**3. TMS paradigm**

Various TMS protocol helps in understanding the neurobiological basis of disorder and specific behaviors by allowing direct probing of the cortical areas and their interconnected networks. While single-pulse TMS can provide insight into the excitability and integrity of the corticospinal tract, paired-pulse TMS (ppTMS) can provide further insight into cortico-cortical connections and repetitive TMS (rTMS) into cortical mapping and modulating plasticity. Few paradigms used are mentioned in **Table 1**.

## **3.1 TMS as a tool to measure cortical excitability**

TMS can be used in humans to measure parameters of cortical excitability *in vivo.* Excitation is mainly facilitated by the action of glutamate on N-methyl-d-aspartate (NMDA), and non-NMDA receptors. Single-pulse TMS had been initially employed to test the functional integrity of human corticospinal pathways. When a stimulus of sufficient intensity is applied to the motor cortex, it will produce a motor evoked potential (MEP) in the muscle supplied by the cortical area that can be measured with electromyographic equipment [13]. Cortical excitability can be assessed by either calculation of resting motor threshold (RMT) or by calculation of MEP. RMT is defined


#### **Table 1.**

*Different cortical function and paradigm assessed using TMS.*

as the minimum TMS intensity (expressed as a percentage of maximum stimulator output) that elicits reproducible MEP responses of at least 50 μV in 50% of 5–10 consecutive trials. The majority of application to date has involved the motor cortex but can be applied to another area of the cortex eg. stimulation in the visual cortex can produce flashes of light known as phosphenes, and stimulation of prefrontal areas can produce TMS-evoked EEG potentials.

Paired pulse stimulation (ppTMS) can also be used to assess cortical excitability and it has been accepted as a tool specifically for corticocortical circuit evaluation, whether interhemispheric, interhemispheric, or interregional. Two reactivity parameters that are commonly assessed are inhibition and excitation [14]. In ppTMS, the baseline single pulse is referred to as the test stimulus (TS), while the priming additional pulse administered a few milliseconds prior to the TS is the conditioning stimulus (CS). Conditioning stimuli strength may vary from less than (subthreshold) to greater than (suprathreshold) the RMT. A high-intensity suprathreshold pulse activates cortical pyramidal neurons directly and indirectly, via excitatory interneurons, leading to a corticospinal output that can be measured peripherally as a MEP. The response to the paired stimuli predominately depends upon interstimulus interval and CS strength. The two most commonly pair pulse paradigms used for facilitatory circuits [15, 16] are Intracortical facilitation (ICF) and short-interval intracortical facilitation (SICF) (**Table 2**). These paradigms typically reflect glutamatergic neurotransmission in the brain.

*Understanding the Neuropathophysiology of Psychiatry Disorder Using Transcranial Magnetic… DOI: http://dx.doi.org/10.5772/intechopen.103748*


**Table 2.**

*Cortical excitation parameters ICF and SICF.*

#### **3.2 TMS as a tool to measure cortical inhibition**

The ability of TMS to measure cortical inhibition depends on the stimulation of interneurons in addition to corticospinal neurons. At low intensities, only intracortical inhibitory and excitatory neurons are stimulated without any effect on the excitability of corticospinal output and, therefore, do not result in an MEP. Thus, by combining a subthreshold pulse with a suprathreshold pulse, one can assess the inhibitory effects of interneurons on cortical output. The paradigms that demonstrate cortical inhibition include paired-pulse TMS (ppTMS), cortical silent period, and transcallosal inhibition (TCI). The cortical silent period is measured as isoelectric EMG (silent period) elicited by delivering a stimulus (110–160% of RMT) in the contralateral motor cortex, while the hand muscle is in a contraction phase. There is evidence that the early and late phase of the silent period may be mediated through different mechanisms with the late phase produced through G-protein coupled GABAB receptor and the early phase potentially complicated by spinal effects [17]. Next, when paired-pulse TMS is applied to the same cortical location, there are at least two inhibitory corticocortical circuits one can activate: short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI) (**Table 3**). The cortical inhibition appears to be produced by the GABAergic receptor.

Various studies in the past have linked the role of GABA in the pathophysiology of different neuropsychiatric disorders, most important among them include major depressive disorder, schizophrenia, and obsessive–compulsive disorder (OCD) [18]. The deficit in GABAergic inhibition is noticed widely in psychiatric disorders, however, each illness may have a distinct profile and varied response to treatment. A meta-analysis in 2013 suggested that deficit in SICI– mediated by the GABA(A)ergic inhibition is a universal finding in severe psychiatric illnesses including Obsessive– Compulsive disorder, Major depressive disorder, Schizophrenia but enhancement of intracortical facilitation was specific to OCD [19]. A recent review for understanding the neurobiological basis of psychiatric disorders using the TMS-based paradigms points to significant impairment in cortical inhibitory, excitatory, and oscillatory activity, especially in the frontal region [20].

