Space around our planet is not empty and the Earth is immersed in the solar energetic charged particles. Space-weather defined as the conditions in space that affect Earth, consequences of flowing ionized particle of the solar wind against GMF 10. However GMF acts like a shield and deflect most of the solar charged particles, it is also impressed and altered by solar wind 10. These GMF alterations are called GMD. GMF has different strength and direction in different areas of the Earth. Its magnitudes vary from ~35000 nano Tesla (nT) in equator to ~70000 nT in the magnetic poles 11. Several periodic variations have also been shown in GMF that most of them are related to various solar cycles, especially 11 year cycle, and others are related to Earth’s rotation and situation in its orbit 11.

For quantifying GMD, several indices such as Planetary K index (Kp) and Planetary A index (Ap) were defined. Kp is a quasi-logarithmic scale for summarizing global geomagnetic activity in the range 0–9, which 1 and 2 being quiet state, 3 and 4 indicating unsettled and 5 or more illustrate geomagnetic storm 12. Like geographical coordinates that are defined among Earth’s geographical poles, there are geomagnetic coordinates that are defined on the basis of Earth’s magnetic dipole. Regarding the fact that the location of magnetic dipoles are different from geographical ones and the fact that magnetic dipoles are not located completely antipodal and their locations change slowly, geomagnetic latitude and longitude of every location are completely different from its geographical coordinates (Figure 1). It is a very important note because the rate of magnetic field changes in every area on the ground level is associated with its location in the geomagnetic coordinate.

Solar activities and inter-planetary magnetic field provoke GMD by causing two different but related phenomena, including magnetospheric substorms and geomagnetic storms. Magnetospheric substorms occur frequently and disturb high latitudes of both hemispheres within ring shaped area known as auroral oval, and can cause up to 2000 nT GMD for few hours 14. Auroral oval lies at geomagnetic latitude ~63° to ~75° of both hemispheres in quiet geomagnetic situations. Equatorward boundary of auroral ovals expand during unsettled situations, i.e. Kp = 3 and 4, to geomagnetic ~60° and ~58° latitude, respectively 15.

In the other hand, geomagnetic storms are less frequent but global phenomena and have impact on low and mid-latitudes, as well as high latitudes. They cause up to 400 nT GMD and last for few days 14. During their occurrence and relative to the degree of GMD, Kp index varies among 5 to 9. It should be noted that during a geomagnetic storm, substorms also occur and the location of the equatorward boundary of auroral ovals depend on the severity of disturbances. For example, they may expand to geomagnetic ~48° latitude in Kp = 9 situation 15.

A good hypothesis about MS should be able to give an acceptable explanation about its pathophysiology, behavior and special distribution.

In recent decades, because of vast development of wireless communication devices, concerns about the effect of VLMF on health have raised and many studies had been conducted toward them. Nevertheless, the magnitude and frequency of wireless appliance electro-magnetic fields are different from GMF and therefore, finding studies about the effect of magnetic field with same characteristics as GMF was very difficult. However such studies were sparse, in this section we tried to describe that GMD hypothesis has the potential ability to explain some aspects of MS pathophysiology and behavior.

Even with its low magnitude, GMF affects living beings. It was shown that in a weakened GMF situation, by using shielded chamber, hormonal disturbances occur in animal models, especially in the blood level of epinephrine, histamine and serotonin. Plants also are influenced by it and weakened GMF can cause changes in root meristems and subcellular structures like mitochondria 11. We know that some species sense GMF, probably by presence of magnetites, i.e. ferromagnetic particles in their central nervous system (CNS), and use it for orientation and migration 11. It was shown that human brain also contains magnetites 16 and it was proposed that observed increases in stress hormones, heart rate, and the amount of myocardial infarctions during geomagnetic storms may induced by causing an adaptive stress reaction through the effect of GMD on brain magnetosomes 17 18. Accordingly, histochemical finding about the presence of considerable iron deposits within myelin loops 19 and evidences from imaging technics about increased iron deposits in subcortical gray matters of MS patients 20, in addition to some results about greater incidence of cardiovascular diseases among MS patients 21, all may be regarded as indirect clues of a probable relation among the effects of GMD on brain magnetosomes and pathogenesis of MS. However, it should be reminded that we don’t know how amount of these iron deposits are in the form of magnetite.

