2. Department of Neurodegenerative Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China
Transcranial magnetic stimulation (TMS) was first used by Barker in human brain function research in 1985[1], and has since been gradually developed into a secure and effective neuromodulation technique. In 1994, Pascual-Leone et al. first used it in the treatment of Parkinson's disease (PD)[2-6], and found marked improvement of motor symptoms in patients. Later studies have shown that motor symptoms include motor dysfunction, tremor, rigidity, gait posture[7-12], and non-motor symptoms such as depression[13, 14], and can be improved with TMS treatment. Animal experiments have shown that following TMS treatment, dopamine levels in the hippocampus and striatum of PD models significantly increased[15].
Different therapeutic purposes can be achieved by adjusting the stimulation parameters[16-18]. This article reviews factors influencing the effects of repetitive transcranial magnetic stimulation (rTMS) on the treat-ment of Parkinson's disease, and provides a reference for future research.
2 Physical factorsAccording to Faraday's law of electromagnetic induction, the instantaneous variable magnetic fields elicited by instantaneous variable currents that flow through the stimulus coil can penetrate the skull and elicit currents in neurons. It can change the exci-tability of the central nervous system and affect the synthesis and release of endogenous neurotransmitters regulating neuronal signal transduction[19]. These factors can be divided into two types: physical and biochemical. Physical factors mainly include stimulating coils and stimulating modes. Some formulae relevant to electromagnetic induction are stated below:
① B = NI1L (B, induced magnetic field strength; N, turn ratio; I1, current through the coil; L, inductance)
② L = kμ0μsN2S/l (k, coefficient related to the coil radius-to-length ratio; μ0, vacuum permeability = 4∏ x 10-7; μs, vacuum permeability; S, vacuum permeability (m2); l, coil length (m))
③ E = ΔΦ/Δt (E, induced electromotive force;ΔΦ/Δt, rate of change of magnetic flux) The direction is deter-mined by Lenz's law and the right-hand rule.
④ ΔΦ = ΔBS (Φ, magnetic flux (Wb); B, magnetic induction intensity of uniform magnetic field (T); S, opposite area (m2))
⑤ E = I2R (I2, induced current; R, tissue resistance)
2.1 CoilThe coil is the key component of rTMS, the essence of which is an inductor.
According to the formulae ③ and ④, the induced electromotive force is only affected by changes in the speed of the magnetic flux of the magnetic field, i.e., changes in the current acceleration. According to the formula ①, the induced magnetic field strength is determined by the inductance of the coil, the size of current flowing through the coil, and the number of turns in the coil. According to the formula ②, the inductance of a coil is determined by its radius, shape, length of coil pitch, winding number, and core material.
(1) Shape of the coil
Coil designs are evaluated by accuracy, efficiency (the amount of stimulator energy required to elicit a physiological response), and stimulation depth. The coil shape is a decisive factor for these evaluation criteria: if we ignore the coil shape, calculate using the linear formula, and try to increase the radius of the coil, it becomes difficult for the stimulation to reach deeper than 3 cm; when the depth is up to 4 cm, the stimulus intensity of the superior cortex will reach 145% of the motor threshold MT and some side-effects will occur, while the maximum stimulus intensity according to guidelines is 130% of the MT[20].
The six most common stimulus coil shapes are listed below:
Circular coil
Its influence range is larger and accuracy is poorer than coils of other shapes: both the cerebral hemispheres will be affected when the coil is placed in the CZ point. The larger the coil is, the larger is the effect on the range. It is important that the magnetic induction intensity is maximum and the stimulus intensity is minimum in the central part of the coil, where the magnetic lines are vertical to the brain tissue.
Figure-of-eight coil
This kind of coil is well-focused and the affected range can be confined to be within a few cm2 [21]. It consists of two planar circular coils, which are tied back-to-back in a direction opposite to that of the current. The current at the central segment is in the same direction, so the intensity of the induced magnetic field here is the maximum; the depth that can be achieved is up to 1.5 cm[22].
Double-cone coil
Like the figure-of-eight coil, this coil consists of twocircular coils which are tied back-to-back. However, the two circular coils are not parallel but angulated, and the expansion angle can effectively reduce the energy attenuation. This coil can be used for deep brain stimulation of controlling pelvic floor muscles, or the lower limb muscles in the primary motor cortex, which are located deep inside and are hard to stimulate[23].
