300–30,000 kHz (or 0.3–30 MHz with wavelengths from 1000 m to 10 m) is used in medicine for ablating, coagulating, and cauterizing tissue
The influence of both EM and static magnetic fields on cells, tissues, plants, and animals has been studied (Berg 1993). Exposure to EM fields has been reported to increase the risk of certain types of cancer, such as leukemia, cancer of the central nervous system, and lymphoma (Wertheimer and Leeper 1979; Savitz et al. 1988). The effects of extremely low-frequency (ELF) EM fields on biological systems have also been evaluated by various groups (Blank 1993; Saunders, Sienkiewicz, and Kowalczuk 1991). Different targets including proliferation, enzyme reactions, biopolymer syntheses, and membrane transport have been investigated with respect to their alteration by EM energy (Berg 1995; Goodman, Greenbaum, and Marron 1995). For example, proliferation yield increased more than 25% over the control when a 0.5 mT, 50 Hz EM field was added to the yeast Saccharomyces cerelisiae (Mehedintu and Berg 1997). With Corynebacterium glutamicum, it was found that an amplitude of 3.4 mT at a frequency of 15 Hz increased the Adenosine Triphosphate (ATP) level more than 20% compared with the control after 8 hours of continuous exposure (Lei and Berg 1998). In another report, the colony-forming efficiency increased 40%– 70% over the control when adding a 1.1 mT, 60 Hz EM field to JB6 cells (West et al. 1994).
Since the late 1950s, the interaction of living cells with EM fields has been the subject of an enormous ongoing research effort. An extremely wide variety of phenomena have being investigated. These range from cellular effects due to weak low-frequency EM fields associated with transmission lines and household wiring (Davis et al. 1992) to electrical trauma arising from exposure to strong electric fields (Lee and Kolodney 1987; Gaylor, Prakah-Asante, and Lee 1988; Bhatt, Gaylor, and Lee 1990; Lee, Canaday, and Hammer 1993; Block et al. 1995). Even in the case of household wiring, a large spectrum of situations is of interest, from commonly occurring domestic and industrial incidents involving low-frequency main voltage to much rarer cases of radio-frequency shock resulting from contact with very high-voltage radio masts (Hocking et al. 1994). The field of electric field interactions with biotissues is vast and includes aspects such as animal navigation, endogenous fields and currents, drug delivery and other medical interventions, human health hazards from environmental and occupational EM fields (Blank and Findl 1987; Reilly 1992; Wiltschko and Wiltschko 1995; Polk and Postow 1996) to cellular electromanipulation (Buescher and Schoenbach 2003), and cancer therapy (Nuccitelli et al. 2006). The influence of both EM and static magnetic fields on cells, tissues, plants, and animals has been studied (Berg 1993). Exposure to EM fields has been reported to increase the risk of certain types of cancer, such as leukemia, cancer of the central nervous system, and lymphoma (Wertheimer and Leeper 1979; Savitz et al. 1988).
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The effects of extremely low-frequency (ELF) EM fields on biological systems have also been evaluated by various groups (Blank 1993; Saunders, Sienkiewicz, and Kowalczuk 1991). Different targets including proliferation, enzyme reactions, biopolymer syntheses, and membrane transport have been investigated with respect to their alteration by EM energy (Berg 1995; Goodman, Greenbaum, and Marron 1995). For example, proliferation yield increased more than 25% over the control when a 0.5 mT, 50 Hz EM field was added to the yeast Saccharomyces cerelisiae (Mehedintu and Berg 1997). With Corynebacterium glutamicum, it was found that an amplitude of 3.4 mT at a frequency of 15 Hz increased the Adenosine Triphosphate (ATP) level more than 20% compared with the control after 8 hours of continuous exposure (Lei and Berg 1998). In another report, the colony-forming efficiency increased 40%– 70% over the control when adding a 1.1 mT, 60 Hz EM field to JB6 cells (West et al. 1994). The earliest report of bioeffects arising from the direct application of voltage using contact techniques (as opposed to contactless exposure using EM radiation) was in 1958. Exposure of the nodes of Ranvier to electric fields was seen to lead to some type of “electrical breakdown” (Stampfli 1958). Almost a decade later, damaging effects of strong electric fields on microorganisms were reported suggesting nonthermal membrane interactions (Sale and Hamilton 1967, 1968). Subsequent experiments showed that strong electric field