Stimularea magnetică transcraniană – partea I

Transcranial magnetic stimulation (TMS) is a method of neurostimulation and neuromodulation that consists in applying a variable magnetic field (using a coil) to the nervous tissue, which causes an electric field to appear in the exposed brain tissue mass through electromagnetic induction.

The magnetic field induces changes in the electrical field of the brain, which significantly influences the polarity and excitability of neurons.

In 1896, A. d’Arsonval was the first to describe the magnetic stimulation of the cerebral cortex. In 1985, A. Barker used a magnetic stimulator for the human cerebral cortex. In 1995, M. George described the clinical effects after using repetitive transcranial magnetic stimulation (rTMS). Thus, TMS is a relatively new method used in psychiatry and neurology.

TMS indications:

• Depressive disorder (FDA approved in 2008).
• Type I bipolar disorder (FDA approved in 2018).
• Negative symptoms in schizophrenia.
• Auditory hallucinations in schizophrenia.
• Posttraumatic stress disorder (approved in 2014).
• Nicotine addiction.
• Obsessive-compulsive disorder (approved in 2018).

TMS Contraindications:

• Presence of magnetic or ferromagnetic objects on the head or neck.
• Pacemaker.
• History of epilepsy, including family history.
• Medication that lowers seizure threshold.
• Brain injury or stroke (with neurological consequences).
• Other factors that can lower the seizure threshold:

sleep disturbance

electrolyte disturbance

discontinuation of psychoactive substance use

increased intracranial pressure.

Pregnancy (more and more studies indicate the likelihood of safety for mother and fetus).

TMS in mental disorders

Depressive disorders

Depressed patients showed an increase in neuronal activity in the right dorsolateral prefrontal cortex (RDFC) and a decrease in activity in the left RDFC. TMS inhibits the right CDLPF neurons with low frequency pulses and stimulates left CDLPF neurons with high frequency pulses:

• right – inhibition (low frequency pulses)
• left – stimulation (increased frequency) (Lefaucher, 2014).

The stimulation can be done unilaterally, alternately or simultaneously, bilaterally. The protocols recommend are one session/day – five days/week. The highest effectiveness was observed with a total of 26-28 sessions. The response prediction is not sufficiently studied and publications are not relevant at this time. Based on efficacy and tolerability studies, guidelines have been developed. Milev and collaborators (2016), in the Canadian Network for the Treatment of Mood and Anxiety (CANMAT), recommend the use of repetitive TMS as the first line of treatment for the patients with depressive episodes who have not responded positively to at least one antidepressant therapy. This approach provides a real cost-effectiveness basis (Voigt et al., 2017) and is consistent with the FDA recommendations for rTMS.

However, most research and recommendations focus on the use of rTMS in conjunction with pharmacological treatment. Berlim et al., in 2013, in a meta-analysis (n=4392), indicated the complementary use of both methods (rTMS and psychopharmacological treatment). High-frequency stimulation (HF-TMS) on the left hemisphere and low-frequency stimulation (LF-TMS) on the right hemisphere were used.

The results of the meta-analysis suggest that, in the absence of a positive response using one of these methods, bilateral stimulation is necessary and recommended as a second line of treatment.

• First line of treatment – unilateral rTMS.
• Second line of treatment – bilateral rTMS.

There is no consensus of opinion. The protocols published in 2017 suggest the advantage of the initial stimulation with high frequency (HF) than with low frequency (LF) sessions, called priming TMS (pTMS).

• Initial HF – TMS/pTMS.
• LF sessions – TMS/pTMS.

Performing EEG during TMS leads to the possibility of synchronizing the pulse with the patient’s alpha rhythm, called synchronized TMS (sTMS). The shape of the coils is very important in terms of influencing a larger number of neurons or including deeper brain structures in the magnetic field. A new coil – the “H-coil”, in the shape of a helmet – allows a stimulation up to 5 cm deep. The method is called deep TMS (dTMS) (Brunon, 2016).

