**2. TMS parameters in clinical application**

## **2.1. Central motor conduction time**

The so-called central motor conduction time (CMCT) can be calculated by subtraction of the peripheral conduction time from spinal cord to muscles from the conduction time of responses evoked by cortical stimulation. Demyelination of motor pathways increases CMCT, while low amplitude MEPs with little delay or absence of responses are rather suggestive of neuronal or axonal loss [4, 5].

The amplitude of the MEP reflects the integrity of the corticospinal tract and the excitability of motor cortex and spinal level, as well as the conduction along the peripheral motor pathway to the muscles [4, 5].

TMS also allows cortical mapping procedures, with single TMS pulses applied on several scalp positions overlying the motor cortex, exploring the site of maximal excitability (hotspot) and the "center of gravity" of motor cortical output [6].

#### **2.2. Motor threshold**

The resting motor threshold (RMT) is by definition the minimum stimulus intensity that produces a motor evoked potential (MEP) greater than 50 μV in 50% out of 10 trials at the completely relaxed tested muscle. RMT provides information about a central core of neurons in the muscle representation in the motor cortex, and reflects both neuronal membrane excitability [7–9] and non-N-methyl-D-aspartate (NMDA) receptors' [8, 9] glutamatergic neurotransmission. The minimum stimulus intensity that produces a MEP (about 200 μV in 50% of 10 trials) during isometric contraction of the tested muscle at about 10% maximum defines the active motor threshold (AMT). AMT provides a measure of corticospinal excitability with greater dependence on the spinal segmental level excitability [4, 5].

#### **2.3. Short-latency afferent inhibition**

Short-latency afferent inhibition (SAI) refers to the suppression of the amplitude of a MEP produced by a conditioning afferent electrical stimulus applied to the median nerve at the wrist approximately 20 ms prior to the TMS pulse to the hand area of the contralateral motor cortex [10] SAI reflects the integrity of central cholinergic neural circuits. It is reduced or absent by the muscarinic antagonist scopolamine in healthy subjects [11]. SAI may also be dependent on the integrity of circuits linking sensory input and motor output [12]. Cholinergic transmission underlies also the neuromodulation of other neurotransmitters.

#### **2.4. Cortical silent period, paired pulse intracortical inhibition and facilitation**

Single-pulse TMS delivered during voluntary muscle contraction produces a period of EMG suppression known as the cortical silent period (cSP). TMS can also investigate the intracortical facilitatory and inhibitory mechanisms that influence motor cortical output. Paired pulse TMS techniques involve paired-stimuli based on a conditioning-test paradigm [13]. Stimulation parameters such as the intensity of the conditioning stimulus (CS) and test stimulus (TS) together with the time between the two stimuli (interstimulus interval, ISI) determine interactions between stimuli. When the conditioning stimulus is below and the test stimulus is above the MT, the conditioning stimulus decreases the MEP to the test stimulus at interstimulus intervals from 1 to 5 ms (short-latency intracortical inhibition, SICI), while the conditioning stimulus induces a facilitation of the response to the test stimulus at interstimulus intervals from 6 to 20 ms (intracortical facilitation, ICF).

Short latency intracortical inhibition reflects to a large extent GABAA-mediated intracortical inhibitory synaptic activity [14]. The early part of the silent period originates from spinal inhibition, while the later part is caused by a long-lasting cortical inhibition mediated by GABAB primarily in the motor cortex [15]. The intracortical facilitation with interstimulus intervals from 6 to 20 ms reflects motorcortical excitatory neurotransmission primarily mediated by NMDA receptors [15].

#### **2.5. Cortical connectivity and plasticity measures**

The chapter reviews studies reporting about applications of TMS in neuropsychiatric disorders. Most reports have applied TMS to characterize important neurophysiologic and pathophysiologic aspects of neurodegenerative diseases. Several studies using TMS have demonstrated abnormalities in cortical excitability, plasticity and functional connectivity between the motor cortex and other cortical regions. Other studies aimed to evaluate and

Long-term neuromodulatory effects applying repetitive TMS (rTMS) can be induced with promising therapeutic potential in neuropsychiatric disorders. These applications can improve our understanding of brain plasticity mechanisms, the basis for the development of

The so-called central motor conduction time (CMCT) can be calculated by subtraction of the peripheral conduction time from spinal cord to muscles from the conduction time of responses evoked by cortical stimulation. Demyelination of motor pathways increases CMCT, while low amplitude MEPs with little delay or absence of responses are rather suggestive of neuronal

The amplitude of the MEP reflects the integrity of the corticospinal tract and the excitability of motor cortex and spinal level, as well as the conduction along the peripheral motor pathway

TMS also allows cortical mapping procedures, with single TMS pulses applied on several scalp positions overlying the motor cortex, exploring the site of maximal excitability (hot-

The resting motor threshold (RMT) is by definition the minimum stimulus intensity that produces a motor evoked potential (MEP) greater than 50 μV in 50% out of 10 trials at the completely relaxed tested muscle. RMT provides information about a central core of neurons in the muscle representation in the motor cortex, and reflects both neuronal membrane excitability [7–9] and non-N-methyl-D-aspartate (NMDA) receptors' [8, 9] glutamatergic neurotransmission. The minimum stimulus intensity that produces a MEP (about 200 μV in 50% of 10 trials) during isometric contraction of the tested muscle at about 10% maximum defines the active motor threshold (AMT). AMT provides a measure of corticospinal excitability with

Short-latency afferent inhibition (SAI) refers to the suppression of the amplitude of a MEP produced by a conditioning afferent electrical stimulus applied to the median nerve at the wrist approximately 20 ms prior to the TMS pulse to the hand area of the contralateral motor cortex [10]

monitor the effects of certain pharmacological agents.

6 Transcranial Magnetic Stimulation in Neuropsychiatry

new therapeutic strategies in neuropsychiatric disorders.

spot) and the "center of gravity" of motor cortical output [6].

greater dependence on the spinal segmental level excitability [4, 5].

**2. TMS parameters in clinical application**

**2.1. Central motor conduction time**

or axonal loss [4, 5].

to the muscles [4, 5].

**2.2. Motor threshold**

**2.3. Short-latency afferent inhibition**

Combined measures of EEG and TMS (EEG) [16–18] can provide real-time information on cortical connectivity and distributed network dynamics.

Several other TMS techniques are currently used to modulate noninvasively the excitability of the cerebral cortex. Cortical responses to rTMS and paired-associative stimulation (PAS) provide information about different aspects of cortical plasticity [4, 15, 19]. TMS can influence brain function if delivered repetitively. RTMS is a technique that delivers single TMS pulses in trains with a constant frequency and intensity for a given time. Depending on the stimulation parameters, particularly the frequency of stimulation, cortical excitability can be modulated and rendered facilitated or suppresses. The modulation induced by rTMS can induce significant and long-lasting changes in focal and non-focal neural plasticity. Generally, lowfrequency rTMS (stimulus rates of 1 Hz or less) induces inhibitory effects on motor cortical excitability allowing creation of a reversible 'virtual lesion' [20], while high-frequency rTMS (5–20 Hz) usually promotes an increase in cortical excitability [21, 22].

PAS involves repeated pairs of electrical stimulation of a peripheral nerve (usually the median nerve) followed by TMS applied over the contralateral hand area of the motor cortex [23]. PAS induces a lasting increase in corticospinal excitability, which can be considered a marker of motor cortical plasticity, with long-term plasticity-like mechanisms thought to play a major role [23].
