Transcranial brain stimulation and EEG/MEG

Noninvasive transcranial brain stimulation (NTBS) techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct or alternating current stimulation (TDCS/TACS) can be combined with electroencephalography (EEG) and magnetoencephalography (MEG). The combination of NTBS and EEG/MEG can 1) inform brain stimulation (where, when, and how to stimulate), and 2) reveal aftereffects of stimulation induced changes in cortical activity, and interregional connectivity (offline approach), as well as the immediate neuronal response to the stimulation (online approach). While offline approaches allow to separate NTBS and EEG/MEG in space and time, online approaches require concurrent stimulation and recording. While TMS and MEG cannot be combined online, concurrent TMS-EEG as well as TDCS/TACS-MEG/EEG are feasible but pose a range of methodological challenges at the technical and conceptual level. This chapter provides an introduction into the principal experimental approaches and research questions that can be tackled by the combination of transcranial brain stimulation and EEG/MEG. We review the technical challenges arising from concurrent recordings as well as measures to avoid or remove stimulation artefacts. We also discuss the conceptual caveats and required control conditions.

Transcranial brain stimulation and structural MRI

Non-invasive transcranial brain stimulation (NTBS) benefits in multiple ways from structural magnetic resonance imaging (sMRI). Individual structural brain scans can be used to guide spatial targeting with frameless stereotaxy. For instance, sMRI informed transcranial magnetic stimulation (TMS) enables personalized cortical mapping aligned to the individual gyral anatomy. Segmented sMRI scans increase the accuracy and robustness of computational dosimetry approaches which are key to standardize the individual dose across individuals, mapping the NTBS induced electrical fields onto the individual brain. Several sMRI modalities can be used to identify macro and microstructural features that are related to the physiological and behavioral effects of NTBS. Structural MRI before NTBS can identify interindividual variations in brain structure that influence NTBS outcomes, including disease or age related anatomical changes. Repeated structural MRI measurements can trace NTBS induced changes in regional macro and microstructure. NTBS based functional markers can be combined with MRI based structural markers to predict disease progression or recovery in individual patients.

Transcranial magnetic stimulation (TMS) measures and voluntary motor function

Transcranial magnetic stimulation (TMS) can be viewed as interacting with voluntary movement in two ways: it can used to probe the excitability of central nervous system (CNS) pathways before, during, and after a movement; alternatively, it can be used to interfere with movement and give information about the role of different cortical areas in different aspects of a task. This chapter concentrates on the role of single and paired pulse TMS methods that have been covered in detail in previous chapters. Long lasting effects of repetitive TMS (rTMS) are described in later chapters. Almost all of the TMS measures described in previous chapters differ in subjects at rest and during tonic voluntary activity.

Motor threshold, motor evoked potential, central motor conduction time

In this chapter, we survey parameters influencing the assessment of the size and latency of motor evoked potentials (MEP), in normal and pathological conditions, and methods to allow for a meaningful quantification of MEP characteristics. In line with the first edition of this textbook, we extensively discuss three established mechanisms of intrinsic physiological variance and collision techniques that aim to minimize their influence. For the first time, in line with the ever wider use of optical navigation and targeting systems in brain stimulation, we discuss novel methods to capture and minimize the influence of extrinsic biophysical variance. Together, following the rules laid out in this chapter, transcranial magnetic stimulation (TMS) can account for spinal and extrinsic biophysical variance to advance investigations of the central origins of MEP size and latency variability.

State-dependent studies on perception and cognition

Neuronal response to an external stimulus is affected not only by stimulus properties, but also by the baseline activation state; this is referred to as state-dependency. Leveraging this principle helps to enhance the specificity and reduce the variability of brain stimulation effects. State-dependent paradigms have proven to be successful in enhancing the functional resolution of brain stimulation to the extent that the tuning of neuronal representations can be revealed, and they have also enhanced clinical benefits in the treatment of disorders such as depression. Furthermore, state-dependent approach has been applied in various brain stimulation protocols, including online and offline transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), transcranial random noise stimulation (tRNS), and paired-pulse associative stimulation. This chapter describes the principles and mechanisms of state-dependent brain stimulation and summarizes its contribution to cognitive neuroscience.

