progressive supranuclear palsyJ Neural Transm Suppl. 1997;50:9–24. . [PubMed]
31. Folland JP, Buckthorpe MW, Hannah R. Human capacity for explosive force production: neural and contractile determinantsScand J Med Sci Sports. 2014;24(6):894–906. 10.1111/sms.12131 . [PubMed] [CrossRef]
32. Samuel D, Rowe P, Nicol A. The functional demand (FD) placed on the knee and hip of older adults during everyday activitiesArch Gerontol Geriatr. 2013;57(2):192–7. 10.1016/j.archger.2013.03.003 . [PubMed] [CrossRef]
33. Fitzgerald PB, Fountain S, Daskalakis ZJ. A comprehensive review of the effects of rTMS on motor cortical excitability and inhibitionClinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology. 2006;117(12):2584–96. 10.1016/j.clinph.2006.06.712 . [PubMed] [CrossRef]
34. Dimitrova D, Horak FB, Nutt JG. Postural muscle responses to multidirectional translations in patients with Parkinson’s diseaseJ Neurophysiol. 2004;91(1):489–501. 10.1152/jn.00094.2003 . [PubMed] [CrossRef]
35. Dietz V, Zijlstra W, Prokop T, Berger W. Leg muscle activation during gait in Parkinson’s disease: adaptation and interlimb coordinationElectroencephalogr Clin Neurophysiol. 1995;97(6):408–15. . [PubMed]
36. Spedden ME, Malling ASB, Andersen KK, Jensen BR. Association Between Gross-Motor and Executive Function Depends on Age and Motor Task ComplexityDev Neuropsychol2017:1–12. 10.1080/87565641.2017.1399129 . [PubMed] [CrossRef]
37. Lidstone SC. Great expectations: the placebo effect in Parkinson’s diseaseHandb Exp Pharmacol. 2014;225:139–47. 10.1007/978-3-662-44519-8_8 . [PubMed] [CrossRef]
38. Strafella AP, Ko JH, Monchi O. Therapeutic application of transcranial magnetic stimulation in Parkinson’s disease: the contribution of expectationNeuroimage. 2006;31(4):1666–72. 10.1016/j.neuroimage.2006.02.005 ; [PMC free article] [PubMed] [CrossRef]
39. Tran MTD, Skovbjerg S, Arendt-Nielsen L, Christensen KB, Elberling J. A randomised, placebo-controlled trial of transcranial pulsed electromagnetic fields in patients with multiple chemical sensitivityActa Neuropsychiatr. 2017;29(5):267–77. 10.1017/neu.2016.51 . [PubMed] [CrossRef]

Logo of crn

Karger Home Alerts Resources
. 2018 May-Aug; 10(2): 242–251.
Published online 2018 Aug 29. doi: 10.1159/000492486
PMCID: PMC6167712
PMID: 30283322

Effects of Long-Term Treatment with T-PEMF on Forearm Muscle Activation and Motor Function in Parkinson’s Disease

aDepartment of Neurology, Odense University Hospital, University of Southern Denmark, Odense, Denmark
bDepartment of Clinical Research, University of Southern Denmark, Odense, Denmark
cThe Danish Rehabilitation Centre for Neuromuscular Diseases, Taastrup, Denmark
dPsychiatric Research Unit, Psychiatric Centre North Zealand, University of Copenhagen, Hillerød, Denmark
*Bente R. Jensen, Department of Neurology, Odense University Hospital, University of Southern Denmark, J.B. Winsløvs Vej 4, DK-5000 Odense C (Denmark), E-Mail moc.liamg@001nesnejrb ro kd.dysr@nesnej.r.etneb
Per Bech has deceased.
Received 2018 Jun 15; Accepted 2018 Jul 24.
This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.

Abstract

Bipolar pulsed electromagnetic stimulation applied to the brain (T-PEMF) is a non-pharmacological treatment which has been shown to stimulate nerve growth, attenuate nerve abnormalities, and improve microcirculation. We report on a 62-year-old, medically well-treated man with idiopathic Parkinson’s disease. He was treated with T-PEMF, 30 min per day for three 8-week periods separated by two 1-week breaks. The disease made his handwriting impossible to read mainly due to small letters and lack of fluency. Forearm EMG measured during standardized conditions showed an involuntary spiky EMG pattern with regular burst activity (on his left side) at baseline. The intervention normalized the handwriting and forearm EMG. The UPDRS-motor score decreased from 25 to 17, and UPDRS-II-handwriting decreased from a pre-intervention value of 3 to 0 after the intervention. Finally, the patient reported improved fine motor function, less muscle stiffness, less muscle cramps and tingling, and less fatigue during the day in response to the T-PEMF treatment. The improved handwriting lasted for approximately 3 months after the treatment. Our results should be considered as preliminary, and large-scale, controlled studies are recommended to elucidate the therapeutic potential of long-term treatment with T-PEMF.

Keywords: Parkinsonism, Motor deficiency, Transcranial pulsed electromagnetic stimulation, Tremor, Handwriting, EMG

Background

Impaired fine motor skills and tremor are common in Parkinson’s disease (PD). It is commonly accepted that the origin of the tremor is in the central nervous system, although the exact pathophysiological mechanisms leading to Parkinsonian tremor are still discussed. Several hypotheses regarding the origin of tremor have been proposed in the literature. There seems to be evidence that both the basal ganglia and the cerebello-thalamo-cortical loop are involved in Parkinsonian tremor. Activity in the basal ganglia is primarily affected by dopamine depletion in PD. Recently, a new model, the “dimmer-switch-model,” has been proposed. The model combines features of previous hypotheses into a complex model. The dimmer-switch-model explains tremor as resulting from the combined action of two neural circuits: the basal ganglia that trigger tremor-related responses in the cerebello-thalamo-cortical circuit initiate the tremor (switch) and the cerebello-thalamo-cortical circuit produces the tremor and modulates tremor intensity (dimmer). Further, the model suggests that these interactions occur in the motor cortex where the two circuits converge []. Tremor is associated with rhythmic, bursty, neuronal firing and is clearly visible on surface electromyographic (EMG) recordings [].

Treatment with bipolar pulsed electromagnetic fields (PEMF) is a non-invasive, rapidly emerging technique. The biophysical effects of PEMF are to depolarize the membrane potential slightly and to induce ion currents in the tissue []. The technique (in animals and in vitro) seems to enhance cellular activity and stimulate growth-related responses and regeneration []. For example, PEMF has been shown to stimulate nerve growth and attenuate nerve abnormalities, to increase the microvascular blood flow and tissue oxygenation, and to increase capillary density []. Thus, a connection between pulsed electromagnetic fields and the physiological response must exist. Treatment with PEMF constitutes a new, potential, non-pharmacological treatment method of PD when applied transcranially to the brain (T-PEMF).

The patient presented in this case report participated in an ongoing study on the effects of long-term treatment with T-PEMF. In this study, we focus on tremor characteristics, muscle activation, and gross motor function in terms of movement speed and functional rate of force development. The reason why this particular patient is presented as a case report was that he produced a detailed written report on signs and symptoms and conducted writing tests during and after the treatment period on his own initiative and blinded to the researchers. The researchers received the patient report and the writing tests after the end of the treatment. These data raised the question whether there were any systematic changes in the activation of the forearm muscles in response to the T-PEMF treatment that could be documented.

Case Report

We report on a male patient (age 62 years, body weight 73 kg, height 1.77 m) who had been diagnosed with PD according to the UK Brain Bank criteria 6 years prior to participation. Total score of the Unified Parkinson Disease Rating Scale (UPDRS) was 50, UPDRS-motor was 25, UPDRS-II-handwriting was 3, Hoehn and Yahr stage was 2, and Mini-Mental State Examination score was 30 at baseline. The patient was left-handed, and the left side was most affected. The patient received 1,010 mg/24 h levodopa equivalent dose (Selegeline, Ropinirole, levodopa/benserazide). The patient was medically well-treated, and the medication had not been changed for more than 6 weeks prior to or throughout the T-PEMF intervention period. The patient had no family history of PD. The patient’s handwriting was characterized by diminution of letter size, a tendency to progressive reduction in size, and lack of fluency, which made his handwriting unreadable at baseline.

The patient was treated with T-PEMF (home-based) in three periods of 8 weeks’ duration separated by a 1-week pause between the treatment periods. Thus, the total intervention period was 26 weeks. Each treatment period included one daily treatment of 30 min duration. No sham treatment was performed. T-PEMF was performed through 7 coils placed in a helmet-like shape, with one coil in the central occipital region, one in the frontal-parietal region (bilateral), and two in the anterior-temporal and posterior-temporal region (bilateral) (Re5 NTS Parkinson Treatment System, Re5, Frederiksberg, Denmark). The coils were connected to an external pulse generator which generated bipolar, squared pulses (amplitude approximately 50 V, duration 3 ms, frequency 55 Hz) to initiate rapid changes in the currents in the coils, which gave rise to a time-dependent, rapidly changing electromagnetic field. The electromagnetic field penetrates through electrically insulated tissue, such as, for example, the skull, and induces a driving force on the charged particles (peak E-field intensity approximately 2.5 mV/cm near the coil) and thereby electrical currents in the brain (Table ?(Table11).

Table 1

Characteristics of the presented T-PEMF stimulation method versus typical high- and low-frequency rTMS [4, 14, 15]

T-PEMF High-frequency rTMS Low-frequency rTMS
Sites, n 7 1 (or 2) 1 (or 2)
Brain target large small small
Coil circular circular/figure 8 circular/figure 8
Intensity about 6th order of magnitude less than motor threshold approximately active or rest motor threshold approximately active or rest motor threshold
Frequency, Hz 55 5–25 (50) ?1
Stimuli/session 99,000 450–3,000 60–1,800
Sessions (total) 168 1–10 1–10
Duration 3 × 8 weeks 1 day to 8 weeks 1 day to 8 weeks
Treatment location home clinic clinic

The outcomes in the present case report are forearm muscle activation, handwriting performance, and reported observations. In addition, UPDRS was measured before and after the intervention. All measurements were performed in self-reported on-phase. Surface EMG (MQ-15, Marq Medical, Denmark) was recorded from wrist/finger extensor and wrist flexor muscles (bilaterally). EMG was recorded with the patient seated on a chair (no back support), the shoulders 90 degrees flexed, elbows stretched, arms parallel, palms facing the floor, and an external load of 0.480 kg in each hand (power grip). EMG was measured at baseline (week 0), after 2 periods of T-PEMF treatment (week 17), and on the day after the last T-PEMF treatment (week 27). Measurements of EMG at the three time points during the treatment period were repeated twice for each time point. Each recording lasted 25 s. Handwriting tests, performed during the treatment period, were saved by the patient and shown to the researchers after the end of the treatment. Observations regarding status and changes in motor and non-motor signs and symptoms were reported by the patient and the patient’s family. The reported observations were given in written form to the researchers after the end of the treatment. EMG results, handwriting tests, and patient observations are presented in Figures ?Figures1,1?,2,2, and ?and3,3, respectively. The total UPDRS score was 38, UPDRS-motor was 17, and UPDRS-II-handwriting was 0 after the intervention.

An external file that holds a picture, illustration, etc. Object name is crn-0010-0242-g01.jpg

EMG findings during a standardized, low-level, isometric contraction. Surface EMG recorded from the forearm extensor and flexor muscles. 0, at baseline; 17, after two 8-week periods with T-PEMF treatment; 27, after three 8-week periods with T-PEMF treatment.

An external file that holds a picture, illustration, etc. Object name is crn-0010-0242-g02.jpg

Handwriting performed before, during, and after the treatment with T-PEMF. a Micrographia before the initiation of the treatment. b Handwriting test performed after the first two treatment periods. Letter size has increased significantly. c Handwriting test performed after the end of the treatment. The patient’s handwriting is now normalized.

An external file that holds a picture, illustration, etc. Object name is crn-0010-0242-g03.jpg

Observations reported by the patient.

In addition, the patient performed writing tests at 2, 7, 11, and 16 weeks after the treatment. The patient’s improved writing performance was largely maintained for at least 11 weeks. At week 16 after the intervention, a marked impairment was seen (online suppl. Fig.; for all online suppl. material, see www.karger.com/doi/10.1159/000492486).

Discussion

The patient had been diagnosed with PD 6 years prior to participation. Handwriting impairment was among the patient’s first visible signs. Surface EMG was measured on the wrist extensor and flexor muscles during a bilateral, prolonged, low-level, static contraction. A static muscle activation pattern was, therefore, expected bilaterally, in both the extensor and flexor muscles, and with the highest activation level in the extensor muscles. The expected muscle activation pattern was found for the muscles on the right side, which was the patient’s less affected side (Fig. ?(Fig.1).1). However, on the left side, a spiky EMG pattern with regular burst activity was measured in the extensor muscles and to some extends in the flexor muscles throughout the contractions at baseline. Such an EMG pattern is common in PD and can result in tremor. However, tremor is the mechanical manifestation of involuntary, intermittent muscle activation, and it occurs when the internal torque generated by the muscles exceeds the external torque generated by gravity. Thus, consequently, involuntary EMG burst activity can occur without visible tremor when the internal torque is less than the external torque. However, this type of involuntary muscle activation pattern can certainly disturb fine motor skills, such as, for example, writing ability, due to a lack of force and movement control.

Figure ?Figure22 shows the patient’s handwriting performance at different time points. Handwriting is a complex motor activity, and dysfunction is a major and common disabling sign of PD, although not included in the diagnosis. In accordance, the lack of readability of his handwriting was a major problem for the patient at baseline. The patient’s handwriting was significantly improved after the treatment period compared to baseline. This is, letter size was increased, and his writing was much more fluent and certainly readable. Handwriting disability is associated with decreased activity and connectivity in the basal ganglia motor circuit []. Furthermore, writing ability and tremor share a common correlate, dopamine, in PD []. Therefore, it is hypothesized that long-term treatment with T-PEMF increases the level of dopamine in the brain [].

EMG measurements at week 17 clearly showed a changed activation pattern of the left forearm muscles compared to baseline. The spiky muscle activation pattern had disappeared, and a pattern corresponding to the right-side EMG was found. The same static activation pattern was found after the third 8-week treatment period. In parallel with this, the three 8-week periods of treatment with T-PEMF improved the readability and the quality of the patient’s handwriting significantly as shown in Figure ?Figure2.2. In accordance, UPDRS-II-handwriting was reduced from 3 to 0 during the treatment period. The major improvement was found after the first two 8-week periods of treatment.

In addition, the patient reported improved fine motor function, less muscle stiffness, and less muscle cramps and tingling in response to the T-PEMF treatment. Furthermore, he experienced less fatigue during day time and became happier (Fig. ?(Fig.3).3). The improved writing ability after the treatment lasted approximately 3 months, indicating a long-term effect.

The present T-PEMF treatment differs significantly from rTMS regarding number of stimulation sites, intensity, frequency, stimuli per session, number of sessions, duration, and location (Table ?(Table1)1) []. Thus, T-PEMF induces a high number of weak, pulsating, electric fields in the brain tissue. The electric field is strong enough to cause protein activation but weaker than the limit for eliciting action potentials of brain cells and for opening voltage-dependent Na+ channels [].

In conclusion, it seems likely that the improved motor control, e.g., writing ability, is associated with the present normalization of forearm muscle activation and that this is an effect of long-term treatment with T-PEMF. The presented results should be considered as preliminary, and the effects of T-PEMF should be studied in large-scale, controlled studies to elucidate the therapeutic potential of the new technique.

Statement of Ethics

Written informed consent was obtained from the patient for his participation in this case report. The study was approved by the Ethics Committee, Project-ID: S-20160106.

Disclosure Statement

The authors have nothing to declare.

Funding Sources

The research group received funding from The Jascha Foundation, Denmark, Den A.P. Møllerske Støttefond, Copenhagen, Denmark, and Grosserer L.F. Foghts Foundation, Charlottenlund, Denmark.

Acknowledgement

We thank the patient for letting us publish his case and Meaghan Spedden for technical assistance.

References

1. Helmich RC, Janssen MJ, Oyen WJ, Bloem BR, Toni I. Pallidal dysfunction drives a cerebellothalamic circuit into Parkinson tremor. Ann Neurol. 2011 Feb;69((2)):269–81. [PubMed]
2. Helmich RC, Hallett M, Deuschl G, Toni I, Bloem BR. Cerebral causes and consequences of parkinsonian resting tremor: a tale of two circuits? Brain. 2012 Nov;135((Pt 11)):3206–26.[PMC free article] [PubMed]
3. Zhang J, Xing Y, Ma X, Feng L. Differential diagnosis of Parkinson’s disease, Essential tremor, and enhanced physiological tremor with the tremor analysis of EMG. Parkinsons Dis. 2017;1597907((17)):1–4.[PMC free article] [PubMed]
4. Rahbek UL, Tritsaris K, Dissing S. Interaction of Low-frequency, Pulsed Electromagnetic Fields with Living Tissue: Biochemical Responses and Clinical Results. Oral Biosci Med. 2005;2:1–12.
5. Pan Y, Dong Y, Hou W, Ji Z, Zhi K, Yin Z, et al. Effects of PEMF on microcirculation and angiogenesis in a model of acute hindlimb ischemia in diabetic rats. Bioelectromagnetics. 2013 Apr;34((3)):180–8.[PubMed]
6. Lei T, Jing D, Xie K, Jiang M, Li F, Cai J, et al. Therapeutic effects of 15 Hz pulsed electromagnetic field on diabetic peripheral neuropathy in streptozotocin-treated rats. PLoS One. 2013 Apr;8((4)):e61414.[PMC free article] [PubMed]
7. Hei WH, Byun SH, Kim JS, Kim S, Seo YK, Park JC, et al. Effects of electromagnetic field (PEMF) exposure at different frequency and duration on the peripheral nerve regeneration: in vitro and in vivo study. Int J Neurosci. 2016 Aug;126((8)):739–48. [PubMed]
8. Urnukhsaikhan E, Cho H, Mishig-Ochir T, Seo YK, Park JK. Pulsed electromagnetic fields promote survival and neuronal differentiation of human BM-MSCs. Life Sci. 2016 Apr;151:130–8. [PubMed]
9. Wu T, Zhang J, Hallett M, Feng T, Hou Y, Chan P. Neural correlates underlying micrographia in Parkinson’s disease. Brain. 2016 Jan;139((Pt 1)):144–60. [PMC free article] [PubMed]
10. Lange KW, Mecklinger L, Walitza S, Becker G, Gerlach M, Naumann M, et al. Brain dopamine and kinematics of graphomotor functions. Hum Mov Sci. 2006 Oct;25((4-5)):492–509. [PubMed]
11. Dovzhenok A, Rubchinsky LL. On the origin of tremor in Parkinson’s disease. PLoS One. 2012;7((7)):e41598. [PMC free article] [PubMed]
12. Dirkx MF, den Ouden HE, Aarts E, Timmer MH, Bloem BR, Toni I, et al. Dopamine controls Parkinson’s tremor by inhibiting the cerebellar thalamus. Brain. 2017 Mar;140((3)):721–34. [PubMed]
13. Strafella AP, Paus T, Fraraccio M, Dagher A. Striatal dopamine release induced by repetitive transcranial magnetic stimulation of the human motor cortex. Brain. 2003 Dec;126((Pt 12)):2609–15.[PubMed]
14. Wagle Shukla A, Shuster JJ, Chung JW, Vaillancourt DE, Patten C, Ostrem J, et al. Repetitive transcranial magnetic stimulation (rTMS) therapy in Parkinson disease: A meta-analysis. PM R. 2016 Apr;8((4)):356–66. [PMC free article] [PubMed]
15. Chung CL, Mak MK. Effect of Repetitive transcranial magnetic stimulation on physical function and motor signs in Parkinson’s disease: a systematic review and meta-analysis. Brain Stimul. 2016 Jul-Aug;9((4)):475–87. [PubMed]

Articles from Case Reports in Neurology are provided here courtesy of Karger Publishers

Logo of nrr

Home Current issue Instructions Submit article
Neural Regen Res. 2016 Dec; 11(12): 1888–1895.
doi:  10.4103/1673-5374.195277
PMCID: PMC5270416

Extremely low frequency electromagnetic fields stimulation modulates autoimmunity and immune responses: a possible immuno-modulatory therapeutic effect in neurodegenerative diseases

Fabio Guerriero, M.D., Ph.D.1,2,* and Giovanni Ricevuti1,2
1Department of Internal Medicine and Medical Therapy, Section of Geriatrics, University of Pavia, Pavia, Italy
2Azienda di Servizi alla Persona, Istituto di Cura Santa Margherita of Pavia, Pavia, Italy
*Correspondence to: Fabio Guerriero, ti.aivapidatisrevinu@10oreirreug.oibaf.

Author contributions: All authors contributed to developing the concepts, designing the structure, and writing/revising the manuscript, and approved the final version before submission and agree to be accountable.

Author information ? Article notes ? Copyright and License information ?
Accepted 2016 Nov 25.

Abstract

Increasing evidence shows that extremely low frequency electromagnetic fields (ELF-EMFs) stimulation is able to exert a certain action on autoimmunity and immune cells. In the past, the efficacy of pulsed ELF-EMFs in alleviating the symptoms and the progression of multiple sclerosis has been supported through their action on neurotransmission and on the autoimmune mechanisms responsible for demyelination. Regarding the immune system, ELF-EMF exposure contributes to a general activation of macrophages, resulting in changes of autoimmunity and several immunological reactions, such as increased reactive oxygen species-formation, enhanced phagocytic activity and increased production of chemokines. Transcranial electromagnetic brain stimulation is a non-invasive novel technique used recently to treat different neurodegenerative disorders, in particular Alzheimer’s disease. Despite its proven value, the mechanisms through which EMF brain-stimulation exerts its beneficial action on neuronal function remains unclear. Recent studies have shown that its beneficial effects may be due to a neuroprotective effect on oxidative cell damage. On the basis of in vitro and clinical studies on brain activity, modulation by ELF-EMFs could possibly counteract the aberrant pro-inflammatory responses present in neurodegenerative disorders reducing their severity and their onset. The objective of this review is to provide a systematic overview of the published literature on EMFs and outline the most promising effects of ELF-EMFs in developing treatments of neurodegenerative disorders. In this regard, we review data supporting the role of ELF-EMF in generating immune-modulatory responses, neuromodulation, and potential neuroprotective benefits. Nonetheless, we reckon that the underlying mechanisms of interaction between EMF and the immune system are still to be completely understood and need further studies at a molecular level.

Keywords: electromagnetic fields, Alzheimer’s disease, transcranial magnetic stimulation, autoimmunity, immunomodulation

Introduction

The etiology of neurodegenerative diseases is multifactorial. Genetic polymorphisms, increasing age and environmental cues are recognized to be primary risk factors. Although different neuronal cell populations are affected across diverse neurodegenerative disorders, hallmark protein modifications is a common feature that supports the differential disease diagnosis and provides a mechanistic basis to gauge disease progression (Bossy-Wetzel et al., 2004).