Regardless of these facts, any hypothesis about MS should have the ability to describe why and how adaptive immune system is activated in a relapsing-remitting manner against myelin that is an immune privileged component 22 23. CNS is regarded as the most sensitive organ to GMF and some studies demonstrated that CNS reactions to magnetic field resulted mainly from magnetic field effects on glial cells and especially blood brain barrier 11 that are the main participants in MS pathophysiology.

However migration of myelin-specific T cells from systemic circulation to CNS has a great role in MS, their sole presence is not more regarded as the main cause of MS; because their presence was also demonstrated in healthy individuals. Rather, what is considered to be important is the activation state of these cells 22. A naïve T cell, primarily for transforming to effector or memory T cell, needs two activator signals: peptide/major histocompatibility complex (MHC) and co-stimulatory signal. Then this effector cell for activation needs only the signal one 22. These signals affect membrane signal transduction systems and by starting a cascade of reactions and production of messenger molecules, finally change gene expression and cell differentiation. After all, adhesion and entering to the CNS are necessary for activated T cells to be capable of exertion an inflammatory response 22 24.

There are evidences that adaptive immune system can be affected by VLMF. Magnetic field as low as GMF can significantly change lymphocyte Ca²⁺ uptake 25. In addition, through three proposed mechanisms, GMF can change leukocyte behavior, activation and adhesion by inducing the membrane-mediated signal transduction cascades, like the time that a ligand-receptor interaction activates the cell 24 25 26 27. Those mechanisms include changes of ion flux, especially Ca²⁺ across cell membrane, cyclotron resonance and dissociation of protein-ion complex by changing quantum states of ions in their structures in the membrane proteins 24. There are also evidences that magnetic fields can enhance release of reactive oxygen species by T cells and macrophages 26. Regarding these facts, we can see that GMD has the potential features to provide the essential neuroimmunological context of MS. Therefore, as the core of our hypothesis we assumed that vulnerable individuals, based on their genetical susceptibility of cell response to magnetic fields, would suffer from MS attacks in the geographical locations and time periods that GMD matches with the sensitivity of their adaptive cell immunity and lasts enough to stimulate various elements of this system for entering to CNS and activating without the presence of a co-stimulatory signal. This viewpoint can explain why the disease often has a relapsing remitting nature.

After structuring GMD hypothesis, we planned to test it. We explained in previous sections that auroral oval boundaries are areas that more frequently and with the greatest magnitude are affected by GMD. As is obvious in Figure 2, most of disturbed days are elapsed in Kp = 3 situation in each solar cycle. In such a situation, the equatorward border of auroral oval locates upon geomagnetic ~60 latitude in both northern and southern hemispheres 15. This means that all living beings in these areas experience more geomagnetic disturbances in comparison to other parts.

Regarding to these facts, the easiest but indirect way to evaluate the possible association of MS with GMD seemed to check the correlation of disease prevalence with angular distance to geomagnetic 60° latitude (AMAG60) as the border of the most affected area by space-weather through an ecological study and to compare it with the well-known association of MS with geographical latitudes, i.e. the angular distance from geographical equator. Therefore, we designed an ecological study with using meta-regression analysis on the prevalence studies of MS to check such a correlation. To have controls, we considered to check likewise correlations with angular distance to geographical 60 latitude (AGRAPH60) and geomagnetic latitudes.

