Biological Action of Combined DC and AC Magnetic Fields Problems and Contemplation Mikhail Zhadin 21.11.2018

Introduction Mikhail Zhadin, Dr. in Physics and Mathematics, Dr. in Biology, Prof. in Biophysics Ass. Member of the Russian Academy of Natural Sciences in Cybernetics and Informatics Head of Laboratory for Neurocybernetics of Cell Ensembles Institute of Cell Biophysics 142290 Pushchino, Moscow Region, Russia 21.11.2018

Areas of Personal Scientific Interests Theoretical and Experimental Research 1. Mechanisms of biological action of magnetic and electromagnetic fields 2. Mechanisms of electroencephalogram formation in conductive brain tissues 3. Mechanisms of formation of rhythmicity in electrical activity in the brain 4. Synaptic mechanisms of reinforcement at learning and memory formation 5. Synaptic mechanisms of multiple sclerosis 21.11.2018

Main Problems (1–2) 1. Occurrence of varied biological effects at simultaneous action of DC and AC magnetic fields among which the most investigated and important ones are the changes in extra- and intracellular concentration of free Ca ions (Liboff, 1985; Blackman et al., 1985) 2. Occurrence of a large number of resonance-like effects with very variable intensities at the action of DC and low frequency AC magnetic fields (Liboff, 1985; Blackman et al., 1985) 21.11.2018

Main Problems (3–4) 3. The most pronounced effects of combined DC and AC magnetic fields are usually observed at the cyclotron frequency of the AC field determined by the DC field value and the charge-to-mass ratio of the ions affected by these fields (Liboff, 1985; Blackman et al., 1985; and others) 4. At the cyclotron frequency, the effects of combined fields essentially increase at strong DC and AC fields an order more than the geomagnetic one (Zhadin et al., 1999). They can still be perceptible at the AC field three orders less than the geomagnetic one, being combined with a DC field compared with the geomagnetic one (Zhadin et al., 1998; Del Giudice et al., 2002) 21.11.2018

Main Problems (5–6) 5. At invariable value of the DC field, the increase in the AC field amplitude is accompanied by wavy-like changes in intensity of observed biological effects where their strengthening periodically alternates with weakening, i.e. “amplitude windows” (Blackman, 1985, 1994). At extremely weak AC magnetic field with the amplitude three orders less than the geomagnetic field, the effects vanish at the increase in the AC field amplitude up to about 1 μT (Zhadin et al., 1998; Del Giudice et al., 2002) 6. The widths of resonance peaks are compared with the cyclotron frequency and the distance apart them is measured by several cyclotron frequencies 21.11.2018

Main Problems (7) 7. In understanding the mechanism of resonant action of combined magnetic fields, the main difficulty is the necessity of very weak damping processes in the medium immediately surrounding a presumptive harmonic oscillator. Judging from the width of experimental resonance peaks, the damping coefficient for such sort of oscillator should be about the cyclotron frequency, that is very small for intra- and intercellular media 21.11.2018

Main Problems (8) 8. There is striking parallelism between biological effects of combined DC and low frequency AC magnetic fields and biological effects of combined DC RF fields modulated with low frequency (Blackman et al., 1985; Liboff et al., 1987). In both the cases, the changes in Ca concentration take place, and also there are similar sets of resonance-like peaks, predominance of effects at the cyclotron frequencies, and similar amplitude windows for effects arising 21.11.2018

Variety of Effects The known effects of changes in intracellular concentration of free Ca ions under the influence of combined DC and AC magnetic fields can underlie most phenomena in the variety of biological effects of the combined fields. Free Ca ions are the second messenger in the chains of intracellular signalization So the fields action can cause varied natural cellular reactions depending on a cell type: the changes in membrane potentials, secretion, proliferation, and so on. For its turn, the increase in free Ca ions within a cell can be caused by the release of Ca ions out of intracellular calcium-binding proteins. So it is very important to study the influence of magnetic fields on motion of a Ca ion in calcium-binding protein 21.11.2018