It is becoming increasingly clear that, particularly for chronic neurodegenerative disorders occurring late in life, a complex combination of risk factors can initiate disease development and modify proteins that have a physiological function into ones with pathological roles via a number of defined mechanisms (Moreno-Gonzalez and Soto, 2011).

Amyloid-beta plaques and tau protein tangles – hallmarks of the pathology – are most likely a non-specific result of the disease process, rather than a cause (Lee et al., 2007). A large body of evidence supports the direct contribution of inflammation in the development and progression of neurodegeneration (Tweedie et al., 2007). A common denominator in the occurrence of different pathogenic mechanisms is oxidative stress accompanied by redox dysregulation, which have a role in mitochondrial dysfunction, toxicity, missignalling by calcium, glial cell dysfunction and neuroinflammation itself. Each of these can influence one another at multiple different levels, and hence oxidative stress can both be secondary to them as well as have a primary part in their initiation (von Bernhardi and Eugenin, 2012).

In the last years, evidence are remarkably revealing that Alzheimer’s disease (AD) has an autoimmune component (D’Andrea, 2005). In older patients the presence of anti-neuronal autoantibodies in the serum frequently occurs; if blood-brain barrier (BBB) dysfunction comes up, these autoantibodies are able to reach their targets and determine deleterious effect (D’Andrea, 2003). In fact, a profound change in BBB permeability has been observed in AD. In these patients amyloid deposits have been observed in microvessels and this overload is associated with degenerating endothelium (decreased mitochondrial content, increased pinocytotic vesicles), damaged smooth muscle cells and pericytes, and basement membrane changes (focal necrosis, reduplication, increased collagen content, disintegrating) (Thomas et al., 1996; Wardlaw et al., 2003). All these components strengthen the possibility that the ‘major pathological role of amyloid in AD may be to inflict vascular damage’ and hence, impair BBB function (Franzblau et al., 2013; Attems and Jellinger, 2014).

Immunoglobulins (IGs) have been detected in serum, cerebrospinal fluid and amyloid plaques of patients with AD. IGs are associated with vessel-associated amyloid, which has been linked to a faulty BBB (Franzblau et al., 2013). As a consequence, the presence of neuronal autoantibodies associated with a BBB dysfunction seems to be a relevant part of AD neuropathology (Attems and Jellinger, 2014).

Additional data about relationship between autoimmune diseases (e.g., thyroid dysfunction, diabetes) and AD has been proven. In fact, patients with AD have a significant increase in the values of anti-thyroglobulin and anti-microsomial autoantibodies compared to healthy controls (Genovesi et al., 1996).

Moreover, typical features of autoimmunity have been associated with both AD and diabetes (e.g., high levels of advanced glycation end products and their receptor have been detected in tissues and in the circulation in both disease) (Mruthinti et al., 2006).

In summary, these data in the context of the underlying mechanisms of many autoimmune diseases indicated that AD has proven autoimmune mechanisms, which provide a link between vascular pathology (altered BBB function) and neuronal cell death. Furthermore, according to these data, BBB dysfunction precedes neuronal degeneration and dementia (Rhodin and Thomas, 2001).

Electromagnetic Brain Stimulation and Immunomodulation in Neurodegenerative Diseases

Over the past decades, neuroscientists and clinicians have been exploring the properties of the brain’s electromagnetic activity for both diagnostic and therapeutic purposes. In the 1990s, research on electromagnetic radiation was motivated by the need to better understand the potential harmful effects of environmental magnetic fields (Bennett, 1995; Bracken and Patterson, 1996); actually, it is becoming increasingly clear that interactions between magnetic fields and biological systems deserve to be studied in their own right because these interactions appear to be fundamental to life processes and could represent a therapeutic agent in several diseases.

In our opinion, one of the more striking observations related to the effects of EMFs on biological systems concerns the presence of a “window effect,” showing that biological effects occur only at particular combinations of frequency and field intensity (Panagopoulos and Margaritis, 2010). These effects have been reported especially for changes in calcium ion flux in cells and tissues. Related window effects are reports of signal-specific quantitative and qualitative response to EMFs in several different tissues (Azanza and del Moral, 1994).

ELF-EMFs interact readily with the central nervous system (CNS). While the high-frequency EMFs encountered in industry can expose workers to an increased risk of AD (Hakansson et al., 2003), amyotrophic lateral sclerosis and multiple sclerosis (MS) (Johansen, 2004), EMFs of weak and very weak intensity can exert interesting and proven therapeutic effects on the CNS (Sandyk, 1992; Sandyk and Iacono, 1994; Boggio et al., 2012). The level of radiation is typically in the range of 1 millitesla (mT) in most studies.

Transcranial magnetic brain stimulation (TMS) is a commonly-used neurostimulation and a neuromodulation technique, based on the principle of electromagnetic induction of an electrical field in the brain. This field can be of sufficient magnitude and density to depolarize neurons, and when TMS pulses are applied repetitively they can modulate cortical excitability, decreasing or increasing it, depending on the parameters of stimulation, even beyond the duration of the train of stimulation (Fregni and Pascual-Leone, 2007; Ridding and Rothwell, 2007).

The last decade has seen a rapid increase in the applications of TMS to study cognition, neurobehavioral relations and the pathophysiology of several neurologic and psychiatric disorders. Evidence has accumulated that demonstrates that TMS provides a valuable tool for modulating brain activity in a specific, distributed, cortico-subcortical network through control and manipulation of cognition, neuromotoricity and behavior (George et al., 2007; Guerriero et al., 2015).

Since the immune system plays a primary role in the control of many diseases and tumor growth, many laboratories have investigated the influence of ELF-EMF stimulation on blood mononuclear cells, various cellular components and cellular processes; other studies have examined electromagnetic effects on specific genes expressions and signal transduction pathways, but the experimental data obtained are currently controversial (Cossarizza et al., 1993; Onodera et al., 2003).

The mechanisms by which ELF-EMFs elicit cellular responses are somewhat still unknown, and it is still unclear which cellular components mediate these fields’ effects. However, there are several hypotheses to explain EMF interaction with the living matter.

It is assumed that some type of initial interaction occurs at the level of the cell membrane and that specific signal amplification processes carry the membrane-mediated effect into the cell (Frey, 1993). Molecular studies of the membrane signaling processes have shown, for example, that the involved cells can use mechanisms such as intracellular second-messenger (e.g., Ca2+, cyclic adenosine monophosphate [cAMP], cyclic guanosine monophosphate [cGMP]) cascades, positive feedback, and linear membrane channel-gating (Grundler et al., 1992). Some of the most important calcium-related processes such as synaptic neurotransmitter and synthesis and release and levels of cAMP (Matthews and Gersdorff, 1996), essential for the functioning of the neurons that are influenced by EMFs (Rosen, 1992). In addition, amplification via calcium flux could also provide the means by which the membrane-mediated effects of EMFs could be carried into the cell (Karabakhtsian et al., 1994).

As described below, EMFs proved to exert a certain immune function modulation. Modulation of neural activity by ELF-EMFs could possibly counteract the aberrant pro-inflammatory responses present in neurodegenerative and neuropsychiatric disorders reducing their severity and, possibly, their onset.

Thus, in the next sections we will address the influence of ELF-EMFs on autoimmunity and immune cells, supposing that ELF-EMF may act on the basis of mechanisms centered on immunomodulation. This could have particular relevance for the treatment of neurodegenerative disorders, such as AD.

Low-frequency Electromagnetic Fields Stimulation and Autoimmunity

Regarding a possible relationship between EMF and autoimmunity, the researches conducted by Sandyk and colleagues deserve great interest. In the 1990s, Sandyk amply demonstrated the efficacy of pulsed ELF-EMFs of a few mT in alleviating the symptoms of MS through their action on axonal and synaptic neurotransmission (Sandyk and Iacono, 1993; Sandyk and Dann, 1995). Weekly treatment administered for years with very weak ELF-EMFs can alter the clinical course of chronic progressive MS, arresting progression of the disease for as long as four years (Sandyk, 1995a, 1997). This observation prompts the hypothesis that, in addition to effects on axonal and synaptic neurotransmission, effects may also be exerted on the autoimmune mechanisms responsible for demyelination.

Other proposals that to use pulsed ELF-EMFs of a few mT aims to modify the autoimmune pathology of the disease by eliciting profound membrane changes (Bistolfi, 2002) (the so-called Marinozzi effect) (Marinozzi et al., 1982) in the MS plaque cells.

While the action of ELF fields of a few pT is characterized by an improvement in neurotransmission, the use of ELF fields of a few mT aims to exert an action of local immunomodulation on the cells of the MS plaque through the induction of the Marinozzi effect. It therefore follows that the targets of ELF fields in the mT range will be the plaque cells (T-lymphocytes, macrophagic monocytes, microglia cells and dendritic cells), those cells disseminated in the seemingly normal nervous tissue (macrophages and microglia cells) (Bistolfi, 2007).

More specifically, the target should be the plasma membrane of these cells, which is almost always carpeted with microvilli and protrusions of various types. Since the plasma membrane is central to the relationships among immune cells (Lassmann et al., 2007) and since the plasma membrane itself is the elective target of ELF-EMF, a possible induction of the Marinozzi effect could slow down the activity of autoimmune cells in the plaque. It may determine an effect of local (on the brain) or regional immunomodulation (on the entire CNS) (Baureus Koch et al., 2003).

In far 1998, Richards et al. (1998) expressed the hope that electromagnetic fields might find application in the therapy of MS, both to manage symptoms and to achieve long-term effects by eliciting beneficial changes in the immune system and in nerve regeneration.

Our personal hypothesis is that – as observed in MS – similar effects could be present and relevant during EMF brain stimulation in patients with other CNS neurodegenerative disorders and be responsible for their therapeutic effect.

Low-frequency Electromagnetic Fields Stimulation and Immunomodulation

ELF-EMF effects on macrophages, nitric oxide and heat shock proteins

Macrophages are responsible for eliminating infectious agents and other cellular debris (Tintut et al., 2002). The recruitment of monocytes/macrophages to inflammatory sites and neoplastic tissues and their activation therein is crucial to the success of an immune reaction, in part because further cell migration is intimately related to leukocyte function. Resting macrophages have low levels of phagocytic activity and become fully active through the binding of pathogens or by local cytokine release. Once activated, macrophages exhibit an increased level of phagocytic activity and an increased production of reactive oxygen species (ROS) enabling the killing of microbes within phagosomes. The first step is the phagocytosis of the infectious agent, which is then transferred to the phagosome where it is killed by ROS and reactive nitrogen oxide species. The main protagonist of this process is nitric oxide (NO), which in turn induces the formation of cGMP, which in turn triggers a cascade of intracellular signaling. In the other hand, ROS also act as a signaling molecule and targets a wide range of physiological pathways. Activation of these cellular pathways also causes the secretion of inflammatory cytokines including IL-1b and TNF-alpha (Laskin and Laskin, 2001). Therefore when stimulated with bacterial toxins, NO and ROS stimulate cells to synthesize heat shock proteins (HSPs) (Polla et al., 1996).

Several studies have shown the effect of ELF-EMFs on macrophages. Kawczyk-Krupka and colleagues aimed to determine the effect of ELF-EMFs on the physiological response of phagocytes to an infectious agent. Human monocytic leukemia cell lines were cultured and 50 Hz, 1 mT EMF was applied for 4–6 hours to cells induced with Staphylococcus aureus. The growth curve of exposed bacteria was lower than the control, while field application increased NO levels. The increase was more prominent for Staphylococcus aureus-induced cells and appeared earlier than the increase in cells without field application (Kawczyk-Krupka et al., 2002). Increased cGMP levels in response to field application were closely correlated with increased NO levels (Azanza and del Moral, 1994).

Another study on mouse macrophages after short-term (45 minutes) exposure to 50 Hz EMF at 1.0 mT showed a significant uptake of carboxylated latex beads in macrophages, suggesting EMFs stimulate the phagocytic activity of their macrophages (Frahm et al., 2006). Tetradecanoylphorbol acetate (TPA) was used as positive control to prove the activating capacity of cells, as TPA is known to activate the protein kinase C and induce cellular processes including pinocytosis and phagocytosis (Laskin et al., 1980). On the basis of these data, ELF-EMF seems to potentially play a role in decreasing the growth rate of bacteria and other pathogens eliminated by phagocytosis.

A significant increase of free radical production has been observed after exposure to 50 Hz electromagnetic fields at a flux density of 1 mT to mouse macrophages (Aktan, 2004). To elucidate whether NADPH- or NADH-oxidase functions are influenced by EMF interaction, the flavoprotein inhibitor diphenyleneiodonium chloride (DPI) was used. EMF-induced free radical production was not inhibited by DPI, whereas TPA-induced free radical production was diminished by approximately 70%. Since DPI lacks an inhibitory effect in EMF-exposed cells, 50 Hz EMF stimulates the NADH-oxidase pathway to produce superoxide anion radicals, but not the NADPH pathway. Furthermore, the oscillation in superoxide anion radical release in mouse macrophages suggests a cyclic pattern of NADH-oxidase activity (Rollwitz et al., 2004).

An important aspect of these phagocytic cells is that they produce high levels of free radicals in response to infection, and the effect of ELF-EMF on free radicals has been widely proposed as a probable direct mechanism for the action of ELF-EMF on the living systems (Simko and Mattsson, 2004).

NO, a free radical, is an intra-cellular and inter-cellular signaling molecule and it constitutes an important host defense effector for the phagocytic cells of the immune system. It is synthesized by NO synthase, which has two major types: “constitutive” and “inducible”. Inducible nitric oxide synthase (iNOS) is particularly expressed in macrophages and other phagocytic cells that are stimulated during an immune response to infection (Aktan, 2004). Although high concentration of NO can be beneficial as an antibacterial and antitumor agent, an excess of NO can be fatal and can lead to cell injury. For example the excessive activity of iNOS has detrimental effects on oligodendrocytes, cells responsible for the myelination of neuron in the CNS (Klostergaard et al., 1991). The roles of NO in the pathophysiology of disease are still being defined, but there is a growing body of evidence that the neutralization of iNOS activity may have a therapeutic value (Parmentier et al., 1999).

Some studies have focused on the potential toxicity of the ensuing high-output NO-synthesis serving as a mean to eliminate pathogens or tumor cells, but the expression of iNOS, contributes to local tissue destruction during chronic inflammation. NO increases the ability of monocytes to respond to chemotactic agents more effectively, and it is considered to be one of the principal effector molecules involved in macrophage-mediated cytotoxicity (Desai et al., 2003).

It has been observed that exposure to ELF-EMFs modifies both NOS and MCP-1 chemokine expression and that these modifications are related to each other and are furthermore mediated by increased NF-?B protein expression (Goodman et al., 1994). EMF represents a non-pharmacological inhibitor of NO and an inducer of MCP-1, the latter of which activates one of these molecules and leads to inhibition of the former and vice versa, establishing a mechanism that protects cells from excess stimulation and contributes to the regulation of cellular homeostasis (Biswas et al., 2001). Moreover in vitro study observed a slight decrease was observed in iNOS levels was observed in cells induced with Staphlococcus aureus after ELF-EMF stimulation (Azanza and del Moral, 1994).

HSPs are evolutionarily conserved proteins known to play a key role in cellular defense against the effect of stressors and their function in modulating apoptosis has been well assessed (Beere, 2004). Concerning the relationship between EMF stimulus and HSPs expressions, Goodman et al. (1994) first demonstrated that HSP expression was enhanced by exposure to electromagnetic fields. Tokalov and Gutzeit (2004) showed the effect of ELF-EMF on heat shock genes and demonstrated that even a low dose of ELF-EMF (10 mT) caused an increase in HSPs, especially hsp70, implying that the cell senses ELF-EMF as a physical stressor.

ELF-EMF stimulation and oxidative stress

Oxidative stress derives from two primary sources: 1) chronic ROS creation that is generated from the mitochondrial electron transport chain during normal cellular function; 2) high levels of acute ROS generation resulting from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, particularly associated with the activation of the CNS immune system (Barja, 1998). In both circumstances, oxidative stress comes up when an imbalance between ROS production and clearance of radical species occurs.

ROS have been implicated as second messengers that activate protein kinase cascades, although the means by which ROS regulate signal transduction remains unclear. ROS release and cytokine production, such as IL-1?, are common cell activation markers in immune relevant cells. ROS is involved in the activation of IL-1? signal transduction pathway (Li and Engelhardt, 2006). To neutralize the detrimental effects of ROS, cells have evolved a hierarchy of sophisticated antioxidant response mechanisms regulated by NF-E2-related factor 2 (Nrf2) transcription factor (Tasset et al., 2010).

Environmental factors including EMFs, stressors or diseases that augment the former or lower the latter can amplify and drive the process. Thus, in practical terms, oxidative stress is determined by excessive exposure to oxidant molecules when there is insufficient availability of antioxidant mechanisms, with the resulting free ROS oxidizing vulnerable cellular constituents, including proteins, nucleic acids and lipids, inducing microglial activation, inducing pro-inflammatory and suppressing anti-inflammatory cytokines and related signaling pathways and ultimately causing both synaptic and neuronal damage and dysfunction (Bonda et al., 2010). Whereas most environmental electromagnetic radiations cause oxidative stress in the brain (Sahin and Gumuslu, 2007), ELF-EMF seems to have an antioxidant and neuroprotective effect (Medina and Tunez, 2010).

As shown by Tunez et al. (2006), ELF-EMF induces the antioxidant pathway Nrf2, which is closely associated with its protective effect against neurotoxicity induced by 3-nitropropionic acid (3-NP) (Tunez et al., 2006). This effect may be due to the induction of Nrf2, increasing its concentration in the nucleus as a result, at least in part, on its translocation from the cytoplasm to the nucleus. These changes in antioxidant systems were associated with a reduction of cell and oxidative damage biomarkers. In fact given that Nrf2 regulates the expression of antioxidant protein systems, its decrease may plausibly be related to a reduction in antioxidant system levels. Thus, the depletion of Nrf2 showed that 3-NP induced a significant decrease in antioxidant enzyme activity in the striatum and an intense depletion of glutathione levels. This was accompanied by clear and intense oxidative damage characterized by lipid and protein oxidation, an increase in cell death and damage markers and neuronal loss. Thus, the reduction in Nrf2 in both cytoplasm and nucleus may have been due to significant cell loss induced by 3-NP (Tunez et al., 2006).

Animal studies have demonstrated that ELF-EMF exposure, in the form of TMS (60 Hz, 0.7 mT) applied to rats for 2 hours twice daily, can be neuroprotective (Tunez et al., 2006; Tasset et al., 2012). Administered prior to and after a toxic insult to the brain, for example in the systemic injection of 3-nitropropionic acid to induce an animal model of Huntington’s disease (Tunez and Santamaria, 2009), ELF-EMF can mitigate oxidative damage, elevate neurotrophic protein levels in brain and potentially augment neurogenesis (Arias-Carrion et al., 2004).

EMF 1.0 mT exposure of mouse macrophages showed a significant increase in extracellular IL-1b release after only 4 hours of exposure, which was continuously increased after 12–24 hours of exposure. This data suggests that EMF stimulation is able to increase cytokines in murine macrophages. Cossarizza and colleagues described the increased release of IL-2, IL-1, and IL-6 in peritoneal lymphocytes after long-term exposure to ELF-EMF (Cossarizza et al., 1989). On the other hand, investigation on cytokine production by Pessina et al. showed no effects after EMF on peritoneal blood cells (Pessina and Aldinucci, 1998).

Beyond these results, such studies reiterate the importance that the cellular effects of ELF-EMFs depend, in a large part, on their intensity and exposure time, as well as on the phenotype of the cellular target and interactions with intracellular structures. The level and timing of exposure can potentially be scheduled to optimize endogenous compensatory mechanisms following an adverse reaction.

ELF-EMF effects on pro-inflammatory chemokines

Chemokines are produced by a variety of cells including monocytes, T lymphocytes, neutrophils, fibroblasts, endothelial cells and epithelial cells (Murdoch and Finn, 2000). Chemokines play a relevant role in inflammatory events, such as trans-endothelial migration and accumulation of leucocytes at the site of damage. In addition, they modulate a number of biological responses, including enzyme secretion, cellular adhesion, cytotoxicity, T-cell activation and tissue regeneration (Zlotnik and Yoshie, 2000).

Since their discovery, chemokines have emerged as important regulators of leukocyte trafficking, and MCP-1, one of the best-studied chemokines, is known to exert multiple effects on target cells, such as increased cytosolic calcium levels, superoxide anion production, lysosomal enzyme release, production of anti-inflammatory cytokines and adhesion molecules in monocytes. MCP-1 is involved in the induction of polarized type Th2 responses and in the enhancement of IL-4 production. A possible feedback loop for Th2 activation would be the production of IL-4 and IL-13 by Th2, which stimulates MCP-1 production and leads to further recruitment of Th2 cells (Moser and Loetscher, 2001).

The fine control of inflammatory mediator levels is critical to neuronal homeostasis and health. For example, a deficiency in neuronal TGF-? signaling promotes neurodegeneration and AD, whereas augmented TGF-? can act as an anti-inflammatory cytokine and has potential neuroprotective action in AD and following other insults to the central nervous system (Ren et al., 1997).

Studies have shown the anti-inflammatory effects of ELF-EMF in vivo; for instance, Selvam used a coil system emitting a 5 Hz frequency to treat rats with rheumatoid arthritis for 90 minutes, producing significant anti-exhudative effects and resulting in the restoration of normal functional parameters (Vianale et al., 2008). This anti-inflammatory effect was reported to be partially mediated through the stabilizing action of ELF-EMF on cell membranes, reflected the restoration of intracellular Ca2+ levels in plasma lymphocytes (Selvam et al., 2007). Other investigators have suggested that ELF-EMF can interact with cells through mechanisms that involve extracellular calcium channels (Cho et al., 1999).

Moreover, incubating mononuclear cells with an iNOS inhibitor showed a significant reduction of iNOS and an increase of MCP-1 levels, and these effects are consistent with iNOS and MCP-1 level modifications observed in mononuclear cells exposed to ELF-EMF. Selective inhibition of the NF-?B signaling pathway by ELF-EMF may be involved in the decrease of chemokine production. If so, ELF-EMF exposure, interfering with many cellular processes, may be included in the plethora of stimuli that modulate NF-?B activation (including pro-inflammatory cytokines such as tumor necrosis factor-? and IL-1?, chemokines, phorbol 12-myristate 13-acetate, growth factors, lipopolysaccharide, ultraviolet irradiation, viral infection, as well as various chemical and physical stresses) (Vianale et al., 2008).

Lymphocyte activity and electrotaxis: a possible link to ELF-EMF stimulation

Recent studies have shown that cells can directionally respond to applied electric fields, in both in vitro and in vivo settings, a phenomenon called electrotaxis. However, the exact cellular mechanisms for sensing electrical signals are still not fully well understood, and it is thus far unknown how cells recognize and respond to electric fields, although some studies have suggested that electro-migration of some cell surface receptors and ion channels in cells could be involved (Cortese et al., 2014). Directed cell migration is essential to numerous physiological processes including immune responses, wound healing, cancer metastasis and neuron guidance (Kubes, 2002). Normal blood lymphocytes and monocytes respond to a steady electric field in Transwell assays. All lymphocyte subsets, including naive and memory CD4+, CD8+ T cells and B cells migrated toward the cathode. Electrotaxisis highly directional and the uniform migration of circulating lymphocytes suggests that other leukocyte subsets (e.g., tissue memory cells) may undergo electrotaxis as well.