The circular coils tied together in an obtuse angle make them more applicable for the head contour. Thus, the induced current in the brain is larger than that induced using the figure-of-eight coil. However, due to its special shape, it is not suitable for simula-tions in the temporal lobe, frontal lobe, and peripheral nervous system.
C-core coil
The shape of this coil is like a stretched C, the opening is downward to wrap the head, and the pitch of the coil windings can be larger, so the coil induc-tance and magnetic field intensity can be effectively reduced at the same time, reducing the side effects[24]. It was shown that the stimulation of the C-core coil could reach depths of 6-7 cm underneath the scalp[25].
The linear attenuation of the magnetic field intensity can be achieved with C-core coil stimulation, which is helpful for studying energy attenuation.
Crown coil
The crown coil is made according to the outline of the head like a hair ribbon loop, and has the same distance from the top of the brain to the mid-latitude. Thus, the crown coil can be used for the stimulation of the peri-callosal, prefrontal, and medial frontal regions.
Hesed coil (H coil, deep stimulation coil)
The H coil is a deep stimulation coil containing rows of wires woven thickly like a helmet wrapped around the head, which can be adjusted in three dimensions according to the target and the induced magnetic field vector needed. Single point stimulation and multi-point focusing with different frequencies at each point can both be achieved by spatial or temporal summation approaches[26]. Its stimulation depth can be up to 6-8 cm underneath the scalp, making its clinical applications promising.
(2) Size of the coil
The size of the coil can influence the penetration of the magnetic field. For example, with an increase in the radius and hem expansion angle of the crown coil, the energy can be effectively decreased, thus making it applicable in deep brain stimulation.
(3) Orientation of placement
Taking the figure-of-eight coil as an example, studies indicate that when the current is perpendicular to the target, the stimulation effect is maximal. Since when the coil is placed vertically in the crack between the two hemispheres of the brain, M1 stimulation can directly affect the pyramidal tract[27]. When the coil is placed parallel to the cerebral fissure and between the two hemispheres, albeit through the connection bet-ween neurons in the brain network[28], TMS treatment will work although the effect may be greatly weakened.
(4) Material of the coil and core
Research has shown that for coils with the same conductivity, permeability, and saturation, the magnetic flux for silicon steel material is 1.8 T, while that for the alum Deming alloy is 2.3 T.
In addition, the thickness of the insulation and the coil-cortex distance can affect the range, shape, and size of the induced magnetic field.
2.2 Stimulus parameters 2.2.1 Stimulus frequency(1) Category
According to the size of the stimulus frequency, rTMS is divided into high-frequency (HF) rTMS (frequency, >1 Hz) and low-frequency (LF) rTMS (frequency, <1 Hz). For low and slow continuous stimulation, the frequency refers to the pulse output (number) per second; for rapid and high frequency stimulation, the frequency refers to the pulse output (number) every second during a series of pulses. For mode rTMS, each string of stimuli is equivalent to a conventional stimulation in a pulse. Thus, there are inter-burst and plexus frequencies: the inter-burst frequency refers to the stimulation burst series output every second (generally 5 Hz), while the plexus fre-quency refers to the stimulation pulse number per second in each string plexus (generally >50 Hz).
(2) Influence
Frequency is the most important parameter in-fluencing the effect of rTMS[29]. Different frequency stimulations can yield different results, and may be associated with either long-term potentiation (LTP) or long-term depression (LTD): LF rTMS causes reduced blood flow and metabolism in the local cerebral area, resulting in the inhibition of local cortical excitability and reduction in the motor evoked potential (MEP) of corresponding target muscle; on the other hand, HF rTMS accelerates the metabolism and blood flow in the local cerebral area[12], resulting in the facilitation of local cortical excitability and an increase in the MEP of the corresponding target muscle[28].
The frequencies of HF rTMS protocols are generally set in the 4-25 Hz range[9]: each string of stimulation lasts for 0.1-1 seconds, with the maximum being up to 30 seconds. The most commonly used frequency is 10 Hz, and the average pulse is always set at 5-6 per string, with a stimulus duration of 0.4-0.5 seconds (average of 3.2 seconds per burst). Some studies have set the intermittent at 10-15 seconds, repeated 250 times, with an average number of pulses of 1400.
