Phantom pain reduction by low-frequency and low-intensity electromagnetic fields.
Bókkon I, Till A, Grass F, Erdöfi Szabó A.
Source
Doctoral School of Pharmaceutical and Pharmacological Sciences, Semmelweis University , Budapest , Hungary.
Abstract
Although various treatments have been presented for phantom pain,
there is little proof supporting the benefits of pharmacological
treatments, surgery or interventional techniques, electroconvulsive
therapy, electrical nerve stimulation, far infrared ray therapy,
psychological therapies, etc. Here, we report the preliminary results
for phantom pain reduction by low-frequency and intensity
electromagnetic fields under clinical circumstances. Our method is
called as Electromagnetic-Own-Signal-Treatment (EMOST). Fifteen people
with phantom limb pain participated. The patients were treated using a
pre-programmed, six sessions. Pain intensity was quantified upon
admission using a 0-10 verbal numerical rating scale. Most of the
patients (n = 10) reported a marked reduction in the intensity of
phantom limb pain. Several patients also reported about improvement in
their sleep and mood quality, or a reduction in the frequency of phantom
pain after the treatments. No improvements in the reduction of phantom
limb pain or sleep and mood improvement were reported in the control
group (n = 5). Our nonlinear electromagnetic EMOST method may be a
possible therapeutic application in the reduction of phantom limb pain.
Here, we also suggest that some of the possible effects of the EMOST may
be achieved via the redox balance of the body and redox-related neural
plasticity.
Case Report Med. 2011;2011:130751. Epub 2011 May 11.
Phantom limb pain: low frequency repetitive transcranial magnetic stimulation in unaffected hemisphere.
Di Rollo A, Pallanti S.
Source
Department of Psychiatry, University of Florence, 50134 Florence, Italy.
Abstract
Phantom limb pain is very common after limb amputation and is often
difficult to treat. The motor cortex stimulation is a valid treatment
for deafferentation pain that does not respond to conventional pain
treatment, with relief for 50% to 70% of patients. This treatment is
invasive as it uses implanted epidural electrodes. Cortical stimulation
can be performed noninvasively by repetitive transcranial magnetic
stimulation (rTMS). The stimulation of the hemisphere that isn’t
involved in phantom limb (unaffected hemisphere), remains unexplored. We
report a case of phantom limb pain treated with 1 Hz rTMS stimulation
over motor cortex in unaffected hemisphere. This stimulation produces a
relevant clinical improvement of phantom limb pain; however, further
studies are necessary to determine the efficacy of the method and the
stimulation parameters.
Clin Neurophysiol. 2003 Aug;114(8):1521-30.
Repetitive transcranial magnetic stimulation of the parietal cortex transiently ameliorates phantom limb pain-like syndrome.
Töpper R, Foltys H, Meister IG, Sparing R, Boroojerdi B.
Source
Department of Neurology, Universitätsklinikum Aachen, Pauwelsstrasse 30, RWTH D-52057 Aachen, Germany.
Abstract
OBJECTIVE:
Phantom pain is linked to a reorganization of the partially
deafferented sensory cortex. In this study we have investigated whether
the pain syndrome can be influenced by repetitive transcranial magnetic
stimulation (rTMS).
METHODS:
Two patients with a longstanding unilateral avulsion of the lower
cervical roots and chronic pain in the arm were studied. As a control
the acute effects of rTMS (15 Hz, 2 s duration) on pain were studied in 4
healthy subjects. Pain intensity was assessed with the Visual Analogue
Scale.
RESULTS:
Stimulation of the contralateral parietal cortex led to a
reproducible reduction in pain intensity lasting up to 10 min.
Stimulation of other cortical areas produced only minor alterations in
the severity of the pain. Both 1 and 10 Hz rTMS trains applied to the
contralateral parietal cortex on weekdays for 3 consecutive weeks did,
however, not lead to permanent changes in the pain intensity.
Experimentally induced pain (cold water immersion of the right hand) in
normal subjects was not influenced by rTMS.
CONCLUSIONS:
These results do not favor the use of rTMS in the treatment of
phantom limb pain. The results, however, support the concept that
phantom pain is due to a dysfunctional activity in the parietal cortex.
The transient rTMS-induced analgesic effect may be due to a temporary
interference with the cerebral representation of the deafferented limb.