As the most accurate MS prevalence studies have been done in western countries, we retrieved English written papers with the keywords of “prevalence” or “epidemiology” and “multiple sclerosis” in the title, published since 1980 up to the 2010, from the PubMed that were done in western countries (Additional file 1:Appendix 1. Search strategy ). In addition, authors combined articles from their archive to results retrieved from the PubMed. Our definition of western countries includes countries of western European and other states regional group of United Nation 28. MS prevalence data including the location of study, the year of estimation of prevalence, the number of prevalent cases and calculated MS prevalence per 100000 were extracted from included studies. Only MS prevalence data were entered in the analyses that their original study used an approved MS diagnostic criterion with more than 20 prevalent cases and clearly indicated the number of prevalent cases. For studies that used patients’ self-report of having MS, according to their neurologists’ diagnosis, we accepted the data only if the study population were such large, i.e. at least one million or more, that choosing self-report method seemed practically inevitable and reasonable.

In the cases that several studies reported prevalence in a same location, only the latest report was entered.

For each entry, the geographical latitude and longitude were retrieved from coordinate index list of a geographical textbook 29. In the cases that the study area involves population of a political region, i.e. whole country, a state, a province or multiple neighbor cities, we considered the coordinates that resemble the point of symmetry of geometrical figure of that political region. By using an online calculator based on the international geomagnetic reference field data source 30, geomagnetic coordinates were calculated from geographical coordinates for each location in the year that MS prevalence was reported or in the nearest available time to that year. For example, geographical latitude of London is 51.5° N, whereas its geomagnetic latitude in 1985, the nearest time to the last MS prevalence report, was recorded as 53.66° N.

For any location, AMAG60 was determined by calculation of absolute value of numerical difference between its geomagnetic latitude from geomagnetic 60° latitude (GM60L). A same manner was done for calculation of AGRAPH60.

By using meta-regression analysis, the association of MS prevalence with geographical latitude, geomagnetic latitude, AMAG60 and AGRAPH60 were evaluated separately. In each analysis, we regarded MS prevalence of populations as dependent variables and geographical or geomagnetic related variables as independent variables. Logarithmic and linear models were tested for each variable and the best fitted model was selected for final inter-variable comparison. Models were compared by their adjusted R² (coefficient of determination) and standard error of estimate (SEE).

In all meta-regression analyses, prevalence data were weighted with the square root of the number of prevalent cases. In all tests, a p-value lesser than 0.05 was regarded as significant. We did analyses by using IBM SPSS statistics (IBM®, New York, USA).

Parabolic gradient of MS prevalence in north hemisphere and linear gradient in the south hemisphere can be explained easily by GMD. As is obvious in Figure 1, there are many inhabitant areas under and beyond GM60L in the Europe and North America, while there are not any inhabitant lands beyond this line in the south hemisphere. If an important environmental factor for MS is related to this line, it would be reasonable that the disease shows parabolic and linear distribution in north and south hemisphere, respectively.

When MS was framed by Charcot in mid-19th century, it was considered as a rare disease and a subject for case report 7. During 20^th century, MS incidence and admission grew very fast. This change was interpreted by some researchers as “an epidemic of recognition rather than the effect of altered biological factors” 7. But from 1930s, an increase of MS incidence was reported initially from high latitudes in north hemisphere like Iceland that became notable from 1945 to 1954 120. Simultaneously, an identical trend of changes was reported from South Africa in south hemisphere 121. Then, remarkable increase of MS incidence and prevalence were reported from various locations such as Denmark, Faroe Islands, Norway and Australia after 1960 44 120.

Afterwards, however higher latitudes experienced a decreasing trend of incidence for a short period after 1965–70 120 122, increasing incidence and prevalence was reported from Scotland, United Kingdom and Netherlands. Such a course of events could not be explained by survival changes or case ascertainment issues easily 120.

Very interestingly, mentioned course of MS prevalence and incidence can be explained by GMD. Fortunately, solar activity has been observed by means of regular recording of sunspot numbers since 1700 123. Sunspot numbers are correlated with solar cycles, solar magnetic activity and hence with the frequency and strength of GMD. Recently, Solanki et al. reconstructed sunspot numbers for the past 11,400 years. Their results illustrated an increasing and longstanding exceptional solar magnetic activity since 70 years ago that is unprecedented during past 8000 years 123. Long-term analysis of recorded GMF activities revealed that GMDs have followed solar activity changes and have been increased, a phenomenon that is known as “centennial increase of geomagnetic activity” 124.

