Transcranial magnetic stimulation is a form of non-invasive brain stimulation which is relatively safe and painless. This has been used for both investigational and therapeutic purposes. It has been utilized in neurological and psychiatric practise for evaluation of cortical functions and also as treatment for various purposes.History of rTMS          Stimulation of selected cortical areas as therapeutic approach to various psychiatric and neurological disorders has been proposed since past 4 decades.

Tsubokawa et al. had shown the role of electrical stimulation of precentral cortex in relieving chronic neuropathic pain (45). This later led to the development of transcranial current stimulation. The Principle that a changing electrical current can induce a magnetic field, and in turn a changing magnetic field can induce a secondary electrical current was postulated by Michael Faraday in 1831.

In 1985 Barker et al. proposed the concept of a magnetic stimulator that can used to stimulate cortical regions trans-cranially (46). This was the basis for subsequent development and usage of TMS in clinical practise (47).

This lead to the development of stimulators that were capable of safely inducing repetitive magnetic fields to induce an efficacious electric current in cortex (48). The first use of magnetic stimulation for depression was done by D’Arsonval (49).  From then on there has been expansion of use of TMS in neurological and psychiatric practise.Principles of rTMS          The equipment consists of an electrical current generator which is capable of producing high intensity electrical current pulse. These electric current flows through a stimulating coil which in turn produces a magnetic field whose strength varies from 1.5 to 3 Tesla which lasts for about 100 ms. When this coil is placed over the head of a subject, magnetic field is produced which undergoes some attenuation as it passes through scalp, cranium and meninges. This magnetic field as it passes through extra cranial tissue induces an electrical field and depolarizes the axons of superficial neurons in the cortex.

This in turn activates the neural networks in the cortex (12)(50).          The extent to which the electrical current that is generated acts on the superficial neural networks depends on many factors including physical and biological parameters (50) :-       Type of the coil-       Orientation of the coil-       Distance between the coil and the cranium-       Pulse waveform of magnetic field (Monophasic, Bi-phasic or Sinusoidal)-       Intensity and frequency of stimulation-       Pattern of stimulation-       Level of cortical excitability in each subject          Large circular coils are not useful in focal stimulation as they have wider action radius. Figure-of-eight coil has better focal stimulation with stimulation zone of few centimetre squares (51). Double cone angulated coil has 2 larger coils meeting at obtuse coil. They have stronger focus and hence used to stimulate deeper targets. The newer coils like H-coil and C – core coil have even better depth and focus (52)(53). Monophasic waveform is used in single pulse experiments.

Monophasic pulses when used repetitively, stimulate relatively uniform group of neurons. Bi-phasic waveform follows a more complex pattern of neural activation and are considered stronger than mono-phasic waveform (54). The intensity of magnetic stimulation also has the impact on the effects of TMS as with increasing intensity the induced electric fields penetrate deeper in the cortex and involve additional neural networks (55).Types of TMS 1.     Single pulse TMS: Stimulation with single magnetic pulse.

2.     Repetitive TMS (rTMS): Stimulation with series of magnetic pulses with specific characteristics.3.

     Paired pulse TMS (ppTMS): Stimulation with paired magnetic pulses where one suprathreshold and another subthreshold stimulus are combined with a fixed time interval in between.4.     Theta burst stimulation (TBS): Stimulation with bursts of magnetic pulses containing 3 pulses at 50 Hz which are repeated at every 200 ms.5.

     Quadripulse magnetic stimulation (QPS): Stimulation with repeated trains of 4 monophasic TMS pulses.Mechanism of action                 A muscle response is obtained in normal subjects when a suprathreshold TMS pulse is delivered to precentral region. This is termed as motor evoked potentials (MEPs) and most of the data on the effects of TMS is based on studying MEPs. The physiological effects of TMS have evaluated mainly on changes in MEP size when motor cortex is stimulated in healthy subjects.