pulses caused molecular transport across a biological membrane (Neumann and Rosenheck 1972). Artificial planar bilayer membrane measurements provided strong support for the transient aqueous pore hypothesis (Abidor et al. 1979; Pastushenko and Chizmadzhev 1982; Melikov 2001). This evidence invoked the structural rearrangement of membrane molecules with charging. The prominent 74 Electromagnetic Fields in Biological Systems observable effect was the rapid increase of electrical conductivity. The conductivity change was attributed to pore formation in the lipid bilayer membrane. Further evidence for chemical transport through membranes involved experiments with red blood cells (Sukhorukov, Mussauer, and Zimmermann 1998; Kinosita and Tsong 1977; Teissie and Tsong 1981; Serpersu, Kinosita and Tsong 1985). Erythrocytes were also used to demonstrate that DNA delivery into a cell is associated with dielectric breakdown of the cell membrane (Auer, Brandner, and Bodemer 1976). A large body of work has also been carried out on the interaction of small spheroidal cells with external fields, motivated by application to cardiac defibrillation. The literature included investigation of cell excitation (Tung and Borderies 1992; Krassowska and Neu 1994; Fishler et al. 1996; Cheng, Tung, and Sobie 1999) and membrane electroporation (O’Neill and Tung 1991; DeBruin and Krassowska 1998, 1999). Applications of cellular electric stimulation can roughly be divided into two broad groups. On the one hand, electric fields can be used as tools to modify various properties and responses of cells such as increases in membrane permeability for introducing various molecules and drugs into cells (Neumann et al. 1982; Mir et al. 1995; Sersa et al. 1995; Mouneimne et al. 1990; Raffy and Teissié 1995), fusion of cells (Zimmermann 1982; Sowers 1987), physical separation of different cell types (Arnold 2001), the killing of nonhealthy cells, and neuromuscular manipulation for therapy (Wang et al. 2002). The other aspect of electric pulsing is geared toward its utility to characterize various properties of biological cells or their constituents, both in suspensions and in tissues. Among the most important approaches in such characterization is the evaluation of cellular responses to electric fields at different frequencies. By varying the frequency of the field, values of the measured parameters form a spectrum. Values of frequencydependent bulk dielectric permittivity of suspensions or tissues, cellular angular velocity in rotating electric fields, and the dielectrophoretic spectrum evaluation are some of the important aspects that can be assessed (Foster and Schwan 1989; Führ, Glaser, and Hagedorn 1985), which would otherwise be difficult to measure. The characterization techniques rely on the fact that dielectric properties of biological systems typically display extremely high dielectric permittivity at low frequencies and fall off in distinct steps with increasing frequency. These frequency-dependent changes permit identification and investigation of a number of completely different underlying processes. The basic mechanism underlying a majority of these methods and field induced biophenomena is the induction of a potential difference across the membrane by the external electric field. The seat of the electric field–driven bioresponses tends to be membranes because these sheaths represent nonconducting barriers that can easily be charged by external voltage pulsing. Consequently, large electric fields can be created across membranes that can then drive a host of bioeffects. The membranes are crucial not only because high electric fields can be created in these regions but also because important biological processes (e.g., irreversible apoptosis) are launched from these sites. For example, the extrinsic apoptotic pathway (Green 2000; Peter and Krammer 2003) involves the clustering of molecules such as the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), Fas-associated protein with death domain (FADD), and procaspase-8 leading to the formation of the death-inducing production. This in turn sets into motion a series of biochemical reactions that eventually lead to apoptosis Pulsed Electric Fields in Biological Cells and Membranes 75 (Song, Joshi, and Beebe 2010; Bagci et al. 2006; Budihardjo et al. 1999; Li, P. et al. 1997). The other apoptosis route (known as the intrinsic pathway) involves cytochrome c release from another membrane—the mitochondria, which is an intracellular organelle (Zoratti and Szabo 1995; Marzo et al. 1998). The classical theory of transmembrane voltage induction was developed