Resonance Peaks and Cyclotron Frequency The data on the set of resonance-like peaks and on the prominent effect at the cyclotron frequency (Liboff, 1985; Blackman et al., 1985) have initiated several models based on the resonance ideas. I would like to pay attention to the following three models of the most capacious ones: 1. Model of ionic cyclotron resonance by Liboff (Liboff,1985; McLeod, Liboff, Smith, 1992) 2. Model of ionic parametric resonance by Lednev-Blackman (Lednev, 1991; Blanchard, Blackman, 1994) 3. Our model of multiple splitting of resonance peak (Zhadin, 1998, 2000; Zhadin, Barnes, 2003) Each of these models has its own advantage and weakness 21.11.2018

Ionic cyclotron resonance This model pioneered the mechanism like the cyclotron resonance for occurrence of multiple resonance peaks with the most prominent effect at the cyclotron frequency under the action of combined DC and AC magnetic fields. The model explained these effects, but highlighted some difficulties. The main of them were the following: 1) viscosity of a liquid medium and 2) huge magnitude (about a meter) of the radius of free Ca ion rotation at room temperature These difficulties were avoided by the suggestion that cyclotron resonance is developing inside the vacuum within ion channels. In such a case there will be an extremely small number of ions acting at the very low- energetic part of Maxwellian distribution tail 21.11.2018

Ionic parametric resonance This model considers the release of a Ca ion out of a calcium-binding molecule to the intracellular medium under the influence of combined fields It was a very forward step because a bound ion is practically without a hydrate shell, which essentially increases free ion mass. Moreover, a bound ion inside a macromolecule experiences less damping compared to a free ion. Besides, this model was able to explain the strange effect of amplitude windows. But it runs into the following serious difficulty. The parametric resonance is the most prominent at the double reference frequency of the exposed harmonic oscillator. In the experiment, the most prominent effect is observed at the cyclotron frequency, equal to the double frequency of Larmor precession under the influence of the DC field in this case. But Larmor precession is not a harmonic oscillator by no Means, because there is not any restoring force in this process. The attempt (Zhadin, 2000) to reduce the ion motion equation under the influence of combined fields to the parametric resonance equation showed that the only harmonic oscillator is the bound ion performing thermal oscillations there and that the reference frequency is the natural frequency of the ion. But in no way this frequency is connected with the cyclotron frequency, and it is too high to give anything similar to experimental resonance peaks 21.11.2018

Model of Multiple Splitting of Resonance Peaks This model showed the multiple splitting of natural frequency of the ion thermal oscillation within a macromolecule under the influence of combined DC and AC magnetic fields. The highest peak arises at the cyclotron frequency due to mutual superposition of Zeeman peak and of one of the highest peaks of multiple splitting at this AC field frequency (Zhadin,1998) Arising of amplitude windows for each peak was shown at these conditions (Zhadin, 2000; Zhadin, Barnes, 2003). The numeral estimation revealed the sufficiency of the resonance energy to change a macromolecule conformation state at the fields compared with the geomagnetic one. As in the previous two models, the main difficulty for this model is the necessity of very low damping in the ion oscillations within a macromolecule. It should be as small as of order of 10 in the third power of cycles/sec. The idea on multiple splitting of resonance peaks under the influence of combined fields was also suggested in recent article of Del Giudice et al. (2002) 21.11.2018

Dependence of effects on the AC field frequency All the above three models showed that at the proportional increase in the DC field and in the frequency of the AC field the biological effects do not qualitatively change, according to the definition of the cyclotron frequency, but became more prominent. It was confirmed experimentally in the wide- ranging simultaneous changes in the DC field magnitude and in the AC field amplitude and frequency (Zhadin et al., 1999). It is the basic attribute of all the considered phenomena of the combined fields. In the experiments with amino acid aqueous solutions, the effect vanished at the AC field amplitude of about 1 μT, when the AC field amplitude increased while the DC field magnitude was invariably equal to 50 μT. But to make sure that it is the same effect as considered here, it is necessary to simultaneously proportionally increase the DC and AC fields magnitudes, keeping the AC field frequency as a cyclotron one. However, the existence of amplitude windows seems to be impossible at the AC field of about 1 μT with DC field of about 50 μT in the frameworks of the last two models 21.11.2018