Pascual-Leone et al. demonstrated that a series of 20 consecutive TMS pulses .delivered at a frequency greater than 2 Hz resulted in enhancement of MEP amplitude (56). Based on various studies on MEP measurements in healthy subjects, if the frequency of pulses is less than 1 Hz it is termed low frequency rTMS (LF-rTMS) and if the frequency of pulses is more than 1 Hz it is termed high frequency rTMS (HF-rTMS) (11).            When the handle of figure-of-eight coil is placed in postero-anterior direction and magnetic stimulation is given, pyramidal tracts are indirectly activated through involvement of cortical interneurons. Further this leads to involvement of spinal interneuron networks producing descending volleys or  indirect waves (I wave) (57).

When the handle of figure-of –eight coil is placed in antero-posterior direction, late indirect waves are generated due to increase in the latency time .When the handle of figure-of-eight coil is placed in latero-medial direction, the pyramidal tracts are directly activated and there by producing direct waves (D waves) (58). The main principle is that in magnetic stimulation axons are stimulated rather than neuronal cell-bodies and hence the biological effects that are elicited are not only local but also at distant site due to activation of various neural networks (59). HF-rTMS decreases the gamma-amino-butyric acid (GABA) mediated intracortical inhibition and there by enhances the excitability of motor cortex (60).

LF-rTMS enhances GABA-B transmission and there by increases cortical silent period and hence it is inhibitory in nature (61). The effect of various protocols of rTMS are due to the net effect of modulation of different neuronal networks (62). The magnetic stimulus delivered also activates the axons of neurons that form the part of neuronal network at distant site (63).         The inter and intra subject variation in the effects of rTMS is also due to the level of cortical excitability at the baseline (11). Biological and clinical effect of rTMS is also modified by several factors like age, gender, genetic aspects, on-going pharmacological treatment and disease related plasticity changes in the cortex.

 Theta burst stimulation               This is a newer paradigm of rTMS. It consists of short bursts of three low intensity pulses which have inner frequency of 50 Hz that are delivered at the frequency of 5 Hz. The continuous application of TBS for 40 seconds is termed as continuous TBS (cTBS) and this results in inhibition of MEP. Whereas application of TBS for 2 seconds for every 10 seconds for a total of 200 seconds is termed as intermittent theta burst stimulation. This results in facilitation of MEP (13).

When compared to the conventional rTMS, TBS produces a relatively less variable effect on the excitability of motor cortex (13).           Within one second the excitatory effects build up whereas it takes several seconds for the inhibitory effects to build up. TBS induces after-effects which lasts for 30 minutes to one hour(14). TBS affects the earliest I-waves (64). The after-effects of TBS are mediated by the NMDA receptors. Calcium influx through synaptic membrane is regulated by NMDA receptors (65).

A moderate enhancement of intracellular calcium levels induces long term depression (LTD) and a large enhancement of intracellular calcium levels induces long term potentiation (LTP) (15) (66). The magnitude of after-effects is dependent on specific alterations of neuronal calcium influx mediated by TBS (67). TBS affects the plasticity of NMDA receptors which in turn through signal transduction brings about plasticity changes in the neuron and this is termed as metaplasticity (16).  Motor threshold(MT)            MT is the lowest level of stimulation which when applied to the scalp overlying the motor cortex that is capable of inducing a twitch in the contralateral hand muscle (68).It is defined as minimum TMS intensity that induces a predefined MEP in the contralateral abductor pollicis brevis in at least 50% of trials (69).It is expressed in terms of percentage of output capacity of TMS machine.

It is highly variable across different subjects but it is fairly constant in a given subject (70). It is dependent on excitability of motor cortex and the distance between the coil and the cortex (68). Assessment of MT is important as overstimulation can cause adverse effects and loss of focus whereas under stimulation may not be therapeutically beneficial (51,71,72).Assessment of MT1.     MEP of hand muscle can be assessed by electromyography after eliciting motor response from TMS stimulation of motor cortex. Through this MT can be estimated (46). The amplitude of measured MEP can vary within the subject or between the subjects (73)(74).2.