Regarding the efficiency of priming TMS, we can cite two studies:

• Carpentrer et al. (2012), with:

positive response in 58% of patients

remission in 37% of patients.

• Berlim et al. (2013) study:

remission in 35% of patients.

Another way of stimulation is theta burst stimulation (TBS) – Berlim et al., 2017; Blumberg et al., 2018. TBS still remains a protocol used by experienced therapists, although CANMAT allows its use as a second line of treatment in depression.

In 2018, Blumberg et al. published the results of a study with a representative number of patients (n=414), comparing the efficacy of TBS with the one of rTMS (following FDA protocol). Both response and remission rates were similar.        

• Response

rTMS – 47;    TBS – 49.

• Remission

rTMS – 27%;    TBS – 29%.

Blumberg noted: similar tolerance and safety, and advantage for TBS, being cost-effective, with shorter session duration and fewer sessions.

A last known stimulation method (which is still in the research phase) is rTMS DMPFG, including the anterior cingulate gyrus (dorsomedial prefrontal cortex).

CANMAT suggests that this method of stimulation is the third line of treatment in depression.

Summing up:

A. Treatment lines in depression (after CANMAT)

rTMS unilateral DLPFC

rTMS bilateral DLPFC

rTMS DMPFC + cingular girus.

B. Types of transcranial magnetic stimulation

rTMS (repetitive)

pTMS (priming)

sTMS (synchronized)

dTMS (deep)

iTBS (theta burst stimulation).

An important research direction is the evaluation of the effectiveness of rTMS in post-stroke depression. One of the first studies was the one of X. Shen (2017), which showed an increased response to rTMS in SSRI-refractory patients.

Currently, when rTMS is confirmed in the treatment of depressive disorder, current studies compare the efficacy and tolerability of TMS with electroconvulsive therapy (ECT).  

According to the World Federation of Societies of Biological Psychiatry, in depression the indications for ECT include (Baner, 2013):

• severe depressive episodes with psychotic symptoms
• catatonic depression
• refusal of food or fluids
• treatment-resistant depression
• high suicide risk
• when other therapeutic options are contraindicated (pregnancy).

Studies have confirmed that the patients refractory to ECT are less likely to respond to rTMS (Rahe et al., 2016; Zhou et al., 2017), recommending the initiation of the rTMS treatment (being better tolerated) in ECT candidates.

An important issue is related to the duration of rTMS treatment to achieve therapeutic effect. CANMAT recommends maintaining therapy because some studies have shown a high probability of recurrence a few months after stopping the treatment (Milev et al., 2016).

Cohen et al. (2009) confirmed that after an acute phase of treatment, without maintenance therapy, the average duration of remission was 119 days. Thus, after two months, 75% of patients were in remission (Cohen et al., 2009); after three months – 60%, after four months – 42.7%, and after six months only 22.6% of patients were in remission.

Factors that increase the chances of maintaining remission:

• a large number of rTMS sessions
• age of the patients (younger people are more likely).

Dunner et al. (2014) demonstrated that the application of rTMS for 12 months allowed the remission in 71% of patients.

Janick et al. (2010) stated that 38% of patients who received only pharmacological treatment after the acute phase of rTMS treatment had recurrence of symptoms after six months. When they underwent rTMS treatment again, 73% had a favorable response, and after another six months, 60% were in remission.

Consistent with these results, the authors suggest as a possible solution the continuation of pharmacological treatment after rTMS, with the rapid reintroduction of rTMS in situations where the patient’s status deteriorates.

The CANMAT guidelines do not specify which protocol is most recommended or how often rTMS sessions should be applied. Future studies are needed.

Treatment of resistant depression

I will refer to two studies published in 2019.