in the 1950s by H. P. Schwan and coworkers (Schwan 1957; Pauly and Schwan 1959). Discussions on the increase in permeability (Neumann and Rosenheck 1972) of the plasma membrane of a biological cell—an effect that was termed electroporation—appeared in 1972. The electric fields required to achieve electroporation depend on the duration of the applied pulse because this process involves the gradual charging of the capacitive sheath followed by the molecular rearrangement of the lipids. Typical pulses range from tens of milliseconds with amplitudes of several hundred V/cm to pulses of a few microseconds or smaller but requiring fields of several kV/cm. More recently, the electrical pulse duration range has been shortened into the nanosecond range. Pulse durations as brief as several nanoseconds and pulse amplitudes as high as 300 kV/cm are being used (Schoenbach et al. 2008). Conceptually, such short pulse durations offer the possibility of triggering purely electrically driven responses without any thermal heating. In principle, fast processes such as electron transfers between molecules (Kranich et al. 2008), electrophoretic separation and self-organization (Groves, Boxer, and McConnell 1997), or field induced changes in reaction kinetics (De Biase et al. 2009) could also be fashioned. An even newer field of research opens up when the pulse duration is decreased further into the subnanosecond range. This push toward further pulse shortening is driven in part by the possibility of using wideband antennas, rather than direct contact electrodes, to deliver electrical energy and create fields in tissues as discussed in the literature (Kumar et al. 2011). Also conceptually, because the dielectric permittivity of membranes (and the aqueous media) has a nonlocal, time-dependent polarization, ultrafast excitation can effectively sample transient permittivities that are different from the steadystate values. This provides for electrical-based value selection of the dielectric parameters. The influence of short pulses has been shown to reach into the cell interior (Schoenbach, Beebe, and Buescher 2001). This can perhaps be better understood through the following simple argument. Consider a spherical shell with a concentric inner organelle as shown in Figure 2.1. We assume for simplicity that the conductivities of both membranes are zero and that current continuity applies across line ABCDE shown in Figure 2.1. For long-duration, slow-rising pulses, a near quasisteady state prevails, and the current density, J, is nearly given by J = σE + εdE/dt ∼ σE, where E, σ, and ε refer to the local electric field, conductivity, and permittivity, respectively. Because σ for the membranes is nearly zero, there is virtually no current through them. Choosing the cell center as the reference voltage, the node potentials are then roughly as follows: VD ∼ 0 and VB ∼ VC. Also, the negligible membrane current, under the quasisteady state forces is VCD ∼ VFG ∼ 0. Thus, the potential across the inner membrane can be expected to be very modest, at best. This implies that membrane poration and other electrical effects would not be strong across cellular substructures and inner organelles, and the outer membrane would shield the cell at almost all times. Fast-rising, ultrashort pulses, on the other hand, would force a large nonequilibrium transient and create substantially large values of VCD and VFG across the inner membranes. This would allow fairly large potentials (∼1 V or so, a value 76 Electromagnetic Fields in Biological Systems A B C D VE = 0V F G I H σ > 0 σ > 0 σ = 0 σ = 0 Figure 2.1 Rough voltage analysis in the quasisteady state for a model double-shelled cell in response to a slow rising, long pulse. (After Joshi, R. P., Q. Hu, K. H. Schoenbach, and S. J. Beebe. 2004. Phys Rev E 69:051901.) close to the electroporation threshold) to be developed across the membranes of inner organelles (e.g., the mitochondria and the endoplasmic reticulum). It becomes possible to initiate a host of intracellular bioeffects through the use of such ultrashort pulsing. High-intensity, nanosecond, pulsed electric fields (nsPEFs) have been shown to be versatile nonthermal tools capable of producing cellular electroporation (Schoenbach et al. 2004), intracellular calcium release (Vernier et al. 2003; Beebe et al. 2004; Joshi et al. 2007), shrinkage of tumors (Nuccitelli et al. 2006) and cellular apoptosis (Beebe et al. 2003), temporary blockage of action potential propagation in nerves (Joshi et al. 2008), activation of platelets, and release of growth factors for accelerated wound healing (Schoenbach et al. 2007).