     ‘Observation of movement’ method or 5 step estimation procedure: Relatively simpler method where the contralateral hand muscle movements are observed while the moto cortex is being stimulated(75). It is most commonly used method in the TMS research and it is considered reliable (76).   Therapeutic uses of rTMS 1.     Neurological disorders (50) –       HF-rTMS to motor area M1 contralateral to the site of body pain has been used in patients with neuropathic pain.-       Unilateral or bilateral M1 area, pre-motor cortex stimulation with HF-rTMS has found to be beneficial in Parkinson disorder.-       LF-rTMS to the supplementary motor area in Tourette’s syndrome has been found to be beneficial.-       HF-rTMS on ipsilateral motor cortex and LF-rTMS on contralateral motor cortex has been found to be beneficial in acute stroke.

–       LF-rTMS in epilepsy is being studied as it is found to be favourable in seizure reduction (77) 2.     Depression:          FDA has approved rTMS for mild depression in 2008. rTMS has higher success rates if started at the acute phase of the episode, in younger subjects, with partial response or resistant to adequate trial of one antidepressant (78). HF-rTMS on left dorsolateral prefrontal cortex (DLPFC) has level A recommendation in depression. LF-rTMS to right DLPFC has also been found to be efficacious.

There have been case reports, open labelled studies and few negative studies on use of rTMS in bipolar depression (50). Further research is needed in this area. 3.     Anxiety disorders          In post-traumatic stress disorder(PTSD), there is level C recommendation for the use of HF-rTMS to right DLPFC (50).Recent sham controlled study has recommended the use HF-rTMS with H-coil to target prefrontal cortex in treating PTSD(79). A recent sham controlled trial showed a significant improvement with LF-rTMS stimulation at right DLPFC in panic disorder(80). However further research is needed in this area.

 4.     Obsessive compulsive disorder         There is no clear evidence on the use of HF or LF rTMS on DLPFC. However, LF-rTMS for supplementary motor area has been found to be beneficial(81). Recent meta-analysis supports the use of LF rTMS targeting orbitofrontal cortex and supplementary motor area(82). 5.     Substance use disorder          There is Level C recommendation for the use of HF-rTMS on left DLPFC in managing nicotine dependence and craving(50).

Further research is necessary in this area.  6.     Alzheimer’s disease:          HF-rTMS delivered to the right or left DLPFC has been found to be beneficial in improving language abilities in Alzheimer’s disease(83). HF-rTMS on right DLPFC has been found to improve cognitive functions in mild to moderate Alzheimer’s disease (84). 7.     Schizophrenia          There have been limited studies that have evaluated the efficacy of rTMS in the treatment of schizophrenia in general. There have been multiple studies that have targeted the therapeutic use of rTMS in positive symptoms of schizophrenia, refractory auditory hallucinations, negative symptoms and cognitive symptoms.

                Adverse effects of rTMS 1.     Headache:             It is the most common adverse effect. It is generally mild in intensity and it subsides within few days. It is generally managed by analgesics. 2.

     Seizures:           It is the most serious side effects of rTMS. The risk has been found to be less than 1 in 10000 TMS sessions. rTMS has pro-convulsive potential if applied in high doses and high frequency (85) .The possible mechanism includes overstimulation of pyramidal neurons which leads to spread of stimulation to surrounding neurons and overwhelming of inhibitory mechanisms.

Many of the reported cases had family history of seizure disorder, were on drugs which reduced seizure threshold, or when the stimulation parameters did not satisfy the TMS safety guidelines. Safety guidelines have been formulated including recommendations on train duration, intensity, frequency for reducing the risk of seizures (71,85). There have been no reports of developing epilepsy after an episode of seizure with rTMS. 3.     Syncope:           It can happen as common as seizures. But it is difficult to distinguish it from seizures. Further rTMS has to be discontinued if syncope occurs.

 4.     Alteration in hearing:          There have been no reports of hearing loss. However there have been reports of increase in auditory threshold which is transient and mild increase in high frequency hearing disturbance. Hence ear plugs are recommended during rTMS administration.

