The ability to recover after stroke depends on many factors, including the regenerative capabilities of the brain. Recovery depends on the plasticity of the brain. The plasticity, or neuroplasticity, required in a damaged brain is very different from the plasticity of a normal functioning brain. The demand for adaptive healing starts immediately after a stroke event where blood supply to the brain is stopped or limited. The availability of various factors in the brain, called neurotrophic or growth factors, affect the potential for the growth of new neurons and the survival of existing neurons. Neurogenesis is regulated by many factors including neurotrophins, growth factors, hormones, neurotransmitters, and micro-environmental factors.
A PEMF STUDY IS CONDUCTED
A study was done to evaluate the effect of extremely low-frequency electromagnetic field therapy (PEMF) on brain plasticity in the rehabilitation of patients after stroke. (2)
The cerebral ischemic event (stroke) in each patient was documented by computer tomography (CT) scan of the brain. Neurological and CT findings were interpreted by 2 or more independent experienced neurologists. All patients were diagnosed with ischemic stroke. Patients with other types of stroke were excluded, as were patients with neurological illness other than stroke; chronic or significant acute inflammatory factors; and/or dementia.
Forty-eight patients were divided into two groups and had the same rehabilitation program. In both the groups, the program was provided by a physiotherapist, every day for a period of 4 weeks with weekend breaks. The rehabilitation program included 15 min of psychotherapy, 60 min neurophysiological session in the morning (30 min of function enhancing techniques and 30 min of repetitive task practice or balance) and 30 min aerobic training (2–3 times a day for 10 min at 60 min intervals).
Neurophysiological rehabilitation consisted mainly of functional rehabilitation techniques and repetitive task practice designed to intensively use the affected upper and lower limbs. The function techniques included activities based on activities of daily living (ADL). However, training time was individually modified depending on the improvement in motor function of the affected limbs, if necessary.
The rehabilitation program in the control group consisted of a 60 min session in the morning (30 min of function improvement techniques and 30 min of balance training), 30 min aerobic training (2–3 times a day for 10 min at 60 min intervals) and 30 min muscle strengthening exercises. The range of physical effort during the rehabilitation programs in both groups of patients was between 13 and 14 according to the Borg functional scale (moderate effort).
Most of the people in the study were between 3 to 4 weeks after their stroke and were on average between 45-48 years of age. In the pulsed electromagnetic field therapy (PEMF) study group, the patients additionally were exposed to a standard series of 10 PEMF treatments, for 15 mins each, at 5 mT (50 G), 40 Hz, to the pelvic girdle. The non-PEMF group received the same rehabilitation program, without PEMF therapy.
That’s right! PEMF treatment was to the pelvis, not to the brain, as would normally be expected. At the time of this research there was a concern about PEMFs precipitating seizures. This concern has largely been discounted with the FDA approved high intensity transcranial magnetic stimulation devices for treatment resistant depression, with seizures being extraordinarily rare and much less likely to happen with the relatively low magnetic field intensities used in this research. As it turns out, from this research, stimulation of the pelvic area with this PEMF set-up still ended up producing significant changes in levels of various biochemical markers. These biochemical factors end up in the circulation, and finally in the brain. In the brain they create various reactions that can help improve the negative effects of stroke.
This research group looked at many factors associated with the outcomes of stroke and associated these outcomes with treatment results. After 4 weeks, during which patients had undergone neurorehabilitation and neurological examinations, they assessed functional recovery using the Barthel Index, Mini-Mental State Examination (MMSE), Geriatric Depression Scale (GDS), National Institutes of Health Stroke Scale (NIHSS), and the modified Rankin Scale (mRS).
The modified Rankin Scale (mRS) is commonly used for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It has become the most widely used clinical outcome measure for stroke clinical trials.
