Transcranial static magnetic field stimulation in man: making things as simple as possible?

At first glance, Albert Einstein's statement ‘Make things as simple as possible, but not simpler’ comes to mind when seeing the work by Oliviero and coworkers in a recent issue of The Journal of Physiology (Oliviero et al. 2011). The authors claim that 10 min continuous transcranial application of a static magnetic field (transcranial static magnetic field stimulation; tSMS) at the motor cortex is able to induce an average reduction of motor cortex excitability of up to 25%, lasting for several minutes after the end of tSMS. Efficacy was determined by transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs). At second glance, skepticism may arise since this area has been poisoned by hosts of medical and paramedical therapists making money with obscure magnetic treatment devices, most likely exploiting the placebo effect (on the reliability of available data see a very critical review by Colbert et al. (2009)). A look at the homepage of the distributor of the magnet used by Oliviero et al. (http://www.supermagnete.de/faq/800gauss) is also worthwhile, namely in the section of frequently asked questions: ‘Do you sell therapeutic magnets? Answer: No. Having said that, the magnets that you can buy elsewhere at unbelievable prices are, in most cases, the same as our neodymium magnets … just much more expensive. Every alternative therapist that works with magnets and every salesperson that sells “therapeutic magnets” will claim that science has not yet developed the necessary methods to detect the true effects of magnets on humans. At best, I can see how a placebo-effect can occur, as with most other alternative healing methods that also have no scientific background. However there are many people who swear by this method and it cannot be said with any certainty that it will not be proven correct in time. ’ Thus Antonio Oliviero and coworkers’ work not only has the potential to open a new, very inexpensive and simple research approach for influencing brain activity, but also to be misused to legitimatize obscure medical treatment methods. The paper by Oliviero et al. (2011) seems to be the first to claim an influence of static magnetic fields on brain excitability as measured by TMS. In another recent experiment, magnetic resonance imaging (MRI) led to a transient prolongation of the silent period and an increase of motor threshold in 12 subjects both at 1.5 and 7 tesla (T) (Schlamann et al. 2010). Since these effects occurred, however, only after scanning and not during sole exposition to the static MRI field, the latter was not assumed to induce effects in brain function. It remains to be investigated whether straight or bent magnetic flux lines play an essential role in this difference. How do the magnetic field intensities compare with those applied in the MRI? The decline of the magnetic field of the magnet S-45–30-N results in the relation between distance and intensity (http://www.supermagnete.de/faq/800gauss) shown in Table 1: Table 1 Relation between distance and intensity Thus roughly at a depth of 2 cm, the static magnetic field is in a range of 0.1 T. Neodymium magnets (NdFeB) as used here are amongst the strongest type of permanent magnet available. They are made from an alloy of neodymium, iron and boron and are very difficult to demagnetize. Developed in 1982, they largely replaced more expensive versions from other materials originating in the 1970s. According to physicists working in the area, no stronger permanent magnets are to be expected in the near future. How do electric DC fields compare with static magnetic fields? Neural networks are sensitive to electric fields as low as 140 μV mm−1 root mean square (Francis et al. 2003). It was shown that a 1 mV mm−1 uniform field induced on average a transmembrane potential change of ∼0.1 mV (Radman et al. 2007). Although this is not sufficient to bring a neuron from rest to threshold and induce spike generation, the authors favoured changes in spike timing as the underlying mechanism. It is difficult to compare DC electric fields directly to static magnetic fields, since local diamagnetic and paramagnetic properties of the tissue play an essential role (Rosen 2003). Magnetic field gradients can intrude into cells avoiding shielding by the high dielectric property of the cell membrane electric fields (overview in Funk et al. 2009). Low-intensity stimuli are investigated not only with static but also with pulsed electromagnetic fields, for which recently an efficacy was claimed for treating depressive patients (Martiny et al. 2010). How do the results of these low-intensity fields compare with traditional methods such as repetitive TMS? Bisecting effect size usually requires quadrupling the number of subjects in any experiment in order to obtain reliable results. Patient numbers, both in the Martiny et al. study (n = 25) and the numbers of subjects in the data by Oliviero et al. (n = 11), suggest a magnitude of effect roughly in the order of other studies using other neuroplasticity-inducing methods, such as transcranial direct current stimulation (tDCS) or theta burst stimulation. In the case of an ideal magnet, it would not be possible to induce an electric field from a static magnetic field. Thus other effects than shifting membrane potentials are needed for explanation. As summarized by Rosen (2003), several mechanisms may explain the effects of static magnetic fields (SMFs). Likely are alterations in membrane calcium ion and to a lesser extent sodium ion flux, amongst others, based on the diamagnetic anisotropic properties of membrane phospholipids. An activation of c-Jun N-terminal kinase (JNK), increasing monotonically with magnetic field strength, with a maximal activation of approximately 10% at 5 T, was also found, whereas the activation of extracellular-regulated kinase (ERK) shows a maximum at 0.75 T. According to the authors, one mechanism involved the activation of voltage-dependent Ca2+ channel opening, since intracellular Ca2+ concentration was also found to be modified by the SMF (Prina-Mello et al. 2006). Why did the authors see inhibition and not excitation? Recent evidence suggests that for theta burst stimulation (Doeltgen & Ridding 2011), first inhibition is induced at intensities above threshold but when increasing intensity further excitation dominates. Another explanation might be that if calcium channels are impeded, fast calcium influx as required for induction of LTP might be more affected than slow calcium influx as required for LTD. Also the movement of ions themselves such as Na+ or Ca2+ may be affected in a magnetic field. The magnet's weight of 360 g makes longer-term stimulation possible, as it might be carried by a patient or subject for hours or longer, or be simply integrated into e.g. a helmet. However, many more questions still have to be answered: will longer use lead to stronger or longer aftereffects or might this cause a switch from MEP inhibition to MEP facilitation similar to doubling the duration of inhibitory theta burst stimulation (Gamboa et al. 2010)? If calcium and sodium channels are the main target of tSMS, in what way will co-medication of calcium or sodium channel blockers affect the results? One problem seems to be insurmountable; whereas fMRI can now be combined with almost any type of magnetic or electric stimulation (Antal et al. 2011), there seems to be no possibility of investigating tSMS during MRI. Thus tSMS may turn out not to be altogether as simple as it appears at first glance.