All latitudinal variables of study showed significant statistical association with MS prevalence. It was expected to some extent, due to the latitudinal dependent nature of MS. Our analyses confirmed that in each continent, the association of MS prevalence with geomagnetic latitude is equal or mildly better than geographic latitude. It should be noted that attention to the association of MS with geomagnetic coordinates
has precedent. About 50 years ago Barlow noticed that geomagnetic latitude could give a better explanation about MS prevalence and some of its special distribution features, such as the cause of lower prevalence of MS in Japan in comparison to other location with identical geographical latitude
]. However he paid attention to an important fact, unfortunately he never realized the critical role of geomagnetic ~60° latitude and possible role of geomagnetic disturbances
. He suggested that the relation of MS with geomagnetic latitude is originated from cosmic-ray related production of radioactive atoms in atmosphere and their radiation effects
]. Nevertheless his opinion is very close to ours in the basic epidemiological aspect, but our hypothesis and its descriptions about MS pathogenesis and special features are completely different from Barlow’s final assumptions. As his hypothesis about mutations due to radioactive effects of cosmic rays could not explain MS pathophysiology and behavior, the whole fact was neglected.
Our results indicated that in each continent, AMAG60 can give the best explanation about the variation of MS prevalence. However, result of Australasia, including Australia and New Zealand, was different from other continents and all latitudinal variables illustrated very strong association with MS distribution. They identically could describe about 80% of variation of MS prevalence. We regarded this as another confirmation for the effect of AMAG60. As is obvious in Figure
, Australasia is located below geomagnetic ~60 latitude. Therefore, it seems rationale that MS distribution shows a linear gradient toward this critical line. This very linear arrangement causes that geomagnetic and geographic latitude are able to explain variation of MS prevalence like AMAG60. Geographic 60° latitude is also located beyond Australasia. Due to this reason, AGRAPH60 could describe 84% of MS prevalence in this continent.
Merging the data of continents, especially in north hemisphere, we found that AMAG60 can give the best explanation about MS prevalence throughout the world in comparison to other latitudinal variables. We regard this advantage of AMAG60 as strong evidence that the mysterious environmental risk factor for MS should be correlated to this line more than other geographical factors. We mentioned in introduction that Earth’s surface is subject to experience magnetic field disturbances up to about 2000 nT under the auroral oval area because of substorms. GM60L is the line that usually represents the border of this oval in the most frequent disturbed situation, i.e. Kp
3 situation. Therefore, considering the supportive results of our meta-regression analyses, we suppose that GMD can be the best candidate to be the mysterious environmental risk factor for MS.
Beyond of being statistically associated to MS prevalence distribution, we believe that GMD hypothesis has the ability to describe other important features of MS. As the core of our hypothesis, we illuminated how GMD hypothesis may provide essential context for explaining MS pathophysiology at molecular and cellular level. In the following paragraphs, the ability of GMD to explain other features of MS will be discussed.
MS prevalence in hemispheres
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
, 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.
Worldwide MS incidence and prevalence trend
When MS was framed by Charcot in mid-19th century, it was considered as a rare disease and a subject for case report
]. During 20th
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”
]. 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
]. Simultaneously, an identical trend of changes was reported from South Africa in south hemisphere
]. Then, remarkable increase of MS incidence and prevalence were reported from various locations such as Denmark, Faroe Islands, Norway and Australia after 1960
Afterwards, however higher latitudes experienced a decreasing trend of incidence for a short period after 1965–70
], 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
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
]. 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
]. 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”
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 19th
century and in medicine history of all previous centuries
], but also it can clarify why MS incidence and prevalence have raised during 20th
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 (20th
cycle), but backed to more than 150 spots in the maximums of the following cycles. Figure
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.
Figure 5 Solar cycles and sunspot numbers. Note: number in the stars indicates to the solar cycle number. Reproduced by the kind permission of National Geophysical Data Center
In both Figures
, 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.
Gradual attenuation of latitudinal gradient of MS
In recent decades, increasing prevalence of MS in some low latitude areas like Italy, against the expected north–south gradient of MS
], led to attenuation of previously prominent latitudinal gradient of MS
]. 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
]. 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.
The effect of month of birth
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
]. Previously, it has been tried to explain this feature by means of maternal exposure to ultraviolet in the first trimester
]. As CNS myelination occurs mainly in the third trimester, mostly from 29–39 gestational weeks
], 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
]. At this time, however both hemispheres are affected, negative interplanetary magnetic field Bx
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
]. In September, the situation is vice versa and reconnection phenomenon is facilitated in the southern hemisphere high latitudes
]. 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
] 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
]. They tried to explain these epidemics by defining a hypothetical pathogen, possibly introduced by British troops in 1945
]. Nevertheless, such a pathogen has not been found
Considering the fact that solar magnetic activities and related GMDs during 20th 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 17th, 18th, 19th and 21st 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.
Comparison with vitamin D hypothesis (VDH)
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
]. 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
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-17th
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
]. 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
]. Moreover, VDH cannot exactly illuminate the cause of recent attenuation of latitudinal gradient of MS prevalence and some phenomenon like MS epidemics
Magnetic resonance imaging (MRI): should we be concerned about it?
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
. 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
], 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
], 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
]. 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.