By Nithin Jacob
What treatment options are there for individuals whose depression is resistant to anti-depressant drugs? What about the individuals who experience intractable epileptic seizures despite anti-epileptic medication? Or those with schizophrenia who experience debilitating symptoms because they do not respond well to anti-psychotic drugs?
Unfortunately, these situations are not uncommon: medications are not cure-alls. In fact, 1 in 3 patients with depression (1) and epilepsy (2), and 1 in 2 patients with schizophrenia (3), have symptoms that do not respond to drug treatment. Non-drug treatments are emerging as adjunctive therapy for patients with various neurological conditions. One of these promising techniques is transcranial magnetic stimulation (TMS) (2,4).
A safe method for magnetically stimulating the brain, TMS is generally well tolerated by patients (2). How TMS works is by placing an insulated coil on the scalp which then emits a strong, pulsating, magnetic field. Rapid pulses in the magnetic field induce electric currents within the brain (5). This electric current stimulates nearby neurons (i.e., brain cells) to become “activated” (6). The magnetic field does not stimulate the entire brain, however, but just the two to three centimeters of the brain directly beneath the coil (7). Therefore, TMS causes targeted responses in brain cells and without being invasive, unlike surgical techniques.
If this description sounds too heady at the moment, here is an analogy. The mechanisms of TMS work like a puppeteer causing a desired physical movement in the puppet by manipulating the attached strings. Manipulation of the puppet strings represents fluctuations in the magnetic field in TMS. The resulting physical movement of the puppet is analogous to the electrical current produced within the brain’s neurons. When the electrical currents are stimulated in the brain regions responsible for muscle movement, the person’s muscles move as the puppet also does ― without voluntary control.
Through vital developmental phases, TMS has become a therapeutic option for patients with intractable symptoms. First, let’s take a trip back to when TMS was in its infancy before we imagine what its full-fledged future could be like.
In the late 1970s, clinicians typically stimulated the brain by sending electricity directly to the scalp (8). This technique was used as a diagnostic tool for patients with multiple sclerosis to evaluate the integrity of the spinal cord and its ability to relay electrical information (9). Although effective, this method often resulted in extreme discomfort, necessitating safer and less painful methods of brain stimulation (8,10).
An encouraging solution was introduced in 1985 by Anthony Barker’s group in England: the world’s first reliable transcranial magnetic stimulator (11). They demonstrated that a single magnetic pulse on the scalp could activate underlying neurons. Clinicians could therefore perform diagnostic tests in patients using this much safer, and far less painful method (10).
Until the late 1980s, TMS was still only used for diagnostic purposes (8). This would change in 1991 when the therapeutic potential of TMS was explored by Alvaro Pascual-Leone in the United States (12). Pascual-Leone and his group discovered that using repetitive transcranial magnetic stimulation (rTMS) not only activated neurons, but also increased the likelihood of future activations. Increasing the chance of a neuron being activated can be referred to as increasing its “excitability.”
Pascual-Leone discovered that these changes in excitability from repeated magnetic pulses lasted even after treatment ended, thus highlighting the therapeutic potential of rTMS (12). For individuals with intractable symptoms, increasing neuronal excitability matters because their brain cells do not respond well or at all to drug treatment ― but may respond to forms of TMS.
With this foundational understanding of TMS’s evolution, let’s investigate the therapeutic uses of rTMS in three clinical conditions: depression, epilepsy, and schizophrenia.
Approximately 35% of individuals with depression report anti-depressant drug treatment as ineffective (13). Depression is primarily considered a disorder of neuronal activity within two brain networks: the dorsolateral prefrontal cortex (i.e., the region responsible for decision-making) and the ventromedial prefrontal cortex (i.e., the region which helps regulate emotion) (14).
Neurons in the decision-making network have low excitability, meaning that it is difficult to activate these cells (15). In contrast, neurons in the emotional network have higher excitability and are therefore more easily activated (15). This imbalance of neuronal activity results in the persistent low mood associated with depression (14).
Using coordinated magnetic pulses, rTMS may increase excitability in the decision-making network while decreasing excitability in the emotional network ― exerting therapeutic effects on depressive symptoms (14). Pulses made 5-20 times per second enhance neuronal excitability (16), while a pulse delivered once per second has a diminishing effect (17).
A review of 23 studies concluded rTMS treatment significantly improved depressive symptoms compared to a placebo treatment (16). However, the improvement was considered minor because patients receiving rTMS scored only 10% better on clinician-rated depression scales compared to the placebo group. Moreover, these benefits lasted only three to four months post-treatment (16).
