Repetitive Transcranial Magnetic Stimulation

Introduction

Transcranial Magnetic Stimulation (TMS) is a non-invasive brain stimulation based on the principles of electrical stimulation. The device is placed on the scalp and single (sTMS) or repeated (rTMS) magnetic pulses are delivered. Frequency intensity duration and interval times of pulses can vary[1].

The exact mechanism of action remains unclear currently evidence points to a role in long-term inhibition and excitation of neurons in certain brain regions.

There is enough evidence to agree:

• Level A (definite efficacy) for:

1. The analgesic efficacy of highfrequency (HF) rTMS in the primary motor cortex (M1) associated with pain
2. Efficacy of HF rTMS in the left dorsolateral prefrontal cortex (DLPFC) in schizophrenia[2].
3. Efficacy of rTMS in the treatment of unipolar depression for both HF rTMS in the left DLPFC and LF rTMS in the right DLPFC.

• A Level B recommendation (probably more efficient) is suggested

1. antidepressant effect of low-frequency (LF) rTMS in the right DLPFC
2. for negative symptoms of depression HF-rTMS of the left DLPFC
3. for chronic motor stroke disease LF-rTMS with contralesional M1 [2].

• Level C (possibly more effective) for the effect of LF rTMS of the left temporoparietal cortex on auditory and auditory hallucinations[2].

Transcranial Magnetic System[3]

Historical Background

Throughout history, brain stimulation techniques such as TMS have proven to be powerful tools for investigating neurophysiology as well as for mapping and modulating neuronal mechanisms[1 ]. First appearing as a potential mechanism for noninvasive nerve stimulation in the early 20th century[4] generally transcranial magnetic stimulation (rTMS) has gone through several stages of development.

In 1985 Anthony Barker developed the first modern TMS device as a means of studying electrophysiology[5]. Barker’s original study was based on a single TMS pulse in which a single stimulus is delivered to a specific region of the brain. The easiest muscles to be mobilized are the brachial and distal muscles the upper limb is partly due to the convenient location of the functional area of the hand in the central spiral of the brain and partly to anatomy; these neurons have the purest corticospinal innervation from the contralateral side. These studies proved infact that TMS can stimulate nerves movement of the hand when applied to the main muscle of the body (M1).

Extending this the technology was designed to allow a device to deliver multiple stimuli in a short period of time to have a sustained effect on cortical excitability that lasted beyond the stimulus delivery itself.

Because of the ability of this treatment to alter cortical function in a focused manner, attention was soon focused on the use of this technique to potentially improve neurodegenerative disorders through the first studies a they tried to cure the depression.

In 1995, George et al.[6] used rTMS to target specific brain regions thought to be involved in the etiology or pathology of major depression in an open-label study. Although most studies have supported the antidepressant effect of rTMS, its clinical benefits have has been variable and in some cases peripheral. However a clear trend toward more robust effects has been observed as both stimulation method (e.g. dose coil placement and course duration) and experimental characteristics (e.g. better sham stimulation and larger sample sizes) improve. rTMS has become accepted acceptable and clinical treatment. Infact since these early studies rTMS has been investigated as a therapeutic intervention for neuropsychiatric diseases such as treatment-resistant depressionnumerous clinical trials of rTMS to treat depression (among others). mental health) has been[7][8][9].

In October 2008, an rTMS device was approved as a U.S. Pat. It is not used by the Food and Drug Administration (FDA) for patients with major depression who have not received at least one antidepressant in their current condition.

With the introduction of more advanced structural and functional neuroimaging over the last several decades the specifics of this network have become better understood [10] .

Functioning

The instrument consists of a high current pulse generator capable of generating a discharge current of several thousand amperes flowing through an excitation coil to generate a short magnetic pulse with field strengths up to several Tesla. This magnetic pulse by the principles of electromagnetism produces a secondary electric field opposite to the voltage produced by the coil[11][12][13][14]. When the coil is placed on a person’s head the magnetic field thus created is not much attenuated by tissues outside the brain (skull bone tissue and cerebrospinal fluid layer) and is able to generate enough electrical current to depolarize surface axons and activate neurons in the cortex.

The extent to which the current density produced in the brain is active depends on many physical and biological factors such as the type of coil and the orientation distance between the coil and the brain magnetic pulse waveform energy frequency and pattern of stimulation and the any route to the brain current wiring and neural stimuli.