RESULTS OF PEMF STUDY ON BRAIN RECOVERY AFTER STROKE
Any kind of damage to the brain causes the brain to adaptively respond. This adaptation process is called neuroplasticity. Neuroplasticity, also known as neural plasticity or brain plasticity, is a process that involves adaptive structural and functional changes to the brain. A good definition is “the ability of the nervous system to change its activity in response to intrinsic or extrinsic stimuli by reorganizing its structure, functions, or connections.” Clinically, it is the process of brain changes after injury, such as a stroke or traumatic brain injury (TBI).These changes can either be beneficial (restoration of function after injury), neutral (no change), or negative (can have pathological consequences). (2)
Neuroplasticity can be broken down into two major mechanisms:
Neuronal regeneration/collateral sprouting: This includes concepts such as synaptic plasticity and neurogenesis.
Functional reorganization: This includes concepts such as equipotentiality, vicariation, and diaschisis. Vicariation is considered a mechanism for recovery of function following brain damage. Essentially, this concept involves the ability of one part of the brain to substitute for the function of another. Diaschisis is a sudden change of function in a portion of the brain connected to a distant, but damaged, brain area. The site of the originally damaged area and of the diaschisis are connected to each other by neurons. Areas of the brain are connected by vast organized neuronal pathways that allow one area of the brain to influence other areas more farther away from it. Understanding these dense pathways helps to link a lesion causing brain damage in one area of the brain to degeneration in a more distal brain area. So, a focal lesion causes damage that also disturbs the structural and functional connectivity to the brain areas away from the lesion.
This research examined various biochemical aspects of neuroplasticity, specifically, several growth factors. They measured the blood level of brain-derived neurotrophic factor (BDNF), the vascular-endothelial growth factor (VEGF), as well as BDNF RNA gene expression. Additionally, they tested the levels of hepatocyte growth factor, stem cell factor, stromal cell-derived factor 1α, nerve growth factor β, and leukemia inhibitory factor.(2)
They found that PEMF significantly increased growth factors and inflammatory cytokine levels involved in neuroplasticity, as well as promoted an enhancement of functional recovery in post-stroke patients. These effects could be related to the increase of gene expression on the mRNA level. The PEMF group had double the amount of blood serum BDNF and 2.5 times more gene expression. Moreover, increase in BDNF plasma levels was reflected in improvement of the Barthel Index, MMSE, and the opposite with the GDS. They concluded that PEMF therapy improves the effectiveness of rehabilitation of post-stroke patients by improving neuroplasticity processes. PEMF also induced a significant improvement in functional (ADL) and mental (MMSE, GDS) status.
VEGF is involved in the improvement of damaged cells by increasing circulation and restoring function. VEGF levels increased by 50%. The PEMF group also had about 35% better cognitive functioning and 45% better depression scores.
In the non-PEMF group, stroke scale severity and function measures were about 65% and 50% worse, respectively.
The PEMF significantly increased enzyme antioxidant activity. The significant improvements in functional (ADL) and mental (MMSE, GDS) status correlated with the level of enzymatic antioxidant protection. (4)
To determine the level of antioxidant gene expression, they evaluated the level of mRNA expression of catalase, superoxide dismutase, and glutathione peroxidase. After PEMF therapy, mRNA expression of the studied genes (CAT, SOD1, SOD2, GPx1, and GPx4) significantly increased. These changes enhanced the antioxidant defenses of the body. (5)
Apoptosis is programmed cell death, and aims to eliminate damaged cells, including those damaged by the hypoxia of stroke, There are many factors that can induce apoptosis of cells: after ischemia, inflammation, cytokine activation, cascade of free radicals, and induction of thrombin. Neuronal apoptosis is regulated by various genes, such as BCL-2 (inhibitor of apoptosis) and BAX (activator of apoptosis). Induced apoptosis promotes the formation of new neurons, that is, neurogenesis, in mice.
To assess apoptosis gene expression level, (8) these researchers measured the mRNA expression of BAX, BCL-2, CASP8, TNFα, and TP53 in these patients. PEMF significantly increased the expression of BAX, CASP8, TNFα, and TP53, whereas the BCL-2 mRNA expression after PEMF remained similar in both PEMF treatment and control groups. Thus, increasing the expression of pro-apoptotic genes in post-stroke patients promotes the activation of brain neurons and hence brain pathways involved in brain plasticity processes.
