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Commonly used repetitive transcranial magnetic stimulation (rTMS) protocols, including regular rTMS, intermittent and continuous theta-burst stimulation (TBS) and quadripulse stimulation (QPS) are presented with respect to their induced neuromodulatory after-effects and the underlying cellular and synaptic neurophysiological mechanisms. The anatomical target is typically primary motor cortex since motor evoked potentials (MEPs) before and after the intervention can be used to assess effects of the respective rTMS protocol. High-frequency regular rTMS and intermittent TBS protocols tend to increase corticospinal excitability as indexed by MEP amplitude, whereas low-frequency regular rTMS and continuous TBS protocols tend to reduce corticospinal excitability. These effects are primarily due to LTP-like and LTD-like synaptic changes mediated by GABA and NMDA receptors. Changes in the balance between excitatory and inhibitory cortical microcircuits play a secondary role, with inconsistent effects as determined by paired-pulse TMS protocols. Finally, the challenge of large inter-subject response variability, and current directions of research to optimize rTMS effects through EEG-dependent personalized TMS are discussed.

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.

This chapter focuses on the utility of transcranial magnetic stimulation (TMS) for clinical diagnosis and follow-up. It first introduces the methods to measure corticospinal excitability, intracortical inhibitory and facilitatory circuits, and cortico-cortical connections. The chapter then discusses the use of TMS in several neurological disorders. Central motor conduction time (CMCT) can be used to detect myelopathy and localize the lesions, although the triple stimulation technique has higher sensitivity. CMCT can also detect upper motor neuron involvement in amyotrophic lateral sclerosis and multiple sclerosis. The ipsilateral silent period and CMCT are helpful for differentiating atypical parkinsonism from Parkinson’s disease. Distinct patterns of cortical excitability findings can be obtained from different genetic forms of hereditary spinocerebellar ataxia. Reduction of short afferent inhibition (SAI) can differentiate Alzheimer’s disease and frontotemporal dementia. Patients with diffuse Lewy body dementia and hallucination also have reduced SAI. The results of motor evoked potential measurements in the early stage of stroke are predictive of the long-term motor outcome. The chapter concludes that TMS has clinical diagnostic utility in a broad range of neurological diseases.

Transcranial brain stimulation (TMS) was introduced in 1985 by Barker and his colleagues. Since then, further improvements in technology have allowed additional applications and new stimulation protocols. In the last decade, while the use of TMS has expanded enormously in basic science as well as in the clinical scenario, the underlying neurophysiological or neurochemical mechanisms are still not fully understood. Positron emission tomography (PET) and single-photon emission computerized tomography (SPECT) are neuroimaging modalities utilized to investigate brain functions. In spite of their lower spatial and time resolution compared with functional magnetic resonance imaging (fMRI) and electroencephalography (EEG), PET/SPECT have helped to elucidate some of the neurochemical mechanisms and neural plastic changes associated with TMS. In this chapter, we will provide an overview of these techniques, describing methodological details and application of TMS-PET/SPECT imaging in basic and clinical studies.

Computational methods for dosimetry allow estimating and optimizing the spatial distribution and strength of the induced fields and waves in the brain, based on detailed models of the head anatomy that are derived from medical imaging data. This chapter gives an overview of the computational dosimetry methods for transcranial magnetic, electric, focused ultrasound and light stimulation. It starts with a brief introduction to the employed numerical methods and a summary of the status of the automatic generation of individual head models from magnetic resonance and computed tomography data. For each stimulation method, the basic physical equations underlying the numerical simulations are outlined, followed by a summary of the key results and validation studies. The chapter concludes with an overview of remaining limitations and open questions.

Computational neurostimulation is the use of biologically grounded computational models to investigate the mechanism of action of brain stimulation and predict the impact of transcranial magnetic stimulation (TMS) on behavior in health and disease. Computational models are now widespread, and their success is incontrovertible, yet they have left a rather small footprint on the field of TMS. We highlight and discuss recent advances in models of primary motor cortex TMS, the brain region for which most models have been developed. These models provide insight into the putative, but unobservable, mechanisms through which TMS influences physiology, and help predicting the effects of different TMS applications. We discuss how these advances in computational neurostimulation provide opportunities for mechanistically understanding and predicting the impact of TMS on behavior.

