Se Hoon Choi and Rudolph E. Tanzi
Alzheimer’s disease (AD) is the most common form of dementia in the elderly; it is clinically characterized by progressive memory loss and catastrophic cognitive dysfunction. Neuropathologically, the brains of AD patients are characterized by abundant beta-amyloid plaques, neurofibrillary tangles, and neuroinflammation. To date, this fatal disease ranks as the sixth leading cause of death; 5.8 million people in the United States are estimated to have the disease, and the total incidence of AD-related dementia is projected to grow to 16 million by 2050. Currently, there is no cure or any reliable means for pre-symptomatic diagnosis of AD. AD is a genetically heterogenous and multifactorial disease, and a variety of molecular mechanisms have been suggested to underlie its etiology and pathogenesis. A better understanding of pathogenic mechanisms underlying the development of AD pathology and symptoms would accelerate the development of effective therapeutic strategies for preventing and treating AD. Here, we present a comprehensive overview of the pathogenetic and molecular mechanisms underlying AD along with current therapeutic and lifestyles interventions being investigated for the prevention and treatment of this devastating neurological disorder.
Changes in TMS measures of cortical excitability induced by transcranial direct and alternating current stimulation
Michael A. Nitsche, Walter Paulus, and Gregor Thut
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.
Robert Chen and Kai-Hsiang Stanley Chen
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.
Axel Thielscher, Kristoffer H. Madsen, Gary E. Strangman, and Bradley E. Treeby
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.
Markus Kofler, Ulf Ziemann, and Vasilios K. Kimiskidis
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.
Leonard Faul and Kevin S. LaBar
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.
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.
Insights into Cognitive Disorders in Aging and Mental Illness: Molecular Influences on Circuits of the Prefrontal Cortex
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.
Alexander D. Jacob, Andrew J. Mocle, Paul W. Frankland, and Sheena A. Josselyn
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.
Dina P. Matheos and Marcelo A. Wood
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.
Robin F. H. Cash and Ulf Ziemann
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.
Boshuo Wang, Aman S. Aberra, Warren M. Grill, and Angel V. Peterchev
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.
Sabrina Mörkl, Mary I. Butler, Franziska Cichini, John F. Cryan, and Timothy G. Dinan
For centuries, individuals have consumed probiotics as a means of improving quality of life and preventing disease. The gut microbiota refers to the collection of microorganisms residing within the gut. Psychiatric disorders show profound alterations of gut microbiota composition along with a lack of bacterial diversity. Specific subtypes of probiotics and prebiotics (fibers that promote the growth of beneficial bacteria) are referred to as psychobiotics, which impact the gut-brain axis and result in modifications of mood, anxiety, and cognitive function. It is essential for psychiatrists to improve their understanding of psychobiotic mechanisms and the evidence that supports their use in practice. In recent years, interventional studies have assessed the effects of psychobiotics for several symptom clusters, including depression and anxiety. However, some significant determinants, including duration of treatment, dosage of psychobiotics, and interactions with concomitant therapies, deserve more detailed investigation, and specific treatment guidelines for psychobiotics have not yet been established. The capacity of pre- and probiotics to modify psychological symptoms, while significant, is likely to be modest. In addition, this psychobiotic ability varies among probiotic strains—not all psychobiotics are right for all diseases. As psychobiotics are generally considered safe, this may justify their use as an add-on-therapy for some psychiatric indications. This chapter reviews the role of psychobiotics for mental health, their definition, their characteristics, and their mechanisms of action. Against the background of recent research, the chapter outlines a “psychobiotic prescription” to justify a condition-specific rationale for the use of psychobiotics based on recommendations in the current literature.
Do insects, like other animals, expect future events, predict the value of potential actions, and decide between behavioral options without having access to the indicating stimuli? These cognitive capacities are captured by the term intentionality. This chapter addresses the question at two levels, behavior and neural correlates. Behavioral studies are performed with freely flying bees in the natural environment and with harnessed bees in the laboratory by applying the proboscis extension response paradigm. Data are presented and discussed on context-dependent learning, selective attention, rule learning, navigation, communication, and sleep-dependent memory consolidation. Although behavioral analyses document the rich repertoire and the cognitive dimensions of honeybee behavior, intentionality is nearly impossible to prove by behavioral analyses only and neural correlates are essential.
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.
Jeffrey S. Johnson, Eva Feredoes, and Bradley R. Postle
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.
Guglielmo Foffani and Antonio Oliviero
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.