1. Meta-analysis (Sehatza et al., 2019)

TMS was effective in stimulating DLPFC (left and right) in TDR patients. Using the unilateral protocol, several important conclusions were drawn:

• the weighted mean difference (WMD) on the Hamilton scale between the test subjects and the control group was 3.36;
• WMD was higher in those treated psychopharmacologically compared to patients without treatment (3.64 versus 2.47);
• higher clinical efficiency using 20 Hz frequency compared to a lower frequency;

remission rate (using a unilateral protocol):

TMS with pharmacological treatment – 17.5%

TMS without pharmacological treatment – 15.1%.

• remission rate (using a bilateral protocol):

16.6% for the study group

2% for the control group.

These results may be interpretable because the meta-analysis studies used both protocols with different stimulation parameters and different methods for reaching neuroanatomical targets.

2. Blumberg’s study (mentioned by Hsu et al., 2019)

This study compares the iTBS protocol with rTMS.

Study conclusions:

• Fewer failures (17.3% using iTBS compared to 29.4% using rTMS).
• Lower remission rate in patients who had three failures with previous pharmacological TMS treatment (regardless of the protocol used).

Bipolar disorder

CANMAT and the International Society for Bipolar Disorders (ISBD), publishing in 2018 the guidelines for bipolar disorder (BD), included the use of rTMS as a potential therapy in the acute-depressive as well as the manic phase of type bipolar disorder I:

• for depressive episodes, it was proposed rTMS – DLPFC – right or left (as second-line treatment)
• for manic episodes, it was proposed rTMS – DLPFC – left (as third-line treatment).

The recommendations do not specify the medication that can be given concomitantly with stimulation. There is still no recommendation for rTMS in type II BD.

Schizophrenia

TMS in schizophrenia is a topic with many expectations and primary rTMS has been used in:

• persistent hallucinations
• reducing the severity of negative symptoms.

1. Hallucinations (stimulation with low frequency)

• rTMS – LF (low frequency)
• left cortex cortex T-P or left superior cingulate girus (studies in progress).

Based on a team of European experts, Lefancheur et al. (2014) recommended combining this method of treatment with pharmacotherapy (hallucinations – category C) especially in the group of patients whose hallucinations persist despite the improvement of other symptoms under treatment with atypical antipsychotics.

Research based on successive protocols has revealed a promising effect of rTMS in reducing the severity of negative symptoms (category B).

2. Negative symptoms (high frequency stimulation):

• rTMS – HF – DLPFC left.     

The authors’ opinions on the effectiveness of rTMS in schizophrenia differ.

Dlabac de Lange et al. (2015) noted a significant improvement (on average, 7.6 points) in negative symptoms based on SANS (Scale for Assessment of Negative Symptoms). However, a similar effect was not observed using PANSS. Of note in this study was the administration of bilateral rTMS.

He et al. (2017), in a meta-analysis, found a lack of efficiency at 10 Hz. Above this frequency, rTMS in DLPFC reduced the severity of negative symptoms, influencing less perceptual disturbances (hallucinations).

Wang et al. (2017), in another meta-analysis, showed a small statistically significant reduction in negative symptoms measured on the PANSS (Positive and Negative Syndrom Scale).

Despite these results, rTMS is an alternative for patients diagnosed with schizophrenia, persistent hallucinations and for those with significant negative symptoms.

Cognitive impairment

There is increasing scientific interest in the use of TMS to improve cognitive function in various mental disorders, including neurodegenerative disorders.

An extensive meta-analysis (Hsu et al., 2015) dedicated to the use of HF – rTMS in Alzheimer’s disease dementia confirms a significant beneficial effect compared to the healthy population. Methods used:

• DLPFC – bilateral TMS or
• DLPFC – alternative TMS – left – right.
• Different studies have compared the effectiveness:
• a single TMS session
• sessions for 5 days
• sessions for 2 weeks
• sessions for 6 weeks.

Interestingly, there was no evidence of increased efficacy after a higher number of sessions (2-6 weeks). Depending on the stage of Alzheimer’s disease, Lee et al. (2016) study observed:

• stage I-II – improvement of memory and language
• stage III – very low or no effect.