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Transcranial magnetic stimulation, for example, single- and paired-pulse TMSs and rTMS, is a useful method to examine dynamic brain function without causing any pain, producing a so-called virtual lesion or virtual excitation for a short period. Accordingly, TMS has become increasingly popular and is now a well-established and noninvasive technique in cognitive neuroscience, in particular, in functional, diagnostic, and therapeutic research on the brain. In brain functional research, magnetic stimulation for the temporary blockage or modification of the facultative information process and cognitive process of various sensory systems has been used to identify localization and connecting pathways of brain function. Single- or paired-pulse TMS and rTMS were reviewed by Pascual-Leone et al. (2002) and Fitzgerald, Fountain, and Daskalakis (2006), respectively. In some cases, applications of TMS disturb brain function temporarily, which results in a virtual lesion in the brain. Zangaladze et al. (1999) showed that the disruption of the function of the occipital cortex with the use of focal TMS interferes with the tactile discrimination of grating orientation. Epstein et al. (2002) used TMS to investigate memory encoding and retrieval, particularly the role of DLPFC in associative memory for visual patterns. TMS was applied on dorsolateral prefrontal cortex of human subjects during 158 Electromagnetic Fields in Biological Systems associative learning task to disturb brain function related to memory and quick retrieval of associative memory. The TMS disrupted associative learning of abstract patterns over the right frontal area, which suggested that the participating cortical networks may be lateralized in accordance with classic concepts of hemispheric specialization. This is the first study to verify the important role of the dorsolateral prefrontal cortex of humans as the retrieval function by TMS method. Traditionally, stimuli are applied at various scalp positions using a latitude- and longitude-based coordinate system referenced to Cz (central midline placement of electrodes at specific intervals along the head) in the 10–20 international system at the vertex, while the amplitude of the MEPs generated in contralateral muscles is also measured (Ueno, Matsuda, and Fujiki 1989, 1990). This gives a “map” of the sites on the scalp from which responses can be obtained by each reference muscle. Rothwell et al. (1987) revealed the enormous clinical importance of TMS in motor function evaluation. Regarding the therapeutic use of TMS, Pascual-Leone et al. (1996) studied the effects of focal rTMS (10 Hz, produced MEP of greater than or equal to 50 μV) on the depressive symptoms in 17 patients with medication-resistant depression of psychotic subtype. The study was designed as a multiple crossover, randomized placebo-controlled trial. Sham rTMS and stimulation of different cortical areas were used as controls. Left DLPFC rTMS resulted in significant decrease in scores on the Hamilton depression rating scale (HDRS) and the self-rated Beck questionnaire (BQ). Eleven of the total 17 patients showed pronounced improvement that lasted for about 2 weeks after 5 days of daily rTMS sessions. No patient experienced any significant undesirable side effects. These findings emphasized the role of the left DLPFC in depression and suggested that rTMS of the left DLPFC might become a safe, nonconvulsive alternative to electroconvulsive treatment for depression. Kujirai et al. (2006) reported that TMS pulses over the hand area of motor cortex activate different subpopulations of synaptic connections if the direction of the induced current in the brain is reversed from posterior–anterior (PA) direction to anterior– posterior (AP) direction. The authors tested whether this also made a difference to the after-effects of paired associative stimulation (PAS: ulnar nerve stimulation followed 25 milliseconds later by a TMS pulse). When 50 pairs of stimuli (0.1 Hz) were applied using conventional suprathreshold PA-PAS in resting subjects, there was no effect on MEPs in the FDI muscle. In contrast, when the same number of pulses were given while subjects made a small tonic (5% maximum) contraction, MEP was facilitated and rMT reduced when AP but not PA pulses were used. Subsequent experiments employed subthreshold TMS (95% of the aMT) during voluntary muscle contraction. Moter-evoked potential facilitation accompanied by reduced AP threshold occurred when PAS was given using AP pulses (AP-Sub-PAS), whereas PAS using PA pulses (PA-Sub-PAS) had no excitatory effect. There was no facilitation if the ulnar nerve stimulus was replaced by digital nerve stimulation. There was a tendency for short-interval intracortical inhibition (SICI) to decrease and