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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.

Across a lifetime, people tend to remember some experiences better than others, and often these biases in memory are fueled by the emotions felt when initially encoding an event. The neuroscientific study of emotional memory has advanced considerably since researchers first detailed a critical role for the amygdala in enhancing memory consolidation for arousing experiences. It is now known that the influence of emotion on memory is both a more selective and multifaceted process than initially thought. Consequently, the neural mechanisms that govern emotional memory involve an expansive set of distributed connections between the amygdala and other medial temporal lobe structures, along with prefrontal and sensory regions, that interact with noradrenergic, dopaminergic, and glucocorticoid neuromodulatory systems to both enhance and impair items in memory. Recent neurocognitive models have detailed specific mechanisms to explain how and why the influence of emotion on memory is so varied, including arousal-based accounts for the selective consolidation of information based on stimulus priority, as well as top-down cognitive factors that moderate these effects. Still other lines of research consider the time-dependent influence of stress on memory, valence-based differences in neural recapitulation at retrieval, and the mechanisms of emotional memory modification over time. While appreciating these many known ways in which emotions influence different stages of memory processing, here we also identify gaps in the literature and present future directions to improve a neurobiological understanding of emotional memory processes.

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.

The main function of brains is to generate adaptive behavior. Far from being the stereotypical, robot-like insect, the fruit fly Drosophila exhibits astounding flexibility and chooses different courses of actions even under identical external circumstances. Due to the power of genetics, we now are beginning to understand the neuronal mechanisms underlying this behavioral flexibility. Interestingly, the evidence from studies of disparate behaviors converges on common organizational principles common to many if not all behaviors, such as modified sensory processing, involvement of biogenic amines in network remodeling, ongoing activity, and modulation by feedback. Seemingly foreseeing these recent insights, the first research fields in Drosophila behavioral neurogenetics reflected this constant negotiation between internal and external demands on the animal as the common mechanism underlying adaptive behavioral choice in Drosophila.

The newly evolved prefrontal cortex underlies our highest order cognitivewe functions yet is remarkably vulnerable to dysfunction in most mental disorders. The prefrontal cortex subserves working memory and top-down control, operations that are weakened in both cognitive and affective disorders. Prefrontal microcircuits contain extensive recurrent excitatory connections that allow representation of information in the absence of sensory stimulation, the foundation of abstract thought and goal-directed behavior. Basic research has discovered that the strength of these prefrontal cortical synaptic connections is governed by unique molecular mechanisms, where both neurotransmission and neuromodulation differ from those in classical circuits. These include exceptionally powerful regulation by the arousal systems, which magnify calcium-cAMP signaling to open or close ion channels near the synapse to rapidly alter synaptic strength, a process called Dynamic Network Connectivity. The magnification of intracellular calcium actions renders these synapses particularly vulnerable to degeneration in schizophrenia, aging, and Alzheimer’s disease.

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.

Throughout the brain, sparse ensembles of neurons, termed “engrams,” are responsible for representing events. Engrams are composed of neurons active at the time of an event, and recent research has revealed how these active neurons compete to gain inclusion into a subsequently formed engram. This competitive selection mechanism, called “memory allocation,” is the process by which individual neurons become components of the engram. Memory allocation is crucially influenced by neuronal excitability, with more highly excitable neurons outcompeting their neighbors for inclusion into the engram. The dynamics of this excitability-dependent memory allocation process have important consequences for the function of the memory circuit, including effects on memory generalization and linking of events experienced closely in time. Memory allocation arises from cellular mechanisms of excitability, governs circuit-level dynamics of the engram, and has higher-order consequences for memory system function.

Memory formation is one of the most important functions of the brain regarding individual identity and survival, as well as propagation of a species. Decades of research at numerous levels has begun to elucidate the complex molecular, cellular, circuit, and brain-wide mechanisms underlying learning and memory. One of the key mechanisms involves gene expression required for changes in cellular structure and function, which ultimately give rise to long-lasting changes in behavior. Here, we review a unique transcription factor family, called the nuclear orphan receptor 4a (NR4A). The Nr4a gene family is involved in the development of the dopaminergic signaling system, and dynamically regulated in the adult brain with regard to memory formation. Intriguing results from studying how epigenetic mechanisms modulate synaptic plasticity and long-term memory formation also highlight the pivotal role the Nr4a genes may have in pushing the boundaries of memory formation. We review the discovery of the Nr4a gene family, the complex nature of their activity in transcriptional regulation, and the evidence suggesting they may be one of the most important set of immediate early genes and transcription factors involved in memory, age-related memory impairments, and neurological disease related cognitive dysfunction.

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.