Plasma cytokines may be protective (anti-inflammatory) or harmful (pro-inflammatory). The measured the levels of the anti-inflammatory/neuroprotective cytokines interleukin 1β (IL-1β) and transforming growth factor β (TGF-β) and the pro-inflammatory cytokines interleukin 2 (IL-2) and interferon-γ (INF-γ). The level of IL-1β mRNA expression that determines the level of serum IL-1β was also tested. After PEMF treatment, both IL-1β plasma level (up 100%) and IL-1β mRNA expression level (up 70%). On the other hand, IL-2 plasma level increased 15%, while IFN-γ and TGF-β had non-significant changes. The PEMF-induced IL-1β improvement found in this study is likely to have a neuroprotective role. (7)
The researchers also evaluated the possible association between plasma protein oxidative/nitrative damage and the development of poststroke depression. By analyzing several metabolic parameters, they found significant (P < 0.001) differences in all oxidative/nitrative stress parameters in brain stroke patients compared to a healthy group. Oxidative damage of proteins is relates to the degree of poststroke depression. The Geriatric Depression Scale is worse as the concentration of -SH groups or catalase activity increases. (3)
Nitric oxide (NO) is a very important signaling molecule, involved in both physiological and pathological processes. As a neurotransmitter in the central nervous system, NO regulates cerebral blood flow, neurogenesis, and synaptic plasticity. They evaluated the effect of the PEMFs on the generation and metabolism of NO, as a neurotransmitter, in the rehabilitation of poststroke patients. (6) They also measured the levels of 3-nitrotyrosine, nitrate/nitrite, and TNFα in plasma samples, and NOS2 expression in whole blood samples. PEMF significantly increased 3-nitrotyrosine and nitrate/nitrite levels, while expression of NOS2 was insignificantly decreased in both groups. So, PEMF therapy increases the metabolism and generation of NO, which has both neuroprotective and cytotoxic properties. An increase in NO level is associated with nNOS and/or eNOS activities. It does not influence iNOS expression, which increases mainly during inflammation. Therefore, in the poststroke state, NO demonstrates a protective effect as reflected in significant improvement in functional status.
Direct brain stimulation and timing and age of the patient
Two hundred twenty and three patients with the initial stroke were divided into three groups. (11)
Besides rehabilitation one group was also treated directly to the brain with TMS beginning
from the 6 -10 days after onset, given once a day for 14 days, In another subgroup TMS was begun within 3 months after the initial attack and another subgroup had TMS beginning 3 months after the initial attack. Except for TMS, the basic treatment was the same for all of the patients. Fugl-Meyer score was measured twice: just before treatment and after the 14th treatment.
The effective rate was 91% with TMS plus rehabilitation vs 68% in the control group (P < 0.05).
The Fugl-Meyer scores were 36 and 34 in the rehabilitation subgroup and control subgroup before treatment respectively and were 52 and 40 after treatment respectively (P < 0.01). The Fugl-Meyer scores were 41 and 59 before and after TMS respectively in the subgroup with early TMS treatment (P < 0.01) and were 34 and 45 respectively in the subgroup with TMS beginning 3 months after the onset (P < 0.05).
One of the most widely recognized and clinically relevant measures of body function impairment after stroke is the Fugl-Meyer (FM) assessment. Of the 5 Fugl-Meyer (FM) domains (motor, sensory, balance, range of motion, joint pain), the motor domain, which includes an assessment of the upper extremity (UE) and lower extremity (LE), has well-established reliability and validity as an indicator of motor impairment severity across different stroke recovery time points.
