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Transcranial magnetic stimulation (TMS) is a safe and non-invasive tool that allows researchers to probe and modulate intracortical circuits. The most important aspect of TMS is its ability to directly stimulate the cortical neurons, generating action potentials, without much effect on intervening tissue. This property can be leveraged to provide insight into the pathophysiology of various neuropsychiatric disorders. Using multiple patterns of stimulations (single, paired, or repetitive), different neurophysiological parameters can be elicited. 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.
All India Institute of Medical Sciences (AIIMS), India
*Address all correspondence to: jitender.jak@gmail.com
1. Introduction
Transcranial magnetic stimulation (TMS) is an experimental tool that allows researchers to noninvasively explore various neural processes and measure a variety of cortical phenomena and different timescales. The most important aspect of TMS is its ability to directly stimulate the cortical neurons, generating action potentials, without much effect on intervening tissue. This property can be leveraged to provide insight into the pathophysiology of various neuropsychiatric disorders. Using multiple patterns of stimulations (single, paired, or repetitive), different neurophysiological parameters can be elicited. In this article, we review the role of TMS as a tool to study motor neurophysiology of major neuropsychiatric disorders. TMS-related parameters reflect underlying cortical excitability changes during any brain motor action. New findings of motor system abnormality through TMS parameters have provided new insight into the pathophysiology of neuropsychiatric disorder.
Since its introduction by Barker in the 1980s [1], who first discovered the induction of finger and foot movements through the use of a magnetic coil placed on the motor cortex, TMS has greatly advanced our ability to explore and understand neural circuitry in neurology, psychiatry, and neuropsychological research.TMS uses principles of electromagnetic induction [2]. According to the principle whenever an electric current is passed through a coil, a transient magnetic field is generated, which induces a current in the corresponding neural tissue, consistent with Faraday’s law. When the induced current is sufficient (several mA/cm2), depolarization of neuronal membranes occurs, and hence generation of action potentials, which is recorded peripherally using electromyography (Figure 1). Based on which area of the cortex is stimulated, different functions can be assessed. In the case of the stimulation of the primary motor cortex, TMS is thought to predominantly activate the pyramidal cells transynaptically through excitatory intraneuronal elements. The corticospinal tract (CST) is the main descending motor pathway from the cerebral cortex to the spinal cord that can be activated by TMS. The CST originates from large pyramidal cells predominantly in the fifth layer of the cerebral cortex. The descending corticospinal tract is known to make monosynaptic connections with spinal motoneurons in humans. This organized electrical activity in the corticospinal tract is also regulated by the balance of GABAergic inhibitory postsynaptic firing and excitatory glutamate receptor activations. This contrasting cortical modulation by GABAergic vs. Glutamatergic fibers in neural tissue can be studied non-invasively in the human brain through TMS parameters. Cortical inhibition by GABAergic neurons mediates the balance between the excitatory and inhibitory systems of the nervous system. TMS has been used to study a variety of neuropsychiatric disorders including anxiety, obsessive–compulsive disorder, attention deficit hyperkinetic disorder, post-traumatic stress disorder, schizophrenia, and mood disorder by assessing these cortical reactivity parameters. Gamma-aminobutyric acid (GABA) is one of the most important inhibitory neurotransmitters in the brain, widely distributed, and plays an important role in the modulation of cortical reactivity and neuroplasticity. GABAergic neurons represent between 20–40% of all neurons present in the central nervous system [3, 4] and they are present throughout all levels of the neuraxis, and play an important role to balance and fine-tune excitatory neurotransmission of various other neuronal systems including the cholinergic and monoaminergic projection to the area of the forebrain. Gamma-aminobutyric acid-ergic (GABAergic) deficit pathology is widely studied in various neuropsychiatric disorders [5, 6]. GABA shows its actions by interacting with two different subtypes of receptors a) GABAA receptors (GABAARs)-ionotropic b) GABAB receptor (GABABRs)-metabotropic. GABAARs are predominately responsible for anxiety and mood disorders, due to marked evidence suggesting altered GABAAR signaling in both disorders [7, 8]. Benzodiazepine act as an allosteric modulator of a major subset of GABAARs demonstrating potent anxiolytic activity and playing key control elements of anxiety state [7, 9]. GABAB Rs, Coded by GABA 1 gene and GABA 2 gene are members of the G-protein coupled receptor family and their role in the causation of affective disorder have been recently implicated in mice who demonstrated alerted anxiety and depression-related behavior after subjecting to pharmacological and genetic manipulations of these receptors [10]. The results from this study reflect that future development of therapeutic anxiolytic can be based on modulating GABAB receptors in the experimental study. In 2010, one review suggested that there are compelling evidence of both GABAA and GABAB inhibitory deficit in the pathophysiology of depressive disorder [11]. Both GABA-A and GABA-B receptors are involved in cortical inhibition with GABA-A mediating short interval cortical inhibition (SICI) and GABA B mediating cortical silent period (CSP), long interval cortical inhibition (LICI), interhemispheric inhibition (IHI) [12].