For one third (18,19) of the 50 million people with epilepsy worldwide (20,21), their seizures cannot be controlled through medication. Epilepsy is a neurological disorder that predisposes a person to recurring seizures because of excessive neuronal excitability (22). Sometimes, a brain region prone to this hyperexcitability is the primary motor cortex (23), whose neurons initiate physical movement (24). Uncontrollable activation of these neurons often result in the archetypical body twitching and jerking associated with seizures (5).
Given what you know so far, which frequency of rTMS do you hypothesize would be helpful for those with hyperexcitable neurons? High frequency, or low frequency?
Remarkably, low frequency rTMS in patients with drug-resistant epilepsy can reduce the risk of seizures by 19-35% (25). Applying rTMS with 0.3 and 0.5 pulses per second suppresses the excessive excitability of the neurons, thus reducing the frequency of seizures (26,27).
Researchers believe that the low frequency rTMS is able to provide “relief” for these neurons (5). Think of this like as a water dam. When the water level behind a dam gets too high, there is a risk for the water to overflow. However, releasing some of this water in a controlled manner before it reaches critical levels would reduce the overall water level, and mitigate the risk of an overflow. Controlling the release of water to lower the risk of overflow ― which could cause flooding and destruction downstream ― is analogous to reducing neuronal excitability levels to lower the risk of uncontrollable activation ― which could result in seizures.
Controlling the release of water to lower the risk of overflow ― which could cause flooding and destruction downstream ― is analogous to reducing neuronal excitability levels to lower the risk of uncontrollable activation ― which could result in seizures.
Paradoxically, while rTMS has therapeutic potential in reducing seizures, there is also a small risk of inducing seizures (5,28). Even for an individual without epilepsy, daily exposure to rTMS can potentially lead to seizure attacks (5). Thankfully, rTMS-induced seizures are quite rare and the risk is only concerning when the frequency of magnetic pulses is 60 times per second (29) – the rTMS treatments described above are well below this threshold.
Approximately 25-50% of patients with schizophrenia experience symptoms even while on medications (3). Schizophrenia is a psychiatric disorder with two main categories of symptoms: positive and negative. Positive symptoms are defined by new experiences of phenomena such as auditory hallucinations, delusions, and disorganized speech; in contrast, negative symptoms blunt the normal experience of reality, resulting in the inability to feel pleasure, emotional and social withdrawal, and loss of motivational drive (30). While positive symptoms respond well to antipsychotic medication (31), negative symptoms do not (32).
Unfortunately, negative symptoms significantly affect social interactions (e.g., social life at work) and overall quality of life (31). Interestingly, negative symptoms are associated with reduced neuronal excitability in a region of the brain where it is more difficult for neurons to be activated: the left prefrontal cortex (33) (i.e., the region responsible for motivation and decision-making) (34).
Given their reduced neuronal excitability in this brain region, should high frequency or low frequency rTMS be used here?
Yes, high frequency ― and this is why: researchers have tested the effect of rTMS at 8-13 pulses per second on the brain’s motivation and decision-making centre. Compared to a placebo treatment, rTMS significantly reduced the negative symptoms by 30% (31,35), with the effect lasting up to 24 weeks post-treatment (36). At the higher frequency (i.e., 18 pulses per second), negative symptoms were reduced by 38-48% (37).
Returning to the water dam analogy, reduced neuronal excitability can be analogous to water levels that are too low. When the water is below a certain threshold in a hydroelectric dam, it is difficult for electricity to be produced. However, if we were to increase the overall water volume back to the correct level, electricity is easily and efficiently generated. Restoring the optimal water level from low volumes is analogous to increasing neuronal excitability back to a level of normal neuronal function.
Restoring the optimal water level from low volumes is analogous to increasing neuronal excitability back to a level of normal neuronal function.
Reconsidering the questions posed at the start, TMS is an effective treatment option for various clinical populations. As TMS gains momentum in the field of rehabilitation, large-scale studies are needed. Although TMS may not be a “magic pill”, to those individuals with depression, epileptic seizures, and schizophrenia for whom traditional drug therapy is ineffective, it does offer promising clinical benefits.
Featured illustration by Ava Schroedl for rehabINK.
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To refer to this article, it can be cited as:
Jacob N. Transcranial magnetic stimulation (TMS): Magnetic fields and electric currents and brain cells, oh my. rehabINK. 2020;8. Available from: https://rehabinkmag.com
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