intracortical facilitation (ICF) to increase after AP-Sub-PAS. The authors proposed that the increased effectiveness of AP-Sub-PAS over PA-Sub-PAS is due to the fact that AP TMS more readily activates I3 inputs to corticospinal neurons, and hence I3 inputs are an important component of associative plasticity in the human motor cortex. Static, Low-Frequency, and Pulsed Magnetic Fields 159 Strafella, Ko, and Monchi (2006) examined placebo effects on patients with PD using sham rTMS (placebo-rTMS) alone. The authors measured the changes in striatal [11C] raclopride binding potentials (BP) together with positron emission tomography (PET). Placebo-rTMS induced significant bilateral reduction in [11C] raclopride BP in dorsal and ventral striatum as compared with the baseline condition. This reduction in BP is indicative of an increase in dopamine neurotransmission. The changes in [11C] raclopride binding were more evident in the hemisphere contralateral to the more affected side, supporting the hypothesis that the more severe the symptoms the greater the drive for symptom relief and therefore the placebo response. This is the first study addressing the placebo contribution during rTMS. Although the results seemed to confirm earlier evidence that expectation induces dopaminergic placebo effects, they also suggested the importance of placebo-controlled studies in future clinical trials involving brain stimulation techniques. Kamida et al. (2007) assessed whether paired-pulse TMS–induced MEP can predict surgical prognosis in patients with intractable epilepsy. The MEP of unilateral hand muscles were recorded following paired-pulse TMS of the motor cortex. The authors concluded that paired-pulse TMS–induced MEP may provide predictive value in terms of surgical outcomes in patients with intractable epilepsy. Jung et al. (2008) investigated the changes in cortical excitability of the human motor cortex induced by rTMS (10 Hz, produced MEP of greater than or equal to 50 μV) of different stimulation durations (5 and 1.5 seconds) over the motor hot spot for left FDI muscle. The authors concluded that with different stimulation durations, highfrequency subthreshold rTMS can produce different patterns of long-lasting changes in corticospinal and intracortical excitability in stimulated and unstimulated motor cortex in healthy subjects. The results have important implications for the selection of stimulation parameters other than the frequency of rTMS. Because DLPFC is a common target for rTMS experiments and therapeutic protocols, Fitzgerald et al. (2009) investigated the optimal method for the localization of DLPFC for use in these studies. Twelve healthy subjects underwent a structural MRI scan, a TMS procedure to establish the location of the motor cortex, and a neuronavigational procedure to assess the relative position of the DLPFC. Several EEG points and a position 5 cm anterior to motor cortex were established. The DLPFC site used was identified as being approximately halfway between the EEG points F3 and AF3. This point is considerably more anterior than the point identified by measuring 5 cm anterior to the motor cortex. The authors concluded that EEG points provide a useful way to optimally identify the DLPFC site. Metaplasticity refers to activity-dependent changes in neural functions that modulate subsequent synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD) (Abraham 2008). Using rTMS (20 Hz, produced MEP of greater than or equal to 50 μV), Cohen et al. (2010) investigated whether metaplasticity is dependent on a particular phase of the normal sleep–wake/circadian cycle. The authors suggested that the timing of sessions relative to the sleep–wake/circadian cycle may be a critical factor in the cumulative effect of treatment. Filipović, Rothwell, and Bhatia (2010) demonstrated that low-frequency (≤1 Hz) rTMS (LF-rTMS) can reduce excitability in the underlying cortex, promote inhibition, or do 160 Electromagnetic Fields in Biological Systems both. In particular, using LF-rTMS the authors found the impaired inhibitory mechanisms in motor cortex of patients with PD. Previously, Filipović et al. (2009) examined the effects of LF-rTMS (1 Hz, 1800 pulses) on dyskinesia in PD. The stimulator intensity was set individually to just below the aMT. The LF-rTMS was applied twice over the motor cortex for four consecutive days; once real stimuli were used and once sham stimulation was used. Evaluations were done at the baseline and one day after the end of each treatment series. Filipović, Rothwell, and Bhatia (2010) further evaluated the delayed (24-hour) effects of LF-rTMS treatment on physiological measures of excitability of the motor cortex in the same patients. The authors found that LF-rTMS delivered over several consecutive days changes the excitability of the motor cortex