Parallels between Effects of Low Frequency and Modulated High Frequency Fields Similarity between biological effects of combined DC and low frequency AC magnetic fields and biological effects of combined DC and low frequency modulated RF fields became clear in the framework of the model of multiple splitting the resonance peak (Zhadin, 2000; Zhadin,Barnes, 2003). At the modulated field, the natural frequency of the ion thermal oscillations within a macromolecule splits into two groups of resonance peaks. Both the groups are symmetrical regarding the natural frequency of the ion oscillation in a macromolecule The structure of each of these groups is similar to the structure of the group of resonance peaks created by the combined DC and low frequency AC magnetic fields, and all the effects of the above fields are qualitatively similar to each other 21.11.2018

Viscosity of the Liquid Medium and Damping Processes For all the three models the main difficulty is the viscosity of the surrounding medium where all the considered processes take place. Statistical physics, in essence, denies the possibility of weak damping in aqueous solutions. Works by Chiabrera (Chiabrera, Bianco, 1991; Chiabrera et al., 1994) gave the hope that in the macromolecular crevices the damping essentially decreases due to partial shielding from water molecules penetration. Recent works by Del Giudice at al. (2002) opening a new page in physics of electrolytes showed that in the microscale the water viscosity can fall practically up to zero. But it is important to know the order of this value, as well as how the experienced damping is connected with the size of the moving particle, its velocity, and with its transitions from the coherent area to the non-coherent area and vise versa. It is interesting also, how about a huge radius (near a meter) of the charged particle rotation at the cyclotron resonance in these conditions 21.11.2018

Resonant increase in current within solution It is absolutely incomprehensible why the current through the solution increases at the combined fields action in the experiment with amino acid aqueous solution at the cyclotron frequency (Zhadin et al., 1998; Del Giudice et al., 2002). The occurrence of cyclotron resonance in free ion motion within the solution does not, nevertheless, mean the arising of changes in the electric current, and even if they take place, it is more likely that the decrease in the current will occur because of lengthening the ion trajectory. By the way, the other two models are only applicable to bound ions. Earlier we (Zhadin, 1998) offered an idea that in the pregnant solution of glutamic acid the microcrystals were formed which dissolved at the cyclotron frequency, increasing the ion concentration in the solution and increasing the current. Maybe, that idea could be combined with Del Guidice's ideas 21.11.2018

One Detail Concerning Our Experiment When thinking over the problem of the increase the current through the solution, I remembered one detail concerning this experiment. At the beginning of the experiment we usually failed to get the effect. Then it appeared and was distinctly observed for several tens of minutes, but it relaxed or even completely vanished at too frequent application of the combined fields. At the further continuation of the experiment, the effect disappeared irretrievably. I remembered further that glutamic acid was not so highly soluble in water, and because of it, we heated up the solution 15-20°C higher at its preparation immediately before the experiment. But, of course, it gradually refrigerated till room temperature during the experiment 21.11.2018

Idea on Crystallization All the described above suggested that, when cooling, the solution was becoming to be saturated one and that the invisible nucleating centers arose within it. In essence, in the framework of our model of multiple splitting resonance peaks, the ion behavior in the depth of a microcrystal differs not at all from the ion behaviors in the depth of a macromolecule under the influence of the combined fields. So at the cyclotron frequency, the combined fields could cause the local heating of the ions in the heart of a microcrystal. This could cause partial melting the microcrystals and the increase in the ion concentration within the solution and the increase in the current through it 21.11.2018

Rise and Disappearance of the Effects Obviously, before saturating, the solution was unable to give the effects which only arose as the microcrystals were formed and the fields were able to melt them. Melting the microcrystals should lead to the decrease in their volume and perhaps, could cause disappearing the effects due to the enhancement of damping. It could be a reason for the peculiar refractoriness in the effect. When further cooling down the solution, the microcrystals should become more massive, and the fields energy could become insufficient for their quick warming-up. Such sort of processes could be the reasons for rise and disappearance of the combined fields effects Unfortunately, the disappearance of the effect at the AC field amplitude near 1 μT stays incomprehensible. But some thoughts about it were advanced by Del Giudice et al., 2002 Maybe, their QED theory could be also applied to microcrystals and macromolecules and to the liquid between their ions and atoms 21.11.2018