Lymphocytes respond to electric fields with activation of Erk-kinases and Akt, which are involved in chemo-attractant receptor signaling and in electrotactic signaling in other cells (Sotsios et al., 1999; Zhao et al., 2006). Activation of these pathways suggests that electrotaxis and chemotaxis engage common intracellular cell motility programs in responding lymphocytes. In fact, electric field exposure induces Erk1/2 and Akt activation in lymphocytes, consistent with the activation of the MAPK and PI3K signaling pathways implicated in coordinated cell motility. Furthermore, it has been proven that an applied electric field induced the electrotactic migration of endogenous lymphocytes to mouse skin (Lin et al., 2008). These data thus define electrotaxis andpotentially present an additional mechanism for the control of lymphocyte and monocyte migration.

ELF-EMFs can either inhibit or stimulate lymphocyte activity as a function not only of the exposure (Petrini et al., 1990), but also of the biological conditions to the cells are exposed, with mitogen-activated cells being more responsive than resting cells (Conti et al., 1986). To explain this ambivalence of the effects of ELF magnetic fields on the immune system, Marino and colleagues have presented the hypothesis that the biological effects of ELF magnetic fields are governed by non-linear laws, and that deterministic responses may therefore occur that are both real and inconsistent, thereby yielding two conflicting types of results (Marino et al., 2000). A particular role in the interaction of ELF-EMFs with lymphocytes seems to be played by the mobilization of intracellular Ca2+from the calciosomes and of extracellular Ca2+ through the membrane channels (Conti et al., 1985). The action of ELF-EMFs on lymphoid cells, however, can also be exerted on the functions of the plasma membrane: the duration of the ligand-receptor bond (Chiabrera et al., 1984), the clustering of membrane proteins (Bersani et al., 1997), the activity of enzymatic macro-molecules (Lindstrom et al., 2001), and the active ion pumps (Ca2+ ATPase and Na+ K+ATPase).

Conclusions

Several studies have shown that ELF-EMF exposure is able to activate primary monocytes and macrophages from different species and also in cell lines. This activation potential is comparable to the activation by certain chemicals resulting in physiologically relevant cellular responses.

In the past, several findings have demonstrated the efficacy of pulsed ELF-EMFs of a few mT in alleviating the symptoms of MS through their action on synaptic neurotransmission and autoimmunity (by determining cell membrane changes in plaques).

Moreover, ELF-EMF exposure contributes to a general activation of macrophages, resulting in changes of numerous immunological reactions, such as increased ROS formation, in an enhanced phagocytic activity, and in an increased IL-1? release. Therefore, we can deduce that EMFs activate physiological functions of immune cells. However, the underlying mechanisms of interaction between EMF and immune system are still to be completely understood and need further studies at the molecular level.

Animal studies have demonstrated that ELF-EMF exposure, in the form of transcranial magnetic stimulation (60 Hz, 0.7 mT) applied to rats for 2 hours twice daily, has been seen to be neuroprotective (Sahin and Gumuslu, 2007; Medina and Tunez, 2010).

The effects of low flux density magnetic fields are exerted on altered functional states, in the sense of hyper- or hypo-function, rather than on normal functional states. The neurophysiological interpretation is that neurotransmission is favored at various sites: partially synapses, the cerebellum, and interhemisphere transcallosal connections, an idea which is strongly supported by the rapid regression seen in certain symptoms in patients with MS (Sandyk, 1995b). Based on all these evidences such effect could be attributed to the correction of perturbations of synaptic conductivity and immunomodulation (Bistolfi, 2007), resulting in clinical therapeutic effect as observed in neurodegenerative disorders such as AD (Mruthinti et al., 2006; Attems and Jellinger, 2014).

However, so far there is still no general agreement on the exact biological effect elicited by EMFs on the physical mechanisms that may be behind their interaction with biological systems. Of course the biological effects of EMFs are dependent on frequency, amplitude, timing and length of exposure, but are also related to intrinsic susceptibility and responsiveness of different cell types (Tenuzzo et al., 2006). Level and timing of exposure can be potentially scheduled to optimize endogenous compensatory mechanisms following an adverse challenge.

In the light of results reviewed here, we conclude that there is growing evidence of the potential role of EMFs in biological modulation of autoimmunity, immune functions and oxidative stress. As a consequence, the hypothesis that ELF-EMFs explicit their therapeutic effect through modulation of immune relevant cells is of clear interest, in particular in neurodegenerative diseases.

It is notable to underline that the effects of ELF-EMFs are not unique as they depend on their intensity, exposure time and cellular targets; further efforts towards more scheduled and well defined level and timing of exposure should be warranted.

Hence, it is necessary to proceed with substantial research on this issue, paying particular attention to the choice of the appropriate biological model and controlled experimental conditions.

Footnotes

Conflicts of interest: The authors report no conflicts of interest in this work. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

References

  • Aktan F. iNOS-mediated nitric oxide production and its regulation. Life Sci. 2004;75:639–653. [PubMed]
  • Arias-Carrion O, Verdugo-Diaz L, Feria-Velasco A, Millan-Aldaco D, Gutierrez AA, Hernandez-Cruz A, Drucker-Colin R. Neurogenesis in the subventricular zone following transcranial magnetic field stimulation and nigrostriatal lesions. J Neurosci Res. 2004;78:16–28. [PubMed]
  • Attems J, Jellinger KA. The overlap between vascular disease and Alzheimer’s disease-lessons from pathology. BMC Med. 2014;12:206.[PMC free article] [PubMed]
  • Azanza MJ, del Moral A. Cell membrane biochemistry and neurobiological approach to biomagnetism. Prog Neurobiol. 1994;44:517–601. [PubMed]
  • Barja G. Mitochondrial free radical production and aging in mammals and birds. Ann N Y Acad Sci. 1998;854:224–238. [PubMed]
  • Baureus Koch CL, Sommarin M, Persson BR, Salford LG, Eberhardt JL. Interaction between weak low frequency magnetic fields and cell membranes. Bioelectromagnetics. 2003;24:395–402. [PubMed]
  • Beere HM. “The stress of dying”: the role of heat shock proteins in the regulation of apoptosis. J Cell Sci. 2004;117:2641–2651. [PubMed]
  • Bennett WR. Electromagnetic fields and power lines. Sci Am. 1995;2:68–77.
  • Bersani F, Marinelli F, Ognibene A, Matteucci A, Cecchi S, Santi S, Squarzoni S, Maraldi NM. Intramembrane protein distribution in cell cultures is affected by 50 Hz pulsed magnetic fields. Bioelectromagnetics. 1997;18:463–469. [PubMed]
  • Bistolfi F. Are microvilli and cilia sensors of electromagnetic fields? Physica Medica. 2002;XVIII:85–94.
  • Bistolfi F. Extremely low-frequency pulsed magnetic fields and multiple sclerosis: effects on neurotransmission alone or also on immunomodulation? Building a working hypothesis. Neuroradiol J. 2007;20:676–693. [PubMed]
  • Biswas SK, Sodhi A, Paul S. Regulation of nitric oxide production by murine peritoneal macrophages treated in vitro with chemokine monocyte chemoattractant protein 1. Nitric Oxide. 2001;5:566–579. [PubMed]
  • Boggio PS, Ferrucci R, Mameli F, Martins D, Martins O, Vergari M, Tadini L, Scarpini E, Fregni F, Priori A. Prolonged visual memory enhancement after direct current stimulation in Alzheimer’s disease. Brain Stimul. 2012;5:223–230. [PubMed]
  • Bonda DJ, Wang X, Perry G, Nunomura A, Tabaton M, Zhu X, Smith MA. Oxidative stress in Alzheimer disease: a possibility for prevention. Neuropharmacology. 2010;59:290–294. [PubMed]
  • Bossy-Wetzel E, Schwarzenbacher R, Lipton SA. Molecular pathways to neurodegeneration. Nat Med. 2004;10(Suppl):S2–9. [PubMed]
  • Bracken TD, Patterson RM. Variability and consistency of electric and magnetic field occupational exposure measurements. J Expo Anal Environ Epidemiol. 1996;6:355–374. [PubMed]
  • Chiabrera A, Grattarola M, Viviani R. Interaction between electromagnetic fields and cells: microelectrophoretic effect on ligands and surface receptors. Bioelectromagnetics. 1984;5:173–191. [PubMed]
  • Cho MR, Thatte HS, Silvia MT, Golan DE. Transmembrane calcium influx induced by ac electric fields. FASEB J. 1999;13:677–683. [PubMed]
  • Conti P, Gigante GE, Cifone MG, Alesse E, Fieschi C. Effect of electromagnetic field on two calcium dependent biological systems. J Bioelectr. 1985;4:227–236.
  • Conti P, Gigante GE, Cifone MG, Alesse E, Fieschi C, Bologna M, Angeletti PU. Mitogen dose-dependent effect of weak pulsed electromagnetic field on lymphocyte blastogenesis. FEBS Lett. 1986;199:130–134. [PubMed]
  • Cortese B, Palama IE, D’Amone S, Gigli G. Influence of electrotaxis on cell behaviour. Integr Biol. 2014;6:817–830. [PubMed]
  • Cossarizza A, Monti D, Bersani F, Paganelli R, Montagnani G, Cadossi R, Cantini M, Franceschi C. Extremely low frequency pulsed electromagnetic fields increase interleukin-2 (IL-2) utilization and IL-2 receptor expression in mitogen-stimulated human lymphocytes from old subjects. FEBS Lett. 1989;248:141–144. [PubMed]
  • Cossarizza A, Angioni S, Petraglia F, Genazzani AR, Monti D, Capri M, Bersani F, Cadossi R, Franceschi C. Exposure to low frequency pulsed electromagnetic fields increases interleukin-1 and interleukin-6 production by human peripheral blood mononuclear cells. Exp Cell Res. 1993;204:385–387. [PubMed]
  • D’Andrea MR. Evidence linking neuronal cell death to autoimmunity in Alzheimer’s disease. Brain Res. 2003;982:19–30. [PubMed]
  • D’Andrea MR. Add Alzheimer’s disease to the list of autoimmune diseases. Med Hypotheses. 2005;64:458–463. [PubMed]
  • Desai A, Miller MJ, Huang X, Warren JS. Nitric oxide modulates MCP-1 expression in endothelial cells: implications for the pathogenesis of pulmonary granulomatous vasculitis. Inflammation. 2003;27:213–223.[PubMed]
  • Frahm J, Lantow M, Lupke M, Weiss DG, Simko M. Alteration in cellular functions in mouse macrophages after exposure to 50 Hz magnetic fields. J Cell Biochem. 2006;99:168–177. [PubMed]
  • Franzblau M, Gonzales-Portillo C, Gonzales-Portillo GS, Diamandis T, Borlongan MC, Tajiri N, Borlongan CV. Vascular damage: a persisting pathology common to Alzheimer’s disease and traumatic brain injury. Med Hypotheses. 2013;81:842–845. [PMC free article] [PubMed]
  • Fregni F, Pascual-Leone A. Technology insight: noninvasive brain stimulation in neurology-perspectives on the therapeutic potential of rTMS and tDCS. Nat Clini Prac Neurol. 2007;3:383–393. [PubMed]
  • Frey AH. Electromagnetic field interactions with biological systems. FASEB J. 1993;7:272–281. [PubMed]
  • Genovesi G, Paolini P, Marcellini L, Vernillo E, Salvati G, Polidori G, Ricciardi D, de Nuccio I, Re M. Relationship between autoimmune thyroid disease Rand Alzheimer’s disease. Panminerva Med. 1996;38:61–63.[PubMed]
  • George MS, Nahas Z, Borckardt JJ, Anderson B, Foust MJ, Burns C, Kose S, Short EB. Brain stimulation for the treatment of psychiatric disorders. Curr Opin Psychiat. 2007;20:250–254. discussion 247-259. [PubMed]
  • Goodman R, Blank M, Lin H, Dai R, Khorkava O, Soo L, Weisbrot D, Henderson A. Increased levels of hsp70 transcripts induced when cells are exposed to low frequency electro-magnetic fields. Bioelectrochem Bioenerg. 1994;33:115–120.
  • Grundler W, Kaiser F, Keilmann F, Walleczek J. Mechanisms of electromagnetic interaction with cellular systems. Naturwissenschaften. 1992;79:551–559. [PubMed]
  • Guerriero F, Botarelli E, Mele G, Polo L, Zoncu D, Renati P, Sgarlata C, Rollone M, Ricevuti G, Maurizi N, Francis M, Rondanelli M, Perna S, Guido D, Mannu P. An innovative intervention for the treatment of cognitive impairment-Emisymmetric bilateral stimulation improves cognitive functions in Alzheimer’s disease and mild cognitive impairment: an open-label study. Neuropsychiatr Dis Treat. 2015;11:2391–2404.[PMC free article] [PubMed]
  • Hakansson N, Gustavsson P, Johansen C, Floderus B. Neurodegenerative diseases in welders and other workers exposed to high levels of magnetic fields. Epidemiology. 2003;14:420–426. discussion 427-428. [PubMed]
  • Johansen C. Electromagnetic fields and health effects–epidemiologic studies of cancer, diseases of the central nervous system and arrhythmia-related heart disease. Scand J Work Environ Health. 2004;30(Suppl 1):1–30. [PubMed]
  • Karabakhtsian R, Broude N, Shalts N, Kochlatyi S, Goodman R, Henderson AS. Calcium is necessary in the cell response to EM fields. FEBS Lett. 1994;349:1–6. [PubMed]
  • Kawczyk-Krupka A, Sieron A, Shani J, Czuba ZP, Krol W. Biological effects of extremely low-frequency magnetic fields on stumlated macrophages J774-2 in cell culture. Electromagn Biol Med. 2002;21:141–153.
  • Klostergaard J, Leroux ME, Hung MC. Cellular models of macrophage tumoricidal effector mechanisms in vitro. Characterization of cytolytic responses to tumor necrosis factor and nitric oxide pathways in vitro. J Immunol. 1991;147:2802–2808. [PubMed]
  • Kubes P. The complexities of leukocyte recruitment. Semin Immunol. 2002;14:65–72. [PubMed]
  • Laskin DL, Laskin JD. Role of macrophages and inflammatory mediators in chemically induced toxicity. Toxicology. 2001;160:111–118. [PubMed]
  • Laskin DL, Laskin JD, Weinstein IB, Carchman RA. Modulation of phagocytosis by tumor promoters and epidermal growth factor in normal and transformed macrophages. Cancer Res. 1980;40:1028–1035.[PubMed]
  • Lassmann H, Bruck W, Lucchinetti CF. The immunopathology of multiple sclerosis: an overview. Brain Pathol. 2007;17:210–218. [PubMed]
  • Lee HG, Zhu X, Castellani RJ, Nunomura A, Perry G, Smith MA. Amyloid-beta in Alzheimer disease: the null versus the alternate hypotheses. J Pharmacol Exp Ther. 2007;321:823–829. [PubMed]
  • Li Q, Engelhardt JF. Interleukin-1beta induction of NFkappaB is partially regulated by H2O2-mediated activation of NFkappaB-inducing kinase. J Biol Chem. 2006;281:1495–1505. [PubMed]
  • Lin F, Baldessari F, Gyenge CC, Sato T, Chambers RD, Santiago JG, Butcher EC. Lymphocyte electrotaxis in vitro and in vivo. J Immunol. 2008;181:2465–2471. [PMC free article] [PubMed]
  • Lindstrom E, Still M, Mattsson MO, Mild KH, Luben RA. ELF magnetic fields initiate protein tyrosine phosphorylation of the T cell receptor complex. Bioelectrochemistry (Amsterdam, Netherlands) 2001;53:73–78.[PubMed]
  • Marino AA, Wolcott RM, Chervenak R, Jourd’Heuil F, Nilsen E, Frilot C., 2nd Nonlinear response of the immune system to power-frequency magnetic fields. Am J Physiol Regul Integr Comp Physiol. 2000;279:R761–768. [PubMed]
  • Marinozzi G, Benedetto A, Brandimarte B, Ripani M, Carpano S, Camporiondo MP. Effetti dei campi magnetici pulsanti su colture cellulari. Giorn Ital Oncol. 1982;2:87–100.
  • Matthews G, Gersdorff H. Calcium dependence of neurotransmitter release. Semin Neurosci. 1996;8:329–334.
  • Medina FJ, Tunez I. Huntington’s disease: the value of transcranial meganetic stimulation. Curr Med Chem. 2010;17:2482–2491. [PubMed]
  • Moreno-Gonzalez I, Soto C. Misfolded protein aggregates: mechanisms, structures and potential for disease transmission. Semin Cell Dev Biol. 2011;22:482–487. [PMC free article] [PubMed]
  • Moser B, Loetscher P. Lymphocyte traffic control by chemokines. Nat Immunol. 2001;2:123–128. [PubMed]
  • Mruthinti S, Schade RF, Harrell DU, Gulati NK, Swamy-Mruthinti S, Lee GP, Buccafusco JJ. Autoimmunity in Alzheimer’s disease as evidenced by plasma immunoreactivity against RAGE and Abeta42: complication of diabetes. Curr Alzheimer Res. 2006;3:229–235. [PubMed]
  • Murdoch C, Finn A. Chemokine receptors and their role in inflammation and infectious diseases. Blood. 2000;95:3032–3043. [PubMed]
  • Onodera H, Jin Z, Chida S, Suzuki Y, Tago H, Itoyama Y. Effects of 10-T static magnetic field on human peripheral blood immune cells. Radiat Res. 2003;159:775–779. [PubMed]
  • Panagopoulos DJ, Margaritis LH. The identification of an intensity ‘window’ on the bioeffects of mobile telephony radiation. Int J Radiat Biol. 2010;86:358–366. [PubMed]
  • Parmentier S, Bohme GA, Lerouet D, Damour D, Stutzmann JM, Margaill I, Plotkine M. Selective inhibition of inducible nitric oxide synthase prevents ischaemic brain injury. Br J Pharmacol. 1999;127:546–552.[PMC free article] [PubMed]
  • Pessina GP, Aldinucci C. Pulsed electromagnetic fields enhance the induction of cytokines by peripheral blood mononuclear cells challenged with phytohemagglutinin. Bioelectromagnetics. 1998;19:445–451.[PubMed]
  • Petrini M, Polidori R, Ambrogi F. Effects of different low-frequency electro-magnetic fields on lymphocyte activation: at which cellular level? J Bioelectr. 1990;9:159–166.
  • Polla BS, Kantengwa S, Francois D, Salvioli S, Franceschi C, Marsac C, Cossarizza A. Mitochondria are selective targets for the protective effects of heat shock against oxidative injury. Proc Natl Acad Sci U S A. 1996;93:6458–6463. [PMC free article] [PubMed]
  • Ren RF, Hawver DB, Kim RS, Flanders KC. Transforming growth factor-beta protects human hNT cells from degeneration induced by beta-amyloid peptide: involvement of the TGF-beta type II receptor. Brain Res Mol Brain Res. 1997;48:315–322. [PubMed]
  • Rhodin JA, Thomas T. A vascular connection to Alzheimer’s disease. Microcirculation. 2001;8:207–220. [PubMed]
  • Richards TL, Lappin MS, Lawrie FW, Stegbauer KC. Bioelectromagnetic applications for multiple sclerosis. Phys Med Rehabil Clin N Am. 1998;9:659–674. [PubMed]
  • Ridding MC, Rothwell JC. Is there a future for therapeutic use of transcranial magnetic stimulation? Nat Rev Neurosci. 2007;8:559–567.[PubMed]
  • Rollwitz J, Lupke M, Simko M. Fifty-hertz magnetic fields induce free radical formation in mouse bone marrow-derived promonocytes and macrophages. Biochim Biophys Acta. 2004;1674:231–238. [PubMed]
  • Rosen AD. Magnetic field influence on acetylcholine release at the neuromuscular junction. Am J Physiol. 1992;262:C1418–1422. [PubMed]
  • Sahin E, Gumuslu S. Immobilization stress in rat tissues: alterations in protein oxidation, lipid peroxidation and antioxidant defense system. Comp Biochem Physiol C Toxicol Pharmacol. 2007;144:342–347.[PubMed]
  • Sandyk R. Successful treatment of multiple sclerosis with magnetic fields. Int J Neurosci. 1992;66:237–250. [PubMed]
  • Sandyk R. Long term beneficial effects of weak electromagnetic fields in multiple sclerosis. Int J Neurosci. 1995a;83:45–57. [PubMed]
  • Sandyk R. Chronic relapsing multiple sclerosis: a case of rapid recovery by application of weak electromagnetic fields. Int J Neurosci. 1995b;82:223–242. [PubMed]
  • Sandyk R. Treatment with electromagnetic fields reverses the long-term clinical course of a patient with chronic progressive multiple sclerosis. Int J Neurosci. 1997;90:177–185. [PubMed]
  • Sandyk R, Iacono RP. Resolution of longstanding symptoms of multiple sclerosis by application of picoTesla range magnetic fields. Int J Neurosci. 1993;70:255–269. [PubMed]
  • Sandyk R, Iacono RP. Multiple sclerosis: improvement of visuoperceptive functions by picoTesla range magnetic fields. Int J Neurosci. 1994;74:177–189. [PubMed]
  • Sandyk R, Dann LC. Resolution of Lhermitte’s sign in multiple sclerosis by treatment with weak electromagnetic fields. Int J Neurosci. 1995;81:215–224. [PubMed]
  • Selvam R, Ganesan K, Narayana Raju KV, Gangadharan AC, Manohar BM, Puvanakrishnan R. Low frequency and low intensity pulsed electromagnetic field exerts its antiinflammatory effect through restoration of plasma membrane calcium ATPase activity. Life Sci. 2007;80:2403–2410. [PubMed]
  • Simko M, Mattsson MO. Extremely low frequency electromagnetic fields as effectors of cellular responses in vitro: possible immune cell activation. J Cell Biochem. 2004;93:83–92. [PubMed]
  • Sotsios Y, Whittaker GC, Westwick J, Ward SG. The CXC chemokine stromal cell-derived factor activates a Gi-coupled phosphoinositide 3-kinase in T lymphocytes. J Immunol. 1999;163:5954–5963. [PubMed]
  • Tasset I, Medina FJ, Jimena I, Aguera E, Gascon F, Feijoo M, Sanchez-Lopez F, Luque E, Pena J, Drucker-Colin R, Tunez I. Neuroprotective effects of extremely low-frequency electromagnetic fields on a Huntington’s disease rat model: effects on neurotrophic factors and neuronal density. Neuroscience. 2012;209:54–63. [PubMed]
  • Tasset I, Perez-De La Cruz V, Elinos-Calderon D, Carrillo-Mora P, Gonzalez-Herrera IG, Luna-Lopez A, Konigsberg M, Pedraza-Chaverri J, Maldonado PD, Ali SF, Tunez I, Santamaria A. Protective effect of tert-butylhydroquinone on the quinolinic-acid-induced toxicity in rat striatal slices: role of the Nrf2-antioxidant response element pathway. Neurosignals. 2010;18:24–31. [PubMed]
  • Tenuzzo B, Chionna A, Panzarini E, Lanubile R, Tarantino P, Di Jeso B, Dwikat M, Dini L. Biological effects of 6 mT static magnetic fields: a comparative study in different cell types. Bioelectromagnetics. 2006;27:560–577. [PubMed]
  • Thomas T, Thomas G, McLendon C, Sutton T, Mullan M. beta-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature. 1996;380:168–171. [PubMed]
  • Tintut Y, Patel J, Territo M, Saini T, Parhami F, Demer LL. Monocyte/macrophage regulation of vascular calcification in vitro. Circulation. 2002;105:650–655. [PubMed]
  • Tokalov SV, Gutzeit HO. Weak electromagnetic fields (50 Hz) elicit a stress response in human cells. Environ Res. 2004;94:145–151. [PubMed]
  • Tunez I, Santamaria A. Model of Huntington’s disease induced with 3-nitropropionic acid. Rev Neurol. 2009;48:430–434. [PubMed]
  • Tunez I, Drucker-Colin R, Jimena I, Medina FJ, Munoz Mdel C, Pena J, Montilla P. Transcranial magnetic stimulation attenuates cell loss and oxidative damage in the striatum induced in the 3-nitropropionic model of Huntington’s disease. J Neurochem. 2006;97:619–630. [PubMed]
  • Tweedie D, Sambamurti K, Greig NH. TNF-alpha inhibition as a treatment strategy for neurodegenerative disorders: new drug candidates and targets. Curr Alzheimer Res. 2007;4:378–385. [PubMed]
  • Vianale G, Reale M, Amerio P, Stefanachi M, Di Luzio S, Muraro R. Extremely low frequency electromagnetic field enhances human keratinocyte cell growth and decreases proinflammatory chemokine production. Br J Dermatol. 2008;158:1189–1196. [PubMed]
  • von Bernhardi R, Eugenin J. Alzheimer’s disease: redox dysregulation as a common denominator for diverse pathogenic mechanisms. Antioxid Redox Signal. 2012;16:974–1031. [PubMed]
  • Wardlaw JM, Sandercock PA, Dennis MS, Starr J. Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia? Stroke. 2003;34:806–812. [PubMed]
  • Zhao M, Song B, Pu J, Wada T, Reid B, Tai G, Wang F, Guo A, Walczysko P, Gu Y, Sasaki T, Suzuki A, Forrester JV, Bourne HR, Devreotes PN, McCaig CD, Penninger JM. Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-gamma and PTEN. Nature. 2006;442:457–460. [PubMed]
  • Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity. 2000;12:121–127. [PubMed]

Articles from Neural Regeneration Research are provided here courtesy of Medknow Publications
Behav Brain Funct. 2015; 11: 26.  Published online 2015 Sep 7. doi: 10.1186/s12993-015-0070-z

Mechanisms and therapeutic applications of electromagnetic therapy in Parkinson’s disease.