Figure 1.
TMS figure explaining the procedure from TMS machine to recording of motor evoked potential from hand; figure depicts TMS machine, figure of 8 coil(green), generation of the magnetic field through the coil, induced current in the cortex and finally TMS elicited motor potential recording of the event through hand muscle. Magnetic pulses activate cortical pyramidal neurons, leading to a corticospinal output that can be measured peripherally as a motor-evoked potential (MEP) using electromyography.
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 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.
Long term potentiation-like: ~High-frequency rTMS ~Intermittent theta burst ~ Paired Associative Stimulation 25
Long term depression-like: ~Low-frequency rTMS ~Continuous theta burst ~ Paired Associative Stimulation 10
5.
Putative mirror neuron system activity
Motor cortical facilitation during action observation relative to rest states
6.
Cortical mapping
Virtual lesion after-effects
7.
Cortical connectivity with a higher temporal and spatial resolution
TMS-EEG
TMS-fMRI
Table 1.
Different cortical function and paradigm assessed using TMS.
1
Intracortical facilitation (ICF)
Subthreshold CS (80%RMT) given 6–25 ms before suprathreshold test stimulus (TS) lead to the facilitation of MEP
2
Short-Interval Intracortical Facilitation (SICF)
A suprathreshold stimulus is followed by a subthreshold stimulus when two stimuli near the motor threshold are given consecutively
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.
1.
Short interval intracortical inhibition(SICI)
Subthreshold CS (80% RMT) given 1-6 ms before suprathreshold test stimulus (TS) leads to inhibition of TS evoked response in the contralateral muscle. This is mediated by the fast-acting, but weaker GABAA receptor neurotransmission.
2.
Long-Interval Intracortical Inhibition (LICI)
Suprathreshold CS delivered 50–200 ms before suprathreshold TS, lead to inhibition of MEP. This is mediated by the slow-acting, but stronger GABAB receptor neurotransmission.
Table 3.
Cortical inhibition parameters SICI and LICI.
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 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.
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].
3.4.2 Repetitive TMS
This can be used to induce sustained changes in cortical reactivity that significantly outlasts the stimulation period. Repetitive TMS can either activate or inhibit cortical activity, depending on stimulation frequency. Low-frequency stimulation results in depression of the target brain area, while high-frequency stimulation induces the facilitation of the region. Low frequency (1 Hz) stimulation for a period of approximately 15 minutes induces a transient inhibition of the cortex. The mechanisms behind such inhibition are unclear, although there are similarities to long-term depression-like synaptic plasticity. In contrast, stimulation at frequencies of 10–20 Hz has been shown to increase cortical activation. Newer theta-burst stimulation technique is a high-frequency stimulation paradigm that can produce either inhibitory (if applied continuously) or facilitatory (if applied intermittently) effects. These effects are thought to be predominantly mediated by NMDA receptors as well as by modulation of GABA receptor functions [28]. Repetitive TMS-induced changes in cortical plasticity can potentially be studied as a marker of brain resilience to neuropathology [29]. It has been demonstrated that individuals with schizophrenia have diminished cortical plasticity as measured by these techniques [26].