Here, we introduce a conceptual framework for studies that combine non-invasive transcranial brain stimulation (NTBS) with neuroimaging. We outline the type of neuroscientific questions that can be addressed with a combined NTBS-neuroimaging approach and describe important experimental considerations. Neuroimaging methods differ with respect to their spatiotemporal resolution and reflect different neurobiological aspects of brain function, structure or metabolism. These characteristics need to be carefully considered in order to select the most appropriate neuroimaging modality. NTBS and neuroimaging can be combined concurrently (online) or sequentially (offline). The “online” approach applies neuroimaging while NTBS is delivered to the brain and thus, can reveal the immediate functional effects of NTBS on the targeted brain networks, but one has to deal with interfering effects of NTBS on brain mapping. The “offline” approach applies neuroimaging and NTBS in sequence: Offline neuroimaging can be performed BEFORE the stimulation session to inform NTBS parameter setting or AFTER the stimulation session to provide functional, metabolic or structural readouts of NTBS-effects. Since NTBS and neuroimaging can be separated in space and time, NTBS does not interfere with offline brain mapping. Finally, we discuss how NTBS and neuroimaging are gaining importance in clinical NTBS applications and how both techniques can be iteratively combined to create open-loop setups.

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.

Transcranial stimulation has recently been gaining momentum as a promising tool for cognitive enhancement. Like other emerging biomedical technologies, however, the promises of transcranial stimulation as cognitive enhancement come with critical ethical and legal challenges. To ensure the safe and responsible use of this technology, we should complement technological development with rigorous ethical and regulatory analysis. This chapter aims to provide a general overview of ethical and legal challenges, lighting a path to maximize the benefits of transcranial stimulation as cognitive enhancement while minimizing the perils of this technology. Focusing on transcranial stimulation, it first introduces some of the major ethical concerns surrounding cognitive enhancement and then reviews previous discussions on the regulation of both cognitive enhancement devices and their uses in real-world settings. Given the impending widespread use of transcranial stimulation by the public, this chapter concludes by emphasizing the need for developing a sound policy for the use of transcranial stimulation as cognitive enhancement.

Faces are rich sources of social information that simultaneously convey someone’s identity, attentional focus, and emotional state. Humans process this wealth of socially relevant information in a network of face-selective regions distributed across the brain. This chapter reviews studies that have used transcranial magnetic stimulation (TMS) to study the cognitive operations and functional connections of the face network. TMS has been used to disrupt brain areas contributing to the processing of facial identity, facial expression, eye-gaze direction, head direction, trustworthiness, and the auditory-visual integration of speech. TMS has also been combined with neuroimaging to map how transient disruption of a targeted face area impacts connectivity across the face network. I also review chronometric TMS studies that have established when faces are processed across different brain areas down to a millisecond resolution.

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.

Effective connectivity between two areas of the human brain can be studied by testing the effects of conditioning stimulation at one site on the effect of test stimulation at another site by using two coils (dual coil, or paired-coil transcranial magnetic stimulation (TMS)). TMS over the bilateral primary motor cortices (M1) induces interhemispheric inhibition (IHI) and weak interhemispheric facilitation (IHF), largely mediated by the corpus callosum. IHI consists of short-interval (~ 10 ms) IHI (SIHI) and long-interval (~ 50 ms) IHI (LIHI). Abnormalities of IHI have been identified in a variety of brain disorders. The cerebello-dentato-thalamo-motor cortical connection is studied with a conditioning stimulus over one cerebellar hemisphere and a test stimulus over the contralateral M1 at interstimulus intervals of 5–8 ms (cerebellar brain inhibition (CBI)). CBI is caused by inhibitory Purkinje cell activation by the cerebellar stimulus, which inhibits the dentato-thalamo-M1 facilitatory projection. Abnormally reduced CBI is a hallmark of disorders of the cerebello-dentato-thalamo-motor cortical connection. Sensory inputs from peripheral nerve stimulation also affect M1 excitability in the form of short-latency afferent inhibition (SAI, interstimulus interval ~ 20 ms) and long-latency afferent inhibition (LAI, interstimulus interval ~ 200 ms). SAI is a marker of central cholinergic function. SAI is reduced in disorders with central cholinergic dysfunction, such as Alzheimer’s disease.