Changes in TMS measures of cortical excitability induced by transcranial direct and alternating current stimulation

Brain stimulation with weak electrical currents (transcranial electrical stimulation, tES) is known already for about 60 years as a technique to generate modifications of cortical excitability and activity. Originally established in animal models, it was developed as a noninvasive brain stimulation tool about 20 years ago for application in humans. Stimulation with direct currents (transcranial direct current stimulation, tDCS) induces acute cortical excitability alterations, as well as neuroplastic after-effects, whereas stimulation with alternating currents (transcranial alternating current stimulation, tACS) affects primarily oscillatory brain activity but has also been shown to induce neuroplasticity effects. Beyond their respective regional effects, both stimulation techniques have also an impact on cerebral networks. Transcranial magnetic stimulation (TMS) has been pivotal to helping reveal the physiological effects and mechanisms of action of both stimulation techniques for motor cortex application, but also for stimulation of other areas. This chapter will supply the reader with an overview about the effects of tES on human brain physiology, as revealed by TMS.

Transcranial static magnetic field stimulation

Focal application of a relatively strong permanent magnet over the human cortex induces neurophysiological and behavioral effects. This discovery led to the inclusion of transcranial static magnetic field stimulation (tSMS) into the family of noninvasive brain stimulation (NIBS) techniques. The safety, simplicity, portability, and low-cost of tSMS make it particularly appealing for possible clinical and research applications. Similarly to all NIBS techniques, we are far from understanding the exact mechanisms by which tSMS produces its effects, but converging evidence suggests that modulation of ionic interchange across the membrane may be responsible for its physiological effects at the cellular level. There are no data yet supporting clear effects of tSMS in clinical applications, but a number of ongoing studies suggest that clinical results will become available soon.

Paired-pulse interactions

Paired-pulse transcranial magnetic stimulation (TMS) techniques provide an opportunity to examine and better understand the excitatory and inhibitory circuitry in the human cortex in health and disease. Typically, a conditioning stimulus is applied and the effect on cortical excitability is inferred by the change in motor evoked potential (MEP) amplitude elicited by a test stimulus delivered shortly (milliseconds) thereafter. This approach has revealed a range of distinct, but generally overlapping, excitatory and inhibitory phenomena, which have been characterized according to their temporal and pharmacological profile, activation threshold, and various other properties. These phenomena have provided new pathophysiological insights into neurological and psychiatric disorders, and paired-pulse TMS measures have demonstrated clinical diagnostic utility. More recently, via implementation of TMS-evoked electroencephalography (TMS-EEG), paired-pulse TMS protocols have started to expand into nonmotor regions.

Cortical silent period

The cortical silent period (cSP) refers to a period of suppression or silencing of ongoing electromyographic (EMG) activity during voluntary muscle contraction induced by a magnetic stimulus over the contralateral primary motor cortex. This chapter summarizes the physiological basis of the cSP, discusses technical aspects and recommendations on how to record and analyze it, and provides an overview of useful clinical applications. Evidence is presented that multiple spinal mechanisms are implicated in the initial part of the cSP, but some may be also active further on, whereas long-lasting cortical inhibitory mechanisms operate throughout the entire cSP, with an emphasis during its later part. The cSP is a highly relevant and clinically useful tool to assess inhibitory corticomotoneuronal mechanisms in health and disease.

Pharmacology of TMS measures

Application of a single dose of a central nervous system (CNS) active drug with a defined mode of action has been proven useful to explore pharmaco-physiological properties of transcranial magnetic stimulation (TMS)-evoked electromyographic (EMG) measures of motor cortical excitability. With this approach, it is possible to demonstrate that TMS-EMG measures reflect axonal, or excitatory or inhibitory synaptic excitability in distinct interneuron circuits. On the other hand, the array of pharmaco-physiologically well-characterized TMS-EMG measures can be employed to study the effects of a drug with unknown or multiple modes of action, and hence to determine its main mode of action at the systems level of the motor cortex. Acute drug effects may be rather different from chronic drug effects, and these differences can also be studied in TMS experiments. Moreover, TMS or repetitive TMS (rTMS) may induce changes in endogenous neurotransmitter or neuromodulator systems. This offers the opportunity to study neurotransmission along defined neuronal projections. Finally, more recently, TMS-evoked electroencephalographic (EEG) responses have been developed to study cortical excitability and connectivity. Pharmaco-physiological testing can be employed to also characterize these TMS-EEG measures. All these aspects of the pharmacology of TMS measures in healthy subjects will be reviewed in this chapter.