**3. TMS in neurophysiological research of schizophrenia**

**2. TMS principles, parameters and mechanism of action**

136 Schizophrenia Treatment - The New Facets

theta burst stimulation (TBS) as the most important [1–3].

of this region, whereas low‐frequency rTMS has the opposite effect [4].

The principle of the TMS method is based on Faraday's law of electromagnetic induction, formulated in 1831. This law states that around the primary coil through which a time‐varying current is flowing, a changing magnetic field is created that is able to induce a secondary current in conductors found within its reach. A patient's brain may be one such conductor. The secondary current induced is, according to Lenz's law, in the direction opposing the primary current. During TMS, an insulated metal coil is placed over the patient's head that delivers a changing electrical current producing a changing magnetic field perpendicular to the current passing through the coil. Magnetic pulses may be administered individually (single‐pulse TMS), or in pairs a few milliseconds apart (paired‐pulse TMS), or repeatedly in a sequence or "train" lasting from seconds to minutes (repetitive transcranial magnetic stimulation or rTMS). The first two options are used primarily for research and diagnostic purposes; rTMS is used mainly in the treatment of certain neuropsychiatric disorders, including schizophrenia [1, 3].

Repetitive transcranial magnetic stimulation is defined by the number of pulses per second or by frequency in Hertz (Hz). The frequency is categorized as "low‐frequency" ("slow") rTMS with 1 Hz or less and "high‐frequency" ("fast") rTMS with more than 1 Hz (usually between 5 and 25 Hz). Another parameter of stimulation is its intensity expressed as the percentage of the individual resting motor threshold (MT). The motor threshold is defined as the minimal intensity of the stimulus able to produce muscle contraction in at least 5 of 10 successive trials (usually in one of the small muscles of the hand, e.g., the abductor pollicis brevis) when the stimulation is applied to the motor cortex. The most commonly used stimulation intensity varies between 80% and 120% of the individual resting motor threshold. Other stimulation parameters include the length of the train of pulses, the duration of the pause between them ("intertrain"), the total number of pulses administered during one session, the total number of individual sessions, the stimulation coil localization, the type of coil (the most commonly used type in rTMS is the "figure‐of‐eight coil"; there are also oval coils, conical coils etc.; the double cone coil is one of the most innovative types), and the coil's position, and orientation on the patient's head. The most frequent stimulation site is the dorsolateral prefrontal cortex (DLPFC). This stimulation site is usually defined as the location 5 cm rostral to the area of the motor cortex, the stimulation of which determines the resting motor threshold. Another method for the localization of the stimulation site uses the international system of EEG electrode placement 10/20; the most precise localization method is performed by stereotactic neuronavigation. An interesting modification of standard rTMS is pattern stimulation, with

Although the specific effect of rTMS on neurotransmission is not entirely clear, it has been proven repeatedly that high‐frequency rTMS (10 to 20 Hz) increases brain excitability, and low‐ frequency rTMS (1 Hz and lower) decreases it. It has also been found that high‐frequency rTMS applied over the left prefrontal cortex (PFC) increases brain perfusion, and thus the metabolism TMS with various single‐pulse protocols and paired‐pulse protocols is a useful tool for the assessment of physiology of the human motor system, including cortical excitability, inhibitory and excitatory mechanisms, conduction time, connectivity, and plasticity [5]. Moreover, Camprodon and Pascual‐Leone [5] suppose that this tool has properties that we now need to understand across affective, behavioral, and cognitive circuits, to establish solid circuit‐based models of neuropsychiatric diseases with the potential to affect clinical practice.

One of the phenomena, studied with TMS, is cortical inhibition. Cortical inhibition (CI) can be defined as a neurophysiological mechanism by which GABAergic interneurons influence the activity of other neurons. Several studies have identified CI impairment in schizophrenia. CI and CI impairment can be measured with a number of markers and protocols, including the cortical silent period (CSP). CSP measurement consists of a suprathreshold TMS pulse over the motor cortex paired with voluntary electromyographic activity, causing a cessation of muscle movement. The duration of this movement cessation is a measure of CI. It is thought that CSP measures GABAB inhibitory activity. Another CI marker is short‐interval cortical inhibition (SICI). SICI measurement consists of a subthreshold conditioning TMS pulse preceding a suprathreshold pulse by several ms (1–5 ms). The amplitude of the motor‐evoked potential (MEP) is then measured; it should be reduced by 50–90%. This marker is thought to measure GABAA‐mediated cortical inhibition [6–13]. Recent studies show that CI impairment can be improved with antipsychotics, especially clozapine, but also with quetiapine and risperidone [13–15]. Kaster et al. [13] suggested that the potentiation of GABAB may be a novel neurotransmitter mechanism that is involved in the pathophysiology and the treatment of schizophrenia. Another recent study found inhibitory deficits directly in the prefrontal cortex specific for schizophrenia using a combination of TMS and electroencephalography (EEG) [9]. Camprodon and Pascual‐Leone [5] suppose that this multimodal combination of TMS and neuroimaging methods (EEG, magnetic resonance imaging, or positron emission tomography) can achieve TMS full potential—to measure the neurobiological effects of TMS even beyond the motor cortex.