So, what they found was that direct brain TMS is effective in the rehabilitation of motor function in patients with stroke. The effectiveness of TMS treatment depended on the age of the patients and timing of beginning treatment. Results are not as good as people get older and the longer the time treatment is started after the stroke. (11)
Since the Cichon research did not compare different intensities, frequencies, durations of treatment of various PEMF devices or how long after a stroke PEMF should be started, it is not known if there is an optimal PEMF protocol. Because of the very low level of risk in using PEMFs, whether to the pelvic girdle or to the brain, different PEMF protocols may be practical and useful. Both direct brain PEMF stimulation and indirect PEMF stimulation help with recovery from stroke. We will have to wait for studies where they compare indirect stimulation with TMS, to see the levels of effectiveness of each. So, for now, both approaches make sense to help with stroke recovery. Indirect stimulation may be more readily available and able to be used in the home setting at a lower cost.
Benefits of direct brain stimulation with PEMFs
Direct transcranial magnetic stimulation of the brain can induce many of the actions of PEMFs in the body reviewed in the book “Power Tools for Health.” Almost all these actions may be seen with brain stimulation as well. Research shows that TMS can reduce the hyperexcitability seen in pain-related areas of the brain. TMS can trigger spinal cord inhibitory pathways to inhibit the conduction of pain signals to the brain (1). TMS increases cerebral blood flow in affected areas of the brain. In addition, the pain reducing effects of TMS not only influence the endogenous opioid system in the brain but also the endocannabinoid system. TMS can also reduce the neuroinflammation seen after stroke (10), a major contributor to poor stroke outcomes. (12) PEMFs have also been shown to increase neural stem cells useful in brain tissue repair. (9)
This research on the use of PEMFs in poststroke recovery and rehabilitation is important in showing some of the mechanisms accounting for the significant benefits from the use of PEMFs seen in those having ischemic strokes, even when applied between 3 to 4 weeks after their stroke. One of the most interesting aspects of this research is the fact that the brain was not even the target of treatment. Even so, peripheral PEMF stimulation appears to be able to provide significant benefits. It might be expected that more direct treatment to the brain would produce even better results, faster. This research was done using relatively low intensity PEMFs over a short treatment course and short treatment times, ie, 10 PEMF treatments, for 15 mins each, at 5 mT (50 G), 40 Hz. Therefore, the benefits seen in the PEMF treated group were impressive for the amount of treatment effort. Even the modified Rankin Scale (mRS), a measure of the degree of disability or dependence in daily activities of people who have suffered a stroke, revealed less disability in those receiving PEMFs.
This is a summary of the results: stroke-related neurological deficit, estimated using NIHSS, decreased approximately 65% more in the PEMF group than in the non-PEMF group. mRS measured disability decreased in both groups, but in the PEMF group the reduction was approximately 50% greater than in the non-PEMF group. About 35% greater improvement was seen in cognitive impairment, as estimated by MMSE, after PEMF treatment. Depressive syndrome, measured in GDS, decreased significantly, with approximately 45% better results in the PEMF group than in the non-PEMF group.
The PEMF treatments used in this study were initiated about 4 weeks after the initial stroke. So, it’s hard to know whether the effects seen of this treatment would have been either earlier or later in the course of recovery from stroke. It is rare to get access to individuals with stroke very early in their disease process, because of the limitations of the complications related to stroke, the hospital environment, the rehabilitation environment and the technology available.
A commonly studied approach to treating stroke is the use of rTMS (repetitive transcranial magnetic stimulation), which uses high intensity PEMFs delivered in highly specialized professional settings. At this point, this therapy is not approved by the FDA or covered by insurance for stroke. Home-based PEMF therapy using medium to high intensity magnetic fields to the brain would be expected to produce good results. This becomes even more feasible when one considers that the PEMF therapy can be started at the home setting, that is, usually after a course of facility-based poststroke rehabilitation. Also, PEMF therapy is not currently
offered in most rehabilitation settings.
Bottom line, PEMF therapies can be a very useful adjunct in the care of people who have suffered strokes, especially when started as soon after stroke as possible, whether the PEMFs are applied directly to the brain or as part of an overall care program. Whole body PEMF therapy with sufficient intensity PEMF equipment should be used to help the whole person, especially considering that people who have a stroke often multiple health needs that would benefit anyway from PEMF therapy.
To determine which PEMF system is best to use specifically for any given person, a free professional consultation is available at https://www.drpawluk.com/consult/
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