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.

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.

Transcranial stimulation induces or modulates neural activity in the brain through basic physical and biophysical processes. Transcranial electrical stimulation and transcranial magnetic stimulation impose an exogenous electric field in the brain that is determined by the stimulation device and the geometric and electric parameters of the head. The imposed electric field drives an electric current through the brain tissue, which macroscopically behaves as a volume conductor. The electric field polarizes neuronal membranes as described by the cable equation, resulting in direct activation of individual neurons and neural networks or indirect modulation of intrinsic activity. Computational modeling can estimate the delivered electric field as well as the resultant responses of individual neurons. This dosimetric information can be used to optimize and individualize stimulation targeting. The field distributions of transcranial stimulation are well understood and characterized, whereas analysis and modeling of the neural responses require further investigation, especially at the network level.

Nondeclarative learning and memory involve acquiring and retaining skills or habits and include subtypes, such as procedural learning, priming, and classical conditioning. Animal studies, lesion, and functional imaging studies in humans have implicated a range of brain areas, including frontal and parietal cortical regions, basal ganglia, cerebellum in these functions. Repetitive transcranial magnetic stimulation (rTMS) can modulate functional connectivity in brain networks and provide causal evidence for their involvement in behavior. In this chapter, we review the use of rTMS to investigate the brain networks underlying nondeclarative learning by stimulating their cortical nodes and examining the effects of these interventions on behavior and imaging measures of brain activity and connectivity, with emphasis on how the timing of stimulation (before, during, or after learning) affects these measures.

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.

This chapter provides a broad overview of research focused on the use of transcranial magnetic stimulation (TMS), both alone and together with neural recording modalities such as magnetic resonance imaging (MRI) and electroencephalography (EEG), to elucidate the cognitive and neural underpinnings of working memory. It first considers research using TMS to create “virtual lesions” in targeted brain areas, with the goal of establishing the causal role, and sometimes the timing, of the targeted area in specific working memory component processes. Next, it highlights research adopting a “perturb-and-measure” approach, in which TMS is used in conjunction with simultaneous neural recording (e.g., functional MRI or EEG) to assess the role of brain excitability and inter-area connectivity in working memory. Finally, research using TMS to assess the role of neural oscillations in working memory is reviewed. Throughout, the chapter highlights how different TMS modalities can be used profitably to clarify the neural bases of working memory and to effect strong tests of predictions derived from psychological models.

This chapter describes the use of electroencephalography (EEG) to measure neuronal activity evoked by transcranial magnetic stimulation (TMS). We discuss the major research and clinical applications of TMS–EEG and review synthetic measures designed to assess the functional status of cortical networks, such as neuronal excitability and effective connectivity. We first highlight that brain reactivity to TMS crucially depends on the anatomical and functional characteristics of the cortical region being stimulated. These findings suggest that the responses to stimulation of the primary motor cortex should be considered a special rather than a representative case of the brain’s reaction to TMS. Next, we describe TMS–EEG-based measures of (i) cortical reactivity in the time and frequency domains, (ii) excitation and inhibition provided by paired-pulse paradigms, and (iii) neuroplasticity induced by non-invasive neuromodulatory interventions. Finally, we discuss the methodological challenges related to concurrent TMS–EEG and review methods for minimizing/suppressing artifacts that may contaminate brain signals. We conclude that TMS–EEG has great potential for becoming an effective research and clinical tool, provided that: 1) data quality is monitored in real time; 2) effective and sound artifact-removal methods are developed and implemented; and 3) sufficient control studies are performed to assess the impact of TMS on the cortex.

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.