Transcranial magnetic stimulation

2.4.1 Introduction of transcranial magnetic stimulation (TMS)

In 1985, Barker and his colleagues⁶⁵ introduced transcranial magnetic stimulation (TMS) as a safe and non-invasive tool to activate the motor cortex and assess the integrity of the corticomotor pathways. Since its development, the use of TMS was widely applied for neurophysiological examination to explore different neurophysiological mechanisms.

Its modulation of cortical excitability was also being developed as a therapeutic tool.⁶⁶ In this study, we focus on the diagnostic application of TMS.

The TMS is based on the principle of electromagnetic induction. The TMS machine consists of high-current generators and a magnetic coil, while our brain consists of many neural networks. A brief electric current passes through a magnetic coil, which is placed over the human’s head, generating a perpendicular, high-intensity magnetic field, and then the secondary electric field is induced underlying the stimulated site of the brain.

The stimuli usually focus on the primary motor cortex (M1). The secondary electric field induced the action potential in the cortical axons, and then the excitation travels along the corticospinal tract to generate muscle twitches or movements of the corresponding muscles according to the motor homunculus. The amplitude of the muscle response to TMS, which termed motor-evoked potential (MEP), is recorded by surface electromyography (EMG). The electrodes of EMG are attached to the muscle belly.

2.4.2 Common TMS parameters for assessing cortical excitability

Various TMS parameters can provide the different information about cortical excitability, the functional integrity of intracortical neurons, the conduction along the corticospinal tract, and the peripheral neural pathway to the muscles. Such measurements are used to detect the neurophysiological changes of the brain in the setting of the cortical plasticity and brain disorder. Compared to other imaging techniques such as positron emission tomography (PET) and electroencephalography (EEG), TMS parameters can be rapidly acquired and they can provide close monitoring of relatively short-duration neuroplastic changes following experimental manipulation. According to the number of stimuli in a session, the diagnostic application of TMS can be classified into two modes:

single-pulse TMS (spTMS) and paired-pulse TMS (ppTMS).⁶⁶ The TMS was applied to the primary motor cortex to obtain above assessments. The following are some common TMS parameters that we used in this study.

Single-pulse TMS (spTMS)

 Motor Evoked Potentials (MEPs)

While TMS is applied to the motor cortex at appropriate stimulation intensity, MEPs are generated through activation of the motor cortex and the corticospinal pathways. The amplitude of MEP reflects the integrity of the cortical tract as well as the excitability of motor cortex, nerve roots, and the conduction along the peripheral

motor pathway to the muscles.⁶⁶ If the TMS is delivered on the M1 under the condition of relaxed target muscle, the MEP that induced is called resting MEP. In contrast, if the TMS is delivered on the M1 under the condition of activated target muscle, the MEP that induced is called active MEP.

 Hot Spot

The hot spot was defined as the site that can induce the most consistent and prominent MEPs with the shortest latency.⁶⁷ It was an optimal stimulation site that represents the target muscle corresponding to the brain. The stimulus intensity was represented by the percentage of maximal stimulator output (MSO).

 Motor Threshold (MT)

The motor threshold includes resting motor threshold (RMT) and active motor threshold (AMT). The RMT is defined as the minimum stimulus intensity that can induce at least 50μV of MEP in at least 5 of 10 trials under complete muscle relaxation⁶⁸, while the AMT is induced under slightly contracted target muscles.^67,68 The MT reflects the neurons’ excitability and their local density.⁶⁹

 Cortical Silent Period (CSP)

The CSP was a period of suppressed EMG activity occurring immediately after the MEP induced by TMS. It is only induced under the condition of activated muscle while the suprathreshold stimulation is delivered. The CSP is defined as the time

from the end of the active MEP to the return of EMG activity.⁶⁶ However, it is difficult to define the end of the MEP in patients with corticospinal tract dysfunction, so some researchers define the CSP as the time interval from stimulus delivery to the return of voluntary activity.⁷⁰ The CSP reflects long-lasting corticospinal inhibitory mechanisms. The cortical inhibition is mediated by gamma aminobutyric type B receptors (GABABR).⁷¹

Paired-pulse TMS (ppTMS)

 Short Intracortical Inhibition (SICI) and facilitation (ICF)

The ppTMS can assess the intracortical inhibitory and facilitatory mechanisms through delivering a subthreshold conditioning stimulus (CS) and a suprathreshold test stimulus (TS). A conditioning stimulus is followed by a test stimulus at different inter-stimulus intervals (ISI). Different MEPs responses depend on the stimulus intensity and the ISI. SICI is obtained at ISIs of 1-4ms, which reflects inhibitory effects.⁶⁹ In terms of facilitatory effects, the ISI at 7-20ms is applied, which called ICF.⁶⁹ SICI is mediated by gamma aminobutyric type A receptors (GABAAR)⁷² while ICF is likely mediated through N-methyl-D-aspartate (NMDA) glutamate receptors.⁷³

2.4.3 Abnormal cortical excitability in Parkinson’s disease

Since the primary motor cortex (M1) is an important target of basal ganglia output, dysfunction of the basal ganglia–thalamocortical (BGTC) circuit in PD leads to functional disturbances of the motor cortex. Such alteration in cortical excitability of M1 can be assessed through TMS. This imaging technique can detect whether facilitatory or inhibitory changes in motor cortex. The majority of TMS studies focused on the hand area of the more affected brain to investigate the cortical excitability in PD. According to the review of Cantello and colleagues,⁷⁴ most studies indicated that RMT in PD was no differences in comparison to the healthy controls. Increased MEP amplitude at resting muscle, shortened duration of CSP, reduced SICI and ICF were found.^74-76 These findings suggested the cortical excitability in PD revealed excessive corticospinal output at rest and reduced intracortical inhibition.

As for the corresponding cortical excitability of the lower limbs area, two studies explored this issue. Tremblay and colleagues⁷⁷ recruited 10 patients with PD to investigate the cortical excitability of the quadriceps muscles. As the patients were assessed during "on" medication, decreased RMT, increased MEP amplitude at rest, and longer duration of CSP were noted in comparison to the healthy controls; whereas, when four out of ten patients were evaluated during "off" medication, all parameters except for the duration of CSP were similar to "on" medication. They exhibited the shorter duration

of CSP during "off" medication compared to "on" medication. It suggested that the dopaminergic medications may normalize the duration of CSP, which reflects the corticospinal inhibition. However, another study reported by Vacherot and colleagues⁷⁸ indicated inconsistent results. They recruited 24 patients with PD and 9 healthy controls to explore the cortical excitability of the tibialis anterior muscle. The results displayed that RMT, amplitude of MEP at rest, duration of CSP, and SICI had no differences between groups and medication states. The only reduction in ICF was noted in PD in comparison to the healthy controls and decreased ICF could be partially normalized during "on" medication. The summarized contents are presented in table 1.

Overall, the patients with PD revealed abnormal cortical excitability, especially in the duration of CSP and paired-pulse parameters. The medicine may modulate the cortical excitability. Despite this, there is the paucity of information regarding TMS evaluation over the lower extremity. Therefore, further evidence concerning the changes in the cortical excitability of the lower limbs in PD is needed to draw a clear conclusion.