As a result, if MS is regarded a phenomenon related to GMD, it not only can explain why MS or reports of clinical manifestations resembling MS were rare in 19^th century and in medicine history of all previous centuries 7, but also it can clarify why MS incidence and prevalence have raised during 20^th century.

Figure 5 shows mean yearly sunspot numbers. Since 1937 solar maximums started an increasing trend, reached to mean yearly sunspot number of 151 in 1947 and then registered a record in 1957. It was followed by a decrease in maximum sunspot number in the next cycle (20^th cycle), but backed to more than 150 spots in the maximums of the following cycles. Figure 2 shows that from 1933 to 1964, cycle average frequency of occurrence of Kp = 3 as well as other Kp situations had an increasing trend. Among 1944 to 1955, the average occurrences of Kp = 3 situation increased considerably and reached to its maximum by 1960. As mentioned, in Kp = 3 situation the edge of auroral oval is located over geomagnetic ~60° latitude, therefore, the disturbances in ground level magnetic field could be the cause of the increase in MS incidence and prevalence in the areas under and near to this line, relative to their angular distance to it. Regarding to these facts, GMD hypothesis has the potential ability to explain why MS incidence and prevalence in high latitudes increased from 1945–54 and dramatically by 1960. It also can be seen that average frequency of occurrences of Kp = 7 situation, that occurs in severe geomagnetic storms, increased about 2.3 folds in 1955–64 in comparison to 1933–44. Such severe storms not only expand the edge of auroral oval to about geomagnetic 50° latitude, equal to geographic 55° latitude in central Europe and to geographic 40° latitude in north America, but also cause global GMD that can explain why MS incidence and prevalence started to increase globally after 1960.

In both Figures 4 and 2, we can see that in 1965-76 (cycle 20), solar activity and frequency of all levels of GMD decreased temporarily. It can explain why MS incidence decreased in higher latitudes at this period.

In recent decades, increasing prevalence of MS in some low latitude areas like Italy, against the expected north–south gradient of MS 75 76, led to attenuation of previously prominent latitudinal gradient of MS 3. An interesting finding about centennial increase of GMD can describe the reason. However centennial increase of GMD has had a latitudinal dependent nature and higher latitudes has experienced the largest disturbances because of proximity to auroral oval, long term studies have revealed surprisingly that the absolute amount of centennial increase of GMD in low-latitudes has been larger than mid-latitudes 124. By this fact, it should not be surprising that the rate of MS prevalence rising in susceptible individuals of low-latitudes becomes even larger than individuals of mid-latitudes over the time, and consequently the prominent latitudinal gradient attenuates gradually.

According to the result of two large epidemiological studies, the risk of MS has associated to the month of birth. Birth in May for inhabitants of north hemisphere and November for south hemisphere have significantly related to higher risk of MS in adulthood 126 127. Previously, it has been tried to explain this feature by means of maternal exposure to ultraviolet in the first trimester 127. As CNS myelination occurs mainly in the third trimester, mostly from 29–39 gestational weeks 128 129, it seems more reasonable that the mysterious environmental factor should be related to this time. Consequently, for individuals born in May and November, the environmental factor that may be related to myelination time should occur at about mid-March and mid-September, respectively.