Literature related to the therapeutic effects of HF rTMS in PD has reported that HF rTMS in the M1 area can improve motor symptoms; recently, theta burst stimulation (TBS) has also shown good efficacy.
The literature related to the effects of LF rTMS treatment in PD remains controversial. A recent meta-analysis showed that LF rTMS is effective for the treatment of PD[30]. While 1 Hz rTMS in the supplementary motor area (SMA) can improve the patients' motor symptoms, 10 Hz stimulation has no significant effect, which may be due to neuronal cell damage caused by the high frequency stimulation[31]. However, Elahi and others have suggested that the effect of LF rTMS on PD treatment is not obvious[32]; Arias and others found that LF rTMS in the M1 does not improve the motor symptoms of patients with PD[33, 34].
In two studies with large sample sizes, Okabe et al. found that 0.2 Hz rTMS is not effective in the treatment of PD[35], while Shirota et al. confirmed that LF rTMS is effective in the treatment of PD[36]. The contradictory results of the two studies may be due to differences in the stimulation coils or other stimula-tion parameters used.
2.2.2 Stimulus intensity(1) Intensity often used
Stimulus intensity refers to the intensity of the induced magnetic field and it is always described as a percentage of MT (80%-120%). In practical applications, it should be adjusted according to the individual nerve excitability. MT is most commonly used in scientific research and clinical practice, and can be controlled by adjusting the current flowing through the coil and its voltage.
(2) Influence
According to the formula ①, the current is the only variable factor: in order to increase the stimulus depth and range, the flux of the induced magnetic field penetrating into the brain tissue must increase, which requires an increase in the current flowing through the coil. By adjusting the size, direction, and change frequency of the stimulus current, the treatment process can be controlled.
It is imported that the magnetic flux of the induced magnetic field reaches saturation at a certain mag-nitude of current, after which increasing the stimulation current will not only be unprofitable, but also harmful, as it will worsen the side-effects resulting from the enlargement of the affected area and an increase in the energy of the brain tissue, especially the scalp.
2.2.3 Other stimulus parametersThe current flowing through the coil changes the acceleration at a certain point, resulting in the induction of a magnetic field to change at a certain speed, causing an induced current to form in the brain tissue.
After an L-C oscillator circuit, the square output current will induce a magnetic field, whose trace of changing is a sine wave. Additionally, single/double phase of the stimulus waveform, the pulse-width (stimulus time), and the string interval are meaningful; changes in these parameters will yield different results.
A recent study showed that monophasic waveform stimulation (1 Hz, 15 min) can reduce the MEP of the corresponding target muscle while having no effect on the target muscle's MEP after the biphasic wave format first, but a delayed response appearing after a period of time[30].Another study showed that the duration of the single-phase waveform stimulus is longer than that of the dual phase waveform[37].
3 Biological factors 3.1 Stimulus target 3.1.1 Target rangeThe part of the primary motor cortex controlling the hand muscle is so small, that the localization of the induced electric field is important in order to minimize the stimulation of non-target regions[38].
3.1.2 Target depthThe subgenual anterior cingulate cortex (sACC) is central to a network named the cortical-subcortical- limbic network, which is associated with depression. It lies at depths of approximately 6 cm underneath the scalp. Other emerging targets include the nucleus accumbens, located 7 cm underneath the scalp, and the only coil designed for deep stimulation could reach these areas, but with limited effect[24].
3.1.3 Target excitabilityThis is a qualitative factor governing the treatment effect.
(1) Primary motor cortex (M1)
According to the functional area proposed by Brodmann, the primary motor cortex is located in the precentral gyrus (Brodmann Area 4), which lies superficially under the scalp and has a thickness of 1-4 mm. It is located in the center to control random movements of the lateral body skeletal muscles.
Studies have shown that patients with PD show improvements in motor symptoms: one week (short- term) after the rTMS, their unified Parkinson's disease rating scale-III (UPDRS-III) score improved by 3.8 points on an average[9]; 10 Hz, 100% RMT HF rTMS using an 8-shaped coil led to a 19% improvement in their UPDRS-III scores—the pain, walking test, and finger activity sub-scores improved, although there was no change in the depression levels[39].
