repetitive Transcranial Magnetic Stimulation (rTMS)

rTMS equipment and positioning
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Image source: http://www.nimh.nih.gov

Only around 33% of patients with Major Depressive Disorder respond to antidepressants such as SSRIs, and research shows that this rate of remission (optimal recovery after treatment) doesn’t change even when a combination of antidepressants are used[1]. Alternative treatments for treatment-resistant depression (TRD) are thus important and include Electroconvulsive Therapy (ECT), Deep Brain Stimulation (DBS) and repetitive Transcranial Magnetic Stimulation (rTMS).

rTMS takes advantage of magnetic waves created by an electrical coil to induce a current in neurons to modify neuronal excitability[2]. Structures usually targeted in patients with depression include the dorsolateral prefrontal cortex (DLPFC) and the dorsomedial prefrontal cortex (DMPFC)[3]. The DMPFC is involved in controlling the interaction of brain networks involved in rumination (Task-Negative Network), somatic markers for physiological states (Somatic Marker Network) and goal-directed behaviour (Task-Positive Network)[3]. DLPFC is a part of the Task-Positive Network. Both DLPFC and DMPFC have decreased activity in depressed patients and are treated by rTMS to increase their neuronal activity[3].

Side-effects associated with rTMS are milder and better known than some other treatments for TRD. For instance, ECT is known to cause temporary retrograde amnesia[4] and the side effects of DBS are still controversial which is why DBS is only a potential treatment for TRD and has not yet been used clinically[5]. Severe side-effects associated with rTMS are very rare and include seizures and increased chances of mania[6]. However, more common rTMS side-effects are only temporary headaches that are mild to moderate in nature and are usually tolerable by patients[6]. It is for these reasons that rTMS, which first emerged in the 1980s[7], is gaining popularity over time as a treatment for TRD and also as an adjunct therapy with antidepressants.

1.1 Introduction to rTMS

Current flow and
magnetic field induction
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The generated magnetic field
penetrates through the skull and affects
the underlying brain regions. Image source:
http://www.epilepsyresearch.org.uk

1.1a What is rTMS?

Taking advantage of electromagnetic wave properties, TMS uses current in a circuit to generate a magnetic field perpendicular to the current. Thus, the rate at which the circuit is turned on and off determines the frequency of the magnetic field that is produced. When the rTMS coil is placed on the head of a patient, the magnetic waves bypass the skull without attenuation and interact with the electrical activity of neurons in the brain which then results in the alteration of neuronal excitation [8].

1.1b History of rTMS

TMS was used for the first time in 1985 and got approved by Health Canada in 1997[8]. rTMS received approval to be used as a treatment for TRD in 2002 and in 2008, it was also approved by the American Food and Drug Association (FDA)[8]. Since then, several clinics have opened up that offer rTMS as a treatment for different disorders, Major Depressive Disorder (MDD) being the most common disorder for which rTMS is used.

1.1c Clinical Usage

Depressed patients are generally referred to rTMS clinics by their family physicians or the specialist that they have been consulting. The first step in rTMS treatment is to determine the parameters that are specific to each patient's brain anatomy and physiology. Every individual requires a different magnetic field strength based on individual differences in skull thickness and the ease with which a person’s neurons respond to the magnetic field[8]. The threshold for the magnetic field strength is determined by applying rTMS on the premotor cortex at the region of the homunculus that controls the hand[8]. An MRI scan is generally used to determine the location of the different brain regions before the motor threshold is determined[8]. The threshold is set by slowly increasing the magnetic field strength starting at the minimum and stopping when jerk movements are observed in the patient’s hand and fingers[8]. After the motor threshold for a patient is determined, the threshold of the magnetic field is adjusted and the rTMS coil is relocated to the region of the brain that needs to be treated. The motor threshold is determined only once after which the fixed value of magnetic strength is used for each following treatment session.

1.2 Types of rTMS stimulation

1.2a High Frequency (HF) Stimulation

High-Frequency (HF) stimulation refers to a magnetic field which is applied at any rate greater than 1 Hz and is usually between 10 – 20 Hz[9]. High Frequency stimulation increases neuronal excitability. Treatment using HF stimulation usually lasts 30-40 minutes per session, with one session every weekday for 2-4 weeks[9]. According to a meta-analysis, after approximately 13 sessions of treatment, 29% of subjects responded and 18% of subjects remitted after HF stimulation [9]. Also, no difference in drop-out rates was observed between patients receiving HF stimulation versus patients only receiving sham treatment [9]. HF stimulation is usually administered on the Left Dorsolateral Prefrontal Cortex (DLPFC) in patients who have treatment-resistant depression (TRD).

1.2b Low Frequency (LF) Stimulation

Low-frequency (LF) stimulation is administered at a rate of 1 Hz or less than 1 Hz for 30 – 40 minutes [10]. Low-frequency stimulation results in a decrease in neuronal excitability. It is most commonly administered on the right DLPFC in patients with TRD [10]. The duration of one session of LF stimulation is similar to HF stimulation, taking about 30-40 minutes[10].