A simple and easily quantifiable measure of contractility is the motor threshold of the stimulus intensity at which the tested muscle is repeatedly activated. A decreased motor threshold is considered to represent a state of greater cortical excitability and higher threshold a state of low excitement

Type of TMS

1. Single-pulse TMS can be used to simply stimulate a given area while recording results and is commonly used in studies that stimulate an area such as the motor cortex and can record motor responses from body muscles using electromyography on [14] the.
2. Paired-pulse TMS can be used to measure the effect of a first stimulus on a second stimulus. While this method is also used primarily in research it allows one area of the brain to be considered over another. For example a TMS pulse sent to the motor cortex of one side of the brain 10ms before a TMS pulse delivered over the contralateral motor cortex produces an inhibitory effect on motor output to the arms indicating a firing pattern that allows for unimanual control of the upper limbs[15][15][16]. 16][17].
3. Repetitive TMS (rTMS) techniques involve wiring a number of consecutive TMS pulses in rapid succession. This technique is used in both research and clinical settings because it can produce changes in cortical function that persist beyond the duration of the TMS protocol. With some reports showing a change in excitation that lasts for a number of hours. The nature of the pulse delivery appears to determine the effect of the rTMS protocol as those delivering pulses at rates of >5Hz (high frequency rTMS) are more likely to produce excitatory effects and those delivered at rates < 1Hz ( low frequency rTMS) are usually inhibitors in the brain. These rTMS techniques have been approved as a treatment modality for patients with major depressive disorder (MDD) in Canada. While the use of rTMS has not yet been approved for clinical use in movement therapy disorders such as stroke spinal cord injury and PD scientific literature suggests that it may provide some benefit for both motor and cognitive symptoms in this population[18][19][20][21].

Frequency

• Changes in motor-evoked potentials suggest that rTMS alters cortical excitability in a frequency-dependent manner[12]. From the results of studies based on MEP measurements in healthy subjects, some consensus appears to measure low-frequency (LF) stimulation (≤1Hz) as “inhibition” and high frequency (HF) stimulation (≥5Hz) as “excitation”. The mechanisms by which these neuroadaptations occur remain unclear but some have hypothesized that rTMS induces Hebbian plasticity similar to long-term potentiation (LTP) or long-term depression (LTD) available.
• Indeed, HF rTMS may result from a decrease in gamma-amminobutyric acid (GABA)-mediated intracortical inhibition (therefore preventing inhibition) rather than a direct increase in motor cortex excitability. For high-frequency TMS, a cooling system is needed to prevent overheating at repeated electromagnet stimulation.
• LF rTMS may enhance net inhibitory corticospinal control possibly through GABA-B release.
• One of the most popular protocols is “theta burst stimulation” delivered as a continuous (cTBS) or intermittent (iTBS) train the former protocol being “inhibitory” and the latter “excitatory”[22].
• However this dichotomy is not entirely clear and it has been shown that both HF and LF rTMS may have mixed excitatory and inhibitory effects[23] . Even when effects on the motor cortex appear specific twice the duration of stimulation for example can shift the results from inhibition towards interest and vice versa[24].

Coils

Since TMS was first introduced, researchers and engineers have proposed sophisticated coil designs all aimed at better focusing electrical impulses in the brain. The use of large needles stimulates a broader and deeper expansion of the lower brain. But this can be a disadvantage if the target can be accurately localized. A recent study[25] reported that the final output of these configurations can be reduced to two main configurations: spherical and double (figure-8).

• Round coils have advantages including simple construction direct heat dissipation stable head contact and relatively eliminate penetration beneath the scalp surface. However the near impossibility of placing the coils on one side of the brain limits their usefulness in most applications[1].

  Transcranial Magnetic Stimulation Coil System.[26]

• The double coil consists of two circular coils placed side by side to form a pattern variously described as figure-8 which slightly improves performance and penetration.[27]
• The most recent technological advancement in TMS is the H-shaped coil which stimulates beyond the conventional figure-8 coils. Recent studies have addressed the safety of these coils in subgroups of patients with bipolar disorder.[28]

Intensity

Stimulation intensity is typically expressed as a percentage of resting motor threshold (RMT) which is the minimum intensity required to elicit an electromyographic (EMG) response (motor-evoked potential [MEP]) of at least 50 μV with a probability of 50% having a resting hand muscle[29]. RMT can also be done determined by monitoring clinical motor activities (finger movements) rather than recording MEP.

Contraindications

The only absolute contraindication to TMS is ferromagnetic material or embedded devices in close contact with the coil (less than 2 cm) due to the risk of deflection or malfunction.

Related countermeasures that require specific reasoning or indication of rTMS.are:

• cochlear implants or other atrial fixation devices
• implanted cortical stimulation or DBS systems are available
• cortical TMS may be considered in cases of coma or stimulation of the vagus nerve or spinal cord if objects greater than 10 cm in diameter are placed on the implanted generator
• pregnant women,
• children (aged >2 years),
• patients with auditory problems require specific estimation or determination of the rTMS sensitivity
• personal history of epilepsy,
• focal cerebral lesion,
• taking or withdrawing drugs that alleviate seizures
• sleep deprivation

TMS for Depression

Commonly involved brain regions include dorsolateral prefrontal cortex (DLPFC) medial prefrontal cortex orbitofrontal cortex cingulate gyrus (including dorsal anterior perigenual subgenual and posterior subdivisions) insular cortex medial temporal lobe regions (hippocampus). parahippocampus and amygdala) parietal cortex thalamus midbrain system (including dorsal and posterior striatum hypothalamus) and brain stem regions. Abnormalities in these areas have been observed in patients with schizophrenia compared to healthy controls. They found a correlation brain metabolic activity and effectiveness of TMS. This was confirmed by the results of TMS treatment in nonresponders who exhibited hypoperfusion in the facial nerve.

