Abstract
Transcranial Magnetic Stimulation (TMS) is a non invasive method used to modulate the excitability of cerebral cortex.
This technique was born in Sheffield in 1985, where a research group has developed the first studies, stimulating cerebral areas without provoking any pain. From 1985 the technology has remained globally the same, but new potential uses and new practical applications are being studied. The cerebral stimulation with TMS is effectuated directly on the scalp, it is not necessary any particular preparation for the subject undergoing this technique, it is painless and can be easily repeated, the effects provoked on the cerebral cortex are reversible. For these reasons it is considered a non invasive technique.
TMS is used in the diagnostic, therapeutic and research fields.

Introduction
Transcranial magnetic stimulation is a device consisting of two parts: a current generator that produces high intensity discharges and a stimulating coil, that is directly placed on the patient's scalp.
TMS works according to the principle of electromagnetic induction. A current flow inside a metal coil generates an electromagnetic field perpendicular to the current flow is generated.
By placing a second conductor (scalp) within the magnetic field, a current on the scalp can be induced.
In this way, it is generated an inducted current, which can produce action potentials in the excitable neurons of the cortex .
It is important to notice how the effects of the technique don't depend directly on the magnetic field, but on the induced electric field, that provokes the neuronal depolarisation. The induced electric field depends on different factors. Concerning the coil, it can have different shape or dimension, although the "8 shaped" one is the most commonly used, as it generates a more focused electric field, thus giving a better control of the spatial extension of cerebral excitation. The stimulating coil is connected to a machine through which the intensity and the number of given impulses can be controlled.
A limit of this technology is the capacity to induce a depolarisation area with a depth of only 1.5-2 cm under the scalp, even if it can also influence more distant cells by a transinaptic mechanism of action [2].
The methods of stimulation are essentially two: the "Single Pulse TMS", where the pulse consists of a single administered discharge (interval among pulses > 3 sec.) and the "Repetitive TMS", where the impulse consists of a n number of discharges in a given time; the latter is the technique we will discuss about.
It is noteworthy that, in contrast with electroconvulsive therapy, where is produced a massive neuronal depolarisation and the scalp act as a resistance, the magnetic fields are not attenuated by tissues, thus resulting in a more focal and painless technique, as nociceptors are not stimulated.

 

 

Fields of application
TMS is used in a wide range of research, clinical and therapeutic applications dealing with the functioning of the human brain.
From a clinical and research point of view, studies range from the primary cortical areas, to neuronal plasticity and cognitive neuroscience.
The functional mapping through transcranial magnetic stimulation, allow to correlate the different motor, sensitive and cognitive cerebral areas, with their own functional properties and consequently foresee which damages follow specific lesions and observe the neuronal modifications due to specific pathologies (synaptic plasticity). In this way the different areas supposed to underlie different functions are stimulated, then the sensitive and motor activities evoked by the stimulation are measured. The stimulation of the primary motor areas generates an involuntary contraction of the contralateral muscles, the stimulation of the primary somatosensory cortex negatively interferes with tactile perception, while the stimulation of the primary visual area evokes the perception of scotomas and phosphenes. TMS is also used in combination with electroencephalography (EEG). The magnetic field can stimulate the superficial neurons of the grey matter while EEG can register the surface electrical activity, allowing to study the cerebral connections, the cerebral reactivity and the speed of conduction between the two hemispheres. In the cognitive neuroscience domain, the technique has been used to study the neural processes linked to the activity of the superior cortical areas, in the context of studies regarding perception, attention, learning, language and awareness. Transcranial magnetic stimulation generates a transient and focal interruption of physiologic cerebral activity, producing a sort of temporary and reversible lesion, thus reproducing the conditions determining the deficit. In clinical psychiatry the main field of application of TMS is the therapy of depression, but its utility is being experimented in obsessive-compulsive disorder (OCD), hallucinatory disorders and cocaine dependence.