Maria Vadalà, Annamaria Vallelunga, Lucia Palmieri, Beniamino Palmieri, Julio Cesar Morales-Medina, and Tommaso Iannitti corresponding author
Department of General Surgery and Surgical Specialties, University of Modena and Reggio Emilia Medical School, Surgical Clinic, Modena, Italy
Department of Medicine and Surgery, Centre for Neurodegenerative Diseases (CEMAND), University of Salerno, Salerno, Italy
Department of Nephrology, University of Modena and Reggio Emilia Medical School, Surgical Clinic, Modena, Italy
Centro de Investigación en Reproducción Animal, CINVESTAV-Universidad Autónoma de Tlaxcala, Tlaxcala, Mexico
Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK
Maria Vadalà, Email: moc.liamg@aladav.yram.
Contributor Information.
corresponding authorCorresponding author.
Author information   Article notes  Copyright and License information
Received 2015 Jan 5; Accepted 2015 Jul 22.
Copyright © Vadalà et al. 2015
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Abstract
Electromagnetic therapy is a non-invasive and safe approach for the management of several pathological conditions including neurodegenerative diseases. Parkinson’s disease is a neurodegenerative pathology caused by abnormal degeneration of dopaminergic neurons in the ventral tegmental area and substantia nigra pars compacta in the midbrain resulting in damage to the basal ganglia. Electromagnetic therapy has been extensively used in the clinical setting in the form of transcranial magnetic stimulation, repetitive transcranial magnetic stimulation, high-frequency transcranial magnetic stimulation and pulsed electromagnetic field therapy which can also be used in the domestic setting. In this review, we discuss the mechanisms and therapeutic applications of electromagnetic therapy to alleviate motor and non-motor deficits that characterize Parkinson’s disease.Keywords: Parkinson’s disease, Electromagnetic therapy, Transcranial magnetic stimulation, Repetitive transcranial magnetic stimulation, High-frequency transcranial magnetic stimulation, Pulsed electromagnetic field therapyBackground
Parkinson’s diseaseParkinson’s disease (PD) is one of the most common neurodegenerative diseases worldwide, second only to Alzheimer’s disease (AD) [1]. PD is accompanied by the impairment of the cortico-subcortical excitation and inhibition systems, hence belonging to the involuntary movement diseases [2]. PD is caused by progressive loss of structure and function of dopaminergic neurons in the ventral tegmental area and substantia nigra pars compacta in the midbrain with subsequent damage to the basal ganglia (BG) [3]. Cumulative evidence supports the hypothesis that PD is the result of complex interactions among genetic abnormalities, environmental toxins and mitochondrial dysfunction [4–6]. The mechanisms of neuronal degeneration characterizing PD have been studied extensively and include a complex interplay among multiple pathogenic processes including oxidative stress, protein aggregation, excitotoxicity and impaired axonal transport [7]. The increasing number of genes and proteins critical in PD is unraveling a complex network of molecular pathways involved in its etiology, suggesting that common mechanisms underlie familial and sporadic PD, the two forms of this pathology. While the sporadic form is the most common (90–95% of PD cases), only 5–10% of PD cases are familial [8, 9]. At least ten distinct loci are responsible for rare Mendelian forms of PD and mutations in five genes have been linked to familial PD [10]. PD is characterized by motor and non-motor symptoms. The main motor symptoms include bradykinesia, tremor at rest (tremor affecting the body part that is relaxed or supported against gravity and not involved in purposeful activities [11]), rigidity and postural instability [12–17]. However, motor symptoms are now considered as the “tip of the iceberg” of PD clinical manifestations. PD non-motor symptoms include cognitive decline, decrease in sleep efficiency, increased wake after sleep onset, sleep fragmentation, and vivid dreams as well as neuropsychiatric symptoms such as depression and psychosis, [18–23]. Pain syndrome and autonomic dysfunctions have also been observed in PD patients [24–26].Neuroimaging and genes: towards a personalized medicine for Parkinson’s diseaseSeveral research groups have begun to perform genome-wide association studies (GWAS) on data or index measures derived from brain images, with the final goal of finding new genetic variants that might account for abnormal variations in brain structure and function that increase the risk of a given disease. Numerous genes have been identified using GWAS and have been associated with PD. They include alpha-synuclein, vacuolar protein sorting-associated protein 35, human leukocyte antigen family, leucine-rich repeat kinase 2 and acid ?-glucosidase [27–29]. Neuroimaging associates individual differences in the human genome to structural and functional variations into the brain. Van der Vegt and colleagues reported structural and functional brain mapping studies that have been performed in individuals carrying a mutation in specific PD genes including PARK1, PARK2, PARK6, PARK7, PARK8, and discussed how this “neurogenetics-neuroimaging approach” provides unique means to study key PD pathophysiological aspects [30]. In addition, neuroimaging of presymptomatic (non-manifesting) mutation carriers has emerged as a valuable tool to identify mechanisms of adaptive motor reorganization at the preclinical stage that may prevent or delay PD clinical manifestation [30]. Neuroimaging may be useful to study the effectiveness of electromagnetic therapy in PD patients.Available therapies for Parkinson’s disease

PD treatment includes the use of pharmacological agents such as the dopaminergic agent l-3,4-dihy-droxy-phenylalanine (Levodopa or l-dopa) and stereotactic brain surgery which are associated with numerous side effects [31]. For example, the on-and-off phenomenon includes profound diurnal fluctuations in the psychomotor state of PD patients treated with l-dopa [32]. Furthermore, l-dopa loses effectiveness over time and can induce motor fluctuations such as the “wearing off” effect and dyskinesia [33]. While l-dopa metabolites are neurotoxic [33], the search for alternate, non-dopaminergic therapies to overcome the l-dopa-induced side effects has positioned adenosine A2A receptor (A2AR) antagonists as a promising therapeutic option for PD treatment [34]. Despite the favorable features of A2AR antagonists, their pharmacological properties, such as poor oral bioavailability and the lack of blood–brain barrier permeability, constitute a major problem to their clinical application [35]. Furthermore, regular physiotherapy and instrumental rehabilitation that have been employed to manage PD symptoms, such as tremor, slowness and difficulty in walking, are only moderately helpful [36]. Electromagnetic therapy has also been extensively used for PD treatment and may represent a promising therapeutic option for this condition since it promotes a lasting improvement in motor and non-motor symptoms [37–41].

Electromagnetic therapy background

Electromagnetic therapy includes the use of six groups of electromagnetic fields as previously described [42, 43] and summarized below:

Static/permanent magnetic fields can be created by various permanent magnets as well as by passing direct current through a coil.
Transcranial magnetic stimulation (TMS) utilizes frequencies in the range 1–200 Hz.
Low-frequency electromagnetic fields mostly utilize 60 Hz (in the US and Canada) and 50 Hz (in Europe and Asia) frequencies in distribution lines.
Pulsed radiofrequency fields utilize frequencies in the range 12–42 MHz.
Millimeter waves refer to very high-frequency in the range 30–100 GHz.
Pulsed electromagnetic fields (PEMFs) utilize frequencies in the range 5–300 Hz with very specific shapes and amplitudes.
Electromagnetic therapy is defined as the use of time-varying electromagnetic fields of low-frequency values (3 Hz–3 kHz) that can induce a sufficiently strong current to stimulate living tissue [44]. Electromagnetic fields can penetrate all tissues including the epidermis, dermis, and subcutaneous tissue, as well as tendons, muscles and bones [45]. The amount of electromagnetic energy used and its effect on the target organ depends on the size, strength and duration of treatment [44]. Electromagnetic fields can be divided into two categories: static and time-varying. Electromagnetic therapy falls into two categories: (1) hospital use which includes TMS, repetitive transcranial magnetic stimulation (rTMS) and high-frequency TMS and (2) home use including PEMF therapy.

Aim and searching criteria

We searched Pubmed/Medline using the keywords “Parkinson’s Disease” combined with “electromagnetic therapy”, “TMS”, “rTMS”, “high-frequency TMS” or “PEMF” and we included articles published between 1971 and 2015. This article aims to review the state of the art of electromagnetic therapy for treatment of PD.

Transcranial magnetic stimulation
TMS is a safe and non-invasive method of electrical stimulation of neurons in the human cerebral cortex, modifying neuronal activity locally and at distant sites when delivered in series of pulses [46]. TMS is also a useful tool to investigate various aspects of human neurophysiology, particularly corticospinal function, in health and disease [47]. An electromagnetic field generator sends a current with a peak amplitude of about 8,000 A that lasts about 1 ms, through an induction coil placed on the scalp [48]. TMS is based on the principle of electromagnetic induction, as discovered by Faraday in 1838. The current flowing briefly in the iron coil placed over a patient’s head generates an electromagnetic field that penetrates the scalp and skull reaching the brain where it induces a secondary ionic current. The site of stimulation of the brain is the point along its length at which sufficient current passes through its membrane to cause depolarization [49]. TMS can be used to determine several parameters associated to different aspects of cortical excitability: (1) the resting motor threshold or active motor threshold which reflects membrane properties; (2) the silent period, which is a quiescent phase in the electromyogram (EMG), is partially of cortical origin and is related to the function of gamma-aminobutyric acid receptors; (3) the short intracortical inhibition and facilitation which occur when a subthreshold stimulus precedes a suprathreshold stimulus by less than 5 ms or 8–30 ms, respectively. The peak of electromagnetic field strength is related to the magnitude of the current and the number of turns of wire in the coil [50]. The electrical current is rapidly turned on and off in the coil through the discharge of electronic components called the capacitors.

Transcranial magnetic stimulation in Parkinson’s disease

TMS clinical applications were first reported by Barker and colleagues who stimulated the brain, spinal cord and peripheral nerves using TMS with low or no pain [51]. Following this work, several TMS protocols that evidenced the correlation of TMS with peripheral EMG and monitored the modulation of TMS-induced motor evoked potentials (MEPs), were described [52–54]. For example, Cantello and coworkers studied the EMG potentials evoked in the bilateral first dorsal interosseus muscle by electromagnetic stimulation of the corticomotoneuronal descending system in 10 idiopathic PD patients without tremor but with rigidity with asymmetric body involvement and 10 healthy controls [55]. The threshold to cortical stimulation measured on the rigid side of PD patients was lower than on the contralateral side or than normal values. PD patients’ MEPs on the rigid side were larger compared to controls when the cortical stimulus was at rest or during slight tonic contraction of the target muscle [55]. Several clinical trials have pointed out the therapeutic efficacy of TMS in PD patients [3, 31, 56, 57]. For example, biomagnetic measurements performed using magnetoencephalography (MEG) in 30 patients affected by idiopathic PD exposed to TMS evidenced that 60% of patients did not exhibit tremor, muscular ache or dyskinesias for at least 1 year after TMS therapy [58]. The patients’ responses to TMS included a feeling of relaxation, partial or complete disappearance of muscular ache and l-dopa-induced dyskinesias as well as rapid reversal of visuospatial impairment [58]. Additional MEG measurements in PD patients also showed abnormal brain functions including slowing of background activity (increased theta and decreased beta waves) and increased alpha band connectivity [59]. These changes may reflect abnormalities in specific networks and neurotransmitter systems, and could be useful for differential diagnosis and treatment monitoring.

Repetitive transcranial magnetic stimulation
rTMS is a non-invasive technique of brain stimulation based on electromagnetic induction [60]. rTMS has the potential to alter cortical excitability depending on the duration and mode of stimulation [61]. The electromagnetic pulse easily passes through the skull, and causes small electrical currents that stimulate nerve cells in the targeted brain region [62]. Since this type of pulse generally does not reach further than two inches into the brain, it is possible to selectively target specific brain areas [62]. Generally, the patient feels a slight knocking or tapping on the head as the pulses are administered. rTMS frequencies of around 1 Hz induce an inhibitory effect on cortical excitability [63] and stimulus rates of more than 5 Hz generate a short-term increase in cortical excitability [64]. rTMS induces a MEP of the muscles of the lower extremities by stimulating the motor and supplementary motor area (SMA) of the cerebral cortex [31].

Repetitive transcranial magnetic stimulation in Parkinson’s disease

Several studies have reported the efficacy of rTMS on PD motor symptoms [65–69]. These effects are primarily directed at surface cortical regions, since the dopaminergic deficiency in PD is localized to the subcortical BG. The BG comprises a group of interconnected deep brain nuclei, i.e. the caudate and putamen, globus pallidus, substantia nigra and the subthalamic nucleus (STN) that, through their connections with the thalamus and the cortex, primarily influence the involuntary components of movement and muscle tone [70]. Several studies have documented the long-term effects of rTMS applied to PD patients for several days, rather than single sessions [71–73]. For instance, Shimamoto and coworkers applied rTMS on a broad area including the left and right motor, premotor and SMAs in nine PD patients for a period of 2 months, and observed improvements in the Unified Parkinson’s Disease Rating Scale (UPDRS), a rating scale used to follow PD progression [74]. A further trial in PD patients reported a shortened interruption of voluntary muscle contraction, defined cortical silent period, suggesting a disturbed inhibitory mechanism in the motor cortex [57]. PD patients show altered activation patterns in the SMA and overall less cortico-cortical excitability [75–81] that play a key role in motor selection in sequentially structured tasks, including handwriting. In a randomized controlled trial with a crossover design in PD patients, rTMS applied over the SMA influenced several key aspects of handwriting, e.g. vertical size and axial pressure, at least in the short term [82]. Ten PD patients treated with rTMS, evidenced short-term changes in functional fine motor task performance. rTMS over the SMA compensated for cortico-striatal imbalance and enhanced cortico-cortical connections. This treatment improved PD patients deficits such as reduction in speed during the writing task and decrease in letter size (micrographia).

Two mechanisms have been proposed to explain how cortically directed rTMS may improve PD symptoms: (1) rTMS induces brain network changes and positively affects the BG function; (2) rTMS directed to cortical sites compensates for PD-associated abnormal changes in cortical function [60]. Indeed, in support of the former mechanism, rTMS might modulate cortical areas, such as the prefrontal cortex and primary motor cortex, which are substantially connected to both the striatum and STN via glutamatergic projection, and thus indirectly modulate the release of dopamine in the BG [83]. Several TMS/functional imaging studies have demonstrated the effects of rTMS on BG and an increase in dopamine in the BG after rTMS applied to the frontal lobe [84].

rTMS can also transiently disrupt the function of a cortical target creating a temporary “virtual brain lesion” [85–87]. Mottaghy and coworkers have studied the ability of rTMS to produce temporary functional lesions in the BG, an area involved in working memory, and correlated these behavioral effects with changes in regional cerebral blood flow in the involved neuronal network [88]. Functional imaging and TMS studies in PD subjects have shown altered cortical physiology in areas associated to the BG such as the SMA, dorsolateral prefrontal cortex and primary motor cortex [57, 89], characterized by excessive corticospinal output at rest, concomitant to, or resulting from a reduced intracortical inhibition [60]. These altered changes in cortical function in PD patients might avoid the suppression of competing motor areas and therefore decrease the motor system performance, resulting in symptoms such as tonic contractions and rigidity [89].

rTMS has not only been applied to a motor area of the brain but has also been used to target PD non-motor deficits. For example, in a study involving six PD patients with mild cognitive impairment, a cognitive dysfunction defined by deficits in memory, rTMS was delivered over the frontal region at 1.2 times the motor threshold (minimum stimulation intensity) of the right abductor pollicis brevis muscle [3]. Over a period of 3 months, rTMS was performed for a total of 1200 stimulations. Improvement in neuropsychological tests (the trail-making test part B and the Wisconsin card-sorting test) was observed in all patients. In addition, an improvement in subjective symptoms and objective findings were also observed by the subjects, their families, and the therapists. The changes observed in PD subjects included “faster reactions”, “better body movement and smoother standing-up and movement”, “more active”, “more cheerful”, and “more expressive”. An increase in the amount of conversation, an increase in the neural mechanisms of mutual understanding within daily living and an improvement in responses to visitors were also noted, if compared to baseline. Additionally, changes such as better hand usage while eating and better sleep were also observed.

Cognitive dysfunction is often seen in PD patients with major depression and its neural basis could be the functional failure of the frontostriatal circuit [3, 90]. Ten days of rTMS in the frontal cortex can effectively alleviate PD-associated depression as shown by an open trial reporting a significant decrease in the Hamilton Depression Rating Scale (HDRS) scores [91]. A further double blind, sham stimulation-controlled, randomized study, involving 42 idiopathic PD patients affected by major or minor depression undergoing rTMS for 10 days, evidenced a mean decrease in HDRS and Beck depression inventory after therapy [92].

In opposition to the above mentioned positive reports concerning the efficacy of rTMS in PD patients, a lack of effectiveness of rTMS on objective or subjective symptoms has also been described. For example, in a study involving 85 idiopathic PD patients, no significant differences in clinical features were observed between patients receiving rTMS and sham stimulation [65]. Moreover, total and motor score of UPDRS were improved by rTMS and sham stimulation in the same manner. Despite this improvement, PD patients treated with rTMS revealed signs of depression, reporting no subjective benefits. In another randomized crossover study, 10 patients affected by idiopathic PD received rTMS to the SMA which resulted in subclinical worsening of complex and preparatory movement [93]. The rTMS protocol was not tolerated by 2 out of 10 patients. Furthermore, this study showed that, following rTMS, subtle regional disruption can persist for over 30 min, raising safety concerns. A further randomized crossover study involving 11 patients with idiopathic PD, treated with rTMS over the motor cortex, did not show any therapeutic effect on concurrent fine movement in PD [94].

In summary, conflicting findings regarding the efficacy of rTMS in PD have been reported and they can be explained by differences in stimulation parameters, including intensity, frequency, total number of pulses, stimulation site and total number of sessions. Therefore, further studies comparing different parameters are required.