1.2c Theta Burst Stimulation (TBS)

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TBS Sequence: This figure shows the sequence of one TBS burst.
Each vertical line represents 1 pulse. There are approximately
5 cycles in every second.

TBS causes long-term potentiation (LTP) and long-term depression (LTD) in neurons as seen in animal research [11]. A big advantage of TBS over HF stimulation and LF stimulation is that one session of TBS only takes 5-6 minutes to administer [11]. Not only does this save time for the patient, but it also enables more patients to be treated by rTMS. TBS comprises of a sequence of steps in which 3 pulses are applied at 50 Hz after every 200 ms time interval [11]. Based on how this sequence is administered in a patient, TBS can be subdivided into two types: Continuous (cTBS) and Intermittent (iTBS). Research has shown that cTBS applied to the right DLPFC is more effective than iTBS applied to the left DLPFC, though the results are not significant [12]. Also, a comparison of cTBS applied at 1800 pulses/day showed significantly more reduction in MDD symptoms, compared to cTBS applied at 1200 pulses/day implying that an increased dose of the stimulation results in greater improvement [12]. TBS is shown to be equally effective for unipolar and bipolar depression [12].

1.2ci Continuous (cTBS)

TBS is referred as cTBS when the TBS sequence is applied continuously for 40 seconds [12]. cTBS decreases neuronal excitability, similar to LF stimulation and is applied using an rTMS coil at the same locations as LF stimulation [12].

1.2cii Intermittent (iTBS)

TBS is referred as iTBS when the TBS sequence is interrupted for 8 seconds after every 2 seconds [12]. iTBS increases neuronal excitability, similar to HF stimulation and is applied using an rTMS coil at the same locations as HF stimulation [12].

rTMS and neuronal excitation
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HF-stimulation (c) heightens neuronal activity
and LF-stimulation (a) diminishes neuronal activity
as compared to sham treatment (b).
Image source: Valero-Cabré et al., 2007.

1.2d Comparison of rTMS types

LF stimulation and HF stimulation are conventional rTMS types whereas TBS is a newer method. LF stimulation is safer at higher intensities than HF stimulation as there is a lower chance of having an epileptic seizure with LF stimulation [13]. HF stimulation on the left DLPFC and LF stimulation on the right DLPFC are seen to be equally effective at improving depressive symptoms [10][14]. As LF stimulation is relatively safer and is as effective as HF stimulation, using LF stimulation might be a better solution for TRD treatment. However, research has also shown that patients with TRD who respond well to HF stimulation do not benefit much from LF stimulation [15]. Also, patients showing improvements after LF stimulation do not show significant improvements after treatment with HF stimulation [15]. This suggests that the efficacy of the different types of rTMS methods might be based on individual differences in response to the methods.

rTMS treatment is known to be helpful in the restoration of balance between the left and right side of the DLPFC [16]. In Major Depressive Disorder, the left DLPFC has decreased neuronal activity so either increasing excitation in the left DLPFC or decreasing neuronal activity in the right DLPFC would help in the restoration of the balance. This explains why inhibitory LF stimulation and cTBS are most commonly applied on the right DLPFC and excitatory HF-stimulation and iTBS are applied to the left DLPFC.

A study compared the efficacy of both TBS with both conventional rTMS methods using three different conditions. In one condition, a combination of LF and HF stimulation was administered in patients on the right and left DLPFC respectively. In the second condition, a combination of iTBS in the left DLPFC and cTBS in the right DLPFC was administered. The third condition was a sham treatment where no magnetic field was introduced in the patient's brain. The results showed that both interventions showed greater improvements than sham treatment and TBS was superior to conventional rTMS with greatest differences in results seen at the last follow-up, after 8 weeks of treatment [17]. Moreover, another study shows that the efficacy of iTBS as applied to the DMPFC is similar to results obtained after HF stimulation as approximately the same number of patients respond to both treatments [18].

1.3 Effectiveness of rTMS in treating TRD

A meta-analysis on the efficacy of HF stimulation for the treatment of TRD showed a 43% response rate and no difference in remission rates compared to sham treatment [9]. A study conducted on 419 patients with TRD showed a response rate of 64% and a remission in 33% of the patients [19]. HF stimulation at 25 Hz was administered on patients in this study with no significant side effects. Another study comparing the efficacy of LF stimulation on TRD showed that response rate was significantly higher after treatment with LF stimulation (49%) compared to sham treatment (25%) [20].

Despite having evidence showing that rTMS is an effective treatment for TRD, some studies show no significant effect of either HF or LF stimulation over sham treatment [13][21]. In fact, a research study not only shows no behavioural change, but also demonstrates no differences in serotonin and dopamine levels in patients receiving LF stimulation or HF stimulation compared to sham treatment [21]. As no consensus has been established yet regarding the efficacy of rTMS in treating treatment-resistent depression, it might be helpful to explore biomarkers to predetermine which patients are most likely to improve after rTMS treatment.