3.5 TMS as a tool to measure mirror neuron system (MNS) activity
Among the various networks involved in the pathology of social cognition, the mirror neuron system is most extensively studied. Typically, there is a quantifiable motor cortical reactivity facilitation (increased motor evoked potentials or reduced intracortical inhibition) or motor resonance in the same muscle group that is observed to be in action. This index of motor resonance in the primary motor cortex is likely to be driven by premotor MNS-activity and is used as a putative or indirect marker of the premotor mirror neuron system activity. Studies using TMS have demonstrated diminished modulation of motor cortical reactivity during both neutral action observation [30] and context-based action in schizophrenia [31]. Also, reduced MNS activity is related to poorer social cognition performance. In contrast, patients with mania demonstrate an elevated MNS response, perhaps reflecting disinhibition of the regulatory prefrontal brain regions. Higher MNS activity in mania was associated with higher manic symptom severity [32].
3.6 TMS as a tool for cortical mapping
TMS methods allow for the identification of a direct association between the studied site and the behavioral outcome in a temporary and non-invasive fashion, allowing for mapping of areas of cortex less accessible by previous techniques, hence providing a powerful tool to identify the brain-behavior relationship. A single TMS pulse or a short sequence of pulses has the potential to transiently disrupt ongoing cortical activity in the region being stimulated. This phenomenon has been termed a virtual lesion. TMS is an important tool in cognitive neuroscience and has changed the way we understand cognitive function [33]. TMS can create virtual lesions, thereby allowing us to obtain information about the contribution of a given cortical region to a specific behavior. For example, subjects asked to memorize and repeat a list of words would likely show increased activity in the prefrontal cortex using fMRI. This increased activity would provide an indirect association between the prefrontal cortex and the task. However, if stimuli from TMS over the prefrontal cortex were found to obstruct the ability to learn and recall the list, then researchers would have more convincing evidence to support the involvement of the prefrontal cortex in short-term memory. Pascual-Leone investigated the role of the dorsolateral prefrontal cortex (DLPFC) in implicit procedural learning. In this study, low-intensity rTMS was applied to the DLPFC, to the supplementary motor area, or directly to the ipsilateral hand used in testing. It was demonstrated that DLPFC stimulation markedly impaired implicit procedural learning, whereas stimulation of the other areas did not impair learning [34].
3.7 CombinatoryTMS approaches
TMS may also be paired with other investigative modalities to investigate connectivity between brain regions and can be used as a brain-mapping tool to complement information gained from functional magnetic resonance imaging (fMRI) and electroencephalography (EEG), thus improving both spatial and temporal accuracy of the biological signals derived.
3.7.1 TMS-EEG-
TMS-evoked surface potentials from any cortical region can be recorded with scalp EEG electrodes and used to estimate the regional excitability of the extra-motor cortex [23]. This increases spatial benefits and also the very high temporal resolution of EEG makes it possible to detect differential effects of brain disturbance on TMS-induced responses. TMS-EEG recording is obtained using specialized amplifiers and electrode caps designed to minimize stimulus artifact. The high sampling frequency and other adjustments in the acquiring of signals permit recording cortical potentials induced with TMS and the spread of such oscillation to the different connected regions from the site of stimulation [35].
3.7.2 TMS- fMRI
Combining TMS and fMRI makes it possible to exploit both the good spatial resolution (can identify changes that occur in both cortical and subcortical structures) and the good temporal resolution of TMS. Such data can provide information on connectivity patterns. These patterns reflect the propagation of activity in the stimulated area to distal areas via a neural connection [36].
A general understanding of single-pulse stimulators is that they are safe. The high frequency of rTMS provides a much stronger effect on the brain and is unlikely, but can induce seizures. Other common side effects include nausea, arms jerking, transient headache, and facial pain caused by the activation of scalp and neck muscles. To help alleviate these problems, safe intensity limits using rTMS are suggested to help reduce the risk of discomfort. The general consensus of TMS is that it is safe; however, should remain mindful to minimize the risks.
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Written By
Jitender Jakhar, Manish Sarkar and Nand Kumar
Submitted: 29 December 2021Reviewed: 16 February 2022Published: 28 May 2022
Open access peer-reviewed chapter