#### **3.3 TMS as a tool to measure connectivity**

Measurement of corpus callosum connectivity in illnesses such as schizophrenia, in which the pathophysiology has been closely linked to dysfunctional cerebral connectivity, is helpful. Additionally, while the application of the TS often remains fixed to a given motor cortical region, the CS location may be varied to interhemispheric or interregional location including the contralateral motor cortex, cerebellum, and


#### **Table 3.**

*Cortical inhibition parameters SICI and LICI.*

peripheral nerves. These circuits correspond to pathways of interhemispheric inhibition (IHI), cerebellar inhibition (CBI), and short- (SAI) or long-latency afferent inhibition (LAI), respectively.

#### *3.3.1 Interhemispheric inhibition (IHI)-*

The relationship between the two motor cortices can be studied by paired-pulse TMS at both motor cortices. In this stimulation paradigm, MEP in the distal hand muscles by test TMS was inhibited by prior CS on the opposite side at ISI between 6 and 30 ms to investigate the transcallosal route and connectivity between brain regions. IHI requires an intact inhibitory system in the contralateral motor cortex as transcallosal fiber from the motor cortex synapse on GABAergic inhibitory interneuron [21]. A similar technique can be used to investigate connectivity between the motor cortex and the cerebellum. Inter-hemispheric inhibition is thought to be mediated through excitatory axons that cross the corpus callosum to act on local inhibitory (mainly GABAB-mediated) neurons in the contralateral motor cortex. Also, in short-latency afferent inhibition, afferent sensory input through stimulation of the median nerve at the wrist or cutaneous fibers at the index finger can modify the excitability of the motor cortex with a complex time course and thought to be regulated by muscarinic and cholinergic cerebral circuits.

#### *3.3.2 Intrahemispheric inhibition*

Functional and anatomical connections between motor and parietal areas have been studied before in Humans and studies have collectively proved distinctly defined connections from parietal (anterior and posterior part) to motor areas [22]. Anatomically, the anterior part of the inferior parietal lobule (IPL) is connected to the ventral premotor and prefrontal regions, whereas the posterior IPL is linked to caudal-lateral prefrontal regions. Hence, we have to use the twin coil TMS (Tc TMS) protocol for investigating these parietal-motor connections in humans. In tcTMS a conditioning stimulus (CS) is delivered to an area of interest and followed by a test stimulus (TS) to the primary motor cortex (M1). Koch and colleagues had shown that this protocol can be used to probe parietal-motor connections and since then widely used to investigate the time course and locality of parietal-motor interaction, both during the task and at rest in studies [23]. Studies have shown the facilitatory connection between the posterior portion of IPL and M1 when a conditioning stimulus is given to the posterior IPL 2-8 ms prior to the test stimulus over M1and the EMG response triggered by M1 pulse is enhanced.

*Understanding the Neuropathophysiology of Psychiatry Disorder Using Transcranial Magnetic… DOI: http://dx.doi.org/10.5772/intechopen.103748*

#### **3.4 TMS as a tool to measure cortical plasticity**

TMS can be used as a strategic tool to probe plastic changes in humans and this approach was used initially in neurorehabilitation to study cortical reorganization. First demonstrated by Classen to measure the effects of neuro-rehabilitative strategies in stroke patients by applying TMS over an optimal position in the motor cortex. He relates that the size of topographic motor maps in the vicinity of a cortical lesion shrinks following inactivity but often expands after the physical activity of the limb affected by the lesion [24] and areas such as the premotor cortex overtakes the functions typically executed by the primary motor cortex. MS cortical motor maps enlarge after intense motor training in stroke patients and such a plasticity effect can also be demonstrated after a yoga intervention. Similarly, another example of transmodal plasticity can also be elicited in patients who are blind from early life read Braille, where somatosensory information gets routed to the visual cortex and show activation sign in the visual cortex in functional neuroimaging studies [25]. But this did not prove that activity in the visual cortex was being used for actual analysis of the information. Using rTMS during reading showed that this function was impaired when the visual cortex was disrupted. Of potential clinical importance, aberrant synaptic plasticity is a pathophysiological characteristic of schizophrenia. and using in-vivo perturbation protocols like TMS and tDCS, studies have demonstrated diminished LTP and LTD-like motor cortical plasticity [26]. The common paradigms in TMS for assessing cortical plasticity are:

#### *3.4.1 Paired associative stimulation (PAS)-*

PAS involves repetitive activation of sensory inputs (mostly median nerve) to the motor cortex using TMS and producing long-term changes in the excitability of the motor cortex that can last for several hours. The effect of PAS on MEP size was found to be dependent on the timing of the TMS pulse with respect to the afferent stimulation. In short, during PAS with an ISI of −10 ms (PAS10), LTD-type effects were induced in the motor cortex as reflected in reduced MEPs. On the other hand, when an ISI of 25 ms (PAS 25) was used, long-term potentiation (LTP-type) effects were induced as evidenced by increases in MEP responses [27].