1.4 Biomarkers for rTMS responders vs. non-responders

Decreased functional connectivity between the subgenual Anterior Cingulate Cortex (sgACC) and the left prefrontal cortex at baseline is associated with better response to HF rTMS stimulation on the left DLPFC [22]. Moreover, increased theta power in the sgACC predicts greater response of vascular depression to rTMS [23]. In another study, patients who did not respond to treatment showed more anhedonia (decreased interest in pleasurable activities) at baseline. They also showed a lower connectivity in the ventromedial prefrontal cortex (VMPFC), striatum and ventral tegmental area (VTA) [18]. Another study shows that patients who respond to rTMS have a stronger connection of the sgACC with the Dorsomedial Prefrontal Cortex (DMPFC) and also with the DLPFC [24]. Biomarkers may help increase the response and remission rate after rTMS treatment by selectively treating patients who are most likely to benefit from the treatment, thus saving precious time and money.

1.5 Brain regions and networks targeted by rTMS

Brain networks affected in Major Depression
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Image source: Downar & Daskalakis, 2013

Three major brain networks are involved in Major Depressive Disorder. These networks are the: Cognitive Control Network, Default Mode Network and Affective Network

1.5a Cognitive Control Network

The cognitive control network (CCN) is implicated in the DLPFC and DMPFC regions of the brain[3]. In MDD, these regions have decreased neuronal activity which is why these areas are stimulated with excitatory types of rTMS. The cognitive control network is also known as the Positive Task Network and is complementary to the Default Mode Network (DMN)[3]. The CCN directs the person to get involved in goal-directed behaviour and interact with the external world[3]. The underactivity of the CCN causes the DMN to become more dominant in depressed patients[3].

1.5b Default Mode Network

The DMN is responsible for self-reflection and rumination[3]. It allows a person to interact with itself internally and monitor its own thoughts and behaviour [3]. This network allows a person to evaluate thoughts of guilt, embarrassment, self-worth and other internally generated thoughts and feelings. Overactivity of this network in depressed patients leads to decreased social interaction, and feelings of guilt and worthlessness[3]. This network is implicated in the frontopolar cortex (FPC) [3].

1.5c Affective Network

The affective network is situated in the ventral regions of the prefrontal cortex and involves the VLPFC and the VMPFC [3]. This network is also known as the somatic marker network. It is generally overactive in depressed patients and needs to be treated by rTMS methods that decrease neuronal activity[3]. This network is responsible for regulating emotional responses and also to cause the physiological changes that are associated with emotions[3].

1.6 Neurobiological changes caused by rTMS

TMS mechanism
Effect of TMS on brain regions and a comparison of MDD treatments

Studies on animals show that the gene expression of c-Fos and zif268 in rats is affected by rTMS treatment using the HF, LF and the iTBS methods[25]. c-Fos is involved in cell differentiation and zif268 is involved in cell proliferation, differentiation and survival in rats[25]. Thus, rTMS might be affecting processes such as cell proliferation. Another study on rats explored the effect of rTMS on proteins that convert glutamate to GABA - GAD proteins [26]. The results of this study showed that both TBS and LF 1 Hz stimulation reduce the expression of GAD67 initially. However, the effect gets reversed after 1 day and the expression increases [26]. This shows that the effect of rTMS can change over a time course after the treatment.

Studies exploring the mechanism behind rTMS treatment have also been conducted in humans. fMRI studies show that patients who improve after rTMS treatment show a greater increase in the connection between the thalamus and the DMPFC and a greater decrease in the connection between the caudate nucleus and the subgenual Anterior Cingulate Cortex (sgACC) [24]. This finding gives us insight into the connections in the brain that are altered by rTMS treatment. Moreover, studies looking at the neurochemical changes caused in the brain by rTMS have also been conducted. In a study conducted on humans, a radio-labelled ligand of the dopamine receptor D2 was introduced and the effect of dopamine binding was analyzed after applying 10 Hz rTMS on the left and right DLPFC [27]. The results showed that the binding affinity of dopamine decreased in the sgACC and orbitofrontal cortex (OFC) after stimulation of the left DLPFC. This suggests that rTMS might be involved in modulating the effects of dopamine in depressed patients.

Accumulating evidence from studies that are reporting a significant effect of rTMS on gene expression, neurochemical changes and changes in connectivity between brain regions suggests that rTMS does indeed cause changes in the brain that is not merely a placebo effect.

1.7 Other uses of rTMS

rTMS treatment has many other uses including reduced cravings for cocaine in cocaine addicts after HF rTMS stimulation [28], increased time perception in patients with Parkinson’s Disease [29] and decreased cigarette smoking in smokers [30]. rTMS has also shown to be effective for the treatment of eating disorders [31] and obsessive compulsive disorder [32].

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