by increasing the excitability of inhibitory circuits. The effects persist for at least a day after rTMS. Shirota et al. (2010) evaluated cerebellar function using TMS to determine whether subclinical cerebellar involvement is present in progressive supranuclear palsy (PSP) patients. The authors studied 11 patients with PSP, 11 patients with PD, and 10 agematched controls. Motor-evoked potentials were recorded from the hand muscle. Cerebellar function was evaluated using suppressive effects of TMS over the cerebellum on MEP elicited by TMS over the contralateral motor cortex, which is called cerebellar inhibition (CBI). Interstimulus intervals of 4–8 milliseconds were used, and the time course of CBI was analyzed. The CBI was found to be reduced in PSP patients. By contrast, the CBI was normal in PD patients in their on state (phases with good response to medication and few symptoms). Although the CBI in their off state (phases with no response to medication and more severe symptoms) should be examined in future studies, the results suggested that Purkinje cells or the dentatothalamocortical pathway assessed by CBI is involved in PSP. These results are compatible with the pathological findings showing severe dentate nucleus degeneration in PSP patients. Hiscock et al. (2008) reviewed evidence regarding the effect of rTMS on corticospinal pathway excitability and motor function in healthy adults and in people in the aftermath of stroke. After stroke there was a trend for MEP recovery (i.e., presence of MEP) after 10 daily sessions of 3 Hz rTMS (one study). Motor function in healthy adults might be adversely affected by 1 Hz rTMS (two studies), whereas combined frequency rTMS was found to have no effect on motor function (one study). The authors concluded that there is as yet insufficient published evidence to guide the dosage of rTMS to the lesioned hemisphere after stroke to improve recovery of a paretic limb. Moreover, apparently there is variability in response to rTMS in healthy adults. Contralesional dorsal premotor cortex (cPMd) may support residual motor function following stroke. Using TMS-fMRI, Bestmann et al. (2010) performed two complementary experiments to explore how cPMd might perform this role in a group of chronic stroke patients. First, they used paired-coil TMS (11 Hz) to establish the physiological influence of cPMd on ipsilesional primary motor cortex (iM1) at rest. They found that this influence became less inhibitory/more facilitatory in patients with greater clinical impairment. Second, they applied TMS over cPMd during fMRI (1.5 T) in these patients to examine the causal influence of cPMd TMS on the whole network of surviving cortical motor areas in both hemispheres and to check whether these influences could change during movement of the affected hand after stroke. The authors confirmed that hand grip–related activation in cPMd was greater in more impaired patients. Furthermore, Static, Low-Frequency, and Pulsed Magnetic Fields 161 the peak ipsilesional sensorimotor cortex activity shifted posteriorly in more impaired patients. Critical new findings were that concurrent TMS-fMRI results correlated with the level of both clinical impairment and neurophysiological impairment. Specifically, greater clinical and neurophysiological impairment was associated with a stronger facilitating influence of cPMd TMS on blood oxygenation level–dependent (BOLD) signal in posterior parts of ipsilesional sensorimotor cortex during hand grip, corresponding to the posteriorly shifted sensorimotor activity seen in more impaired patients. The cPMd TMS was not found to influence activity in other brain regions in either hemisphere. The authors suggested that this state-dependent influence on ipsilesional sensorimotor regions provides a mechanism by which cPMd supports recovered function after stroke. Dimyan and Cohen (2010) discussed the use of TMS in the diagnosis, prognosis, and therapy of poststroke motor disability and emphasized that TMS is a useful tool to explore mechanisms of neuroplasticity during spontaneous and treatment-induced recovery of motor function to develop more rational and clinically useful interventions for stroke rehabilitation. The spatial extent of the effects of TMS on neural tissue is only coarsely understood. One key problem is the realistic calculation of the electric field induced in the brain, which proves difficult due to the complex gyral folding pattern that results in an inhomogeneous conductivity distribution within the skull. Thielscher, Opitz, and Windhoff (2011) estimated the electric field induced in the brain using the finite element method (FEM) together with a high-resolution volume mesh of the human head to better characterize the field induced in cortical gray matter (GM). The volume mesh was constructed from T1-weighted