One promising solution seems to be the stimulation of different brain regions in the same patient (Anderkowa et al., 2014) – DLPFC:

Broca area

somatosensory association cortex (parietal lobe) of both cerebral hemispheres.   

Most studies include a systematic review of randomized, placebo-controlled trials in which participants did not receive pro-cognitive medication during the study.

There are few studies in Alzheimer’s dementia evaluating the efficacy of combining rTMS and psychopharmacological treatment, with small groups of participants and conflicting results. The discrepancy of the results was explained by difference in methodology, stimulation parameters, selection of stimulation areas and the absence of a hippocampal stimulation scheme (Birba et al., 2017).

Interesting results were published in 2015 by Trebbastoni et al. who used rTMS and EMG (electromyography). Two EMG parameters were analyzed:

• the value of the motor evoked potentials (MEP)
• the value of the resting motor threshold (rMT).

The patients participating in the study were monitored.

Within four years, 60% of patients with moderate cognitive impairment (MCI) developed Alzheimer’s dementia (AD). The authors conclude that reduced threshold excitability in MCI patients may be a negative prognostic focus for developing AD.

Regarding vascular dementia (VD), in 2017, Lanza et al. recommended TMS in determining groups at high risk of developing VD. The authors highlighted a characteristic cortical excitability for various subtypes of vascular cognitive disorder. In diagnosed VD, Lanza supports the use of TMS to increase neural network plasticity and improve cognitive function.

These observations require confirmation by future randomized, placebo-controlled studies.

Obsessive-compulsive disorder (OCD)

Many publications on rTMS in OCD had conflicting results. However, the latest meta-analysis, including 20 studies published by Zhou et al. in 2017 confirms that rTMS is justified in OCD, but protocols and guidelines are needed for the correct interpretation of the data. At that time (2017), the most effective method in OCD was stimulation: high and low frequency (alternating) DLPFC right.

Bilateral or left-sided stimulation has shown less therapeutic effect. Zhou et al. believe that in OCD other brain areas should be stimulated alternatively:

• orbitofrontal cortex
• motor cortex.

One therapeutic promise is dTMS in OCD which allows the interaction between the prefrontal medial cortex and anterior cingulate cortex neurons. In 2018, Carmi et al. were the ones who published the first study with this method, with high stimulation frequency, with reduction of obsessive ideation and compulsions in patients refractory to treatment. Of note, in 2018 dTMS was also registered by the FDA for OCD.

Posttraumatic stress disorder (PTSD)

In 2014, the International Federation of Clinical Neurophysiology (IFCN) guidelines recommended for PTSD right stimulation HF-rTMS in DLPFC (as third-level recommendation – Lefancheur et al., 2014).

A systematic review of rTMS literature in PTSD led to new recommendation published in 2017 by T. Jan – bilateral stimulation.

The most effective protocol in PTSD seems to be bilateral low-frequency DLPFC stimulation (Jan, 2017), with:

• decrease in excessive arousal
• decrease in the intensity of avoidance behavior
• decreasing the re-experiencing of trauma
• decreasing the severity of depressive symptoms.

It does not influence anxiety!

Despite these promising results, large group studies with group uniformity are needed to establish protocols.

Alcohol and nicotine addiction

A meta-analysis (Maiti et al., 2017) demonstrated an increased efficacy of rTMS in craving in nicotine dependence syndrome. The subgroup analysis of participants showed not only a reduction in nicotine craving, but also regarding the amount (number) of cigarettes consumed after rTMS-HF-DLPFC. The neurophysiological mechanism of this phenomenon consists (Maiti et al., 2017) in the inhibition of the effects of DLPFC on the reward system via the mesofronto-limbic pathway.

There are no benefits in alcohol addiction using rTMS (Lefancheur et al., 2014)

In 2014, IFCN guide recommended (level C) HF-DLPFC in nicotine addiction.

A recent study (meta-analysis) (Zhang et al., 2019) demonstrated how effective was rTMS in reducing craving, but emphasized that the magnitude of this effect was dose-dependent.