Date: August 2021
Prepared by SIC Member: Han-Lin Chiang, MD
Authors: John Rothwell, MS, PhD., Robert Chen, MA, MBBChir, MSc, FRCPC, Yoshikazu Ugawa, MD, PhD.
Editor: Un Jung Kang, MD
Repetitive transcranial magnetic stimulation (rTMS) and transcranial electrical stimulation (tES)* are the two non-invasive brain stimulation technique that can modulate brain plasticity and has been applied to various neurological disorders, including Parkinson’s disease (PD). However, the effect of such techniques on PD has been controversial. In this blog entry, we invited three experts in this field, Prof. John Rothwell, Prof. Robert Chen, and Prof. Yoshikazu Ugawa to discuss about the mechanisms, effects, and future research directions of rTMS and tES.
*tES is an umbrella term that includes transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and others.
What are the possible mechanisms of rTMS and tES in treating PD symptoms?
Prof. Rothwell: Both rTMS and tES can sometimes produce effects on the brain that outlast the period of application. The effects are thought to result from changes in the effectiveness of synaptic connections, commonly referred to as “plasticity”. They are transient, at least after a single application, and last around 30 min. They are also variable and small, meaning that it is difficult to predict with certainty how any individual will respond on any particular occasion.
The idea is that rTMS- or tES-induced plasticity might be able to restore function in malfunctioning areas of brain, or to improve compensation by enhancing function in non-damaged parts of the brain. In order to achieve a long-lasting therapeutic effect, several sessions of rTMS or tES are applied with the idea that the effects of each session will summate over time.
A final point to note is that rTMS and tES are much more effective at stimulating the surface of the brain (mainly cerebral cortex and perhaps cerebellum) than deep structures. Thus they are unlikely to influence the primary pathology of PD in the basal ganglia.
Prof. Chen: There are different mechanisms for TMS vs. tES. TMS activates neurons whereas tES is thought to bias membrane potentials that changes neuronal excitability and firing rates rather than directly activating neurons. The mechanisms for neuromodulation are not fully understood but they are generally thought to induce neuroplasticity and the effects outlast the stimulation. Long-term potentiation and long-term depression mechanisms may be involved. Also, the stimulation not only affected the stimulated areas but also regions interconnected to the stimulated area. Multiple sessions are generally needed to produce lasting clinical effects.
Prof. Ugawa: The most plausible mechanism underlying the treatment is the synaptic plasticity induction in both of them. rTMS may induce some local area and tDCS may induce plasticity at large areas. Where the plasticity occurs remains to be solved. The direct effects on the cortex, indirect effect on the basal ganglia through cortical changes, or the network changes in the whole brain.
What is the most promising effect of rTMS and tES on non-motor and motor symptoms of PD?
Prof. Rothwell: rTMS: There have been a small number of small trials of the effects of rTMS on symptoms of gait, tremor, akinesia, rigidity, dyskinesias and depression in PD which have targeted various areas of cortex and cerebellum. Promising effects have been seen on gait and dyskinesias in several studies as well as depression. However, the overall effects are small and it is difficult to compare the results of different trials because they often use quite different stimulation parameters. My summary would be that some patients may experience useful clinical benefit, but at present the methods are not sufficiently reliable to survive any sort of mass clinical roll-out. Many centres are opting to find ways to detect which patients may benefit most and then targeting treatment at those populations.
tES: Very similar answer to rTMS above. However, there is less data on trials with tES.
rTMS: The effects on improving motor symptoms are promising. There are smaller studies on levodopa-induced dyskinesia and gait disturbance that are also encouraging. For non-motor symptoms, there is evidence that it can benefit depression (approved in many countries for treatment-resistant depression)
tES: There are less studies than rTMS, but tES may also help with motor symptoms and some studies suggested that it may help cognitive symptoms.
rTMS: From my experience, the most promising effect is the beneficial effect on rigidity and akinesia. It is not effective on tremor. rTMS over SMA may be promising. rTMS over M1 is also effective.
What are the limitations and future research directions of rTMS and tES in treating PD?
rTMS: The main limitation is that the effects are small, particularly compared with the effects of conventional medications. There may be some scope for using rTMS to treat side effects of present treatments, or symptoms that are not well-controlled conventionally. Another problem is in understanding exactly what rTMS might be doing in the brain. At one level the notion that rTMS might modulate “plasticity” is highly attractive, but the reality is complex. It is not easy to target rTMS to particular sets of synapses in the brain, and it is unlikely that any symptoms can be treated by changing just a limited number of connections in the brain. It is possible that rTMS temporarily puts the brain into a state in which connectivity is temporarily more malleable, which might increase the effectiveness of conventional therapies that offer a more holistic way of changing brain circuits. This is the rationale for combining rTMS with a session of conventional therapy, such as gait training or exercise. Future research might help us understand more about what we are achieving with rTMS.
tES: As with rTMS above.
rTMS: It will be an adjunctive treatment and will not replace treatments such a levodopa or DBS. It will be relative expensive as technical personnel is needed. Large randomized controlled trials are still needed to provide efficacy. Combination with other treatments (e.g. rehabilitation, even DBS) should be explored further.
tES: Similar to rTMS but the cost of the device is lower, it can potentially be applied by patient at home. Also, easier to apply simultaneously with certain treatments such as rehabilitation.
rTMS: The effect is not large enough as compared with anti-PD drugs, and also rTMS intervention needs considerable time and medical staffs when applying to the patients. A few possibilities for the future direction of rTMS treatment include simultaneous rTMSs over several parts of the brain, combination with other treatment methods, such as tES or TUS (transcranial ultrasound stimulation), and cerebellar stimulation.
rTMS and tES are non-invasive brain stimulations that can modulate neuroplasticity through their effect on cortical regions and their connecting pathways. The duration of the effect is short and the magnitude is small, but they can be enhanced through multiple sessions or in combination with physical trainings. For patients with PD, the motor effect of rTMS, particularly rigidity, bradykinesia, gait and dyskinesias, is promising. There is also evidence that supports its treatment on PD depression. The treatment effect of tES is thought to be similar with rTMS, except that there is less data. Currently, rTMS/tES can only serve as adjunctive therapies. Future researches focusing on combination therapies with other treatment methods, simultaneous stimulations of different brain regions, and patient selection, will hopefully tell us more.