Repeated stimulation of the left DLPFC reduces depressive symptoms while repeated stimulation of the right DLPFC helps relieve symptoms of both depression and anxiety. Infact this result correlates with and could be the decrease in synaptic strength seen in depression attributed to the fact that fast rTMS (> 10 Hz) excites neurons while slow rTMS (< 1 Hz) has the opposite effect. [30] .

Studies show that while daily TMS over the DLPFC increases cortical activity and decreases activity in peripheral areas. The neurophysiological response to TMS is particularly important because repetitive stimuli enhance synaptic plasticity to persist even after the stimulation has ceased. Many randomized clinical trials have shown that daily TMS of the left prefrontal cortex is effective in treating symptoms of depressive mood[31][32] .

One study showed prolonged benefit from TMS with or without pharmacotherapy after 6 months.[33][34] TMS demonstrates long-term statistical and clinical significance with strong benefits as well at 12-month follow-up. However all these effects were observed in a pragmatic regimen of continuation antidepressant medication and repeated TMS therapy for symptom relapse.[35]

TMS for Neurological Disease

The most recent guidelines for TMS in rheumatoid arthritis suggest the following:[2]

• Despite the amount of published work, the data in the literature are still too limited to date to support any recommendation for the therapeutic use of rTMS in:

1. cerebellar ataxia,
2. myoclonia,
3. Huntington’s disease,
4. Amyotrophic lateral sclerosis,
5. Multiple sclerosis,
6. Alzheimer’s disease
7. Tinnitus a single session of LF rTMS or repeated sessions of rTMS when delivered to the opposite ear canal seems to warrant a Level C recommendation.[36]
8. Anxiety disorders

• In contrast, there is more concrete information about:

1. Parkinson’s Disease; for more information, please see RTMS Treatment For Parkinson’s
2. dystonia (especially writer’s epilepsy) .
3. essential tremor,
4. Tourette’s syndrome.
5. Epilepsy

• Stroke patients:

1. There are some indications of motor potential improvement in the epileptic patient: the increased excitability of HF rTMS in the ipsilesional M1 or the decreased excitability of LF rTMS in the contralesional M1 at Levels B or C recommendation. It should be emphasized that the therapeutic value of the modality of it remains to be determined which stimulus relates to the recovery phase of stroke (acute or mild vs. chronic).
2. There is also a potential effect (Level C suggestion) for cTBS trains delivered to the posterior parietal cortex of the contralesional left hemisphere with repeated applications of hemispatial neglect. For more information, please see Unilateral Neglect.
3. Promising results are expected to be confirmed soon for the use of LF rTMS in the pars triangularis of the IFG of the contralesional right hemisphere in non-fluent Broca’s aphasia

• Schizophrenia: the efficacy of HF rTMS of the left DLPFC in schizophrenia is confirmed by Level A recommendation.
• unipolar or bipolar depression: efficacy of rTMS in unipolar depression with a Level A recommendation (“efficacy”) for both HF rTMS in the left DLPFC and LF rTMS in the right DLPFC.

Transcranial Magnetic Stimulation: A New Approach to the Treatment of Psychiatric Disorders[37]

TMS for Neuropathic Pain

Several areas of the brain including the hypothalamus amygdala thalamus somatosensory cortex insula anterior cingulate cortex and prefrontal cortex are associated with the experience of pain. Furthermore some patients with chronic pain do not respond to conventional treatments including injections and anesthesia and corticosteroids and behavioral therapy. rTMS is postulated to induce changes in the activity of cortical and subcortical brain systems related to pain modulation and activation of orbitofrontal cortices medial thalamus anterior cingulate and periaqueductal matter whitish. In particular rTMS is known to modulate neural activities in the periaqueductal gray matter related to pain processing[38].

• Most studies directed the coils of rTMS to the posteroanterior zone of the motor cortex (M1). Patients achieved optimal results with 10 sessions of HF rTMS over M1.
• Good results were obtained with a coil directed to the right DLPFC. Infact stimulation of the appropriate DLPFC was also effective in precipitating the onset of pain.
• No results in patients with chronic neuropathic pain after stroke or spinal cord injury who received deep stimulation time of the anterior cingulated cortex (ACC) or posterior superior insula (PSI). compared with sham rTMS

TMS for Migraine

Studies have reported that the mechanisms of migraine likely involve neural and neurological causes including brain cell hyperexcitability sensitization of the trigeminovascular pathway genetics and environmental factors As shown above RTMS has the potential to it will provide the functionality of cortical systems involved in pain relief or reducing cortical excitability. Plasma β endorphin levels were also found to be lower in patients with migraine than in patients without migraine and HF rTMS increased β endorphin levels[41][42].

HF rTMS was applied to the left M1 and left DLPFC with positive results for headaches during the 4-week study after treatment[43][44].