structural MRI to ensure an anatomically accurate modeling of the gyrification pattern. Five tissue types were taken into account, corresponding to skin, skull, cerebrospinal fluid (CSF) including the ventricles, cortical GM, and cortical white matter. The authors characterized the effect of current direction on the electric field distribution in GM. The field strength in GM was increased by up to 51% when the induced currents were perpendicular to the local gyrus orientation. This effect was mainly restricted to gyral crowns and lips, and did not extend into the sulcal walls. As a result, the focality of the fields induced in GM was increased. The authors speculated that this enhancement effect might in part explain the dependency of stimulation thresholds on coil orientation, which is commonly observed in TMS motor cortex studies. In contrast to the clear-cut effects of the gyrification pattern on induced field strength, current directions were predominantly influenced by the CSF–skull boundary. In general, exposure to time-varying EMFs results in internal electric (E) fields, body currents, and energy absorption in tissues that depend on the coupling mechanisms and frequency involved. In the case of ELF-EMFs of less than 300 Hz, nonthermal (no heating) effect is expected because the absorbed energy in terms of the local specific absorption rate (SAR; watts per gram) in biological tissues is negligible according to the following equation (Caorsi, Pastorino, and Raffetto 1999): Local SAR = σ E 2 (3.4) 2δ 162 Electromagnetic Fields in Biological Systems where E is the electric field (in volts per meter), σ is the electric conductivity (in siemens per meter; approximately 0.2 S/m in average tissue conductivity [ICNIRP 1998; Reilly 1998]; approximately 0.1 S/m in brain tissue conductivity [Saunders and Jefferys 2002]), and δ is the human body density (in kilogram per cubic meter; approximately l000 kg/m3 in human body [Schult et al. 2010]). For instance, the whole-body average SAR limits of 0.4 W/kg for controlled environments and 0.08 W/kg for uncontrolled environments estimated by Gandhi (2002) are identical to those mentioned in the International Commission on Non-Ionizing Radiation Protection (ICNIRP) 1998 standard. In contrast, heating abnormal tissue with high-SAR power such as microwave cardiac ablation (MCA) is used to treat heart tissue that allows abnormal electrical conduction by heating it to the point of inactivation (Lin 1999; Rappaport 2004). Lin (2007) commented that most exposure guidelines are promulgated on a 4-W/kg SAR to prevent any whole-body exposure from raising the body temperature to 1°C above the norm at 37°C. However, the Lin research group later suggeted that temperature distributions do not always correlate well with SAR distributions and the regulatory limits on local temperature may not be exceeded as readily as those on local SAR (Wang et al. 2007). In modeling temperature increase during MRI of the human head in a head-sized volume coil at up to 3.0-W/kg head-average SAR, the Lin research group concluded that it may not be necessary to consider thermally induced changes in physiological response (Wang et al. 2008). In addition, Barnes (2006) mentioned that there is a debate regarding whether effects other than the increase in temperature should be used to limit the amount of radiated power. In the case of EMFs over about 100 kHz, it was assumed that “Joule energy” could contribute to the thermal effect through large induced currents. In contrast, at frequencies below 100 kHz, it was presumed that electric fields and currents are induced in the body by time-varying external magnetic fields and then the induced E fields in the body may lead to a variation of membrane potentials at the cellular level. Electric excitation of the membrane might be the result of such changes in membrane potentials (ICNIRP 2004). For TMS and rTMS, a high-intensity, fast magnetic pulse produces a cortical stimulus or excitation through the induction of locally confined eddy currents and induces a rapid depolarization of the nerve cells; therefore, safety guidelines have been reviewed and discussed for avoiding excitation of the central nervous system (e.g., IEEE 2002; Gandhi 2002; Medical Advisory Secretariat 2004; Reilly 2005; Barnes 2006; Blackman 2006, 2009; ARPANSA 2007; Lin 2007; WHO 2007; Wang et al. 2007, 2008; Wood 2008; Rossi et al. 2009; Casali et al. 2010; ICNIRP 2010; Sandrini, Umiltà, and Rusconi 2011). It has been assumed that the greatest stimulation efficiency occurs if the TMS coil’s induced electric field (y axis) is parallel to cortical columns (Rábago et al. 2009). Multiple target sites within the cortical area of activation were created from the coregistered anatomical and functional images. Electromyography (EMG) feedback from the left