A total of 103 patients with exacerbation of chronic generalized
periodontitis of moderate and high severity were treated using running
alternating magnetic field generated by ATOS device and transcutaneous
laser biostimulation of the blood. These treatment modalities
accelerated preoperative treatment and allowed performing the operations
on the periodontal tissues in the optimal status under conditions of
improved defense forces of the organism.
Stomatologiia (Mosk). 2003;82(4):20-4.
Magnetic laser therapy in the treatment of apical periodontitis.
A new method for the treatment of apical periodontitis, making use of
Optodan laser, differs from the known method by more rapid periapical
tissue regeneration, which is paralleled by high antiinflammatory effect
of magnetic laser therapy at early stages of treatment.
Application of magnet laser radiation to stimulate healing of perineum injuries in the maternity patients.
[Article in Russian]
Rzakulieva LM,
Israfilbeili SG,
Gasymova G.
The study is aimed at developing the new complex effective method of
treatment with an application of magnet laser radiation as a stimulating
aid in healing of perineum injuries in the maternity patients. 86
maternity patients with perineotomy and/or episiotomy were studied in
treatment. The injury on the perineum was conventionally treated by
antiseptics in 40 maternity patients (control group); the magnet laser
therapy (MLT) by means of device “MILTA” was applied to 46 maternity
patients in concomitantly with the conventional methods. The therapeutic
effect was based on the combined influence of the constant magnetic
field and impulsive laser radiation of the red and infra-red range on
the body. The patients reported less discomfort during MLT, which
promotes the decrease of pain intensity and hyperaemia instantly after
2-3 procedures. We have not observed any sutures divergence in the
maternity patients who received MLT, in comparison to the control group
where full divergence of sutures was registered in 2.5%, and partial–in
7.5%. The proposed complex method of treatment with the application of
MLT improves the process of the healing considerably, promotes the rapid
disappearance of inflammatory signs and renders analgesic effect.
The combined use of electromagnetic decimeter waves and deresinated
naphthalan in patients with vertebrogenic humeroscapular periarthrosis
(its experimental and clinical validation).
[Article in Russian]
Musaev AV, Guse?nova SG, Mamedov AP.
Abstract
Physicochemical and experimental studies on pond snail neuron were
made to validate combined or simultaneous usage of decimeter microwaves
and deresinified naphthalane. Clinical and neurophysiological trials in
133 patients with vertebrogenic scapulohumeral periarthritis revealed
that the above treatment is clinically beneficial and corrects
functional activity of segmental-peripheral neuromotor system.
The cerebral hemodynamics in patients with humeroscapular
periarthritis under the influence of decimeter waves and deresinated
naphthalan.
[Article in Russian]
Musaev AV, Guse?nova SG.
Abstract
110 patients with scapulohumeral periarthritis of vertebrogenic
origin were exposed to decimetric waves or received salt-free
naphthalan. There were also patients who got combined treatment with
decimetric waves and salt-free naphthalan. REG recorded positive shifts
in cerebral hemodynamics due to these factors utilization.
Zh Nevropatol Psikhiatr Im S S Korsakova. 1993;93(6):50-2.
A psychoautonomic syndrome in duodenal peptic ulcer patients and its
correction by magnetic puncture using an alternating magnetic field.
[Article in Russian]
Kravtsova TIu, Rybolovtsev EV, Shutov AA.
86 duodenal ulcer patients were diagnosed to have serious
psychovegetative disorders. Among other treatment, the patients were
exposed to AMF puncture of biologically active points. The puncture
produced optimization of the function of cerebral (suprasegmental)
vegetative structures, promoted a regress of vegetative dystonia
clinical symptoms and speeded up ulcer healing.
The use of magnetic puncture in patients with duodenal peptic ulcer.
[Article in Russian]
Kravtsova TIu, Rybolovlev EV, Kochurov AP.
Sixty-six patients with duodenal ulcer were found to have apparent
shifts in psychovegetative correlations. The patients underwent puncture
with alternating magnetic field of active biological points responsible
for general adaptation (E 36, G 14, VB 20) and gastroduodenal function
(E 20, T 9, T 8). The treatment improved emotional, personality and
vegetative regulation. The symptoms declined and ulcer healed more
rapidly.
Radiodensitometric
Assessment of the Effect of Pulsed Electromagnetic Field Stimulation
Versus Low Intensity Laser Irradiation on Mandibular Fracture Repair: A
Preliminary Clinical Trial.