However it is very complicated and is far beyond the scope of this article, but it is well established that there are semiannual increases in GMD which take place near the time of equinoxes. In March, the earth reaches to the highest southern solar latitudes, in the region that is exposed to the fast solar winds 130. At this time, however both hemispheres are affected, negative interplanetary magnetic field B_x component and positive dipole tilt of the earth cause favorable situation for northern hemisphere high latitude reconnection phenomenon that leads to accentuation of transpolar arcs and magnetic field disturbances predominantly in auroral oval of northern hemisphere 131. In September, the situation is vice versa and reconnection phenomenon is facilitated in the southern hemisphere high latitudes 131. If we assume that GMD can increase the risk of MS by affecting adaptive cell immunity and causing memory T-cells that will be activated in the future when identical temporary changes occur due to magnetic field disturbances, therefore, it could be hypothesized that genetically vulnerable individuals who were exposed to more GMD during their CNS myelination process, when various antigens of myelin structures are exposed and are prone to be recognized by immunity, will have increased risk for developing MS in the future. By this manner, GMD hypothesis not only can efficiently explain the relation of month of birth with the risk of MS, but also can describe why immigrants born in high-risk area mostly preserve the risk of their birthplace when immigrate to low-risk places. In the other hand, we hypothesize that genetically susceptible immigrants from low-risk to high-risk areas, however experience lower exposures in their fetal period that result in lower likelihood of production of memory T-cells against myelin structures, but will show increased MS risk 2 in their new residence area due to greater frequency of exposure to GMD that will increase the chance of being exposed to a matched GMD with their memory T-cells sensitivity.

Moreover, we predict that if studies about the effect of birth month on MS risk would be conducted in mid to low latitude geomagnetic areas, we would see the increasing risk attributed to both equinox time of spring and autumn, because these locations experience approximately identical increase in geomagnetic disturbances at these times.

Kurtzke et al. reported evidences of four epidemics of MS in small population of Faroe Islands during 1940–1991 132. They tried to explain these epidemics by defining a hypothetical pathogen, possibly introduced by British troops in 1945 132. Nevertheless, such a pathogen has not been found 2.

Considering the fact that solar magnetic activities and related GMDs during 20^th solar cycle were significantly lesser than previous and next cycles, and as a consequence assuming that they were not strong enough to cause MS in susceptible Faroese, we can hypothesize that what were seen in limited population of Faroe as separated MS epidemics, were reflections of solar magnetic activities and their related geomagnetic consequences on vulnerable individuals during 17^th, 18^th, 19^th and 21^st solar cycles. Albeit this statement needs to be tested by exact superposed epoch analysis of solar magnetic activities, GMDs and MS incidence in Faroe during mentioned period.

Finally and as a comparison, VDH has important weaknesses. We mentioned before that VDH cannot describe the cause of parabolic prevalence of MS. In fact, the relationship between the amount of solar ultraviolet B (UVB) penetration and latitude are complex, due to some factors such as differences in the thickness of atmosphere, cloud coverage and ozone cover situation. A recent modeling study has shown that the notion of latitudinal gradient of vitamin D levels in population is not accurate 133 134. Accordingly, geophysical studies has confirmed that the amount of received UVB in a high latitude area like Canada, over 24 h during summer times, equals or even surpasses the received UVB at the equator 133.

In the other hand, VDH cannot explain chronobiological changes in MS incidence and prevalence. We know that vitamin D related rickets was endemic in many areas such as England in mid-17^th centuries. It was a common problem up to 1930 when finally by finding the cause and using cod liver oil and enough sun exposure, medicine overcame the disease 135. Therefore, if MS actually is related to vitamin D deficiency, it is reasonable that we had records of more incidence and prevalence of MS or reported clinical manifestation that resembling MS before 1930. We know that it is in contrast with what has happened during history of MS. Ecological and genetic studies did not support the significant association between serum vitamin D level and MS, and observational studies did not find strong direct evidences of vitamin D effects on MS incidence 133. Moreover, VDH cannot exactly illuminate the cause of recent attenuation of latitudinal gradient of MS prevalence and some phenomenon like MS epidemics 4.