How to do it
In the preliminary phase are defined some parameters necessary for the use of TMS technique. First, the motor threshold (MT) necessary to settle the intensity of stimulation must be determined. The MT is defined as the minimal intensity of magnetic stimulation (administered on the left motor area) capable to evoke at least five out of ten stimuli, and involuntary movement of the brevis abductor muscle of the right thumb, that is visually detected. Cortical excitability, in fact, is an extremely variable measure, according to different factors such as the scalp thickness, the skull shape, the electrical conductivity in the cortical tissue. Once determined the MT it is possible to start the repetitive administration of pulses at a given percentage of the threshold itself.
In the treatment of depression is generally used an intensity from 80 to 120 % of MT and the left dorsolateral prefrontal cortex (DLPFC) is stimulated with rapid TMS, which means > 5 Hz up to 20 Hz and the right DLPFC in the slow way, that is < 1 Hz.
The duration of rapid TMS stimulation is in general of 2-10 seconds, with an interval between trains ranging from few seconds to 90 seconds. For slow stimulation, is used a single train of impulses lasting several minutes.
The choice of these parameters derives from numerous studies that compared the effects of stimulations in different areas and with different intensity and frequencies.
Areas of stimulation
The area of stimulation depends on the pathology to be treated. There are some reference point for each area; a common pre-cabled cup for electroencefalography can be helpful, but the most scientifically correct method consists of matching TMS with a Magnetic Resonance; this method allows to place the coil in the exact point of stimulation. TMS can also be matched to a stereotaxic neuronavigation system that can drive the placement of the stimulating coil. The neuronavigation system can visualize the direction of propagation of the magnetic field and the target cerebral area, using spatial cerebral information given by magnetic resonance images (MRI). In the absence of the patient's own MRI, the system uses template MRI adapted to each subject through an innovative procedure of 3D warping. The integration between the subject's physical space and the MRI's space is obtained using 3 craniometric points referred to a common stereotaxic space by using a magnetic digitizer.
Depression: The rationale of using rTMS on the left DLPFC depends on the observation carried on the metabolism of this portion of cortex in depressed patients. Left DLPFC was stimulated for the first time with high frequency by George et al, with encouraging results [3]; then this has been the stimulated area in the majority of following studies. It is generally found 5 cm ahead the motor threshold area, even if the precision of this determination is not very high.
Other researchers instead, have stimulated the right DLPFC, especially at low frequency and some others have combined the stimulation of both areas in the same session. Obsessive-Compulsive Disorder (OCD): neuroimaging studies have evaluated the cerebral metabolism (PET) and cerebral blood flow (fMR) and neuropsychological studies indicate that patients with OCD and Tourette Syndrome [6] show functional abnormalities at basal ganglia/ pre central circuit, which result in a state of "tonic" hyperexcitability and lack of inhibitory control in the related motor areas. Researchers have recently focused their attention on the slow magnetic stimulation on the right supplementary motor and orbitofrontal cortex.
Auditory verbal hallucinations: frequent in schizophrenia where are refractory to antipsychotic drugs in 25% of cases. The 1Hz repeated stimulation reduces the excitability of the left temporo-parietal area involved in this pathology, significantly reducing the hallucinatory symptoms [7].
Cocaine addiction, preliminary results: our group is also evaluating the therapeutic potential of TMS in cocaine abuse and dependence. In a preliminary study, 8 patients underwent TMS on prefrontal cortex, during the first phase of cocaine detoxification. Seven subjects have shown an improvement on different parameters related to primary craving (adversative phase, especially characterized by anxiety, physical tension and irritability).
It is also being evaluated the introduction of a second cycle of TMS to manage the symptoms of secondary craving (appetitive) with the aim to modulate the cocaine-dependent positive reinforcement system.

Stimulation parameters
Through the evaluation of prefrontal TMS at different intensities, it has been observed that higher intensities evokes greater changes in the electric and metabolic brain activity and generate more consistent clinical improvement [8,9,10].
In general "rapid TMS" refers to stimuli with >1 Hz frequency, while "slow TMS" indicates <1 Hz frequency.
The use of left rapid and right slow stimulation derives from two kind of evidences. First, it has been proposed that a greater activation of right hemisphere than the left one is the expression of a reduction in mood [11,12]. Then, lesions of the left hemisphere result in depressed mood, while those of the right one cause indifference reactions or even euphoria [13,14]. Also in functional imaging and electroencephalographic studies, a reduction of the activation of left prefrontal areas has been documented. Second, it has been proven an increase of the cerebral activity, flow and metabolism in left dorsolateral prefrontal cortex, after rapid TMS and a contralateral reduction after slow TMS [18].
In depression can be hypothesized an imbalance between left hypoactive and right hyperactive cortex, that can be minimized by TMS that will be left -activating and right -inhibiting.