1Department of Oral and Maxillofacial Surgery, Faculty of Oral and Dental Medicine, Cairo University, Cairo, Egypt.
Abstract
PURPOSE:
Closed reduction of mandibular fractures usually entails a relatively
long period of immobilization, with the subsequent delay of
rehabilitation. Therefore, shorter immobilization period with various
approaches to protect or enhance bone healing have been investigated.
The aim of this study was to analyze the effects of pulsed
electromagnetic field (PEMF) and low intensity laser irradiation (LILI)
on the fracture healing process, through radiodensitometric assessment
of the bone callus.
PATIENTS AND METHODS:
Eighteen patients with mandibular fractures at the tooth bearing area
participated in this prospective study. They were treated by closed
reduction using maxillo-mandibular fixation (MMF) and were consecutively
assigned into 1 of 3 groups. In group A, the fracture sites were
exposed to PEMF for 2 h daily for 12 days. In group B, the fracture
sites were exposed to LILI on the tenth and twelfth postoperative days
(2 sessions of 6 min per day 2 h apart). The fracture sites in group C
acted as controls. MMF was maintained for 2 weeks in group A and 4 weeks
in groups B and C. The bone fracture healing was evaluated clinically
by investigating the union of the fractured segments and
radiographically using computerized densitometry. The union of the
fractured segments was tested by manual manipulation and the occlusion
was assessed upon removal of MMF. Standardized digital panoramic
radiographs were performed for each patient, immediately postoperatively
as well as at 2 and 4 weeks. The digital images were manipulated using
the IDRISI software. A rectangular area of 10 × 15 mm was drawn along
the center of the fracture line. The obtained densitometry values were
expressed in gray levels from 0 to 256. The collected data were then
tabulated and statistically analyzed.
RESULTS:
After releasing the MMF, the bimanual mobility test of the fractured
segments in all patients showed stability of the segments. The preinjury
occlusion was maintained in all patients. The postoperative radiographs
of all patients revealed good bony alignment of the bony segments. In
all groups, comparison between the study intervals with respect to both
means and changes percentages of the bone density values showed
insignificant differences. At 2nd postoperative week, the mean bone
density at the fracture sites decreased by 4.74, 6.6 and 27.89 % in
groups A, B and C respectively. The period from the 2nd to the 4th
postoperative weeks showed increase in the bone density by 1.49, 1.95
and 14.12 % in groups A, B and C respectively. Insignificant difference
was found between the means of bone densities of group A and B
throughout the study intervals. On the other hand, both groups showed
insignificant difference with group C immediately postoperative and
significant increase in bone density at the 2nd and 4th postoperative
weeks.
CONCLUSIONS:
Short period immobilization of mandibular fractures for 2 weeks
supplemented with PEMF is recommended. Further studies are needed to
evaluate the efficacy of LILI as a supplement to reduce the mandibular
fracture immobilization period.
Sacral magnetic stimulation in non-inflammatory chronic pelvic pain syndrome.
Leippold T, Strebel RT, Huwyler M, John HA, Hauri D, Schmid DM.
Department of Urology, University Hospital Zurich, Switzerland.
Abstract
OBJECTIVES: To prospectively evaluate sacral magnetic high-frequency
stimulation as a treatment option for patients with non-inflammatory
chronic pelvic pain syndrome (CPPS, category IIIB).
PATIENTS AND METHODS: Fourteen men with CPPS IIIB were treated with
high-frequency sacral magnetic stimulation, with 10 treatment sessions
once a week for 30 min at a frequency of 50 Hz. The National Institutes
of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and
quality-of-life index were determined before and after treatment.
RESULTS: All patients tolerated the stimulation well and 12 of 14
reported agreeable sensations during stimulation. There were no
complications; only one patient did not complete the treatment course.
The mean (range) total NIH-CPSI score did not change with treatment, at
27 (18-38) before and 27 (4-40) after treatment. Moreover, there was no
sustained effect on the mean scores for pain, micturition complaints or
quality of life.
CONCLUSIONS: High-frequency sacral magnetic stimulation in patients
with CPPS IIIB only reduces pain during stimulation, with no sustained
relief of symptoms. Therefore, intermittent sacral magnetic stimulation
cannot be recommended as a treatment option for CPPS IIIB.
Urol Nefrol (Mosk). 1996 Sep-Oct;(5):10-4.