(2) Supplementary motor area (SMA)
The SMA can be anatomically and functionally divided into two sub-areas, namely SMA proper and pre-SMA. Different from the anterior motor cortex, the SMA is related to the voluntary movement plan. Studies have shown that bradykinesia symptoms in patients with PD improved after 5 Hz rTMS of the SMA[40]. A meta-analysis of rTMS in the treatment of PD confirms that the regulation of the SMA by LF rTMS may be more effective than that of the M1 region. Studies have also shown abnormal spontaneous neural activities in the SMA of patients with PD, which are relevant to bradykinesia, freezing of gait, and other motor symptoms.
At the same time, functional imaging (functional magnetic resonance imaging, fMRI) showed that the functional relation between the prefrontal cortex and the SMA during a complex finger movement task was different before and after the treatment.
(3) Dorsolateral prefrontal cortex (DLPFC)
This area is mainly involved in depression in patients with PD. A 5 Hz, 120% RMT rTMS stimulation in the left prefrontal DLPFC for 4 weeks led to an improvement in the depressive symptoms of the patients similar to that observed following treatment with fluoxetine. Activity in the left fusiform gyrus, cerebellum, and right DLPFC decreased, while activity in the left DLPFC and anterior cingulate gyrus in-creased following rTMS. On the other hand, activity in the right premotor area and right DLPFC increased after fluoxetine treatment. Thus, the mechanisms underlying these two antidepressant treatments are different.
(4) Cerebellum
The cerebellum is superficial and easy to reach through TMS. Growing anatomical, pathophysiological, and clinical evidence points to the fact that the cerebellum contributes substantially to the clinical symptoms of PD[41-45]. Cerebellar magnetic stimulation can decrease levodopa-induced dyskinesia in PD[46], and theta burst stimulation (TBS) at the cerebellum of patients with PD with main symptoms of bradykinesia and rigidity leads to an improvement in their symptoms lasting up to 4 weeks.
Except relations to the SMA and other motor cortices, there may be other mechanisms to explain this, so more studies are needed. For the stimulation of other targets, fMRI and functional relationships may help.
3.2 Circadian rhythmA recent study showed that the patients' responses to TMS treatment are different between morning and afternoon[16]. The mechanism for this is unclear, although variations in hormone and neuromodulator levels and neuroplasticity due to the circadian rhythm may be involved. Future studies and practical treatment approaches could allow choice of a proper time of the day to maximize the effect of treatment, with special attention focused on other physiological effects such as those on neuroplasticity and excitability.
3.3 Tissue resistanceThe tissue resistance is influenced by the type and quantity of neurons in the brain, in addition to the myelination status[47-50]. More detailed study of the characteristics and functional connectivity of these therapeutic targets will provide a better explanation of the pathogenesis of PD and the mechanisms of rTMS treatment.
3.4 Other physiological and pathological statesOther physiological and pathological states of the patients such as age, emotional factors such as anxiety, stage in the menstrual cycle, sleep, drug intake, brain atrophy, alcoholism, smoking, coexisting diseases, and so on are known to influence brain excitability. Thus, these factors must be considered while suggesting a treatment protocol. For example, the activity of the DLPFC is often reduced in patients with depression; thus, LF rTMS treatment will aggravate this condition.
4 ProspectFirst, rTMS is a safe, painless, non-invasive, and effec-tive neuromodulation technique: it is a new treatment method that can be applied to many neurophysiological, emotional, and cognitive disorders. While rTMS can lead to improvements in the motor and non-motor symptoms of patients with PD, the duration for which the treatment is effective is limited, as the long-term effects are negative. Moreover, some deep brain nuclei are difficult to stimulate, and the effective stimulation range of rTMS is difficult to control. Improvements in the rTMS instruments and technology remain to be investigated; the H-coil for deep stimulation mentioned earlier is a good start.
Second, several factors influencing the efficacy of rTMS remain controversial, and more detailed large- scale multi-center randomized controlled clinical trials may be needed in order to design more definite protocols for patients.
Third, with the development of fMRI and other methods to study brain networks, quantitative assessment and target orientation for high precision personalized rTMS treatment have been made possible; quantitative research to further develop these methods is the need of the hour.
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