High-frequency transcranial magnetic stimulation
High-frequency TMS consists of continuous high-frequency stimulation of specific brain regions, including the motor cortex, cerebellum and BG, through implanted large four-contact electrodes connected to a pulse generator and positioned into the center of the target region [70]. Such stimulation induces an electrical field that spreads and depolarizes neighboring membranes of cell bodies, afferent and efferent axons, depending on neuronal element orientation and position in the field and on stimulation parameters [95]. Optimal clinical results are obtained by using pulses of 60–200 ms duration and 1–5 V amplitude, delivered in the STN at 120–180 Hz [96]. For example, high-frequency TMS produces a transient blockade of spontaneous STN activity, defined HFS-induced silence. During HFS-induced silence, the persistent Na+ current is totally blocked and the Ca2+-mediated responses are strongly reduced, suggesting that T- and L-type Ca2+ currents are transiently depressed by high-frequency TMS [97].Indeed, recent evidence suggests that the stimulation of the motor cortex, the cerebellum and the BG not only produces inhibitory and excitatory effects on local neurons, but also influences afferent and efferent pathways. Therefore, the mechanism of action of high-frequency TMS depends on changes in neural activity generated in the stimulated, afferent and efferent nuclei of the BG and motor cortex [98].High-frequency transcranial magnetic stimulation in Parkinson’s diseaseIn the first PD patients treated with high-frequency TMS in 1993, motor symptoms, tremor, rigidity and akinesia improved significantly allowing to decrease the administration of l-dopa by a mean of 55% [99]. Since then, several thousands of patients worldwide have been fitted with high-frequency TMS implants achieving marked improvements in their symptoms, making this method the reference procedure for advanced PD [100]. The time course of improvement following high-frequency TMS treatment differs for different cardinal symptoms of PD [101]. For instance, rigidity and resting tremor decrease immediately, within a few seconds after high-frequency TMS [102]. Different clinical effects are observed in PD patients depending on the site of stimulation [103]. For example, stimulation of the ventral intermediate nucleus of the thalamus can dramatically relieve PD-associated tremor [104]. Similarly, stimulation of the STN or globus pallidus interna (GPi) can substantially reduce rigidity, tremor, and gait difficulties in patients affected by idiopathic PD [105]. Stimulation of the GPi also reduces all of the major PD motor manifestations, including the reduction of l-dopa-induced dyskinesias and involuntary movements produced by individual doses of dopaminergic medications that can limit treatment efficacy [106]. Thalamic stimulation in the region of the ventral intermediate nucleus reduces limb tremor but it has little effect on other manifestations of the disease [107]. In order to explain the beneficial effects of high-frequency TMS, two fundamental mechanisms have been proposed by Garcia and coworkers: silencing and excitation of STN neurons [95]. They reported that high-frequency TMS using stimulus parameters that yield therapeutic effects has a dual effect, i.e. it suppresses spontaneous activity and drives STN neuronal activity. High-frequency TMS switches off a pathological disrupted activity in the STN (i.e. silencing of STN neurons mechanism) and imposes a new type of discharge in the upper gamma-band frequency (60–80 Hz range) that is endowed with beneficial effects (i.e. excitation of STN neurons mechanism) [95]. This improvement generated by high-frequency TMS is due to parallel non-exclusive actions, i.e. silencing of ongoing activity and generation of an activity pattern in the gamma range [108]. There is an important advantage in silencing spontaneous activity and generating a pattern: the signal to noise ratio and the functional significance of the new signal are enhanced [109].Techniques and preparations employed to study the mechanisms of high-frequency TMS include electrophysiological techniques, measurement of neurotransmitter release in vivo, post-mortem immunohistochemistry of a metabolic marker such as cytochrome oxidase and imaging studies in vivo [95]. Such results consistently show a post-stimulus period of reduced neuronal firing followed by the slow recovery of spontaneous activity. High-frequency TMS, at frequencies >50 Hz, applied to the STN of PD patients undergoing functional stereotactic procedures [110–112], to the STN of rats in vivo [113, 114] and rat STN slices in vitro [97, 115, 116], produces a period of neuronal silence of hundreds of milliseconds to tens of seconds. During brief high-frequency TMS in PD patients off medication and in the murine model of parkinsonism obtained by acute injections of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine for 5 consecutive days, a reduced STN activity, as response to stimulation, is observed at 5–14 Hz and this response is frequency-dependent [114]. High-frequency TMS has two main advantages: (a) it reduces the time a patient spends in the “off” state because the individual dose of these profound diurnal fluctuations leaves a person slow, shaky, stiff, and unable to rise from a chair; (b) it allows the reduction of medications and their consequent side effects [117].Pulsed electromagnetic field therapy
PEMF therapy is a non-static energy delivery system, characterized by electromagnetic fields inducing microcurrents in the target body tissues [118]. These microcurrents elicit specific biological responses depending on field parameters such as intensity, frequency and waveform [119]. The benefits of PEMF therapy have been observed in several clinical studies for treatment of several medical conditions including knee osteoarthritis [120], shoulder impingement syndrome [121], lower back pain [122, 123], multiple sclerosis [124, 125], cancer [121, 123, 125, 126], PD [127], AD [128] and reflex sympathetic dystrophy syndrome [129]. A large number of PEMF therapy devices contains user-friendly software packages with pre-recorded programs with the ability to modify programs depending on the patient’s needs [43, 130–132]. Examples of PEMF devices are the Curatron® (Amjo Corp, West Chester, PA, USA), Seqex® system (S.I.S.T.E.M.I. Srl, Trento, Italy), MRS 2000®, iMRS®, QRS® (all produced by Swiss Bionic Solutions Schweiz GmbH, Dulliken, Switzerland) and TESLA Stym (Iskra Medical, Ljubljana, Slovenia).Pulsed electromagnetic field therapy in Parkinson’s diseaseIn October 2008 the Food and Drug Administration approved the use of PEMF therapy for treatment of major depressive disorder in PD patients who failed to achieve satisfactory improvement from very high dosages of antidepressant medications [133, 134]. Several studies reported PEMF therapy improved cognitive functions and motor symptoms. For example, an investigation involving three elderly PD patients with cognitive impairment assessed the effect of PEMF therapy on macrosomatognosia, a disorder of the body image in which the patient perceives a part or parts of his body as disproportionately large [135]. After receiving PEMF therapy, PD patients’ drawings showed reversal of macrosomatognosia (assessed by Draw-a-Person test) with reduction of the right parietal lobe dysfunction. Furthermore, PEMF therapy applied to a 49-year-old male PD patient with stage 3 disease, as assessed by Hoehn and Yahr scale, resulted in a marked improvement in motor and non-motor symptoms such as mood swings, sleeplessness, pain and sexual and cognitive dysfunctions, suggesting that PEMF therapy should be tested in large cohorts of PD patients as monotherapy and should also be considered as a treatment modality for de novo diagnosed PD patients [136]. PEMF therapy was also effective in improving visuospatial deficits in four PD patients, as assessed by the clock-drawing test [137]. Moreover, PEMF therapy improved PD-associated freezing (a symptom manifesting as a sudden attack of immobility usually experienced during walking) in 3 PD patients through the facilitation of serotonin neurotransmission at both junctional and non-junctional neuronal target sites [127].

Discussion
Although many studies on electromagnetic therapy included only a small number of participants, several investigations suggest that this therapy is effective in treating PD patients’ motor and non-motor symptoms. In the development of electromagnetic therapies, it is important to clarify the pathophysiological mechanisms underlying the symptoms to treat in order to determine the appropriate brain region to target. Thus, in the future, electromagnetic therapy must tend towards a more personalized approach, tailored to the specific PD patient’s symptoms. All the types of electromagnetic therapy described in this review can be used in combination with pharmacological and non-pharmacological therapies but this approach is understudied in PD patients. Therefore, specific protocols should be designed and tested in combination with other therapies in future controlled trials in patients affected by PD.

Transcranial magnetic stimulation

TMS increases the release of dopamine in the striatum and frontal cortex, which in turn improves PD symptoms including motor performance [138]. Furthermore, TMS applied in the prefrontal cortex induces the release of endogenous dopamine in the ipsilateral caudate nucleus as observed by positron emission tomography in healthy human subjects [89]. TMS application results in partial or complete disappearance of muscular pain and l-dopa-induced dyskinesia as well as regression of visuospatial impairment. This clinical improvement is followed by MEG improvement and normalization recorded after TMS, suggesting that TMS has an immediate and beneficial effect on corticostriatal interactions that play an important role in the pathophysiology of PD [58]. Cerasa and coworkers observed that repetitive TMS applied over the inferior frontal cortex reduced the amount of dyskinesia induced by a supramaximal single dose of levodopa in PD patients, suggesting that this area may play a key role in controlling the development of dyskinesia [139]. The mechanism underlying TMS effectiveness in PD remains an unanswered question due to the complexity of behavioral and neuroendocrine effects exerted by the TMS when applied to biological systems and their potential impact on neurotransmitter functions [140]. The effect of TMS differs depending on the stage of the disease, the age of disease onset, the amount of cerebral atrophy and genetic factors [37]. TMS has a low cost and is simple to operate and portable, opening the possibility for patients to perform at home stimulation which could be of high relevance in the elderly and in patients who are severely disabled. As far as side effects are concerned, the muscles of the scalp, jaw or face may contract or tingle during the procedure and mild headache or brief lightheadedness may occur [141, 142]. A recent large-scale study on the safety of TMS found that most side effects, such as headaches or scalp discomfort, were mild or moderate, and no seizures occurred [143]. Although evidence shows that TMS exerts complex cellular, systemic and neuroendocrine effects on biological systems impacting neurotransmitter functions [58], future controlled studies in larger cohorts of patients and with a long term follow-up are needed to further clarify the mechanisms underlying TMS efficacy in PD patients.

Repetitive transcranial magnetic stimulation

rTMS can be defined as a safe and non-invasive technique of brain stimulation which allows to specifically treat PD with low-frequency electromagnetic pulses [60]. As opposed to high-frequency TMS, which can induce convulsions in healthy subjects, rTMS does not affect the electroencephalogram pattern [71, 144]. Slow waves have been induced by rTMS over the right prefrontal area, a brain area involved in executive dysfunction that is observed in early stages of PD and is characterized by deficits in internal control of attention, set shifting, planning, inhibitory control, dual task performance, decision-making and social cognition tasks [3, 145]. rTMS applied to PD patients, enhances not only executive function, but also motor function, subjective symptoms and objective findings [3]. rTMS also increases cognitive function and other symptoms associated to the prefrontal area in PD patients [146]. In PD patients, therapeutic efficacy and long-term benefits of rTMS are obtained following multiple regular sessions rather than single sessions, but side effects associated to this therapy still warrant investigation in large controlled trials.

High-frequency magnetic stimulation

The observations that STN activity is disorganized in PD patients and that a lesion or chemical inactivation of STN neurons ameliorate motor symptoms led to the hypothesis that high-frequency TMS silences STN neurons and, by eliminating a pathological pattern, alleviates PD symptoms [147–151]. Garcia and colleagues proposed another hypothesis suggesting that high-frequency TMS suppresses not only the pathological STN activity but also imposes a new activity on STN neurons [95]. They proposed that high-frequency TMS excites the stimulated structure and evokes a regular pattern time-locked to the stimulation, overriding the pathological STN activity. As a consequence, high-frequency TMS removes the STN spontaneous activity and introduces a new and regular pattern that improves the dopamine-deficient network [95]. Elahi and coworkers found that high-frequency TMS modulates the excitability of the targeted brain regions and produces clinically significant motor improvement in PD patients [66]. This improvement is due to parallel non-exclusive actions, i.e. silencing of ongoing activity and generation of an activity pattern in the high gamma range [152]. Several clinical studies reported positive clinical results following high-frequency TMS in l-dopa-responsive forms of PD, including patients with selective brain dopaminergic lesions [153]. It remains unclear whether the mechanisms of action of high-frequency TMS and l-dopa are similar or they could be even synergic. However, high-frequency TMS improves the l-dopa-sensitive cardinal motor symptoms of PD patients with benefits similar to those given by l-dopa, though with reduced motor complications [154, 155]. The interactions with the dopaminergic system seem to be a key factor explaining the efficacy of both treatments [156]. High-frequency TMS changes dopamine lesion-induced functional alterations in the BG of PD animal models and gives an insight into the mechanisms underlying its antiparkinsonian effects [114, 157, 158]. The intrinsic capacity of the BG to generate oscillations and change rapidly from a physiological to a pathogenic pattern is crucial; the next step will be to identify how high-frequency TMS is propagated inside the BG. Disadvantages of this therapy are the high cost and limited availability of the devices to specialized medical centers, limited knowledge of potential long-term side effects and the necessity to employ highly trained personnel.

Pulsed electromagnetic fields

PEMF therapy improves PD symptoms including tremor, slowness of movement and difficulty in walking [159]. It is non-invasive, safe and improves PD patients’ quality of life [124, 160]. PEMF therapy, employed for PD treatment, supports the body’s own healing process for 4–6 h after therapy session [161–163]. It can be used at home and applied to the entire body or locally to target a specific body area and, if compared with dopaminergic systemic therapy, e.g. l-dopa, it can offer an alternative treatment avoiding systemic side effects such as hepatotoxicity and nephrotoxicity.

Conclusions
Electromagnetic therapy opens a new avenue for PD treatment. Each electromagnetic therapy technique described in this review can be applied according to a single protocol or as a combination of different protocols specifically tailored to the PD patient’s needs. Beyond the necessity to choose coil or electrode size and placement, there is a variety of parameters that have to be taken into account when designing electromagnetic therapy approaches and they include stimulation intensity, duration, frequency, pattern, electrode polarity and size. Furthermore, electromagnetic therapy can also be combined with pharmacological or non-pharmacological treatments, e.g. physical therapy and cognitive tasks, to produce additive or potentiated clinical effects. In conclusion, electromagnetic therapy represents a non-invasive, safe and promising approach that can be used alone or combined with conventional therapies for the challenging treatment of PD motor and non-motor symptoms.

Authors’ contributions
MV, AV, LP, BP, JCMM, and TI contributed equally to this review. All authors read and approved the final manuscript.

Acknowledgements

JCMM thanks CONACyT, México for membership. The authors thank Iskra Medical (Stegne 23, 1000 Ljubljana, Slovenia) for supporting the open access publication of this article.

Compliance with ethical guidelines

Competing interests The authors declare that they have no competing interests.

Contributor Information
Maria Vadalà, Email: moc.liamg@aladav.yram.

Annamaria Vallelunga, Email: moc.liamg@airamannaagnulellav.

Lucia Palmieri, Email: moc.liamg@ireimlap.aicul.

Beniamino Palmieri, Email: ti.erominu@ireimlap.

Julio Cesar Morales-Medina, Email: xm.vatsevnic@mselaromj.

Tommaso Iannitti, Email: moc.liamg@ittinnai.osammot.