FDI was used to assess each target site. The site chosen as the final target site was the one that elicited the best MEP response at the lowest rMT. The TMS-induced MEP response has been used in experiments regarding mirror neurons (Catmur, Walsh, and Heyes 2007). Static, Low-Frequency, and Pulsed Magnetic Fields 163 More recently, guidelines for limiting exposure to time-varying EMFs (1 Hz to 100 kHz) have been proposed as a safety standard by ICNIRP (2010). For example, in the ICNIRP 2010 standard, for EMF exposures in the 1 Hz to 3 kHz range the basic restrictions for induced internal E fields in all tissues of the head and body are 0.8 and 0.4 V/m for occupational and general public exposures, respectively. Perception of surface electric charge, direct stimulation of nerve and muscle tissues, and induction of retinal phosphenes are the only well-established adverse effects, and serve as the basis for exposure guidelines (ICNIRP 2010). Typical values of induced internal E fields in exposures to EMFs are shown in Table 3.2. There are several studies indicating that induced E fields can stimulate excitable tissues that may influence neuronal activity and excitability, and therefore these values should be taken into account in estimations based on the conditions. Wood (2008) evaluated thresholds for nerve excitation elicited by time-varying magnetic stimulation based on the experimental data from published papers (see Table 3.2). Ueno, Matsuda, and Hiwaki (1991) obtained a threshold of 9.5 V/m for frog sciatic nerves at 45° to the induced E field direction by direct measurements using magnetic stimulation. These authors further suggested that the existence of vectorial characteristics of stimulating currents for neural excitation reflects both the functional and the anatomical organization of neural fibers in the brain. Estimating threshold values (e.g., threshold intensity for eliciting MEP) is extremely important for standardization of stimulation in double-pulse TMS (Kujirai et al. 1993; Ilic et al. 2002), and good threshold estimates for brain areas would be helpful in therapeutic applications of TMS (Lisanby, Kinnunen, and Crupain 2002).Table 3.2 Typical Values of Induced Internal Electric (E) Fields in Exposures to Time-Varying EMFs Tissues Induced E Fields Authors, Year Central nerve 10 V/m Reilly (1998, 2002) Motor cortex 25 V/m (at 50 Hz, 3.7 T) Kowalski, Silny, and Buchner (2002) Motor cortex 50 V/m Casali et al. (2010) Peripheral nerve 9.5 V/m Ueno, Matsuda, and Hiwaki (1991) Peripheral nerve 2 V/m (in 10 Hz to 1 kHz range) ICNIRP (1998) Peripheral nerve 6 V/m Reilly (1998, 2002) Peripheral nerve 2 V/m Nyenhuis et al. (2001) Peripheral nerve 6 V/m Liu, Zhao, and Crozier (2003) Peripheral nerve 4–6 V/m So, Stuchly, and Nyenhuis (2004) Peripheral nerve 2 V/m Wood (2008) Retinal phosphenes 4–16 mV/m (at 20 Hz, 5 mT) Taki, Suzuki, and Wake (2003) Retinal phosphenes 50–100 mV/m (at 20 Hz, 5 mT) Saunders and Jefferys (2007) Retinal phosphenes 56 mV/m (at 20 Hz) Wood (2008) MEP 20 mV/m Roth, Pell, and Zangen (2010
Conclusion
Over the last three decades, various studies have been carried out to examine the effects of nonthermal magnetic fields, including TMS and MRI fields, on biological systems.
This chapter consisted of two main parts. The first part focused on recent experiments covering topics such as magnetic sensing and behavior, cardiovascular system responses, reproduction and development, genotoxicity, molecular and cellular systems, and free radical and enzyme activity. The second part concentrated on the recent development of diagnostic and therapeutic applications of various magnetic fields together with magnetic orientation for tissue engineering. As shown in this chapter, current studies are more directed toward the development of diagnosis and therapy using biomagnetic phenomena.
With more recent and advanced applications, MEG studies have neurophysiological conditions of neural activities, and brain functions and disorders for mammals, in particular for humans. Moreover, a comparison of the results of MRI and fMRI shows the relationship between brain neural activities associated with BOLD effects and neural current distributions, which may lead to various new observations of dynamics in brain function localizations. The development of new bioimaging technologies such as current-distribution MRI and conductivity MRI, which can directly visualize electrical activities of neurons, enables us to decipher and better understand the dynamics of brain function. These methods have higher temporal resolution (millisecond level) compared with conventional fMRI. The focal and vectorial TMS selectively facilitates or inhibits neuronal activities in targeted regions or hot spots, which is useful for understanding 174 Electromagnetic Fields in Biological Systems