Magnetic-laser therapy in inflammatory and posttraumatic lesions of the urinary system.
[Article in Russian]
Loran OB, Kaprin AD, Gazimagomedov GA.
The authors discuss disputable problem of renal and ureteral tissue
after trauma or inflammation. These cause irreversible morphological
changes in the tissue. Poor results of the standard therapy urged the
authors to try magnetic-laser therapy in urological clinic. The
technique has been developed on experimental animal models. The
resultant morphological characteristics of ureteral wall and parenchyma
support the validity of magnetic-laser therapy in urological
practice.
The effect of a low-frequency magnetic field on the
clinico-immunological indices of patients with chronic inflammatory
diseases of the organs of the female genital system.
Low-frequency magnetic field generated by the vaginal inductor used
in 120 females with chronic genital inflammation promoted a decrease
in leukocytosis, elevation of total population of T-lymphocytes,
inhibition of high proliferative activity in PHA test. However, marked
immunocorrection was not reached.
Clin Exp Obstet Gynecol. 1995;22(4):350-4.
Analgesic properties of electromagnetic field therapy in patients with chronic pelvic pain.
Varcaccio-Garofalo G, Carriero C, Loizzo MR, Amoruso S, Loizzi P.
Institute of Obstetrics and Gynecology II Clinic, University of Bari, Italy.
Abstract
AIM: Demonstration of analgesic effects of electromagnetic field treatment in cases of chronic refractory pelvic pain.
STUDY DESIGN: Prospective non-controlled trial, 64 women complaining
about pelvic pain of at least 6 months duration, resistant to standard
therapies, submitted to electromagnetic field applications on both iliac
regions by Thelf Systems apparatus by two applications daily lasting 2
hours each for 20-40 days. Control visit after 3 months.
RESULTS: Complete subsidence of pain in 39 cases (61%), in 15
patients (23%) relief during treatment, then mild endopelvic tension
after a 3-month control; in 10 cases (16%) symptoms reduced only during
application hours, unchanged at follow-up. Outcome of treatment appears
to be independent of pre-existent psychosocial variables.
CONCLUSION: Magnetic therapy shows a real analgesic effect on pelvic
pain, and seems to contribute to resolution of complex interactions
between somatic nociceptive stimuli and psychosocial implications
affecting pain perception in these patients.
Channelopathy: hypothesis of a common pathophysiologic mechanism in different forms of paroxysmal dyskinesia.
Margari L, Presicci A, Ventura P, Margari F, Perniola T.
Child Neuropsychiatric Service, Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy.
Paroxysmal dyskinesias are a rare heterogeneous group of neurologic
disorders, characterized by transient sudden choreoathetoid or dystonic
attacks without loss of consciousness. This study reports a family with
six affected members in three generations, and two sporadic cases of
paroxysmal dyskinesia. Familial cases of paroxysmal dyskinesia are
affected by idiopathic long-lasting paroxysmal exertion-induced
dyskinesia and the sporadic cases by idiopathic short-lasting paroxysmal
kinesigenic dyskinesia. Familial cases also suffer from epilepsy,
mainly of generalized type, with benign outcome; one sporadic case is
affected by migraine. Results presented in this neurophysiologic study
include electromyography, somatosensory evoked potentials by median
nerve stimulation, somatosensory evoked potentials by posterior tibial
nerve stimulation, motor evoked potentials by magnetic transcranial
cortical stimulation, visual evoked potentials, brainstem auditory
evoked potentials, blink reflex, reflex H, and electroencephalography.
The clinical and neurophysiologic findings presented here suggest a
condition of hyperexcitability at the muscular and brain level, perhaps
as a result of an ion channel disorder, which is in agreement with
reports in the literature.
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 Ricevuti1,21Department 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.
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.
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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.
Parkinson’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 disease
Several 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 disease
In 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.
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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
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.
The efficacy of the combined use of 5-fluorouracil electrophoresis and magnetotherapy in experimental pancreatitis.
[Article in Russian]
Kents VV, Tsympilova TA, Mavrodii VM, Godlevskii LS.
As shown on the experimental model of rat acute pancreatitis, an
intensive 5-fluorouracil electrophoresis course in combination with
magnetotherapy significantly reduces the activity of blood trypsin,
amylase, lipase and corticosterone. The treatment is thought effective
in experimental pancreatitis.