References
1. Granado N, Ares-Santos S, Moratalla R. Methamphetamine and Parkinson’s disease. Parkinsons Dis. 2013;1:1–10.
2. Popa LCA, Constantinescu A, Popescu CD. Differences of cortical excitability between Parkinson’s disease patients and healthy subjects. A comparative TMS study. Romanian J Neurol. 2012;11:1.
3. Furukawa T, Izumi S, Toyokura M, Masakado Y. Effects of low-frequency repetitive transcranial magnetic stimulation in Parkinson’s disease. Tokai J Exp Clin Med. 2009;34(3):63–71. [PubMed]
4. Desplats P, Patel P, Kosberg K, Mante M, Patrick C, Rockenstein E, et al. Combined exposure to Maneb and Paraquat alters transcriptional regulation of neurogenesis-related genes in mice models of Parkinson’s disease. Mol Neurodegener. 2012;7:49. doi: 10.1186/1750-1326-7-49. [PMC free article] [PubMed] [Cross Ref]
5. Subramaniam SR, Chesselet MF. Mitochondrial dysfunction and oxidative stress in Parkinson’s disease. Prog Neurobiol. 2013;106–107:17–32. doi: 10.1016/j.pneurobio.2013.04.004. [PMC free article] [PubMed] [Cross Ref]
6. Vallelunga A, Ragusa M, Di Mauro S, Iannitti T, Pilleri M, Biundo R, et al. Identification of circulating microRNAs for the differential diagnosis of Parkinson’s disease and Multiple System Atrophy. Front Cell Neurosci. 2014;8:156. doi: 10.3389/fncel.2014.00156. [PMC free article] [PubMed] [Cross Ref]
7. Uttara B, Singh AV, Zamboni P, Mahajan RT. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol. 2009;7(1):65–74. doi: 10.2174/157015909787602823. [PMC free article] [PubMed] [Cross Ref]
8. Dauer W, Przedborski S. Parkinson’s disease: mechanisms and models. Neuron. 2003;39(6):889–909. doi: 10.1016/S0896-6273(03)00568-3. [PubMed] [Cross Ref]
9. Valente EM, Salvi S, Ialongo T, Marongiu R, Elia AE, Caputo V, et al. PINK1 mutations are associated with sporadic early-onset parkinsonism. Ann Neurol. 2004;56:336–341. doi: 10.1002/ana.20256. [PubMed] [Cross Ref]
10. Polymeropoulos MHLC, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276(5321):2045–2047. doi: 10.1126/science.276.5321.2045. [PubMed] [Cross Ref]
11. Chou KL. Diagnosis and management of the patient with tremor. Med Health R I. 2004;87(5):135–138. [PubMed]
12. Dauer W, Przedborski S. Parkinson’s disease: mechanisms and models. Neuron. 2003;39(6):889–909. doi: 10.1016/S0896-6273(03)00568-3. [PubMed] [Cross Ref]
13. McGeer PL, McGeer EG. Inflammation and neurodegeneration in Parkinson’s disease. Parkinsonism Relat Disord. 2004;10(1):S3–S7. doi: 10.1016/j.parkreldis.2004.01.005. [PubMed] [Cross Ref]
14. Mendez I, Viñuela A, Astradsson A, Mukhida K, Hallett P, Robertson H, et al. Dopamine neurons implanted into people with Parkinson’s disease survive without pathology for 14 years. Nat Med. 2008;14(5):507–509. doi: 10.1038/nm1752. [PMC free article] [PubMed] [Cross Ref]
15. Richardson PJ, Kase H, Jenner PG. Adenosine A2A receptor antagonists as new agents for the treatment of Parkinson’s disease. Trends Pharmacol Sci. 1997;18(9):338–344. doi: 10.1016/S0165-6147(97)01096-1. [PubMed] [Cross Ref]
16. Schapira AH, Bezard E, Brotchie J, Calon F, Collingridge GL, Ferger B, et al. Novel pharmacological targets for the treatment of Parkinson’s disease. Nat Rev Drug Discov. 2006;5(10):845–854. doi: 10.1038/nrd2087. [PubMed] [Cross Ref]
17. Bezard E, Gerlach I, Moratalla R, Gross CE, Jork R. 5-HT1A receptor agonist-mediated protection from MPTP toxicity in mouse and macaque models of Parkinson’s disease. Neurobiol Dis. 2006;23(1):77–86. doi: 10.1016/j.nbd.2006.02.003. [PubMed] [Cross Ref]
18. Poryazova RG, Zachariev ZI. REM sleep behavior disorder in patients with Parkinson’s disease. Folia Med (Plovdiv) 2005;47(1):5–10. [PubMed]
19. Eisensehr I, v Lindeiner H, Jäger M, Noachtar S. REM sleep behavior disorder in sleep-disordered patients with versus without Parkinson’s disease: is there a need for polysomnography? J Neurol Sci. 2001;186(1–2):7–11. doi: 10.1016/S0022-510X(01)00480-4. [PubMed] [Cross Ref]
20. Kales A, Ansel RD, Markham CH, Scharf MB, Tan TL. Sleep in patients with Parkinson’s disease and normal subjects prior to and following levodopa administration. Clin Pharmacol Ther. 1971;12(2):397–406. [PubMed]
21. Factor SA, McAlarney T, Sanchez-Ramos JR, Weiner WJ. Sleep disorders and sleep effect in Parkinson’s disease. Mov Disord Off J Mov Disord Soc. 1990;5(4):280–285. doi: 10.1002/mds.870050404. [PubMed] [Cross Ref]
22. Lees AJ, Blackburn NA, Campbell VL. The nighttime problems of Parkinson’s disease. Clin Neuropharmacol. 1988;11(6):512–519. doi: 10.1097/00002826-198812000-00004. [PubMed] [Cross Ref]
23. Comella CL, Nardine TM, Diederich NJ, Stebbins GT. Sleep-related violence, injury, and REM sleep behavior disorder in Parkinson’s disease. Neurology. 1998;51(2):526–529. doi: 10.1212/WNL.51.2.526. [PubMed] [Cross Ref]
24. Chaudhuri KR, Healy DG, Schapira AH, FmedSci Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol. 2006;5(3):235–245. doi: 10.1016/S1474-4422(06)70373-8. [PubMed] [Cross Ref]
25. Lieberman A. Depression in Parkinson’s disease—a review. Acta Neurol Scand. 2006;113(1):1–8. doi: 10.1111/j.1600-0404.2006.00536.x. [PubMed] [Cross Ref]
26. Poewe W. Non-motor symptoms in Parkinson’s disease. Eur J Neurol. 2008;15(1):14–20. doi: 10.1111/j.1468-1331.2008.02056.x. [PubMed] [Cross Ref]
27. Trinh J, Farrer M. Advances in the genetics of Parkinson disease. Nat Rev Neurol. 2013;9(8):445–454. doi: 10.1038/nrneurol.2013.132. [PubMed] [Cross Ref]
28. Lubbe S, Morris HR. Recent advances in Parkinson’s disease genetics. J Neurol. 2014;261(2):259–266. doi: 10.1007/s00415-013-7003-2. [PubMed] [Cross Ref]
29. Taymans JM, Baekelandt V. Phosphatases of alpha-synuclein, LRRK2, and tau: important players in the phosphorylation-dependent pathology of Parkinsonism. Front Genet. 2014;5:382. doi: 10.3389/fgene.2014.00382. [PMC free article] [PubMed] [Cross Ref]
30. van der Vegt JP, van Nuenen BF, Bloem BR, Klein C, Siebner HR. Imaging the impact of genes on Parkinson’s disease. Neuroscience. 2009;164(1):191–204. doi: 10.1016/j.neuroscience.2009.01.055. [PubMed] [Cross Ref]
31. Kimura H, Kurimura M, Kurokawa K, Nagaoka U, Arawaka S, Wada M, et al. A comprehensive study of repetitive transcranial magnetic stimulation in Parkinson’s disease. ISRN Neurol. 2011;2011:845453. doi: 10.5402/2011/845453. [PMC free article] [PubMed] [Cross Ref]
32. Lees AJ. The on-off phenomenon. J Neurol Neurosurg Psychiatry. 1989;52(1):29–37. doi: 10.1136/jnnp.52.Suppl.29. [PMC free article] [PubMed] [Cross Ref]
33. Hattoria N, Wanga M, Taka H, Fujimura T, Yoritaka A, Kubo S, et al. Toxic effects of dopamine metabolism in Parkinson’s disease. Parkinsonism Relat Disord. 2009;15(1):S35–S38. doi: 10.1016/S1353-8020(09)70010-0. [PubMed] [Cross Ref]
34. Belcastro V, Tozzi A, Tantucci M, Costa C, Di Filippo M, Autuori A, et al. A2A adenosine receptor antagonists protect the striatum against rotenone-induced neurotoxicity. Exp Neurol. 2009;217(1):231–234. doi: 10.1016/j.expneurol.2009.01.010. [PubMed] [Cross Ref]
35. Benabid AL, Chabardes S, Mitrofanis J, Pollak P. Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson’s disease. Lancet Neurol. 2009;8(1):67–81. doi: 10.1016/S1474-4422(08)70291-6. [PubMed] [Cross Ref]
36. Wang Z, Che PL, Du J, Ha B, Yarema KJ. Static magnetic field exposure reproduces cellular effects of the Parkinson’s disease drug candidate ZM241385. PLoS One. 2010;5(11):e13883. doi: 10.1371/journal.pone.0013883. [PMC free article] [PubMed] [Cross Ref]
37. Anderkova L, Rektorova I. Cognitive effects of repetitive transcranial magnetic stimulation in patients with neurodegenerative diseases—clinician’s perspective. J Neurol Sci. 2014;339(1–2):15–25. doi: 10.1016/j.jns.2014.01.037. [PubMed] [Cross Ref]
38. Caspar S. Invasive and non-invasive stimulation in Parkinson’s disease. Germany: Department of Clinical Neurophysiol; 2011.
39. Sandyk R. Weak magnetic fields as a novel therapeutic modality in Parkinson’s disease. Int J Neurosci. 1992;66(1–2):1–15. [PubMed]
40. Sandyk R. Treatment with weak electromagnetic fields restores dream recall in a parkinsonian patient. Int J Neurosci. 1997;90(1–2):75–86. doi: 10.3109/00207459709000627. [PubMed] [Cross Ref]
41. Vonloh M, Chen R, Kluger B. Safety of transcranial magnetic stimulation in Parkinson’s disease: a review of the literature. Parkinsonism Relat Disord. 2013;19(6):573–585. doi: 10.1016/j.parkreldis.2013.01.007. [PMC free article] [PubMed] [Cross Ref]
42. Wade B. A review of pulsed electromagnetic field (PEMF) mechanisms at a cellular level: a rationale for clinical use. Am J Health Res. 2013;1(3):51–55. doi: 10.11648/j.ajhr.20130103.13. [Cross Ref]
43. Markov MS. Expanding use of pulsed electromagnetic field therapies. Electromagn Biol Med. 2007;26(3):257–274. doi: 10.1080/15368370701580806. [PubMed] [Cross Ref]
44. Weintraub MI. Magnetotherapy: historical background with a stimulating future. Phys Rehabil Med. 2004;16(2):95–108.
45. De Loecker W, Cheng N, Delport PH. Emerging electromagnetic medicine. New York: Springer; 1990. Effects of pulsed electromagnetic fields on membrane transport; pp. 45–57.
46. Wassermann EM, Lisanby SH. Therapeutic application of repetitive transcranial magnetic stimulation: a review. Clin Neurophysiol Off J Int Fed Clin Neurophysiol. 2001;112(8):1367–1377. doi: 10.1016/S1388-2457(01)00585-5. [PubMed] [Cross Ref]
47. Wassermann EM, Grafman J, Berry C, Hollnagel C, Wild K, Clark K, et al. Use and safety of a new repetitive transcranial magnetic stimulator. Electroencephalogr Clin Neurophysiol. 1996;101(5):412–417. doi: 10.1016/0924-980X(96)96004-X. [PubMed] [Cross Ref]
48. Edwards MJ, Talelli P, Rothwell JC. Clinical applications of transcranial magnetic stimulation in patients with movement disorders. Lancet Neurol. 2008;7(9):827–840. doi: 10.1016/S1474-4422(08)70190-X. [PubMed] [Cross Ref]
49. Kobayashi M, Pascual-Leone A. Transcranial magnetic stimulation in neurology. Lancet Neurol. 2003;2:145–156. doi: 10.1016/S1474-4422(03)00321-1. [PubMed] [Cross Ref]
50. Rudiak D, Marg E. Finding the depth of magnetic brain stimulation: a re-evaluation. Electroencephalogr Clin Neurophysiol. 1994;93(5):358–371. doi: 10.1016/0168-5597(94)90124-4. [PubMed] [Cross Ref]
51. Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of human motor cortex. Lancet. 1985;1(8437):1106–1107. doi: 10.1016/S0140-6736(85)92413-4. [PubMed] [Cross Ref]
52. Fuhr P, Agostino R, Hallett M. Spinal motor neuron excitability during the silent period after cortical stimulation. Electroencephalogr Clin Neurophysiol. 1991;81(4):257–262. doi: 10.1016/0168-5597(91)90011-L. [PubMed] [Cross Ref]
53. Inghilleri M, Berardelli A, Cruccu G, Manfredi M. Silent period evoked by transcranial stimulation of the human cortex and cervicomedullary junction. J Physiol. 1993;466:521–534. [PMC free article] [PubMed]
54. Farzan F, Barr MS, Hoppenbrouwers SS, Fitzgerald PB, Chen R, Pascual-Leone A, et al. The EEG correlates of the TMS-induced EMG silent period in humans. Neuroimage. 2013;83:120–134. doi: 10.1016/j.neuroimage.2013.06.059. [PMC free article] [PubMed] [Cross Ref]
55. Cantello R, Gianelli M, Bettucci D, Civardi C, De Angelis MS, Mutani R. Parkinson’s disease rigidity: magnetic motor evoked potentials in a small hand muscle. Neurology. 1991;41(9):1449–1456. doi: 10.1212/WNL.41.9.1449. [PubMed] [Cross Ref]
56. Khedr EM, Farweez HM, Islam H. Therapeutic effect of repetitive transcranial magnetic stimulation on motor function in Parkinson’s disease patients. Eur J Neurol. 2003;10(5):567–572. doi: 10.1046/j.1468-1331.2003.00649.x. [PubMed] [Cross Ref]
57. Lefaucheur JP. Motor cortex dysfunction revealed by cortical excitability studies in Parkinson’s disease: influence of antiparkinsonian treatment and cortical stimulation. Clin Neurophysiol. 2005;116(2):244–253. doi: 10.1016/j.clinph.2004.11.017. [PubMed] [Cross Ref]
58. Anninos P, Adamopoulos A, Kotini A, Tsagas N, Tamiolakis D, Prassopoulos P. MEG evaluation of Parkinson’s diseased patients after external magnetic stimulation. Acta Neurol Belg. 2007;107(1):5–10. [PubMed]
59. Stam CJ. Use of magnetoencephalography (MEG) to study functional brain networks in neurodegenerative disorders. J Neurol Sci. 2010;289(1–2):128–134. doi: 10.1016/j.jns.2009.08.028. [PubMed] [Cross Ref]
60. Fregni F, Simon DK, Wu A, Pascual-Leone A. Non-invasive brain stimulation for Parkinson’s disease: a systematic review and meta-analysis of the literature. J Neurol Neurosurg Psychiatry. 2005;76(12):1614–1623. doi: 10.1136/jnnp.2005.069849. [PMC free article] [PubMed] [Cross Ref]
61. Hallett M. Transcranial magnetic stimulation: a primer. Neuron. 2007;55(2):187–199. doi: 10.1016/j.neuron.2007.06.026. [PubMed] [Cross Ref]
62. Greenberg BD, Malone DA, Friehs GM, Rezai AR, Kubu CS, Malloy PF, et al. Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol. 2006;31(11):2384–2393. doi: 10.1038/sj.npp.1301165. [PubMed] [Cross Ref]
63. Chen R, Classen J, Gerloff C, Celnik P, Wassermann EM, Hallett M, et al. Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology. 1997;48(5):1398–1403. doi: 10.1212/WNL.48.5.1398. [PubMed] [Cross Ref]
64. Pascual-Leone A, Valls-Solé J, Wassermann EM, Hallett M. Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain J Neurol. 1994;117(Pt 4):847–858. doi: 10.1093/brain/117.4.847. [PubMed] [Cross Ref]
65. Okabe S, Ugawa Y, Kanazawa I. 0.2-Hz repetitive transcranial magnetic stimulation has no add-on effects as compared to a realistic sham stimulation in Parkinson’s disease. Mov Disord. 2003;18(4):382–388. doi: 10.1002/mds.10370. [PubMed] [Cross Ref]
66. Elahi B, Chen R. Effect of transcranial magnetic stimulation on Parkinson motor function—systematic review of controlled clinical trials. Mov Disord. 2009;24(3):357–363. doi: 10.1002/mds.22364. [PubMed] [Cross Ref]
67. Wang M, Ping GU, Xiao-wei MA, Yan-min LI. Effects of low frequency repetitive transcranial magnetic stimulation on motor function and affective disorder in patients with Parkinson’s disease. Chin J Geriatr. 2009;28:729–732.
68. Niu X, G Y. Observation of repetitively transcranial magnetic stimulation in the treatment of depression induced by Parkinson’s disease. Chin J Pract Nerv Dis. 2012;15:11–13.
69. Shirota Y, Ohtsu H, Hamada M, Enomoto H, Ugawa Y. Supplementary motor area stimulation for Parkinson disease: a randomized controlled study. Neurology. 2013;80(15):1400–1405. doi: 10.1212/WNL.0b013e31828c2f66. [PubMed] [Cross Ref]
70. Pizzolato G, Mandat T. Deep brain stimulation for movement disorders. Mini Rev Art Front Integr Neurosci. 2012;6(2):1–5.
71. Boutros NN, Berman RM, Hoffman R, Miano AP, Campbell D, Ilmoniemi R. Electroencephalogram and repetitive transcranial magnetic stimulation. Depress Anxiety. 2000;12(3):166–169. doi: 10.1002/1520-6394(2000)12:3<166::AID-DA8>3.0.CO;2-M. [PubMed] [Cross Ref]
72. Fregni F, Boggio PS, Valle AC, Rocha RR, Duarte J, Ferreira MJ, et al. A sham-controlled trial of a 5-day course of repetitive transcranial magnetic stimulation of the unaffected hemisphere in stroke patients. Stroke. 2006;37(8):2115–2122. doi: 10.1161/01.STR.0000231390.58967.6b. [PubMed] [Cross Ref]
73. Fox MD, Liu H, Pascual-Leone A. Identification of reproducible individualized targets for treatment of depression with TMS based on intrinsic connectivity. Neuroimage. 2013;66:151–160. doi: 10.1016/j.neuroimage.2012.10.082. [PMC free article] [PubMed] [Cross Ref]
74. Shimamoto H, Takasaki K, Shigemori M, Imaizumi T, Ayabe M, Shoji H. Therapeutic effect and mechanism of repetitive transcranial magnetic stimulation in Parkinson’s disease. J Neurol. 2001;248(3):III48–III52. doi: 10.1007/PL00007826. [PubMed] [Cross Ref]
75. Eckert T, Peschel T, Heinze HJ, Rotte M. Increased pre-SMA activation in early PD patients during simple self-initiated hand movements. J Neurol. 2006;253(2):199–207. doi: 10.1007/s00415-005-0956-z. [PubMed] [Cross Ref]
76. Buhmann C, Glauche V, Stürenburg HJ, Oechsner M, Weiller C, Büchel C. Pharmacologically modulated fMRI–cortical responsiveness to levodopa in drug-naive hemiparkinsonian patients. Brain. 2003;126(Pt 2):451–461. doi: 10.1093/brain/awg033. [PubMed] [Cross Ref]
77. Ceballos-Baumann AO, Boecker H, Bartenstein P, von Falkenhayn I, Riescher H, Conrad B, et al. A positron emission tomographic study of subthalamic nucleus stimulation in Parkinson disease: enhanced movement-related activity of motor-association cortex and decreased motor cortex resting activity. Arch Neurol. 1999;56(8):997–1003. doi: 10.1001/archneur.56.8.997. [PubMed] [Cross Ref]
78. Jahanshahi M, Jenkins IN, Brown RG, Marsden CD, Passingham RE, Brooks DJ. Self-initiated versus externally triggered movements. I. An investigation using measurement of regional cerebral blood flow with PET and movement-related potentials in normal and Parkinson’s disease subjects. Brain. J Neurol. 1995;118(Pt 4):913–933. [PubMed]
79. Jenkins IH, Fernandez W, Playford ED, Lees AJ, Frackowiak RS, Passingham RE, et al. Impaired activation of the supplementary motor area in Parkinson’s disease is reversed when akinesia is treated with apomorphine. Ann Neurol. 1992;32(6):749–757. doi: 10.1002/ana.410320608. [PubMed] [Cross Ref]
80. Playford ED, Jenkins IH, Passingham RE, Nutt J, Frackowiak RSJ, Brooks DJ. Impaired mesial frontal and putamen activation in Parkinson’s disease: a positron emission tomography study. Ann Neurol. 1992;32(2):151–161. doi: 10.1002/ana.410320206. [PubMed] [Cross Ref]
81. Rascol O, Sabatini U, Chollet F, Fabre N, Senard JM, Montastruc JL, et al. Normal activation of the supplementary motor area in patients with Parkinson’s disease undergoing long-term treatment with levodopa. J Neurol Neurosurg Psychiatry. 1994;57(5):567–571. doi: 10.1136/jnnp.57.5.567. [PMC free article] [PubMed] [Cross Ref]
82. Randhawa BK, Farley BG, Boyd LA. Repetitive transcranial magnetic stimulation improves handwriting in Parkinson’s disease. Parkinsons Dis. 2013;2013:751925. [PMC free article] [PubMed]
83. Morari M, Marti M, Sbrenna S, Fuxe K, Bianchi C, Beani L. Reciprocal dopamine-glutamate modulation of release in the basal ganglia. Neurochem Int. 1998;33(5):383–397. doi: 10.1016/S0197-0186(98)00052-7. [PubMed] [Cross Ref]
84. Keck ME, Welt T, Müller MB, Erhardt A, Ohl F, Toschi N, et al. Repetitive transcranial magnetic stimulation increases the release of dopamine in the mesolimbic and mesostriatal system. Neuropharmacology. 2002;43(1):101–109. doi: 10.1016/S0028-3908(02)00069-2. [PubMed] [Cross Ref]
85. Grafman J, Pascual-Leone A, Alway D, Nichelli P, Gomez-Tortosa E, Hallett M. Induction of a recall deficit by rapid-rate transcranial magnetic stimulation. Neuroreport. 1994;5(9):1157–1160. doi: 10.1097/00001756-199405000-00034. [PubMed] [Cross Ref]
86. Jahanshahi M, Profice P, Brown RG, Ridding MC, Dirnberger G, Rothwell JC. The effects of transcranial magnetic stimulation over the dorsolateral prefrontal cortex on suppression of habitual counting during random number generation. Brain. 1998;121(Pt 8):1533–1544. doi: 10.1093/brain/121.8.1533. [PubMed] [Cross Ref]
87. Pascual-Leone A, Bartres-Faz D, Keenan JP. Transcranial magnetic stimulation: studying the brain-behaviour relationship by induction of ‘virtual lesions’ Philos Trans R Soc Lond B Biol Sci. 1999;354(1387):1229–1238. doi: 10.1098/rstb.1999.0476. [PMC free article] [PubMed] [Cross Ref]
88. Mottaghy FM, Krause BJ, Kemna LJ, Töpper R, Tellmann L, Beu M, et al. Modulation of the neuronal circuitry subserving working memory in healthy human subjects by repetitive transcranial magnetic stimulation. Neurosci Lett. 2000;280(3):167–170. doi: 10.1016/S0304-3940(00)00798-9. [PubMed] [Cross Ref]
89. Strafella AP, Paus T, Barrett J, Dagher A. Repetitive transcranial magnetic stimulation of the human prefrontal cortex induces dopamine release in the caudate nucleus. J Neurosci. 2001;21(15):RC157. [PubMed]
90. Gessler M, Bruns GA. A physical map around the WAGR complex on the short arm of chromosome 11. Genomics. 1989;5(1):43–55. doi: 10.1016/0888-7543(89)90084-0. [PubMed] [Cross Ref]
91. Dragasevic N, Potrebic A, Damjanovi? A, Stefanova E, Kosti? VS. Therapeutic efficacy of bilateral prefrontal slow repetitive transcranial magnetic stimulation in depressed patients with Parkinson’s disease: an open study. Mov Disord Off J Mov Disord Soc. 2002;17(3):528–532. doi: 10.1002/mds.10109. [PubMed] [Cross Ref]
92. Fregni F, Santos CM, Myczkowski ML, Rigolino R, Gallucci-Neto J, Barbosa ER, et al. Repetitive transcranial magnetic stimulation is as effective as fluoxetine in the treatment of depression in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2004;75(8):1171–1174. doi: 10.1136/jnnp.2003.027060. [PMC free article] [PubMed] [Cross Ref]
93. Boylan LS, Pullman SL, Lisanby SH, Spicknall KE, Sackeim HA. Repetitive transcranial magnetic stimulation to SMA worsens complex movements in Parkinson’s disease. Clin Neurophysiol. 2001;112(2):259–264. doi: 10.1016/S1388-2457(00)00519-8. [PubMed] [Cross Ref]
94. Ghabra MB, Hallett M, Wassermann EM. Simultaneous repetitive transcranial magnetic stimulation does not speed fine movement in PD. Neurology. 1999;52(4):768–770. doi: 10.1212/WNL.52.4.768. [PubMed] [Cross Ref]
95. Garcia L, D’Alessandro G, Bioulac B, Hammond C. High-frequency stimulation in Parkinson’s disease: more or less? Trends Neurosci. 2005;28(4):209–216. doi: 10.1016/j.tins.2005.02.005. [PubMed] [Cross Ref]
96. Moro E, Esselink RJA, Xie J, Hommel M, Benabid AL, Pollak P. The impact on Parkinson’s disease of electrical parameter settings in STN stimulation. Neurology. 2002;59(5):706–713. doi: 10.1212/WNL.59.5.706. [PubMed] [Cross Ref]
97. Beurrier C, Bioulac B, Audin J, Hammond C. High-frequency stimulation produces a transient blockade of voltage-gated currents in subthalamic neurons. J Neurophysiol. 2001;85(4):1351–1356. [PubMed]
98. McIntyre CC, Savasta M, Walter BL, Vitek JL. How does deep brain stimulation work? Present understanding and future questions. J Clin Neurophysiol. 2004;21(1):40–50. doi: 10.1097/00004691-200401000-00006. [PubMed] [Cross Ref]
99. Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med. 2003;349(20):1925–1934. doi: 10.1056/NEJMoa035275. [PubMed] [Cross Ref]
100. Maltete D, Jodoin N, Karachi C, Houeto JL, Navarro S, Cornu P, et al. Subthalamic stimulation and neuronal activity in the substantia nigra in Parkinson’s disease. J Neurophysiol. 2007;97(6):4017–4022. doi: 10.1152/jn.01104.2006. [PubMed] [Cross Ref]
101. Kita H, Tachibana Y, Nambu A, Chiken S. Balance of monosynaptic excitatory and disynaptic inhibitory responses of the globus pallidus induced after stimulation of the subthalamic nucleus in the monkey. J Neurosci Off J Soc Neurosci. 2005;25(38):8611–8619. doi: 10.1523/JNEUROSCI.1719-05.2005. [PubMed] [Cross Ref]
102. Zhao XD, Cao YQ, Liu HH, Li FQ, You BM, Zhou XP. Long term high frequency stimulation of STN increases dopamine in the corpus striatum of hemiparkinsonian rhesus monkey. Brain Res. 2009;1286:230–238. doi: 10.1016/j.brainres.2009.06.069. [PubMed] [Cross Ref]
103. Putzke JD, Wharen RE, Wszolek ZK, Turk MF, Strongosky AJ, Uitti RJ. Thalamic deep brain stimulation for tremor-predominant Parkinson’s disease. Parkinsonism Relat Disord. 2003;10(2):81–88. doi: 10.1016/j.parkreldis.2003.09.002. [PubMed] [Cross Ref]
104. Dipti P, Yogesh B, Kain AK, Pauline T, Anju B, Sairam M, et al. Lead induced oxidative stress: beneficial effects of Kombucha tea. Biomed Environ Sci. 2003;16(3):276–282. [PubMed]
105. Anderson VC, Burchiel KJ, Hogarth P, Favre J, Hammerstad JP. Pallidal vs subthalamic nucleus deep brain stimulation in Parkinson disease. Arch Neurol. 2005;62(4):554–560. doi: 10.1001/archneur.62.4.554. [PubMed] [Cross Ref]
106. Peppe A, Pierantozzi M, Altibrandi MG, Giacomini P, Stefani A, Bassi A, et al. Bilateral GPi DBS is useful to reduce abnormal involuntary movements in advanced Parkinson’s disease patients, but its action is related to modality and site of stimulation. Eur J Neurol Off J Eur Fed Neurol Soc. 2001;8(6):579–586. [PubMed]
107. Benabid AL, Pollak P, Gao D, Hofmann D, Limousin P, Gay E, et al. Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders. J Neurosurg. 1996;84(2):203–214. doi: 10.3171/jns.1996.84.2.0203. [PubMed] [Cross Ref]
108. Brown P, Mazzone P, Oliviero A, Altibrandi MG, Pilato F, Tonali PA, et al. Effects of stimulation of the subthalamic area on oscillatory pallidal activity in Parkinson’s disease. Exp Neurol. 2004;188(2):480–490. doi: 10.1016/j.expneurol.2004.05.009. [PubMed] [Cross Ref]
109. Hassani OK, Fèger J. Effects of intrasubthalamic injection of dopamine receptor agonists on subthalamic neurons in normal and 6-hydroxydopamine-lesioned rats: an electrophysiological and c-Fos study. Neuroscience. 1999;92(2):533–543. doi: 10.1016/S0306-4522(98)00765-9. [PubMed] [Cross Ref]
110. Filali M, Hutchison WD, Palter VN, Lozano AM, Dostrovsky JO. Stimulation-induced inhibition of neuronal firing in human subthalamic nucleus. Exp Brain Res. 2004;156(3):274–281. doi: 10.1007/s00221-003-1784-y. [PubMed] [Cross Ref]
111. Lozano AM, Dostrovsky J, Chen R, Ashby P. Deep brain stimulation for Parkinson’s disease: disrupting the disruption. Lancet Neurol. 2002;1(4):225–231. doi: 10.1016/S1474-4422(02)00101-1. [PubMed] [Cross Ref]
112. Welter ML, Houeto JL, Bonnet AM, Bejjani PB, Mesnage V, Dormont D, et al. Effects of high-frequency stimulation on subthalamic neuronal activity in parkinsonian patients. Arch Neurol. 2004;61(1):89–96. doi: 10.1001/archneur.61.1.89. [PubMed] [Cross Ref]
113. Burbaud P, Gross C, Bioulac B. Effect of subthalamic high frequency stimulation on substantia nigra pars reticulata and globus pallidus neurons in normal rats. J Physiol Paris. 1994;88(6):359–361. doi: 10.1016/0928-4257(94)90029-9. [PubMed] [Cross Ref]
114. Tai CH, Boraud T, Bezard E, Bioulac B, Gross C, Benazzouz A. Electrophysiological and metabolic evidence that high-frequency stimulation of the subthalamic nucleus bridles neuronal activity in the subthalamic nucleus and the substantia nigra reticulata. FASEB J Off Publ Fed Am Soc Exp Biol. 2003;17(13):1820–1830. [PubMed]
115. Garcia L, Audin J, D’Alessandro G, Bioulac B, Hammond C. Dual effect of high-frequency stimulation on subthalamic neuron activity. J Neurosci Off J Soc Neurosci. 2003;23(25):8743–8751. [PubMed]
116. Lee KH, Chang SY, Roberts DW, Kim U. Neurotransmitter release from high-frequency stimulation of the subthalamic nucleus. J Neurosurg. 2004;101(3):511–517. doi: 10.3171/jns.2004.101.3.0511. [PubMed] [Cross Ref]
117. Jaggi JL, Umemura A, Hurtig HI, Siderowf AD, Colcher A, Stern MB, et al. Bilateral stimulation of the subthalamic nucleus in Parkinson’s disease: surgical efficacy and prediction of outcome. Stereotact Funct Neurosurg. 2004;82(2–3):104–114. doi: 10.1159/000078145. [PubMed] [Cross Ref]
118. Holden KR (2012) Biological effects of pulsed electromagnetic field (PEMF) therapy. Med News
119. Siskin BF, Walker J. Therapeutic aspects of electromagnetic fields for soft-tissue healing. In: Blank M, editor. Electromagnetic fields: biological interactions and mechanisms. Washington, DC: American Chemical Society; 1995. pp. 277–285.
120. Iannitti T, Fistetto G, Esposito A, Rottigni V, Palmieri B. Pulsed electromagnetic field therapy for management of osteoarthritis-related pain, stiffness and physical function: clinical experience in the elderly. Clin Interv Aging. 2013;8:1289–1293. doi: 10.2147/CIA.S35926. [PMC free article] [PubMed] [Cross Ref]
121. Aktas I, Akgun K, Cakmak B. Therapeutic effect of pulsed electromagnetic field in conservative treatment of subacromial impingement syndrome. Clin Rheumatol. 2007;26(8):1234–1239. doi: 10.1007/s10067-006-0464-2. [PubMed] [Cross Ref]
122. Thomas AW, Graham K, Prato FS, McKay J, Forster PM, Moulin DE, et al. A randomized, double-blind, placebo-controlled clinical trial using a low-frequency magnetic field in the treatment of musculoskeletal chronic pain. Pain Res Manage J Can Pain Soc (journal de la societe canadienne pour le traitement de la douleur) 2007;12(4):249–258. [PMC free article] [PubMed]
123. Lee PB, Kim YC, Lim YJ, Lee CJ, Choi SS, Park SH, et al. Efficacy of pulsed electromagnetic therapy for chronic lower back pain: a randomized, double-blind, placebo-controlled study. J Int Med Res. 2006;34(2):160–167. doi: 10.1177/147323000603400205. [PubMed] [Cross Ref]
124. Lappin MS, Lawrie FW, Richards TL, Kramer ED. Effects of a pulsed electromagnetic therapy on multiple sclerosis fatigue and quality of life: a double-blind, placebo controlled trial. Altern Ther Health Med. 2003;9(4):38–48. [PubMed]
125. Richards TL, Lappin MS, Acosta-Urquidi J, Kraft GH, Heide AC, Lawrie FW, et al. Double-blind study of pulsing magnetic field effects on multiple sclerosis. J Altern Complement Med. 1997;3(1):21–29. doi: 10.1089/acm.1997.3.21. [PubMed] [Cross Ref]
126. Barbault A, Costa FP, Bottger B, Munden RF, Bomholt F, Kuster N, et al. Amplitude-modulated electromagnetic fields for the treatment of cancer: discovery of tumor-specific frequencies and assessment of a novel therapeutic approach. J Exp Clin Cancer Res. 2009;28:51. doi: 10.1186/1756-9966-28-51. [PMC free article] [PubMed] [Cross Ref]
127. Sandyk R. Freezing of gait in Parkinson’s disease is improved by treatment with weak electromagnetic fields. Int J Neurosci. 1996;85(1–2):111–124. doi: 10.3109/00207459608986356. [PubMed] [Cross Ref]
128. Arendash GW, Sanchez-Ramos J, Mori T, Mamcarz M, Lin X, Runfeldt M, et al. Electromagnetic field treatment protects against and reverses cognitive impairment in Alzheimer’s disease mice. J Alzheimers Dis. 2010;19(1):191–210. [PubMed]
129. Ericsson AD, Hazlewood CF, Markov M, Crawford F. Biological effects of EMF’s. Greece: KOS; 2004. Specific Biochemical changes in circulating lymphocytes following acute ablation of symptoms in Reflex Sympathetic Dystrophy (RSD): a pilot study; pp. 683–688.
130. Yost MG, Liburdy RP. Time-varying and static magnetic fields act in combination to alter calcium signal transduction in the lymphocyte. FEBS Lett. 1992;296(2):117–122. doi: 10.1016/0014-5793(92)80361-J. [PubMed] [Cross Ref]
131. Edmonds DT. Larmor precession as a mechanism for the detection of static and alternating magnetic fields. Bioelectrochem Bioenerg. 1993;30:3–12. doi: 10.1016/0302-4598(93)80057-2. [Cross Ref]
132. Liboff AR, Cherng S, Jenrow KA, Bull A. Calmodulin-dependent cyclic nucleotide phosphodiesterase activity is altered by 20 microT magnetostatic fields. Bioelectromagnetics. 2003;24(1):32–38. doi: 10.1002/bem.10063. [PubMed] [Cross Ref]
133. Demitrack MA, Thase ME. Clinical significance of transcranial magnetic stimulation (TMS) in the treatment of pharmacoresistant depression: synthesis of recent data. Psychopharmacol Bull. 2009;42(2):5–38. [PubMed]
134. Liboff AR (2004) Signal shapes in electromagnetic therapies: a primer. In: Rosch PJ, Markov MS (eds) Bioelectromagnetic medicine. Marcel Dekker, NY, pp 17–37
135. Sandyk R. Reversal of a body image disorder (macrosomatognosia) in Parkinson’s disease by treatment with AC pulsed electromagnetic fields. Int J Neurosci. 1998;93(1–2):43–54. doi: 10.3109/00207459808986411. [PubMed] [Cross Ref]
136. Sandyk R. A drug naive parkinsonian patient successfully treated with weak electromagnetic fields. Int J Neurosci. 1994;79(1–2):99–110. [PubMed]
137. Sandyk R. Reversal of visuospatial deficit on the Clock Drawing Test in Parkinson’s disease by treatment with weak electromagnetic fields. Int J Neurosci. 1995;82(3–4):255–268. doi: 10.3109/00207459508999805. [PubMed] [Cross Ref]
138. Ben-Shachar D, Belmaker RH, Grisaru N, Klein E. TMS induces alterations in brain monoamines. J Neural Trans. 1997;104:191–197. doi: 10.1007/BF01273180. [PubMed] [Cross Ref]
139. Cerasa A, Koch G, Donzuso G, Mangone G, Morelli M, Brusa L, et al. A network centred on the inferior frontal cortex is critically involved in levodopa-induced dyskinesias. Brain. 2015;138(2):414–427. doi: 10.1093/brain/awu329. [PubMed] [Cross Ref]
140. Keck ME, Welt T, Post A, Müller MB, Toschi N, Wigger A, et al. Neuroendocrine and behavioral effects of repetitive transcranial magnetic stimulation in a psychopathological animal model are suggestive of antidepressant-like effects. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol. 2001;24(4):337–349. doi: 10.1016/S0893-133X(00)00191-3. [PubMed] [Cross Ref]
141. Fitzgerald PB, Brown TL, Marston NA, Daskalakis ZJ, De Castella A, Kulkarni J. Transcranial magnetic stimulation in the treatment of depression: a double-blind, placebo-controlled trial. Arch Gen Psychiatry. 2003;60(10):1002–1008. [PubMed]
142. Loo CK, Mitchell PB, Croker VM, Malhi GS, Wen W, Gandevia SC, et al. Double-blind controlled investigation of bilateral prefrontal transcranial magnetic stimulation for the treatment of resistant major depression. Psychol Med. 2003;33(1):33–40. doi: 10.1017/S0033291702006839. [PubMed] [Cross Ref]
143. Janicak PG, O’Reardon RJ, et al. Transcranial magnetic stimulation in the treatment of major depressive disorder: a comprehensive summary of safety experience from acute exposure, extended exposure, and during reintroduction treatment. J Clin Psychiatry. 2008;69(2):222–232. doi: 10.4088/JCP.v69n0208. [PubMed] [Cross Ref]
144. Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5–7, 1996. Electroencephalogr Clin Neurophysiol. 1998;108(1):1–16. doi: 10.1016/S0168-5597(97)00096-8. [PubMed] [Cross Ref]
145. Dirnberger G, Jahanshahi M. Executive dysfunction in Parkinson’s disease: a review. J Neuropsychol. 2013;7(2):193–224. doi: 10.1111/jnp.12028. [PubMed] [Cross Ref]
146. Narayanan NS, Rodnitzky RL, Uc EY. Prefrontal dopamine signaling and cognitive symptoms of Parkinson’s disease. Rev Neurosci. 2013;24(3):267–278. doi: 10.1515/revneuro-2013-0004. [PMC free article] [PubMed] [Cross Ref]
147. Aziz TZ, Peggs D, Sambrook MA, Crossman AR. Lesion of the subthalamic nucleus for the alleviation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the primate. Mov Disord Off J Mov Disord Soc. 1991;6(4):288–292. doi: 10.1002/mds.870060404. [PubMed] [Cross Ref]
148. Benazzouz A, Gross C, Féger J, Boraud T, Bioulac B. Reversal of rigidity and improvement in motor performance by subthalamic high-frequency stimulation in MPTP-treated monkeys. Eur J Neurosci. 1993;5(4):382–389. doi: 10.1111/j.1460-9568.1993.tb00505.x. [PubMed] [Cross Ref]
149. Bergman H, Wichmann T, DeLong MR. Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science. 1990;249(4975):1436–1438. doi: 10.1126/science.2402638. [PubMed] [Cross Ref]
150. Lang AE. Surgery for Parkinson disease: a critical evaluation of the state of the art. Arch Neurol. 2000;57(8):1118–1125. doi: 10.1001/archneur.57.8.1118. [PubMed] [Cross Ref]
151. Levy R, Lang AE, Dostrovsky JO, Pahapill P, Romas J, Saint-Cyr J, et al. Lidocaine and muscimol microinjections in subthalamic nucleus reverse Parkinsonian symptoms. Brain J Neurol. 2001;124(Pt 10):2105–2118. doi: 10.1093/brain/124.10.2105. [PubMed] [Cross Ref]
152. Hashimoto T, Elder CM, Okun MS, Patrick SK, Vitek JL. Stimulation of the subthalamic nucleus changes the firing pattern of pallidal neurons. J Neurosci Off J Soc Neurosci. 2003;23(5):1916–1923. [PubMed]
153. Lacombe E, Carcenac C, Boulet S, Feuerstein C, Bertrand A, Poupard A, et al. High-frequency stimulation of the subthalamic nucleus prolongs the increase in striatal dopamine induced by acute l-3,4-dihydroxyphenylalanine in dopaminergic denervated rats. Eur J Neurosci. 2007;26(6):1670–1680. doi: 10.1111/j.1460-9568.2007.05747.x. [PMC free article] [PubMed] [Cross Ref]
154. Benabid AL, Krack PP, Benazzouz A, Limousin P, Koudsie A, Pollak P. Deep brain stimulation of the subthalamic nucleus for Parkinson’s disease: methodologic aspects and clinical criteria. Neurology. 2000;12(6):S40–S44. [PubMed]
155. Welter ML, Houeto J, Tezenas du Montcel S, Mesnage V, Bonnet AM, Pillon B, et al. Clinical predictive factors of subthalamic stimulation in Parkinson’s disease. Brain J Neurol. 2002;125(Pt 3):575–583. doi: 10.1093/brain/awf050. [PubMed] [Cross Ref]
156. Stoffers D, Bosboom JL, Wolters E, Stam CJ, Berendse HW. Dopaminergic modulation of cortico-cortical functional connectivity in Parkinson’s disease: an MEG study. Exp Neurol. 2008;213(1):191–195. doi: 10.1016/j.expneurol.2008.05.021. [PubMed] [Cross Ref]
157. Degos B, Deniau JM, Thierry AM, Glowinski J, Pezard L, Maurice N. Neuroleptic-induced catalepsy: electrophysiological mechanisms of functional recovery induced by high-frequency stimulation of the subthalamic nucleus. J Neurosci Off J Soc Neurosci. 2005;25(33):7687–7696. doi: 10.1523/JNEUROSCI.1056-05.2005. [PubMed] [Cross Ref]
158. Salin P, Manrique C, Forni C, Kerkerian-Le Goff L. High-frequency stimulation of the subthalamic nucleus selectively reverses dopamine denervation-induced cellular defects in the output structures of the basal ganglia in the rat. J Neurosci. 2002;22(12):5137–5148. [PubMed]
159. Poulet E, Haesebaert F, Saoud M, Suaud-Chagny MF, Brunelin J. Treatment of schizophrenic patients and rTMS. Psychiatr Danub. 2010;22(1):S143–S146. [PubMed]
160. Markov MS (2007) History of Pulsed Electro Magnetic Field Therapy. PEMF Systems Inc
161. Sklar B (2014) Announcing the iMRS from swiss bionic solutions. Relax Restore Massage
162. Sklar B (2009) MRS 2000 + the revolutionary “sawtooth” wave impulse. Relax and Restore Massage Services
163. Andras V (1999) Proof of ion transport due to application of QRS System Salut-II. Quantron Medizin GmbH zHd Dr Fischer Nußloch