 5.     Psychiatric changes:            There have been reports of occurrence of delusions, anxiety, insomnia, agitation and suicidal ideation. However, it is uncertain whether these symptoms are because of rTMS or due to the psychiatric illness (86).  Contraindications for rTMS  (64): 1.     Absolute contraindication:            Presence of metallic implants, cochlear implants, pacemakers, medication pumps or internal pulse generators. 2.     Conditions associated with increased/uncertain risk for inducing seizures:Patient factors-       Personal history of epilepsy or family history of epilepsy-       History of cerebral vascular event, tumours, head trauma or metabolic lesions of the brain.

–       If on medications that reduce the seizure threshold.-       Sleep deprivation-       Alcoholism Stimulation factors-       Any novel paradigm or conventional protocol which violates safety guidelines. 3.     Conditions of increased or uncertain risk:-       Implanted brain electrodes-       Pregnancy-       Cardiac diseases.      rTMS and Schizophrenia                    During early phase of research rTMS was used in treating overall symptoms of schizophrenia without specifically addressing any particular domains of symptoms. These studies are very few in number and they had addressed the use of rTMS in overall illness. These studies have shown equivocal results.

Table: Summary of studies on rTMS and schizophrenia (overall illness) Author Study design N Stimulus parameters Number of sessions outcome Geller et al., (1997) (88) Open labelled study 10 1 stimuli per 30 seconds at 100% RMT; 15 stimuli per each side 1 Non-specific improvement in 2 patients. Feinsod et al., (1998)(89) Open labelled study 10 2 trains of 60 stimuli each at 1Hz frequency targeted at right prefrontal cortex 10 Improvement in non- specific symptoms in BPRS scale. Klein et al., (1999) (90) Double blind sham controlled study 31 2 one minute trains at 1 Hz frequency at 110% RMT at right prefrontal cortex. 10 No significant difference. Rollnick et al.

, (2000) Double blind cross over design 12 20 trains of 2 seconds duration at 20 Hz and 80% RMT to left prefrontal cortex. 10 Significant improvement in BPRS scores.  N= number of subjectsEfficacy of rTMS on negative symptoms of schizophrenia         It has been hypothesized that pre-frontal dysfunction contributes to the negative symptoms in schizophrenia. It has been proposed that HF-rTMS delivered to DLPFC might be beneficial in managing negative symptoms. Initial open labelled studies have shown beneficial effect, however sham controlled studies have shown mixed results. There have been no conclusive results from few of the recent meta-analyses. Also, there has been no data on long term effects or duration of treatment.

Table: Summary of meta-analysis and reviews on the use of rTMS in negative symptoms of schizophrenia Author Study design conclusion  Freitas et al., (2009) (91) Meta-analysis (3 open labelled studies and 5 RCTs) (HF-rTMS to left DLPFC) Effect size of 0.27 for rTMS in negative symptoms. Suggestion for more controlled studies.

Matheson et al., (2010) Meta- review rTMS is found to be not useful in negative symptoms of schizophrenia. Dlabac-de-lange et al., (2010) (92) Systematic review and meta-analysis (9 RCTs) Large effect size with studies involving higher frequency of stimulation and small – medium effect size with studies involving lower frequencies. Slotema et al.

, (2010) (93) Meta-analysis (7 RCTs) Mean effect size of 0.39 for LF-rTMS on DLPFC. Shi et al., (2014) Meta-analysis (10 RCTs) Effect size of 0.53 for HF-rTMS and 0.

63 for LF-rTMS for negative symptoms.    Efficacy of rTMS in the treatment of persistent auditory hallucinations:            Decreasing the pathological hyperactivity and excitability of TPJ by LF-rTMS has been area of research for the treatment of resistant AVH. Hoffman et al. were the pioneers to test this hypothesis (94).

Many studies have come thereafter including cross-over studies, parallel studies, meta-analysis and reviews. They have described in the tables that follow.   


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