Antidepressant effect of rTMS
It has been accidentally found that patients with neurological diseases, effectuating TMS with diagnostic purposes and having a concomitant mood disorder, showed an improvement of depression. This finding has initiated the study of the use of rTMS as a therapeutic treatment in psychiatry.
Several pre-clinic studies have shown that TMS can modulate the functions of fronto-limbic circuitries, which are reversibly altered in major depression and that it can act on neurotransmission systems involved in the pathphysiology of the disorder, for example on the stimulation of dopamine release and the interaction with the hypothalamus-pituitary axis. Many open and controlled clinical studies, with very different stimulation parameters, have investigated the antidepressant potential of rTMS. Although led on relatively small samples, the majority of placebo-controlled trials has shown a significant therapeutic effect of active stimulation versus sham. Anyway, the efficacy degree is highly variable and the selected patients are in most cases drug-resistant; moreover, the treatment duration is approximately 2 weeks, a short period if compared to that of common antidepressant treatments [19]. There are basically 3 possibilities to use TMS in depression: alone, without antidepressant drugs; as drug-hastener at the beginning of treatment; in drug-resistant depression; anyway, the results are extremely variable among studies, ranging from little or no effect, to an effectiveness similar to ECT [20,21,22].

 

 

Direct experiences
In our department we carried out two randomised trials to test the efficacy of TMS in the treatment of depression.
In the first study [23] we treated 54 drug-resistant patients with two different intensity of stimulation ( 80% and 100% of the motor threshold) or with sham stimulation, obtaining a significant difference in response between the group stimulated at 100% and the control group. In the second study [24] we administered TMS (active or sham) in combination since the beginning with a randomized antidepressant drug (escitalopram, sertraline, venlafaxine). The group on active treatment has shown a faster antidepressant response than the control group, independently from the drug administered. We are now working on a trial in drug-resistant Obsessive-Compulsive Disorder. The stimulated area is the left orbitofrontal cortex with a frequency of 1Hz , 900 impulses per day for 15 days. Five schizophrenic patients with hallucinations refractory to common antipsychotic drugs and clozapine, underwent slow TMS on the temporo-parietal cortex , 900 impulses/day at 100% of motor threshold for 10 days, obtaining a significant reduction of hallucinations and related discomfort. Unfortunately all patients relapsed within 3 months. There is also a study project about the efficacy of TMS as maintenance therapy for the Verbal Hallucinatory Disease, in agreement with a case report recently published.

Side effects and contra-indications
Transcranial magnetic stimulation, if administered following the current international safety guidelines, is a safe technique. A recent review about the TMS side effects reported in different studies has shown rare and mild side effects. The side effects that have most frequently been found are a feeling of discomfort in the site of application of the coil and headache in 23% of subjects, while most serious effects have been found to be rare [26]. Over the years, the most often reported side effects during TMS application are:
useizures (in liable subjects; 10 cases reported)
uheadache (frequent but tolerable)
utransient reduction of hearing ( avoidable with ear plugs)
uthe induction of a manic state in bipolar patients
To avoid any risk it is necessary to follow the TMS contra-indications, that are the presence of cerebral organic disease, instable medical disease, pace-maker, implanted metallic pumps, mobile metallic implants, seizures (or familiarity for the disorder); children and pregnant women are also excluded.

Adelio Lucca, David Rossini, Lorenzo Magri, Alessia Malaguti, Silvia Giordani, Danilo Dotoli, Luca Polledri, Eugenia Fauci, Ernestina Politi, Chiara Ruffini, Cristina Lorenzi, Adele Pirovano, Elena Marino, Raffaella Zanardi, Enrico Smeraldi.
Hospital San-Raffaele-Turro,
University Vita-Salute San-Raffaele, Milan, Italy