Brain.  2012 Oct 5. [Epub ahead of print]

Magnetic flimmers: ‘light in the electromagnetic darkness’

Martens JW, Koehler PJ, Vijselaar J.

Source

1 Department of Humanities, Utrecht University, Utrecht, The Netherlands.

Abstract

Transcranial magnetic stimulation has become an important field for both research in neuroscience and for therapy since Barker in 1985 showed that it was possible to stimulate the human motor cortex with an electromagnet. Today for instance, transcranial magnetic stimulation can be used to measure nerve conduction velocities and to create virtual lesions in the brain. The latter option creates the possibility to inactivate parts of the brain temporarily without permanent damage. In 2008, the American Food and Drugs Administration approved repetitive transcranial magnetic stimulation as a therapy for major depression under strict conditions. Repetitive transcranial magnetic stimulation has not yet been cleared for treatment of other diseases, including schizophrenia, anxiety disorders, obesity and Parkinson’s disease, but results seem promising. Transcranial magnetic stimulation, however, was not invented at the end of the 20th century. The discovery of electromagnetism, the enthusiasm for electricity and electrotherapy, and the interest in Beard’s concept of neurasthenia already resulted in the first electromagnetic treatments in the late 19th and early 20th century. In this article, we provide a history of electromagnetic stimulation circa 1900. From the data, we conclude that Mesmer’s late 18th century ideas of ‘animal magnetism’ and the 19th century absence of physiological proof had a negative influence on the acceptance of this therapy during the first decades of the 20th century. Electromagnetism disappeared from neurological textbooks in the early 20th century to recur at the end of that century.

J Recept Signal Transduct Res. 2010 Aug;30(4):214-26.

Electromagnetic fields: mechanism, cell signaling, other bioprocesses, toxicity, radicals, antioxidants and beneficial effects.

Kovacic P, Somanathan R.

Department of Chemistry, San Diego State University, San Diego, California, USA. pkovacic@sundown.sdsu.edu

Abstract

Electromagnetic fields (EMFs) played a role in the initiation of living systems, as well as subsequent evolution. The more recent literature on electrochemistry is documented, as well as magnetism. The large numbers of reports on interaction with living systems and the consequences are presented. An important aspect is involvement with cell signaling and resultant effects in which numerous signaling pathways participate. Much research has been devoted to the influence of man-made EMFs, e.g., from cell phones and electrical lines, on human health. The degree of seriousness is unresolved at present. The relationship of EMFs to reactive oxygen species (ROS) and oxidative stress (OS) is discussed. There is evidence that indicates a relationship involving EMFs, ROS, and OS with toxic effects. Various articles deal with the beneficial aspects of antioxidants (AOs) in countering the harmful influence from ROS-OS associated with EMFs. EMFs are useful in medicine, as indicated by healing bone fractures. Beneficial effects are recorded from electrical treatment of patients with Parkinson’s disease, depression, and cancer.

Ann Neurol. 2005 Oct 20; [Epub ahead of print]

Altered plasticity of the human motor cortex in Parkinson’s disease.

Ueki Y, Mima T, Ali Kotb M, Sawada H, Saiki H, Ikeda A, Begum T, Reza F, Nagamine T, Fukuyama H.

Human Brain Research Center, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.

Interventional paired associative stimulation (IPAS) to the contralateral peripheral nerve and cerebral cortex can enhance the primary motor cortex (M1) excitability with two synchronously arriving inputs. This study investigated whether dopamine contributed to the associative long-term potentiation-like effect in the M1 in Parkinson’s disease (PD) patients. Eighteen right-handed PD patients and 11 right-handed age-matched healthy volunteers were studied. All patients were studied after 12 hours off medication with levodopa replacement (PD-off). Ten patients were also evaluated after medication (PD-on). The IPAS comprised a single electric stimulus to the right median nerve at the wrist and subsequent transcranial magnetic stimulation of the left M1 with an interstimulus interval of 25 milliseconds (240 paired stimuli every 5 seconds for 20 minutes). The motor-evoked potential amplitude in the right abductor pollicis brevis muscle was increased by IPAS in healthy volunteers, but not in PD patients. IPAS did not affect the motor-evoked potential amplitude in the left abductor pollicis brevis. The ratio of the motor-evoked potential amplitude before and after IPAS in PD-off patients increased after dopamine replacement. Thus, dopamine might modulate cortical plasticity in the human M1, which could be related to higher order motor control, including motor learning. Ann Neurol 2006.

Neuron. 2005 Jan 20;45(2):181-3.

Toward establishing a therapeutic window for rTMS by theta burst stimulation.

Paulus W.

Department of Clinical Neurophysiology, University of Goettingen, D-37075 Goettingen, Germany.

In this issue of Neuron, Huang et al. show that a version of the classic theta burst stimulation protocol used to induce LTP/LTD in brain slices can be adapted to a transcranial magnetic stimulation (TMS) protocol to rapidly produce long lasting (up to an hour), reversible effects on motor cortex physiology and behavior. These results may have important implications for the development of clinical applications of rTMS in the treatment of depression, epilepsy, Parkinson’s, and other diseases.

Rev Neurol (Paris). 2005 Jan;161(1):27-41.

Motor cortex stimulation for Parkinson’s disease and dystonia: lessons from transcranial magnetic stimulation? A review of the literature

[Article in French]

Lefaucheur JP.

Service de Physiologie, Explorations Fonctionnelles, Hôpital Henri Mondor, Créteil. jean-pascal.lefaucheur@hmn.ap-hop-paris.fr

Abstract

INTRODUCTION: Over the last few years, deep brain stimulation techniques, with targets such as the subthalamic nucleus or the pallidum, have bee found to be beneficial in the treatment of Parkinson’s disease and dystonia. Conversely, therapeutic strategies of cortical stimulation have not yet been validated in these diseases, although they are known to be associated with various cortical dysfunctions. Transcranial magnetic stimulation (TMS) is a valuable tool for non-invasive study of the role played by the motor cortex in the pathophysiology of movement disorders, in particular by assessing various cortical excitability determinants using single or paired pulse paradigms. In addition, repetitive TMS (rTMS) trains can be used to study the effects of transient activity changes of a targeted cortical area.

BACKGROUND: Studies with TMS revealed significant motor cortex excitability changes, particularly regarding intracortical inhibitory pathways, both in Parkinson’s disease and in dystonia, and these changes can be distinguished owing to the resting state or to the phases of movement preparation or execution. However, more specific correlation between electrophysiological features and clinical symptoms remains to be established. In addition, the stimulation of various cortical targets by rTMS protocols applied at low or high frequencies have induced some clear clinical effects.

PERSPECTIVES: The TMS effects are and will remain applied in movement disorders to better understand the role played by the motor cortex, to assess various types of treatment and appraise the therapeutic potential of cortical stimulation.

CONCLUSION: TMS provides evidence for motor cortex dysfunction in Parkinson’s disease or dystonia. Moreover, rTMS results have opened new perspectives for therapeutic strategies of implanted cortical stimulation. By these both aspects, TMS techniques show their usefulness in the assessment of movement disorders.

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.

Int J Neurosci. 1999 Aug;99(1-4):139-49.

AC pulsed electromagnetic fields-induced sexual arousal and penile erections in Parkinson’s disease.

Sandyk R.

Department of Neuroscience at the Institute for Biomedical Engineering and Rehabilitation Services, Touro College, Bay Shore, NY 11706, USA.

Sexual dysfunction is common in patients with Parkinson’s disease (PD) since brain dopaminergic mechanisms are involved in the regulation of sexual behavior. Activation of dopamine D2 receptor sites, with resultant release of oxytocin from the paraventricular nucleus (PVN) of the hypothalamus, induces sexual arousal and erectile responses in experimental animals and humans. In Parkinsonian patients subcutaneous administration of apomorphine, a dopamine D2 receptor agonist, induces sexual arousal and penile erections. It has been suggested that the therapeutic efficacy of transcranial administration of AC pulsed electromagnetic fields (EMFs) in the picotesla flux density in PD involves the activation of dopamine D2 receptor sites which are the principal site of action of dopaminergic pharmacotherapy in PD. Here, 1 report 2 elderly male PD patients who experienced sexual dysfunction which was recalcitrant to treatment with anti Parkinsonian agents including selegiline, levodopa and tolcapone. However, brief transcranial administrations of AC pulsed EMFs in the picotesla flux density induced in these patients sexual arousal and spontaneous nocturnal erections. These findings support the notion that central activation of dopamine D2 receptor sites is associated with the therapeutic efficacy of AC pulsed EMFs in PD. In addition, since the right hemisphere is dominant for sexual activity, partly because of a dopaminergic bias of this hemisphere, these findings suggest that right hemispheric activation in response to administration of AC pulsed EMFs was associated in these patient with improved sexual functions

Int J Neurosci. 1999 Apr;97(3-4):225-33.

Treatment with AC pulsed electromagnetic fields improves olfactory function in Parkinson’s disease.

Sandyk R.

Department of Neuroscience at the Institute for Biomedical Engineering and Rehabilitation Services of Touro College, Dix Hills, NY 11746, USA.

Abstract

Olfactory dysfunction is a common symptom of Parkinson’s disease (PD). It may manifest in the early stages of the disease and infrequently may even antedate the onset of motor symptoms. The cause of olfactory dysfunction in PD remains unknown. Pathological changes characteristic of PD (i.e., Lewy bodies) have been demonstrated in the olfactory bulb which contains a large population of dopaminergic neurons involved in olfactory information processing. Since dopaminergic drugs do not affect olfactory threshold in PD patients, it has been suggested that olfactory dysfunction in these patients is not dependent on dopamine deficiency. I present two fully medicated Parkinsonian patients with long standing history of olfactory dysfunction in whom recovery of smell occurred during therapeutic transcranial application of AC pulsed electromagnetic fields (EMFs) in the picotesla flux density. In both patients improvement of smell during administration of EMFs occurred in conjunction with recurrent episodes of yawning. The temporal association between recovery of smell and yawning behavior is remarkable since yawning is mediated by activation of a subpopulation of striatal and limbic postsynaptic dopamine D2 receptors induced by increased synaptic dopamine release. A high density of dopamine D2 receptors is present in the olfactory bulb and tract. Degeneration of olfactory dopaminergic neurons may lead to upregulation (i.e., supersensitivity) of postsynaptic dopamine D2 receptors. Presumably, small amounts of dopamine released into the synapses of the olfactory bulb during magnetic stimulation may cause activation of these supersensitive receptors resulting in enhanced sense of smell. Interestingly, in both patients enhancement of smell perception occurred only during administration of EMFs of 7 Hz frequency implying that the release of dopamine and activation of dopamine D2 receptors in the olfactory bulb was partly frequency dependent. In fact, weak magnetic fields have been found to cause interaction with biological systems only within narrow frequency ranges (i.e., frequency windows) and the existence of such frequency ranges has been explained on the basis of the cyclotron resonance model.

Int J Neurosci. 1998 Sep;95(3-4):255-69.

Reversal of the bicycle drawing direction in Parkinson’s disease by AC pulsed electromagnetic fields.

Sandyk R.