Nowadays MRI is the mainstay of diagnosis and follow- up of MS patients. During preparation of this manuscript and regarding used facts and mechanisms to construct and describe our hypothesis, we realized that the presence of the words “magnetic” and “resonance” in the name of MRI will inevitably evoke questions about its safety for MS patients. Authors, as designers of GMD hypothesis, cannot answer such questions definitely at present time. The main cause of uncertainty in this issue originates from the fact that we are not aware about the exact mechanism that GMD or other magnetic fields may probably elicit an immune response in CNS. Undoubtedly, the answer to this matter is completely dependent to the mechanism of such effect. For example, if future studies confirm that GMD may elicit immune response in human body mainly by changing lymphocyte Ca⁺², as was described in introduction and subsection of “the hypothesis”, then with a high probability, at least in the case of inducing cyclotron resonance in Ca²⁺, we should not be concerned about MRI.

However MRI works by inducing cyclotron resonance, but the target of this technic is hydrogen nucleus. It is a physical fact that resonant frequency of atomic nucleus of any element is different from others and is related to its electric charge, atomic mass and albeit the strength of exerted magnetic field. In quantum mechanics, this resonant frequency can be calculated by means of Larmor equation. The Larmor equation is ω₀ = yB₀. Where ω₀ is the resonant frequency, y is a unique constant for any element that is called gyromagnetic ratio and B₀ is the strength of external magnetic field. Gyromagnetic ratio of hydrogen is 42.58 mega Hertz per Tesla (MHz/T), while this ratio is 2.86 MHz/T for calcium. Therefore, in magnetic fields of clinical MRI, i.e. 1.5 and 3 Tesla, resonant frequencies of hydrogen are about 63 and 127 MHz, respectively. While these frequencies for calcium is about 4 and 8 MHz, respectively. As clinical MRI appliances use pulse frequencies of 60 MHz up to 128 MHz 136, their pulse frequencies are not match with calcium nucleus to elicit cyclotron resonance in them. It is the physical basis of a known fact in clinical practice that MRI is not the appropriate technic for imaging calcified tissues or bony structures.

In contrast, if future studies confirm GMD hypothesis and show that the mechanism of GMD effects is related to its impact on brain magnetosomes and their magnetite contents, that physically are sensitive to magnetic fields, then the safety of MRI for MS patients should necessarily be revaluated regarding to this matter.

In conclusion, the recommendation of authors at present time is to use MRI only for evaluating the presence of demyelinating lesions at the first attack or eventually for confirmation of dissemination of lesions in time for necessary cases, and then to follow-up MS patient clinically and to avoid ordering repeated MRI for this aim as far as possible.

However ecological study is a very suitable and inexpensive way for hypothesis evaluation in large scale and in population level, but it should be reminded that such studies are subject to be impressed by ecological fallacy. In the time of interpretation of the result, it should be noted that findings related to aggregate population may not always be applicable to individuals.

Other limitation of the study is its limitation in regarding the exact amount and time of exposure of population to GMD. Geomagnetic coordinates and experienced GMD of any locations change over time. However we determined AMAG60 of any location in the nearest time of its MS prevalence study and considered it as a variable related to the amount of experienced GMD by population, but we did not know the actual time in the life that experiencing GMD may affect individual susceptible for MS. It may be during fetal time, neonatal period, childhood or adulthood.

Nevertheless we provided evidences of how GMD possibly can provide essential components for causing MS, but it should be noticed that all of these evidences are from in vitro studies. In the other hand, however we assumed that there may be a genetical basis that can be the cause of sensitivity of susceptible individuals to GMD, such a genetic basis, except than a new finding about human cryptochrome CRY2 gene 137, was not confirmed or evaluated up to now.

Another important limitation of GMD hypothesis, at least at present time, is related to the issues of difference among sexes in the case of MS incidence and prevalence, and other related factors such as the effect of pregnancy or post-partum period on alteration of MS attacks. The main cause of inability of GMD hypothesis to provide a reasonable description about these issues originates from the lack of information about the exact mechanism of the effect of GMD. There are evidences that hormones, for example melatonin, may have a role in the response of brain to GMD 137. But, we could not find such studies about sexual hormones. Therefore, providing probable explanations about these phenomena is dependent to future studies in this field.