Department of Neuroscience, Touro College, Dix Hills, NY 11746, USA.

Abstract

The Draw-a-Bicycle Test is employed in neuropsychological testing of cognitive skills since the bicycle design is widely known and also because of its complex structure. The Draw-a-Bicycle Test has been administered routinely to patients with Parkinson’s disease (PD) and other neurodegenerative disorders to evaluate the effect of transcranial applications of AC pulsed electromagnetic fields (EMFs) in the picotesla flux density on visuoconstructional skills. A seminal observation is reported in 5 medicated PD patients who demonstrated reversal of spontaneous drawing direction of the bicycle after they received a series of transcranial treatments with AC pulsed EMFs. In 3 patients reversal of the bicycle drawing direction was observed shortly after the administration of pulsed EMFs while in 2 patients these changes were observed within a time lag ranging from several weeks to months. All patients also demonstrated a dramatic clinical response to the administration of EMFs. These findings are intriguing because changes in drawing direction do not occur spontaneously in normal individuals as a result of relateralization of cognitive functions. This report suggests that administration of AC pulsed EMFs may induce in some PD patients changes in hemispheric dominance during processing of a visuoconstructional task and that these changes may be predictive of a particularly favourable response to AC pulsed EMFs therapy.

Int J Neurosci. 1998 May;94(1-2):41-54.

Transcranial AC pulsed applications of weak electromagnetic fields reduces freezing and falling in progressive supranuclear palsy: a case report.

Sandyk R.

Department of Neuroscience, Institute for Biomedical Engineering and Rehabilitation Services, Touro College, Dix Hills, NY 11746, USA.

Abstract

Freezing is a common and disabling symptom in patients with Parkinsonism. It affects most commonly the gait in the form of start hesitation and sudden immobility often resulting in falling. A higher incidence of freezing occurs in patients with progressive supranuclear palsy (PSP) which is characterized clinically by a constellation of symptoms including supranuclear ophthalmoplegia, postural instability, axial rigidity, dysarthria, Parkinsonism, and pseudobulbar palsy. Pharmacologic therapy of PSP is currently disappointing and the disease progresses relentlessly to a fatal outcome within the first decade after onset. This report concerns a 67 year old woman with a diagnosis of PSP in whom freezing and frequent falling were the most disabling symptoms of the disease at the time of presentation. Both symptoms, which were rated 4 on the Unified Parkinson Rating Scale (UPRS) which grades Parkinsonian symptoms and signs from 0 to 4, with 0 being normal and 4 being severe symptoms, were resistant to treatment with dopaminergic drugs such as levodopa, amantadine, selegiline and pergolide mesylate as well as with the potent and highly selective noradrenergic reuptake inhibitor nortriptyline. Weekly transcranial applications of AC pulsed electromagnetic fields (EMFs) of picotesla flux density was associated with approximately 50% reduction in the frequency of freezing and about 80-90% reduction in frequency of falling after a 6 months follow-up period. At this point freezing was rated 2 while falling received a score of 1 on the UPRS. In addition, this treatment was associated with an improvement in Parkinsonian and pseudobulbar symptoms with the difference between the pre-and post EMF treatment across 13 measures being highly significant (p < .005; Sign test). These results suggest that transcranial administration AC pulsed EMFs in the picotesla flux density is efficacious in the treatment of PSP.

Int J Neurosci. 1999 Mar;97(1-2):139-45.

Yawning and stretching induced by transcranial application of AC pulsed electromagnetic fields in Parkinson’s disease.

Sandyk R.

Department of Neuroscience at the Institute for Biomedical Engineering and Rehabilitation Services of Touro College, Dix Hills, NY 11746, USA.

Abstract

Yawning is considered a brainstem regulated behavior which is associated with changes in arousal and activity levels. Yawning and stretching are dopamine (DA) mediated behaviors and pharmacological studies indicate that these behaviors are associated with increased DA release coupled with stimulation of postsynaptic DA-D2 receptors. Despite their relation to the dopaminergic system, yawning and stretching are poorly documented in untreated or treated patients with Parkinson’s disease (PD). A 49 year old fully medicated female patient with juvenile onset PD is presented in whom recurrent episodes of yawning and stretching developed during transcranial administration of AC pulsed electromagnetic fields (EM Fs) of picotesla flux density. These episodes have not been observed previously in this or other patients during treatment with levodopa or DA receptor agonists or in unmedicated PD patients during treatment with AC pulsed EMFs. It is suggested that yawning and stretching behavior resulted in this patient from a synergistic interaction between EMFs and DA derived from levodopa supplementation with EMFs possibly facilitating the release of DA and simultaneously activating postsynaptic DA-D2 receptors in the nigrostriatal dopaminergic pathways. In addition, it is postulated that the release of ACTH/MSH peptides from peptidergic neurons in the brain upon stimulation of the DA-D2 receptors reinforced the yawning and stretching behavior.

Int J Neurosci. 1998 Sep;95(3-4):255-69.

Reversal of the bicycle drawing direction in Parkinson’s disease by AC pulsed electromagnetic fields.

Sandyk R.

Department of Neuroscience, Touro College, Dix Hills, NY 11746, USA.

The Draw-a-Bicycle Test is employed in neuropsychological testing of cognitive skills since the bicycle design is widely known and also because of its complex structure. The Draw-a-Bicycle Test has been administered routinely to patients with Parkinson’s disease (PD) and other neurodegenerative disorders to evaluate the effect of transcranial applications of AC pulsed electromagnetic fields (EMFs) in the picotesla flux density on visuoconstructional skills. A seminal observation is reported in 5 medicated PD patients who demonstrated reversal of spontaneous drawing direction of the bicycle after they received a series of transcranial treatments with AC pulsed EMFs. In 3 patients reversal of the bicycle drawing direction was observed shortly after the administration of pulsed EMFs while in 2 patients these changes were observed within a time lag ranging from several weeks to months. All patients also demonstrated a dramatic clinical response to the administration of EMFs. These findings are intriguing because changes in drawing direction do not occur spontaneously in normal individuals as a result of relateralization of cognitive functions. This report suggests that administration of AC pulsed EMFs may induce in some PD patients changes in hemispheric dominance during processing of a visuoconstructional task and that these changes may be predictive of a particularly favourable response to AC pulsed EMFs therapy.

Int J Neurosci. 1998 May;94(1-2):41-54.

Transcranial AC pulsed applications of weak electromagnetic fields reducing freezing and falling in progressive supranuclear palsy: a case report.

Sandyk R.

Department of Neuroscience, Institute for Biomedical Engineering and Rehabilitation Services, Touro College, Dix Hills, NY 11746, USA.

Freezing is a common and disabling symptom in patients with Parkinsonism. It affects most commonly the gait in the form of start hesitation and sudden immobility often resulting in falling. A higher incidence of freezing occurs in patients with progressive supranuclear palsy (PSP) which is characterized clinically by a constellation of symptoms including supranuclear ophthalmoplegia, postural instability, axial rigidity, dysarthria, Parkinsonism, and pseudobulbar palsy. Pharmacologic therapy of PSP is currently disappointing and the disease progresses relentlessly to a fatal outcome within the first decade after onset. This report concerns a 67 year old woman with a diagnosis of PSP in whom freezing and frequent falling were the most disabling symptoms of the disease at the time of presentation. Both symptoms, which were rated 4 on the Unified Parkinson Rating Scale (UPRS) which grades Parkinsonian symptoms and signs from 0 to 4, with 0 being normal and 4 being severe symptoms, were resistant to treatment with dopaminergic drugs such as levodopa, amantadine, selegiline and pergolide mesylate as well as with the potent and highly selective noradrenergic reuptake inhibitor nortriptyline. Weekly transcranial applications of AC pulsed electromagnetic fields (EMFs) of picotesla flux density was associated with approximately 50% reduction in the frequency of freezing and about 80-90% reduction in frequency of falling after a 6 months follow-up period. At this point freezing was rated 2 while falling received a score of 1 on the UPRS. In addition, this treatment was associated with an improvement in Parkinsonian and pseudobulbar symptoms with the difference between the pre-and post EMF treatment across 13 measures being highly significant (p < .005; Sign test). These results suggest that transcranial administration AC pulsed EMFs in the picotesla flux density is efficacious in the treatment of PSP.

J Neurosci. 1998 Feb;93(1-2):43-54.

Reversal of a body image disorder (macrosomatognosia) in Parkinson’s disease by treatment with AC pulsed electromagnetic fields.

Sandyk R.

Department of Neuroscience, Institute for Biomedical Engineering and Rehabilitation Services of Touro College, Dix Hills, NY 11746, USA.

Macrosomatognosia refers to a disorder of the body image in which the patient perceives a part or parts of his body as disproportionately large. Macrosomatognosia has been associated with lesions in the parietal lobe, particularly the right parietal lobe, which integrates perceptual-sensorimotor functions concerned with the body image. It has been observed most commonly in patients with paroxysmal cerebral disorders such as epilepsy and migraine. The Draw-a-Person-Test has been employed in neuropsychological testing to identify disorders of the body image. Three fully medicated elderly Parkinsonian patients who exhibited, on the Draw-a-Person Test, macrosomatognosia involving the upper limbs are presented. In these patients spontaneous drawing of the figure of a man demonstrated disproportionately large arms. Furthermore, it was observed that the arm affected by tremor or, in the case of bilateral tremor, the arm showing the most severe tremor showed the greatest abnormality. This association implies that dopaminergic mechanisms influence neuronal systems in the nondominant right parietal lobe which construct the body image. After receiving a course of treatments with AC pulsed electromagnetic fields (EMFs) in the picotesla flux density applied transcranially, these patients’ drawings showed reversal of the macrosomatognosia. These findings demonstrate that transcranial applications of AC pulsed EMFs affect the neuronal systems involved in the construction of the human body image and additionally reverse disorders of the body image in Parkinsonism which are related to right parietal lobe dysfunction.

Int J Neurosci. 1997 Nov;92(1-2):63-72.

Speech impairment in Parkinson’s disease is improved by transcranial application of electromagnetic fields.

Sandyk R.

Department of Neuroscience, Touro College, Dix Hills, NY 11746, USA.

A 52 year old fully medicated physician with juvenile onset Parkinsonism experienced 4 years ago severe “on-off” fluctuations in motor disability and debilitating speech impairment with severe stuttering which occurred predominantly during “on-off” periods. His speech impairment improved 20%-30% when sertraline (75 mg/day), a serotonin reuptake inhibitor, was added to his dopaminergic medications which included levodopa, amantadine, selegiline and pergolide mesylate. A more dramatic and consistent improvement in his speech occurred over the past 4 years during which time the patient received, on a fairly regular basis, weekly transcranial treatments with AC pulsed electromagnetic fields (EMFs) of picotesla flux density. Recurrence of speech impairment was observed on several occasions when regular treatments with EMFs were temporarily discontinued. These findings demonstrate that AC pulsed applications of picotesla flux density EMFs may offer a nonpharmacologic approach to the management of speech disturbances in Parkinsonism. Furthermore, this case implicates cerebral serotonergic deficiency in the pathogenesis of Parkinsonian speech impairment which affects more than 50% of patients. It is believed that pulsed applications of EMFs improved this patient’s speech impairment through the facilitation of serotonergic transmission which may have occurred in part through a synergistic interaction with sertraline.

Int J Neurosci. 1997 Oct;91(3-4):189-97.

Treatment with AC pulsed electromagnetic fields improves the response levodopa in Parkinson’s disease.

Sandyk R.

Department of Neuroscience, Touro College, Dix Hills, NY 11746, USA.

A 52 year old fully medicated Parkinsonian patient with severe disability (stage 4 on the Hoehn & Yahr disability scale) became asymptomatic 10 weeks after he received twice weekly transcranial treatments with AC pulsed electromagnetic fields (EMFs) of picotesla flux density. Prior to treatment with EMFs, his medication (Sinemet CR) was about 50% effective and he experienced end-of-dose deterioration and diurnal-related decline in the drug’s efficacy. For instance, while his morning medication was 90% effective, his afternoon medication was only 50% effective and his evening dose was only 30% effective. Ten weeks after introduction of treatment with EMFs, there was 40% improvement in his response to standard Sinemet medication with minimal change in its efficacy during the course of the day or evening. These findings demonstrate that intermittent, AC pulsed applications of picotesla flux density EMFs improve Parkinsonian symptoms in part by enhancing the patient’s response to levodopa. This effect may be related to an increase in the capacity of striatal DA neurons to synthesize, store and release DA derived from exogenously supplied levodopa as well as to increased serotonin (5-HT) transmission which has been shown to enhance the response of PD patients to levodopa. Since decline in the response to levodopa is a phenomenon associated with progression of the disease, this case suggests that intermittent applications of AC pulsed EMFs of picotesla flux density reverse the course of chronic progressive PD.

Int J Neurosci. 1997 Sep;91(1-2):57-68.

Reversal of cognitive impairment in an elderly parkinsonian patient by transcranial application of picotesla electromagnetic fields.

Sandyk R.

Department of Neuroscience, Touro College, Dix Hills, NY 11746, USA.

A 74 year old retired building inspector with a 15 year history of Parkinson’s disease (PD) presented with severe resting tremor in the right hand, generalized bradykinesia, difficulties with the initiation of gait with freezing, mental depression and generalized cognitive impairment despite being fully medicated. Testing of constructional abilities employing various drawing tasks demonstrated drawing impairment compatible with severe left hemispheric dysfunction. After receiving two successive transcranial applications, each of 20 minutes duration, with AC pulsed electromagnetic fields (EMFs) of 7.5 picotesla flux density and frequencies of 5Hz and 7Hz respectively, his tremor remitted and there was dramatic improvement in his drawing performance. Additional striking improvements in his drawing performance occurred over the following two days after he continued to receive daily treatments with EMFs. The patient’s drawings were subjected to a Reliability Test in which 10 raters reported 100% correct assessment of pre- and post drawings with all possible comparisons (mean 2 = 5.0; p < .05). This case demonstrates in PD rapid reversal of drawing impairment related to left hemispheric dysfunction by brief transcranial applications of AC pulsed picotesla flux density EMFs and suggests that cognitive deficits associated with Parkinsonism, which usually are progressive and unaffected by dopamine replacement therapy, may be partly reversed by administration of these EMFs. Treatment with picotesla EMFs reflects a “cutting edge” approach to the management of cognitive impairment in Parkinsonism.

Int J Neurosci. 1997 Jun;90(1-2):75-86.

Treatment with weak electromagnetic fields restores dream recall in a parkinsonian patient.

Sandyk R.

Department of Neuroscience, Institute for Biomedical Engineering and Rehabilitation Services, Touro College, Dix Hills, NY 11746, USA.

Absent or markedly reduced REM sleep with cessation of dream recall has been documented in numerous neurological disorders associated with subcortical dementia including Parkinson’s disease, progressive supranuclear palsy and Huntington’s chorea. This report concerns a 69 year old Parkinsonian patient who experienced complete cessation of dreaming since the onset of motor disability 13 years ago. Long term treatment with levodopa and dopamine (DA) receptor agonists (bromocriptine and pergolide mesylate) did not affect dream recall. However, dreaming was restored after the patient received three treatment sessions with AC pulsed picotesla range electromagnetic fields (EMFs) applied extracranially over three successive days. Six months later, during which time the patient received 3 additional treatment sessions with EMFs, he reported dreaming vividly with intense colored visual imagery almost every night with some of the dreams having sexual content. In addition, he began to experience hypnagogic imagery prior to the onset of sleep. Cessation of dream recall has been associated with right hemispheric dysfunction and its restoration by treatment with EMFs points to right hemispheric activation, which is supported by improvement in this patient’s visual memory known to be subserved by the right temporal lobe. Moreover, since DA neurons activate REM sleep mechanisms and facilitate dream recall, it appears that application of EMFs enhanced DA activity in the mesolimbic system which has been implicated in dream recall. Also, since administration of pineal melatonin has been reported to induce vivid dreams with intense colored visual imagery in normal subjects and narcoleptic patients, it is suggested that enhanced nocturnal melatonin secretion was associated with restoration of dream recall in this patient. These findings demonstrate that unlike chronic levodopa therapy, intermittent pulsed applications of AC picotesla EMFs may induce in Parkinsonism reactivation of reticular-limbic-pineal systems involved in the generation of dreaming.

Int J Neurosci. 1996 Nov;87(3-4):209-17.

Brief communication: electromagnetic fields improve visuospatial performance and reverse agraphia in a parkinsonian patient.

Sandyk R.

Department of Neuroscience, Touro College, Dix Hills, NY 11746, USA.

A 73 year old right-handed man, diagnosed with Parkinson’s disease (PD) in 1982, presented with chief complaints of disabling resting and postural tremors in the right hand, generalized bradykinesia and rigidity, difficulties with the initiation of gait, freezing of gait, and mild dementia despite being fully medicated. On neuropsychological testing the Bicycle Drawing Test showed cognitive impairment compatible with bitemporal and frontal lobe dysfunction and on attempts to sign his name he exhibited agraphia. After receiving two successive treatments, each of 20 minutes duration, with AC pulsed electromagnetic fields (EMFs) of 7.5 picotesla intensity and 5 Hz frequency sinusoidal wave, his drawing to command showed improvement in visuospatial performance and his signature became legible. One week later, after receiving two additional successive treatments with these EMFs each of 20 minutes duration with a 7 Hz frequency sinusoidal wave, he drew a much larger, detailed and visuospatially organized bicycle and his signature had normalized. Simultaneously, there was marked improvement in Parkinsonian motor symptoms with almost complete resolution of the tremors, start hesitation and freezing of gait. This case demonstrates the dramatic beneficial effects of AC pulsed picotesla EMFs on neurocognitive processes subserved by the temporal and frontal lobes in Parkinsonism and suggest that the dementia of Parkinsonism may be partly reversible.

Int J Neurosci. 1996 Mar;85(1-2):111-24.

Freezing of gait in Parkinson’s disease is improved by treatment with weak electromagnetic fields.

Sandyk R.

NeuroCommunication Research Laboratories, Danbury, CT 06811, USA.

Freezing, a symptom characterized by difficulty in the initiation and smooth pursuit of repetitive movements, is a unique and well known clinical feature of Parkinson’s disease (PD). It usually occurs in patients with long duration and advanced stage of the disease and is a major cause of disability often resulting in falling. In PD patients freezing manifests most commonly as a sudden attack of immobility usually experienced during walking, attempts to turn while walking, or while approaching a destination. Less commonly it is expressed as arrest of speech or handwriting. The pathophysiology of Parkinsonian freezing, which is considered a distinct clinical feature independent of akinesia, is poorly understood and is believed to involve abnormalities in dopamine and norepinephrine neurotransmission in critical motor control areas including the frontal lobe, basal ganglia, locus coeruleus and spinal cord. In general, freezing is resistant to pharmacological therapy although in some patients reduction or increase in levodopa dose may improve this symptom. Three medicated PD patients exhibiting disabling episodes of freezing of gait are presented in whom brief, extracerebral applications of pulsed electromagnetic fields (EMFs) in the picotesla range improved freezing. Two patients had freezing both during “on” and “off” periods while the third patient experienced random episodes of freezing throughout the course of the day. The effect of each EMFs treatment lasted several days after which time freezing gradually reappeared, initially in association with “off” periods. These findings suggest that the neurochemical mechanisms underlying the development of freezing are sensitive to the effects of EMFs, which are believed to improve freezing primarily through the facilitation of serotonin (5-HT) neurotransmission at both junctional (synaptic) and nonjunctional neuronal target sites.

Int J Neurosci. 1995 Mar;81(1-2):47-65.

Weak electromagnetic fields reverse visuospatial hemi-inattention in Parkinson’s disease.

Sandyk R.

NeuroCommunication Research Laboratories, Danbury, CT 06811, USA.

Abstract

Drawing tasks, both free and copied, have achieved a central position in neuropsychological testing of patients with unilateral cerebral dysfunction by virtue of their sensitivity to different kinds of organic brain disorders and their ability to provide information on lateralized brain damage. In the drawings of patients with right hemispheric damage, visuospatial neglect is revealed by the omission of details on the side of the drawing contralateral to the hemispheric lesion. Patients with unilateral cerebral damage, particularly those with left hemispheric damage, also demonstrate a tendency to place their drawings on the side of the page ipsilateral to the cerebral lesion, a phenomenon which has been termed visuospatial hemi-inattention. It has been reported previously that brief external application of alternating pulsed electromagnetic fields (EMFs) in the picotesla (pT) range intensity improved visuoperceptive and visuospatial functions and reversed neglect in Parkinsonian patients. The present communication concerns four fully medicated elderly nondemented Parkinsonian patients (mean age: 74.7 +/- 4.6 yrs; mean duration of illness: 7.7 +/- 5.2 yrs) in whom application of these EMFs produced reversal of visuospatial hemi-inattention related to left hemispheric dysfunction. These findings support prior observations demonstrating that pT EMFs may bring about reversal of certain cognitive deficits in Parkinsonian patients.

Rev Environ Health. 1994 Apr-Jun;10(2):127-34.

Pulsed magnetotherapy in Czechoslovakia–a review.

Jerabek J.

National Institute of Public Health, Praha, Czech Republic.

Abstract

Pulsed magnetotherapy has been used in Czechoslovakia for more than one decade. It has been proved that this type of physical therapy is very efficient mainly in rheumatic diseases, in paediatrics (sinusitis, enuresis), and in balneological care of patients suffering from ischaemic disorders of lower extremities. Promising results have also been obtained in neurological diseases (multiple sclerosis, spastic conditions) and in ophthalmology, in degenerative diseases of the retina.

Int J Neurosci, 66(3-4):209-35 1992 Oct

Magnetic fields in the therapy of parkinsonism.

Sandyk R NeuroCommunication Research Laboratories, Danbury, CT 06811.

In a recent Editorial published in this Journal, I presented a new and revolutionary method for the treatment of Parkinson’s disease (PD). I reported that extracranial treatment with picoTesla magnetic fields (MF) is a highly effective, safe, and revolutionary modality in the symptomatic management of PD. My conclusion was based on experience gained following the successful treatment of over 20 Parkinsonian patients, two of whom had levodopa-induced dyskinesias. None of the patients developed side effects during a several month period of follow-up. In the present communication, I present two reports. The first concerns four Parkinsonian patients in whom picoTesla MF produced a remarkable and sustained improvement in disability. Three of the patients had idiopathic PD and the fourth patient developed a Parkinsonian syndrome following an anoxic episode. In all patients, treatment with MF was applied as an adjunct to antiParkinsonian medication. The improvement noted in these patients attests to the efficacy of picoTesla MF as an additional, noninvasive modality in the therapy of the disease. The second report concerns two demented Parkinsonian patients in whom treatment with picoTesla MF rapidly reversed visuospatial impairment as demonstrated by the Clock Drawing Test. These findings demonstrate, for the first time, the efficacy of these MF in the amelioration of cognitive deficits in Parkinson’s disease. Since Alzheimer’s pathology frequently coexists with the dementia of Parkinsonism, these observations underscore the potential efficacy of picoTesla MF in the treatment of dementias of various etiologies.